Gene E Alexander

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Chapters

• Alexander, G. E., & Ryan, L. (2007). Neuroimaging: Overview of Methods and Applications.. Sage Press.
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  Chapter on methods and application of neuroimaging to health psychology and for the study of aging and age-related disease.;Your Role: Co-wrote the book chapter.;Full Citation: Ryan, L & Alexander, G.E. (2007). Neuroimaging: Overview of Methods and Applications. In L.J. Luecken and L.C. Gallo (Eds.) Handbook of Physiological Research Methods in Health Psychology. Thousand Oaks, California: Sage Press.;Collaborative with faculty member in unit: Yes;

Journals/Publications

• Hardcastle, C., Hausman, H. K., Kraft, J. N., Albizu, A., Evangelista, N. D., Boutzoukas, E. M., O'Shea, A., Langer, K., Van Van Etten, E., Bharadwaj, P. K., Song, H., Smith, S. G., Porges, E., DeKosky, S. T., Hishaw, G. A., Wu, S. S., Marsiske, M., Cohen, R., Alexander, G. E., & Woods, A. J. (2022). Higher-order resting state network association with the useful field of view task in older adults. GeroScience, 44(1), 131-145.
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  Speed-of-processing abilities decline with age yet are important in performing instrumental activities of daily living. The useful field of view, or Double Decision task, assesses speed-of-processing and divided attention. Performance on this task is related to attention, executive functioning, and visual processing abilities in older adults, and poorer performance predicts more motor vehicle accidents in the elderly. Cognitive training in this task reduces risk of dementia. Structural and functional neural correlates of this task suggest that higher-order resting state networks may be associated with performance on the Double Decision task, although this has never been explored. This study aimed to assess the association of within-network connectivity of the default mode network, dorsal attention network, frontoparietal control network, and cingulo-opercular network with Double Decision task performance, and subcomponents of this task in a sample of 267 healthy older adults. Multiple linear regressions showed that connectivity of the cingulo-opercular network is associated with visual speed-of-processing and divided attention subcomponents of the Double Decision task. Cingulo-opercular network and frontoparietal control network connectivity is associated with Double Decision task performance. Stronger connectivity is related to better performance in all cases. These findings confirm the unique role of the cingulo-opercular network in visual attention and sustained divided attention. Frontoparietal control network connectivity, in addition to cingulo-opercular network connectivity, is related to Double Decision task performance, a task implicated in reduced dementia risk. Future research should explore the role these higher-order networks play in reduced dementia risk after cognitive intervention using the Double Decision task.
• Hardcastle, C., Hausman, H. K., Kraft, J. N., Albizu, A., O'Shea, A., Boutzoukas, E. M., Evangelista, N. D., Langer, K., Van Etten, E. J., Bharadwaj, P. K., Song, H., Smith, S. G., Porges, E., DeKosky, S. T., Hishaw, G. A., Wu, S. S., Marsiske, M., Cohen, R., Alexander, G. E., & Woods, A. J. (2022). Proximal improvement and higher-order resting state network change after multidomain cognitive training intervention in healthy older adults. GeroScience.
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  Prior randomized control trials have shown that cognitive training interventions resulted in improved proximal task performance, improved functioning of activities of daily living, and reduced dementia risk in healthy older adults. Neural correlates implicated in cognitive training include hub brain regions of higher-order resting state networks including the default mode network, dorsal attention network, frontoparietal control network, and cingulo-opercular network. However, little is known about resting state network change after cognitive training, or the relation between functional brain changes and improvement in proximal task performance. We assessed the 1) change in proximal task performance, 2) change in higher-order resting state network connectivity via functional magnetic resonance imaging, and 3) association between these variables after a multidomain attention/speed-of-processing and working memory randomized control trial in a sample of 58 healthy older adults. Participants in the cognitive training group improved significantly on seven out of eight training tasks immediately after the training intervention with the largest magnitude of improvement in a divided attention/speed-of-processing task, the Double Decision task. Only the frontoparietal control network had significantly strengthened connectivity in the cognitive training group at the post-intervention timepoint. Lastly, higher frontoparietal control network connectivity was associated with improved Double Decision task performance after training in the cognitive training group. These findings show that the frontoparietal control network may strengthen after multidomain cognitive training interventions, and this network may underlie improvements in divided attention/speed-of-processing proximal improvement.
• Parra, K. L., Alexander, G. E., Raichlen, D. A., Klimentidis, Y. C., & Furlong, M. A. (2022). Exposure to air pollution and risk of incident dementia in the UK Biobank. Environmental research, 112895.
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  Air pollution may cause inflammatory and oxidative stress damage to the brain, leading to neurodegenerative disease. The association between air pollution and dementia, and modification by apolipoprotein E genotype 4 (APOE-ε4) has yet to be fully investigated.
• Boutzoukas, E. M., O'Shea, A., Albizu, A., Evangelista, N. D., Hausman, H. K., Kraft, J. N., Van Etten, E. J., Bharadwaj, P. K., Smith, S. G., Song, H., Porges, E. C., Hishaw, A., DeKosky, S. T., Wu, S. S., Marsiske, M., Alexander, G. E., Cohen, R., & Woods, A. J. (2021). Frontal White Matter Hyperintensities and Executive Functioning Performance in Older Adults. Frontiers in aging neuroscience, 13, 672535.
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  Frontal lobe structures decline faster than most other brain regions in older adults. Age-related change in the frontal lobe is associated with poorer executive function (e.g., working memory, switching/set-shifting, and inhibitory control). The effects and presence of frontal lobe white matter hyperintensities (WMH) on executive function in normal aging is relatively unknown. The current study assessed relationships between region-specific frontal WMH load and cognitive performance in healthy older adults using three executive function tasks from the NIH Toolbox (NIHTB) Cognition Battery. A cohort of 279 healthy older adults ages 65-88 completed NIHTB and 3T T1-weighted and FLAIR MRI. Lesion Segmentation Toolbox quantified WMH volume and generated lesion probability maps. Individual lesion maps were registered to the Desikan-Killiany atlas in FreeSurfer 6.0 to define regions of interest (ROI). Independent linear regressions assessed relationships between executive function performance and region-specific WMH in frontal lobe ROIs. All models included age, sex, education, estimated total intracranial volume, multi-site scanner differences, and cardiovascular disease risk using Framingham criteria as covariates. Poorer set-shifting performance was associated with greater WMH load in three frontal ROIs including bilateral superior frontal (left β = -0.18, FDR- = 0.02; right β = -0.20, FDR- = 0.01) and right medial orbitofrontal (β = -0.17, FDR- = 0.02). Poorer inhibitory performance associated with higher WMH load in one frontal ROI, the right superior frontal (right β = -0.21, FDR- = 0.01). There were no significant associations between working memory and WMH in frontal ROIs. Our study demonstrates that location and pattern of frontal WMH may be important to assess when examining age-related differences in cognitive functions involving switching/set-shifting and inhibition. On the other hand, working memory performance was not related to presence of frontal WMH in this sample. These data suggest that WMH may contribute selectively to age-related declines in executive function. Findings emerged beyond predictors known to be associated with WMH presence, including age and cardiovascular disease risk. The spread of WMH within the frontal lobes may play a key role in the neuropsychological profile of cognitive aging. Further research should explore whether early intervention on modifiable vascular factors or cognitive interventions targeted for executive abilities may help mitigate the effect of frontal WMH on executive function.
• Evangelista, N. D., O'Shea, A., Kraft, J. N., Hausman, H. K., Boutzoukas, E. M., Nissim, N. R., Albizu, A., Hardcastle, C., Van Etten, E. J., Bharadwaj, P. K., Smith, S. G., Song, H., Hishaw, G. A., DeKosky, S., Wu, S., Porges, E., Alexander, G. E., Marsiske, M., Cohen, R., & Woods, A. J. (2021). Independent Contributions of Dorsolateral Prefrontal Structure and Function to Working Memory in Healthy Older Adults. Cerebral cortex (New York, N.Y. : 1991), 31(3), 1732-1743.
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  Age-related differences in dorsolateral prefrontal cortex (DLPFC) structure and function have each been linked to working memory. However, few studies have integrated multimodal imaging to simultaneously investigate relationships among structure, function, and cognition. We aimed to clarify how specifically DLPFC structure and function contribute to working memory in healthy older adults. In total, 138 participants aged 65-88 underwent 3 T neuroimaging and were divided into higher and lower groups based on a median split of in-scanner n-back task performance. Three a priori spherical DLPFC regions of interest (ROIs) were used to quantify blood-oxygen-level-dependent (BOLD) signal and FreeSurfer-derived surface area, cortical thickness, and white matter volume. Binary logistic regressions adjusting for age, sex, education, and scanner type revealed that greater left and right DLPFC BOLD signal predicted the probability of higher performing group membership (P values.05). Importantly, this suggests BOLD signal and surface area may independently contribute to working memory performance in healthy older adults.
• Furlong, M. A., Alexander, G. E., Klimentidis, Y. C., & Raichlen, D. A. (2021). Association of Air Pollution and Physical Activity With Brain Volumes. Neurology.
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  In high pollution areas, physical activity may have a paradoxical effect on brain health by increasing particulate deposition in the lungs. We examined whether physical activity modifies associations of air pollution with brain volumes in an epidemiological framework.
• Hausman, H. K., Hardcastle, C., Albizu, A., Kraft, J. N., Evangelista, N. D., Boutzoukas, E. M., Langer, K., O'Shea, A., Van Etten, E. J., Bharadwaj, P. K., Song, H., Smith, S. G., Porges, E., DeKosky, S. T., Hishaw, G. A., Wu, S., Marsiske, M., Cohen, R., Alexander, G. E., & Woods, A. J. (2021). Cingulo-opercular and frontoparietal control network connectivity and executive functioning in older adults. GeroScience.
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  Executive function is a cognitive domain that typically declines in non-pathological aging. Two cognitive control networks that are vulnerable to aging-the cingulo-opercular (CON) and fronto-parietal control (FPCN) networks-play a role in various aspects of executive functioning. However, it is unclear how communication within these networks at rest relates to executive function subcomponents in older adults. This study examines the associations between CON and FPCN connectivity and executive function performance in 274 older adults across working memory, inhibition, and set-shifting tasks. Average CON connectivity was associated with better working memory, inhibition, and set-shifting performance, while average FPCN connectivity was associated solely with working memory. CON region of interest analyses revealed significant connections with classical hub regions (i.e., anterior cingulate and anterior insula) for each task, language regions for verbal working memory, right hemisphere dominance for inhibitory control, and widespread network connections for set-shifting. FPCN region of interest analyses revealed largely right hemisphere fronto-parietal connections important for working memory and a few temporal lobe connections for set-shifting. These findings characterize differential brain-behavior relationships between cognitive control networks and executive function in aging. Future research should target these networks for intervention to potentially attenuate executive function decline in older adults.
• Kraft, J. N., Albizu, A., O'Shea, A., Hausman, H. K., Evangelista, N. D., Boutzoukas, E., Hardcastle, C., Van Etten, E. J., Bharadwaj, P. K., Song, H., Smith, S. G., DeKosky, S., Hishaw, G. A., Wu, S., Marsiske, M., Cohen, R., Alexander, G. E., Porges, E., & Woods, A. J. (2021). Functional Neural Correlates of a Useful Field of View (UFOV)-Based fMRI Task in Older Adults. Cerebral cortex (New York, N.Y. : 1991).
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  Declines in processing speed performance occur in aging and are a critical marker of functional independence in older adults. Studies suggest that Useful Field of View (UFOV) training may ameliorate cognitive decline. Despite its efficacy, little is known about the neural correlates of this task. Within the current study, 233 healthy older adults completed a UFOV-based task while undergoing functional magnetic resonance imaging (fMRI). During the "stimulus" portion of this task, participants must identify a target in the center of the screen and the location of a target in the periphery, among distractors. During the "probe" portion, participants must decide if the object in the center and the location of the target in the periphery were identical to the "stimulus" screen. Widespread bilateral whole-brain activation was observed when activation patterns of the "probe" contrast were subtracted from the "stimulus" contrast. Conversely, the subtraction of "stimulus" from "probe" was associated with discrete activation patterns consisting of 13 clusters. Additionally, when evaluating the variance associated with task accuracy, specific subregions were identified that may be critical for task performance. Our data elucidate the functional neural correlates of a UFOV-based task, a task used in both cognitive training paradigms and assessment of function.
• Van Etten, E. J., Bharadwaj, P. K., Hishaw, G. A., Huentelman, M. J., Trouard, T. P., Grilli, M. D., & Alexander, G. E. (2021). Influence of regional white matter hyperintensity volume and apolipoprotein E ε4 status on hippocampal volume in healthy older adults. Hippocampus.
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  While total white matter hyperintensity (WMH) volume on magnetic resonance imaging (MRI) has been associated with hippocampal atrophy, less is known about how the regional distribution of WMH volume may differentially affect the hippocampus in healthy aging. Additionally, apolipoprotein E (APOE) ε4 carriers may be at an increased risk for greater WMH volumes and hippocampal atrophy in aging. The present study sought to investigate whether regional WMH volume mediates the relationship between age and hippocampal volume and if this association is moderated by APOE ε4 status in a group of 190 cognitively healthy adults (APOE ε4 status [carrier/non-carrier] = 59/131), ages 50-89. Analyses revealed that temporal lobe WMH volume significantly mediated the relationship between age and average bilateral hippocampal volume, and this effect was moderated by APOE ε4 status (-0.020 (SE = 0.009), 95% CI, [-0.039, -0.003]). APOE ε4 carriers, but not non-carriers, showed negative indirect effects of age on hippocampal volume through temporal lobe WMH volume (APOE ε4 carriers: -0.016 (SE = 0.007), 95% CI, [-0.030, -0.003]; APOE ε4 non-carriers: .005 (SE = 0.006), 95% CI, [-0.006, 0.017]). These findings remained significant after additionally adjusting for sex, years of education, hypertension status and duration, cholesterol status, diabetes status, Body Mass Index, history of smoking, and the Wechsler Adult Intelligence Scale-IV Full Scale IQ. There were no significant moderated mediation effects for frontal, parietal, and occipital lobe WMH volumes, with or without covariates. Our findings indicate that in cognitively healthy older adults, elevated WMH volume regionally localized to the temporal lobes in APOE ε4 carriers is associated with reduced hippocampal volume, suggesting greater vulnerability to brain aging and the risk for Alzheimer's disease.
• Alexander, G. E., Lin, L., Yoshimaru, E. S., Bharadwaj, P. K., Bergfield, K. L., Hoang, L. T., Chawla, M. K., Chen, K., Moeller, J. R., Barnes, C. A., & Trouard, T. P. (2020). Age-Related Regional Network Covariance of Magnetic Resonance Imaging Gray Matter in the Rat. Frontiers in aging neuroscience, 12, 267.
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  Healthy human aging has been associated with brain atrophy in prefrontal and selective temporal regions, but reductions in other brain areas have been observed. We previously found regional covariance patterns of gray matter with magnetic resonance imaging (MRI) in healthy humans and rhesus macaques, using multivariate network Scaled Subprofile Model (SSM) analysis and voxel-based morphometry (VBM), supporting aging effects including in prefrontal and temporal cortices. This approach has yet to be applied to neuroimaging in rodent models of aging. We investigated 7.0T MRI gray matter covariance in 10 young and 10 aged adult male Fischer 344 rats to identify, using SSM VBM, the age-related regional network gray matter covariance pattern in the rodent. SSM VBM identified a regional pattern that distinguished young from aged rats, characterized by reductions in prefrontal, temporal association/perirhinal, and cerebellar areas with relative increases in somatosensory, thalamic, midbrain, and hippocampal regions. Greater expression of the age-related MRI gray matter pattern was associated with poorer spatial learning in the age groups combined. Aging in the rat is characterized by a regional network pattern of gray matter reductions corresponding to aging effects previously observed in humans and non-human primates. SSM MRI network analyses can advance translational aging neuroscience research, extending from human to small animal models, with potential for evaluating mechanisms and interventions for cognitive aging.
• Franchetti, M. K., Bharadwaj, P. K., Nguyen, L. A., Van Etten, E. J., Klimentidis, Y. C., Hishaw, G. A., Trouard, T. P., Raichlen, D. A., & Alexander, G. E. (2020). Interaction of Age and Self-reported Physical Sports Activity on White Matter Hyperintensity Volume in Healthy Older Adults. Frontiers in aging neuroscience, 12, 576025.
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  Cerebral white matter (WM) lesion load, as measured by white matter hyperintensity (WMH) volume with magnetic resonance imaging (MRI), has been associated with increasing age and cardiovascular risk factors, like hypertension. Physical sports activity (PSA) may play an important role in maintaining WM in the context of healthy aging. In 196 healthy older adults, we investigated whether participants reporting high levels of PSA ( = 36) had reduced total and regional WMH volumes compared to those reporting low levels of PSA ( = 160). Age group [young-old (YO) = 50-69 years; old-old (OO) = 70-89 years], PSA group, and age by PSA group interaction effects were tested, with sex, hypertension, and body mass index (BMI) as covariates. We found significant main effects for age group and age by PSA group interactions for total, frontal, temporal, and parietal WMH volumes. There were no main effects of PSA group on WMH volumes. The OO group with low PSA had greater total, frontal, temporal, and parietal WMH volumes than the YO with low PSA and OO with high PSA groups. WMH volumes for the YO and OO groups with high PSA were comparable. These findings indicate an age group difference in those with low PSA, with greater WMH volumes in older adults, which was not observed in those with high PSA. The results suggest that engaging in high levels of PSA may be an important lifestyle factor that can help to diminish WMH lesion load in old age, potentially reducing the impact of brain aging.
• Glisky, E. L., Alexander, G. E., Hou, M., Kawa, K., Woolverton, C. B., Zigman, E. K., Nguyen, L. A., Haws, K., Figueredo, A. J., & Ryan, L. (2020). Differences between young and older adults in unity and diversity of executive functions. Neuropsychology, development, and cognition. Section B, Aging, neuropsychology and cognition, 1-26.
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  Miyake and colleagues (2000) identified three independent but correlated components of executive function in young adults - set shifting, inhibition, and updating. The present study compared the factor structure in young adults to two groups of older adults (ages 60-73 and 74-98). A three-factor model of shifting, inhibition and updating was confirmed in young adults, but the factors were weakly or uncorrelated. In both older groups, a two-factor solution was indicated, updating/inhibition and shifting, which were moderately correlated in young-older adults, and strongly correlated in the old-older group. A nested factors model in the oldest group revealed a common factor, which loaded on all but one of the tests, and a shifting-specific factor. We concluded that in young adulthood, shifting, updating and inhibition may operate relatively independently. As people age and processing becomes less efficient, they may rely increasingly on general executive control processes, reallocating their limited resources to optimize performance.
• Hardcastle, C., O'Shea, A., Kraft, J. N., Albizu, A., Evangelista, N. D., Hausman, H. K., Boutzoukas, E. M., Van Etten, E. J., Bharadwaj, P. K., Song, H., Smith, S. G., Porges, E. C., Dekosky, S., Hishaw, G. A., Wu, S. S., Marsiske, M., Cohen, R., Alexander, G. E., & Woods, A. J. (2020). Contributions of Hippocampal Volume to Cognition in Healthy Older Adults. Frontiers in aging neuroscience, 12, 593833.
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  : The association between hippocampal volume and memory is continuing to be characterized in healthy older adults. Prior research suggests smaller hippocampal volume in healthy older adults is associated with poorer episodic memory and processing speed, as well as working memory, verbal learning, and executive functioning as measured by the NIH Toolbox Fluid (Fluid Cognition Composite, FCC) and Crystalized Cognition Composites (CCC). This study aimed to replicate these findings and to evaluate the association between: (1) hippocampal asymmetry index and cognition; and (2) independent contributions of the left and right hippocampal volume and cognition in a large sample of healthy older adults. : One-hundred and eighty-three healthy older adults (M age = 71.72, SD = 5.3) received a T1-weighted sequence on a 3T scanner. Hippocampal subfields were extracted using FreeSurfer 6.0 and combined to provide left, right, and total hippocampal volumes. FCC subtests include Dimensional Change Card Sort, Flanker Inhibitory Control and Attention, List Sorting, Picture Sequence Memory, and Pattern Comparison. CCC subtests include Picture Vocabulary and Oral Reading Recognition. Multiple linear regressions were performed predicting cognition composites from the total, left and right, and asymmetry of hippocampal volume, controlling for sex, education, scanner, and total intracranial volume. Multiple comparisons in primary analyses were corrected using a false discovery rate (FDR) of < 0.05. : FCC scores were positively associated with total ( = 0.226, FDR = 0.044) and left ( = 0.257, FDR = 0.024) hippocampal volume. Within FCC, Picture Sequence Memory scores positively associated with total ( = 0.284, = 0.001) and left ( = 0.98, = 0.001) hippocampal volume. List Sorting scores were also positively associated with left hippocampal volume ( = 0.189, = 0.029). : These results confirm previous research suggesting that bilateral hippocampal volume is associated with FCC, namely episodic memory. The present study also suggests the left hippocampal volume may be more broadly associated with both episodic and working memory. Studies should continue to investigate lateralized hippocampal contributions to aging processes to better identify predictors of cognitive decline.
• Hausman, H. K., O'Shea, A., Kraft, J. N., Boutzoukas, E. M., Evangelista, N. D., Van Etten, E. J., Bharadwaj, P. K., Smith, S. G., Porges, E., Hishaw, G. A., Wu, S., DeKosky, S., Alexander, G. E., Marsiske, M., Cohen, R., & Woods, A. J. (2020). The Role of Resting-State Network Functional Connectivity in Cognitive Aging. Frontiers in aging neuroscience, 12, 177.
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  Aging is associated with disruptions in the resting-state functional architecture of the brain. Previous studies have primarily focused on age-related declines in the default mode network (DMN) and its implications in Alzheimer's disease. However, due to mixed findings, it is unclear if changes in resting-state network functional connectivity are linked to cognitive decline in healthy older adults. In the present study, we evaluated the influence of intra-network coherence for four higher-order cognitive resting-state networks on a sensitive measure of cognitive aging (i.e., NIH Toolbox Fluid Cognition Battery) in 154 healthy older adults with a mean age of 71 and education ranging between 12 years and 21 years (mean = 16). Only coherence within the cingulo-opercular network (CON) was significantly related to Fluid Cognition Composite scores, explaining more variance in scores than age and education. Furthermore, we mapped CON connectivity onto fluid cognitive subdomains that typically decline in advanced age. Greater CON connectivity was associated with better performance on episodic memory, attention, and executive function tasks. Overall, the present study provides evidence to propose CON coherence as a potential novel neural marker for nonpathological cognitive aging.
• Kraft, J. N., O'Shea, A., Albizu, A., Evangelista, N. D., Hausman, H. K., Boutzoukas, E., Nissim, N. R., Van Etten, E. J., Bharadwaj, P. K., Song, H., Smith, S. G., Porges, E., DeKosky, S., Hishaw, G. A., Wu, S., Marsiske, M., Cohen, R., Alexander, G. E., & Woods, A. J. (2020). Structural Neural Correlates of Double Decision Performance in Older Adults. Frontiers in aging neuroscience, 12, 278.
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  Speed of processing is a cognitive domain that encompasses the speed at which an individual can perceive a given stimulus, interpret the information, and produce a correct response. Speed of processing has been shown to decline more rapidly than other cognitive domains in an aging population, suggesting that this domain is particularly vulnerable to cognitive aging (Chee et al., 2009). However, given the heterogeneity of neuropsychological measures used to assess the domains underpinning speed of processing, a diffuse pattern of brain regions has been implicated. The current study aims to investigate the structural neural correlates of speed of processing by assessing cortical volume and speed of processing scores on the POSIT Double Decision task within a healthy older adult population ( = 186; mean age = 71.70 ± 5.32 years). T1-weighted structural images were collected via a 3T Siemens scanner. The current study shows that less cortical thickness in right temporal, posterior frontal, parietal and occipital lobe structures were significantly associated with poorer Double Decision scores. Notably, these include the lateral orbitofrontal gyrus, precentral gyrus, superior, transverse, and inferior temporal gyrus, temporal pole, insula, parahippocampal gyrus, fusiform gyrus, lingual gyrus, superior and inferior parietal gyrus and lateral occipital gyrus. Such findings suggest that speed of processing performance is associated with a wide array of cortical regions that provide unique contributions to performance on the Double Decision task.
• Raichlen, D. A., & Alexander, G. E. (2020). Why your brain needs exercise: Key transitions in the evolutionary history of humans may have linked body and mind in ways that we can exploit to slow brain aging.. Scientific American, 322(1), 27-31.
• Raichlen, D. A., Bharadwaj, P. K., Nguyen, L. A., Franchetti, M. K., Zigman, E. K., Solorio, A. R., & Alexander, G. E. (2020). Effects of simultaneous cognitive and aerobic exercise training on dual-task walking performance in healthy older adults: results from a pilot randomized controlled trial. BMC geriatrics, 20(1), 83.
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  The ability to walk and perform cognitive tasks simultaneously is a key aspect of daily life. Performance declines in these dual-tasks may be associated with early signs of neurodegenerative disease and increased risk of falls. Thus, interventions to improve dual-task walking performance are of great interest for promoting healthy aging. Here, we present results of a pilot randomized controlled trial (RCT) to evaluate the effects of a simultaneous aerobic exercise and cognitive training intervention on dual-task walking performance in healthy older adults.
• Raichlen, D. A., Klimentidis, Y. C., Bharadwaj, P. K., & Alexander, G. E. (2020). Differential associations of engagement in physical activity and estimated cardiorespiratory fitness with brain volume in middle-aged to older adults. Brain imaging and behavior, 14(5), 1994-2003.
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  Previous work has confirmed the benefits of aerobic exercise for brain aging, however mechanisms underlying these effects remain unclear. Two measures of exercise, time spent in moderate-to-vigorous physical activity (MVPA) and cardiorespiratory fitness (CRF), may reflect different pathways linking activity to brain health. Using data from the UK Biobank, the largest sample combining neuroimaging and objectively measured MVPA available to date (n = 7148, n = 3062, n = 4086; age = 62.14 ± 7.40 years), we found that, when adjusted for covariates including MVPA, CRF was positively associated with overall gray matter volume (FDR p = 1.28E-05). In contrast, when adjusted for covariates including CRF, MVPA was positively associated with left and right hippocampal (FDR p = 0.01; FDR p = 0.02) volumes, but not overall gray matter volume. Both CRF and MVPA were inversely associated with white matter hyperintensity lesion loads (FDR p = 0.002; p = 0.02). Our results suggest separable effects of engagement in exercise behaviors (MVPA) and the physiological effects of exercise (CRF) on structural brain volumes, which may have implications for differential pathways linking exercise and brain benefits.
• Sayre, M. K., Pontzer, H., Alexander, G. E., Wood, B. M., Pike, I. L., Mabulla, A. Z., & Raichlen, D. A. (2020). Ageing and physical function in East African foragers and pastoralists. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 375(1811), 20190608.
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  Human lifespans are exceptionally long compared with those of other primates. A key element in exploring the evolution of human longevity is understanding how modern humans grow older. Our current understanding of common age-related changes in human health and function stems mostly from studies in industrialized societies, where older adulthood is often associated with an increased incidence of chronic diseases. However, individuals who engage in different lifestyles across industrialized and non-industrialized contexts may display variance in age-related changes in health and function. Here, we explore aspects of physical function in a non-industrialized context using three objective measures of physical function. We assessed physical activity levels, walking endurance and muscle strength in two East African populations: Hadza hunter-gatherers in Tanzania and Pokot pastoralists in Kenya. Both Hadza and Pokot participants displayed significant age-related differences in most, but not all, functional measures. Our results suggest that some age-related differences in physical function seen in industrialized contexts could be consistently experienced by most humans, while other age-related differences may vary across populations. Studies of ageing should expand to include a broad range of populations so we can create a more comprehensive understanding of how senescence varies across different lifestyle contexts. This article is part of the theme issue 'Evolution of the primate ageing process'.
• Van Etten, E. J., Bharadwaj, P. K., Nguyen, L. A., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2020). Right hippocampal volume mediation of subjective memory complaints differs by hypertension status in healthy aging. Neurobiology of aging, 94, 271-280.
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  Subjective memory complaints (SMCs) may be an important early indicator of cognitive aging and preclinical Alzheimer's disease risk. This study investigated whether age-related differences in right or left hippocampal volume underlie SMCs, if these relationships differ by hypertension status, and how they are related to objective memory performance in a group of 190 healthy older adults, 50-89 years of age. Analyses revealed a significant mediation of the relationship between age and mild SMCs by right hippocampal volume that was moderated by hypertension status. This moderated mediation effect was not observed with left hippocampal volume. Additionally, a moderated serial mediation model showed that age predicted right hippocampal volume, which predicted SMCs, and in turn predicted objective memory performance on several measures of verbal selective reminding in individuals with hypertension, but not in non-hypertensives. Together, these findings suggest that even mild SMCs, in the context of hypertension, provide an early indicator of cognitive aging, reflecting a potential link among vascular risk, SMCs, and the preclinical risk for Alzheimer's disease.
• Raichlen, D. A., Klimentidis, Y. C., Hsu, C. H., & Alexander, G. E. (2019). Fractal Complexity of Daily Physical Activity Patterns Differs With Age Over the Life Span and Is Associated With Mortality in Older Adults. The journals of gerontology. Series A, Biological sciences and medical sciences, 74(9), 1461-1467.
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  Accelerometers are included in a wide range of devices that monitor and track physical activity for health-related applications. However, the clinical utility of the information embedded in their rich time-series data has been greatly understudied and has yet to be fully realized. Here, we examine the potential for fractal complexity of actigraphy data to serve as a clinical biomarker for mortality risk.
• Willeman, M. N., Chawla, M. K., Zempare, M. A., Biwer, L. A., Hoang, L. T., Uprety, A. R., Fitzhugh, M. C., De Both, M., Coleman, P. D., Trouard, T. P., Alexander, G. E., Mitchell, K. D., Barnes, C. A., Hale, T. M., & Huentelman, M. (2019). Gradual hypertension induction in middle-aged Cyp1a1-Ren2 transgenic rats produces significant impairments in spatial learning. Physiological reports, 7(6), e14010.
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  Hypertension is a major health concern in the developed world, and its prevalence increases with advancing age. The impact of hypertension on the function of the renal and cardiovascular systems is well studied; however, its influence on the brain regions important for cognition has garnered less attention. We utilized the Cyp1a1-Ren2 xenobiotic-inducible transgenic rat model to mimic both the age of onset and rate of induction of hypertension observed in humans. Male, 15-month-old transgenic rats were fed 0.15% indole-3-carbinol (I3C) chow to slowly induce renin-dependent hypertension over a 6-week period. Systolic blood pressure significantly increased, eventually reaching 200 mmHg by the end of the study period. In contrast, transgenic rats fed a control diet without I3C did not show significant changes in blood pressure (145 mmHg at the end of study). Hypertension was associated with cardiac, aortic, and renal hypertrophy as well as increased collagen deposition in the left ventricle and kidney of the I3C-treated rats. Additionally, rats with hypertension showed reduced savings from prior spatial memory training when tested on the hippocampus-dependent Morris swim task. Motor and sensory functions were found to be unaffected by induction of hypertension. Taken together, these data indicate a profound effect of hypertension not only on the cardiovascular-renal axis but also on brain systems critically important for learning and memory. Future use of this model and approach may empower a more accurate investigation of the influence of aging on the systems responsible for cardiovascular, renal, and neurological health.
• Klimentidis, Y. C., Raichlen, D. A., Bea, J., Garcia, D. O., Wineinger, N. E., Mandarino, L. J., Alexander, G. E., Chen, Z., & Going, S. B. (2018). Genome-wide association study of habitual physical activity in over 377,000 UK Biobank participants identifies multiple variants including CADM2 and APOE. International journal of obesity, 42(6), 1161-1176.
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  Physical activity (PA) protects against a wide range of diseases. Habitual PA appears to be heritable, motivating the search for specific genetic variants that may inform efforts to promote PA and target the best type of PA for each individual.
• Klimentidis, Y. C., Raichlen, D. A., Bea, J., Garcia, D. O., Wineinger, N. E., Mandarino, L. J., Alexander, G. E., Chen, Z., & Going, S. B. (2018). In response to: 'Information bias in measures of self-reported physical activity'. International journal of obesity, 42(12), 2064-2065.
• Stonnington, C. M., Chen, Y., Savage, C. R., Lee, W., Bauer, R. J., Sharieff, S., Thiyyagura, P., Alexander, G. E., Caselli, R. J., Locke, D. E., Reiman, E. M., & Chen, K. (2018). Predicting Imminent Progression to Clinically Significant Memory Decline Using Volumetric MRI and FDG PET. Journal of Alzheimer's disease : JAD, 63(2), 603-615.
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  Brain imaging measurements can provide evidence of possible preclinical Alzheimer's disease (AD). Their ability to predict individual imminent clinical conversion remains unclear.
• Woods, A. J., Cohen, R., Marsiske, M., Alexander, G. E., Czaja, S., & Wu, S. (2018). Augmenting cognitive training in older adults (The ACT Study): Design and Methods of a Phase III tDCS and cognitive training trial. Contemp Clin Trials, 65, 19-32.
• Alexander, G. E. (2017). An Emerging Role for Imaging White Matter in the Preclinical Risk for Alzheimer Disease: Linking β-Amyloid to Myelin. JAMA neurology, 74(1), 17-19.
• Alexander, G. E. (2017). An emerging role for imaging white matter in the preclinical risk for Alzheimer’s disease - Linking b-amyloid to myelin. JAMA Neurology, 74, 17-19.
• Cohen, R. A., & Alexander, G. E. (2017). Using the Telephone Interview for Cognitive Status and Telephone Montreal Cognitive Assessment for Evaluating Vascular Cognitive Impairment: Promising Call or Put on Hold?. Stroke, 48(11), 2919-2921.
• Kern, K. C., Wright, C. B., Bergfield, K. L., Fitzhugh, M. C., Chen, K., Moeller, J. R., Nabizadeh, N., Elkind, M. S., Sacco, R. L., Stern, Y., DeCarli, C. S., & Alexander, G. E. (2017). Blood Pressure Control in Aging Predicts Cerebral Atrophy Related to Small-Vessel White Matter Lesions. Frontiers in aging neuroscience, 9, 132.
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  Cerebral small-vessel damage manifests as white matter hyperintensities and cerebral atrophy on brain MRI and is associated with aging, cognitive decline and dementia. We sought to examine the interrelationship of these imaging biomarkers and the influence of hypertension in older individuals. We used a multivariate spatial covariance neuroimaging technique to localize the effects of white matter lesion load on regional gray matter volume and assessed the role of blood pressure control, age and education on this relationship. Using a case-control design matching for age, gender, and educational attainment we selected 64 participants with normal blood pressure, controlled hypertension or uncontrolled hypertension from the Northern Manhattan Study cohort. We applied gray matter voxel-based morphometry with the scaled subprofile model to (1) identify regional covariance patterns of gray matter volume differences associated with white matter lesion load, (2) compare this relationship across blood pressure groups, and (3) relate it to cognitive performance. In this group of participants aged 60-86 years, we identified a pattern of reduced gray matter volume associated with white matter lesion load in bilateral temporal-parietal regions with relative preservation of volume in the basal forebrain, thalami and cingulate cortex. This pattern was expressed most in the uncontrolled hypertension group and least in the normotensives, but was also more evident in older and more educated individuals. Expression of this pattern was associated with worse performance in executive function and memory. In summary, white matter lesions from small-vessel disease are associated with a regional pattern of gray matter atrophy that is mitigated by blood pressure control, exacerbated by aging, and associated with cognitive performance.
• Raichlen, D. A., & Alexander, G. E. (2017). Adaptive Capacity: An Evolutionary Neuroscience Model Linking Exercise, Cognition, and Brain Health. Trends in neurosciences, 40(7), 408-421.
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  The field of cognitive neuroscience was transformed by the discovery that exercise induces neurogenesis in the adult brain, with the potential to improve brain health and stave off the effects of neurodegenerative disease. However, the basic mechanisms underlying exercise-brain connections are not well understood. We use an evolutionary neuroscience approach to develop the adaptive capacity model (ACM), detailing how and why physical activity improves brain function based on an energy-minimizing strategy. Building on studies showing a combined benefit of exercise and cognitive challenge to enhance neuroplasticity, our ACM addresses two fundamental questions: (i) what are the proximate and ultimate mechanisms underlying age-related brain atrophy, and (ii) how do lifestyle changes influence the trajectory of healthy and pathological aging?
• Nguyen, L. A., Haws, K. A., Fitzhugh, M. C., Torre, G. A., Hishaw, G. A., & Alexander, G. E. (2016). Interactive effects of subjective memory complaints and hypertension on learning and memory performance in the elderly. Neuropsychology, development, and cognition. Section B, Aging, neuropsychology and cognition, 23(2), 154-70.
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  This study evaluated whether the relation between subjective memory complaints and cognitive performance is influenced by the presence of hypertension in the elderly. One hundred and five healthy older adults, 70-89 years of age, with and without hypertension treatment or diagnosis, completed a scale of subjective memory complaints. Participants were divided into those with mild memory concerns and those with minimal or no complaints. All participants completed a battery of neuropsychological tests including measures of verbal and nonverbal memory. After controlling for differences in age, gender, education, and overall intellectual ability, there were significant main effects for memory concerns and significant interactions for memory complaints and hypertension on several measures of memory performance. There were no main effects for hypertension on memory performance. Simple effects analyses of the interactions showed that the hypertensive complainers demonstrated poorer performance on measures of long-term memory and greater reliance on short-term recall than the hypertensive non-complainers. There were no differences in memory performance for the non-hypertensive groups. Among healthy elderly community-dwelling adults, those with mild subjective memory complaints in the context of hypertension demonstrated greater objective cognitive difficulties than those without hypertension as well as a greater reliance on a less efficient learning strategy. These findings suggest that memory concerns in the presence of hypertension may be important when evaluating treatment efficacy in these individuals and for identifying differences in cognitive aging.
• Raichlen, D. A., Bharadwaj, P. K., Fitzhugh, M. C., Haws, K. A., Torre, G. A., Trouard, T. P., & Alexander, G. E. (2016). Differences in Resting State Functional Connectivity between Young Adult Endurance Athletes and Healthy Controls. Frontiers in human neuroscience, 10, 610.
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  Expertise and training in fine motor skills has been associated with changes in brain structure, function, and connectivity. Fewer studies have explored the neural effects of athletic activities that do not seem to rely on precise fine motor control (e.g., distance running). Here, we compared resting-state functional connectivity in a sample of adult male collegiate distance runners ( = 11; age = 21.3 ± 2.5) and a group of healthy age-matched non-athlete male controls ( = 11; age = 20.6 ± 1.1), to test the hypothesis that expertise in sustained aerobic motor behaviors affects resting state functional connectivity in young adults. Although generally considered an automated repetitive task, locomotion, especially at an elite level, likely engages multiple cognitive actions including planning, inhibition, monitoring, attentional switching and multi-tasking, and motor control. Here, we examined connectivity in three resting-state networks that link such executive functions with motor control: the default mode network (DMN), the frontoparietal network (FPN), and the motor network (MN). We found two key patterns of significant between-group differences in connectivity that are consistent with the hypothesized cognitive demands of elite endurance running. First, enhanced connectivity between the FPN and brain regions often associated with aspects of working memory and other executive functions (frontal cortex), suggest endurance running may stress executive cognitive functions in ways that increase connectivity in associated networks. Second, we found significant anti-correlations between the DMN and regions associated with motor control (paracentral area), somatosensory functions (post-central region), and visual association abilities (occipital cortex). DMN deactivation with task-positive regions has been shown to be generally beneficial for cognitive performance, suggesting anti-correlated regions observed here are engaged during running. For all between-group differences, there were significant associations between connectivity, self-reported physical activity, and estimates of maximum aerobic capacity, suggesting a dose-response relationship between engagement in endurance running and connectivity strength. Together these results suggest that differences in experience with endurance running are associated with differences in functional brain connectivity. High intensity aerobic activity that requires sustained, repetitive locomotor and navigational skills may stress cognitive domains in ways that lead to altered brain connectivity, which in turn has implications for understanding the beneficial role of exercise for brain and cognitive function over the lifespan.
• Nguyen, L. A., Haws, K. A., Fitzhugh, M. A., Hishaw, G. A., & Alexander, G. E. (2015). Interactive Effects of Subjective Memory Complaints and Hypertension on Cognitive Performance in the Elderly. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn, 154-70.
• Raichlen, D. A., & Alexander, G. E. (2014). Exercise, APOE genotype, and the evolution of the human lifespan. Trends in neurosciences, 37(5), 247-55.
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  Humans have exceptionally long lifespans compared with other mammals. However, our longevity evolved when our ancestors had two copies of the apolipoprotein E (APOE) ɛ4 allele, a genotype that leads to a high risk of Alzheimer's disease (AD), cardiovascular disease, and increased mortality. How did human aging evolve within this genetic constraint? Drawing from neuroscience, anthropology, and brain-imaging research, we propose the hypothesis that the evolution of increased physical activity approximately 2 million years ago served to reduce the amyloid plaque and vascular burden of APOE ɛ4, relaxing genetic constraints on aging. This multidisciplinary approach links human evolution with health and provides a complementary perspective on aging and neurodegenerative disease that may help identify key mechanisms and targets for intervention.
• Raichlen, D., & Alexander, G. E. (2014). Exercise, APOE genotype, and the evolution of the human lifespan. Trends in Neuroscience, 37, 247-55.
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• Yoshimaru, E., Totenhagen, J., Alexander, G. E., & Trouard, T. P. (2014). Design, manufacture, and analysis of customized phantoms for enhanced quality control in small animal MRI systems. Magn Reson Med, 71, 880-84.
• Yoshimaru, E., Totenhagen, J., Alexander, G. E., & Trouard, T. P. (2014). Design, manufacture, and analysis of customized phantoms for enhanced quality control in small animal MRI systems. Magnetic resonance in medicine, 71(2), 880-4.
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  Magnetic resonance imaging (MRI) is widely used in human brain research to evaluate the effects of healthy aging and development, as well as neurological disorders. Although standardized methods for quality assurance of human MRI instruments have been established, such approaches have typically not been translated to small animal imaging. We present a method for the generation and analysis of customized phantoms for small animal MRI systems that allows rapid and accurate system stability monitoring.
• Burns, C. M., Chen, K., Kaszniak, A. W., Lee, W., Alexander, G. E., Bandy, D., Fleisher, A. S., Caselli, R. J., & Reiman, E. M. (2013). Higher serum glucose levels are associated with cerebral hypometabolism in Alzheimer regions. Neurology, 80(17), 1557-64.
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  To investigate whether higher fasting serum glucose levels in cognitively normal, nondiabetic adults were associated with lower regional cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer disease (AD).
• Burns, C. M., Chen, K., Kaszniak, A. W., Lee, W., Alexander, G. E., Bandy, D., Fleisher, A., Caselli, R. J., & Reiman, E. R. (2013). Higher serum glucose levels are associated with cerebral hypometabolism in Alzheimer's regions. Neurology, 80, 1557-64.
• Protas, H. D., Chen, K., Langbaum, J. B., Fleisher, A. S., Alexander, G. E., Lee, W., Bandy, D., de Leon, M. J., Mosconi, L., Buckley, S., Truran-Sacrey, D., Schuff, N., Weiner, M. W., Caselli, R. J., & Reiman, E. M. (2013). Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease. JAMA neurology, 70(3), 320-5.
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  To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middle-aged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) ε4 allele, reflecting 3 levels of risk for late-onset Alzheimer disease.
• Schraml, F., Chen, K., Ayutyanont, N., Auttawut, R., B., J., Lee, W., Liu, X., Bandy, D., Reeder, S. Q., Alexander, G. E., Caselli, R. J., Fleisher, A. S., & Reiman, E. M. (2013). Association between an Alzheimer's Disease-Related Index and APOE ε4 Gene Dose. PLoS ONE, 8(6).
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  Abstract: Background:We introduced a hypometabolic convergence index (HCI) to characterize in a single measurement the extent to which a person's fluorodeoxyglucose positron emission tomogram (FDG PET) corresponds to that in Alzheimer's disease (AD). Apolipoprotein E ε4 (APOE ε4) gene dose is associated with three levels of risk for late-onset AD. We explored the association between gene dose and HCI in cognitively normal ε4 homozygotes, heterozygotes, and non-carriers.Methods:An algorithm was used to characterize and compare AD-related HCIs in cognitively normal individuals, including 36 ε4 homozygotes, 46 heterozygotes, and 78 non-carriers.Results:These three groups differed significantly in their HCIs (ANOVA, p = 0.004), and there was a significant association between HCIs and gene dose (linear trend, p = 0.001).Conclusions:The HCI is associated with three levels of genetic risk for late-onset AD. This supports the possibility of using a single FDG PET measurement to help in the preclinical detection and tracking of AD. © 2013 Schraml et al.
• Schraml, F., Chen, K., Ayutyanont, N., Auttawut, R., Langbaum, J. B., Lee, W., Liu, X., Bandy, D., Reeder, S. Q., Alexander, G. E., Caselli, R. J., Fleisher, A. S., Reiman, E. M., & , A. D. (2013). Association between an Alzheimer's Disease-Related Index and APOE ε4 Gene Dose. PloS one, 8(6), e67163.
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  We introduced a hypometabolic convergence index (HCI) to characterize in a single measurement the extent to which a person's fluorodeoxyglucose positron emission tomogram (FDG PET) corresponds to that in Alzheimer's disease (AD). Apolipoprotein E ε4 (APOE ε4) gene dose is associated with three levels of risk for late-onset AD. We explored the association between gene dose and HCI in cognitively normal ε4 homozygotes, heterozygotes, and non-carriers.
• Smith, J. F., Braun, A. R., Alexander, G. E., Chen, K., & Horwitz, B. (2013). Separating lexical-semantic access from other mnemonic processes in picture-name verification. Front Psychol, 4, 706.
• Smith, J. F., Braun, A. R., Alexander, G. E., Chen, K., & Horwitz, B. (2013). Separating lexical-semantic access from other mnemonic processes in picture-name verification. Frontiers in psychology, 4, 706.
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  We present a novel paradigm to identify shared and unique brain regions underlying non-semantic, non-phonological, abstract, audio-visual (AV) memory vs. naming using a longitudinal functional magnetic resonance imaging experiment. Participants were trained to associate novel AV stimulus pairs containing hidden linguistic content. Half of the stimulus pairs were distorted images of animals and sine-wave speech versions of the animal's name. Images and sounds were distorted in such a way as to make their linguistic content easily recognizable only after being made aware of its existence. Memory for the pairings was tested by presenting an AV pair and asking participants to verify if the two stimuli formed a learned pairing. After memory testing, the hidden linguistic content was revealed and participants were tested again on their recollection of the pairings in this linguistically informed state. Once informed, the AV verification task could be performed by naming the picture. There was substantial overlap between the regions involved in recognition of non-linguistic sensory memory and naming, suggesting a strong relation between them. Contrasts between sessions identified left angular gyrus and middle temporal gyrus as key additional players in the naming network. Left inferior frontal regions participated in both naming and non-linguistic AV memory suggesting the region is responsible for AV memory independent of phonological content contrary to previous proposals. Functional connectivity between angular gyrus and left inferior frontal gyrus and left middle temporal gyrus increased when performing the AV task as naming. The results are consistent with the hypothesis that, at the spatial resolution of fMRI, the regions that facilitate non-linguistic AV associations are a subset of those that facilitate naming though reorganized into distinct networks.
• Alexander, G. E., Bergfield, K. L., Chen, K., Reiman, E. M., Hanson, K. D., Lin, L., Bandy, D., Caselli, R. J., & Moeller, J. R. (2012). Gray matter network associated with risk for Alzheimer's disease in young to middle-aged adults. Neurobiology of aging, 33(12), 2723-32.
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  The apolipoprotein E (APOE) ε4 allele increases the risk for late-onset Alzheimer's disease (AD) and age-related cognitive decline. We investigated whether ε4 carriers show reductions in gray matter volume compared with ε4 non-carriers decades before the potential onset of AD dementia or healthy cognitive aging. Fourteen cognitively normal ε4 carriers, aged 26 to 45 years, were compared with 10 age-matched, ε4 non-carriers using T1-weighted volumetric magnetic resonance imaging (MRI) scans. All had reported first- or second-degree family histories of dementia. Group differences in gray matter were tested using voxel-based morphometry (VBM) and a multivariate model of regional covariance, the Scaled Subprofile Model (SSM). A combination of the first two SSM MRI gray matter patterns distinguished the APOE ε4 carriers from non-carriers. This combined pattern showed gray matter reductions in bilateral dorsolateral and medial frontal, anterior cingulate, parietal, and lateral temporal cortices with covarying relative increases in cerebellum, occipital, fusiform, and hippocampal regions. With these gray matter differences occurring decades before the potential onset of dementia or cognitive aging, the results suggest longstanding, gene-associated differences in brain morphology that may lead to preferential vulnerability for the later effects of late-onset AD or healthy brain aging.
• Alexander, G. E., Ryan, L., Bowers, D., Foster, T. C., Bizon, J. L., Geldmacher, D. S., & Glisky, E. L. (2012). Characterizing cognitive aging in humans with links to animal models. Frontiers in aging neuroscience, 4, 21.
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  With the population of older adults expected to grow rapidly over the next two decades, it has become increasingly important to advance research efforts to elucidate the mechanisms associated with cognitive aging, with the ultimate goal of developing effective interventions and prevention therapies. Although there has been a vast research literature on the use of cognitive tests to evaluate the effects of aging and age-related neurodegenerative disease, the need for a set of standardized measures to characterize the cognitive profiles specific to healthy aging has been widely recognized. Here we present a review of selected methods and approaches that have been applied in human research studies to evaluate the effects of aging on cognition, including executive function, memory, processing speed, language, and visuospatial function. The effects of healthy aging on each of these cognitive domains are discussed with examples from cognitive/experimental and clinical/neuropsychological approaches. Further, we consider those measures that have clear conceptual and methodological links to tasks currently in use for non-human animal studies of aging, as well as those that have the potential for translation to animal aging research. Having a complementary set of measures to assess the cognitive profiles of healthy aging across species provides a unique opportunity to enhance research efforts for cross-sectional, longitudinal, and intervention studies of cognitive aging. Taking a cross-species, translational approach will help to advance cognitive aging research, leading to a greater understanding of associated neurobiological mechanisms with the potential for developing effective interventions and prevention therapies for age-related cognitive decline.
• Alexander, G., Ryan, L., Cardoza, J. A., Barense, M. D., Kawa, K. H., Wallentin-Flores, J., Arnold, W. T., & Alexander, G. E. (2012). Age-related impairment in a complex object discrimination task that engages perirhinal cortex. Hippocampus, 22(10).
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  Previous lesion studies have shown compromised complex object discrimination in rats, monkeys, and human patients with damage to the perirhinal cortical region (PRC) of the medial temporal lobe. These findings support the notion that the PRC is involved in object discrimination when pairs of objects have a high degree of overlapping features but not when object discrimination can be resolved on the basis of a single feature (e.g., size or color). Recent studies have demonstrated age-related functional changes to the PRC in animals (rats and monkeys) resulting in impaired complex object discrimination and object recognition. To date, no studies have compared younger and older humans using paradigms previously shown to engage the PRC. To investigate the influence of age on complex object discrimination in humans, the present study used an object matching paradigm for blob-like objects that have previously been shown to recruit the PRC. Difficulty was manipulated by varying the number of overlapping features between objects. Functional MRI data was acquired to determine the involvement of the PRC in the two groups during complex object discrimination. Results indicated that while young and older adults performed similarly on the easy version of the task, most older adults were impaired relative to young participants when the number of overlapping features increased. fMRI results suggest that older adults do not engage bilateral anterior PRC to the same extent as young adults. Specifically, complex object matching performance in older adults was predicted by the degree to which they engage left anterior PRC. These results provide evidence for human age-related changes in PRC function that impact complex object discrimination.
• Bizon, J. L., Foster, T. C., Alexander, G. E., & Glisky, E. L. (2012). Characterizing cognitive aging of working memory and executive function in animal models. Frontiers in aging neuroscience, 4, 19.
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  Executive functions supported by prefrontal cortical (PFC) systems provide essential control and planning mechanisms to guide goal-directed behavior. As such, age-related alterations in executive functions can mediate profound and widespread deficits on a diverse array of neurocognitive processes. Many of the critical neuroanatomical and functional characteristics of prefrontal cortex are preserved in rodents, allowing for meaningful cross species comparisons relevant to the study of cognitive aging. In particular, as rodents lend themselves to genetic, cellular and biochemical approaches, rodent models of executive function stand to significantly contribute to our understanding of the critical neurobiological mechanisms that mediate decline of executive processes across the lifespan. Moreover, rodent analogs of executive functions that decline in human aging represent an essential component of a targeted, rational approach for developing and testing effective treatment and prevention therapies for age-related cognitive decline. This paper reviews behavioral approaches used to study executive function in rodents, with a focus on those assays that share a foundation in the psychological and neuroanatomical constructs important for human aging. A particular emphasis is placed on behavioral approaches used to assess working memory and cognitive flexibility, which are sensitive to decline with age across species and for which strong rodent models currently exist. In addition, other approaches in rodent behavior that have potential for providing analogs to functions that reliably decline to human aging (e.g., information processing speed) are discussed.
• Chen, K., Ayutyanont, N., Langbaum, J. B., Fleisher, A. S., Reschke, C., Lee, W., Liu, X., Alexander, G. E., Bandy, D., Caselli, R. J., & Reiman, E. M. (2012). Correlations between FDG PET glucose uptake-MRI gray matter volume scores and apolipoprotein E ε4 gene dose in cognitively normal adults: a cross-validation study using voxel-based multi-modal partial least squares. NeuroImage, 60(4), 2316-22.
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  We previously introduced a voxel-based, multi-modal application of the partial least square algorithm (MMPLS) to characterize the linkage between patterns in a person's complementary complex datasets without the need to correct for multiple regional comparisons. Here we used it to demonstrate a strong correlation between MMPLS scores to characterize the linkage between the covarying patterns of fluorodeoxyglucose positron emission tomography (FDG PET) measurements of regional glucose metabolism and magnetic resonance imaging (MRI) measurements of regional gray matter associated with apolipoprotein E (APOE) ε4 gene dose (i.e., three levels of genetic risk for late-onset Alzheimer's disease (AD)) in cognitively normal, late-middle-aged persons. Coregistered and spatially normalized FDG PET and MRI images from 70% of the subjects (27 ε4 homozygotes, 36 ε4 heterozygotes and 67 ε4 non-carriers) were used in a hypothesis-generating MMPLS analysis to characterize the covarying pattern of regional gray matter volume and cerebral glucose metabolism most strongly correlated with APOE-ε4 gene dose. Coregistered and spatially normalized FDG PET and MRI images from the remaining 30% of the subjects were used in a hypothesis-testing MMPLS analysis to generate FDG PET-MRI gray matter MMPLS scores blind to their APOE genotype and characterize their relationship to APOE-ε4 gene dose. The hypothesis-generating analysis revealed covarying regional gray matter volume and cerebral glucose metabolism patterns that resembled those in traditional univariate analyses of AD and APOE-ε4 gene dose and PET-MRI scores that were strongly correlated with APOE-ε4 gene dose (p
• Ewers, M., Walsh, C., Trojanowski, J. Q., Shaw, L. M., Petersen, R. C., Jack, C. R., Feldman, H. H., Bokde, A. L., Alexander, G. E., Scheltens, P., Vellas, B., Dubois, B., Weiner, M., & Hampel, H. (2012). Prediction of conversion from mild cognitive impairment to Alzheimer's disease dementia based upon biomarkers and neuropsychological test performance. Neurobiology of Aging, 33(7), 1203-1214.e2.
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  PMID: 21159408;PMCID: PMC3328615;Abstract: The current study tested the accuracy of primary MRI and cerebrospinal fluid (CSF) biomarker candidates and neuropsychological tests for predicting the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. In a cross-validation paradigm, predictor models were estimated in the training set of AD (N = 81) and elderly control subjects (N = 101). A combination of CSF t-tau/Aβ1-4 ratio and MRI biomarkers or neuropsychological tests (free recall and trail making test B (TMT-B)) showed the best statistical fit in the AD vs. HC comparison, reaching a classification accuracy of up to 64% when applied to the prediction of MCI conversion (3.3-year observation interval, mean = 2.3 years). However, several single-predictor models showed a predictive accuracy of MCI conversion comparable to that of any multipredictor model. The best single predictors were right entorhinal cortex (prediction accuracy = 68.5% (95% CI (59.5, 77.4))) and TMT-B test (prediction accuracy 64.6% (95% CI (55.5, 73.4%))). In conclusion, short-term conversion to AD is predicted by single marker models to a comparable degree as by multimarker models in amnestic MCI subjects. © 2012 Elsevier Inc.
• Henry, M. L., Beeson, P. M., Alexander, G. E., & Rapcsak, S. Z. (2012). Written language impairments in primary progressive aphasia: A reflection of damage to central semantic and phonological processes. Journal of Cognitive Neuroscience, 24, 261-75.
• Henry, M. L., Beeson, P. M., Alexander, G. E., & Rapcsak, S. Z. (2012). Written language impairments in primary progressive aphasia: a reflection of damage to central semantic and phonological processes. Journal of cognitive neuroscience, 24(2), 261-75.
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  Connectionist theories of language propose that written language deficits arise as a result of damage to semantic and phonological systems that also support spoken language production and comprehension, a view referred to as the "primary systems" hypothesis. The objective of the current study was to evaluate the primary systems account in a mixed group of individuals with primary progressive aphasia (PPA) by investigating the relation between measures of nonorthographic semantic and phonological processing and written language performance and by examining whether common patterns of cortical atrophy underlie impairments in spoken versus written language domains. Individuals with PPA and healthy controls were administered a language battery, including assessments of semantics, phonology, reading, and spelling. Voxel-based morphometry was used to examine the relation between gray matter volumes and language measures within brain regions previously implicated in semantic and phonological processing. In accordance with the primary systems account, our findings indicate that spoken language performance is strongly predictive of reading/spelling profile in individuals with PPA and suggest that common networks of critical left hemisphere regions support central semantic and phonological processes recruited for spoken and written language.
• Reiman, E. M., Quiroz, Y. T., Fleisher, A. S., Chen, K., Velez-Pardo, C., Jimenez-Del-Rio, M., Fagan, A. M., Shah, A. R., Alvarez, S., Arbelaez A, A., Giraldo, M., Acosta-Baena, N., Sperling, R. A., Dickerson, B., Stern, C. E., Tirado, V., Munoz, C., Reiman, R. A., Huentelman, M. J., , Alexander, G. E., et al. (2012). Brain abnormalities in young adults at genetic risk for autosomal dominant Alzheimer’s disease. The Lancet Neurology, 11, 1048-56.
• Reiman, E. M., Quiroz, Y. T., Fleisher, A. S., Chen, K., Velez-Pardo, C., Jimenez-Del-Rio, M., Fagan, A. M., Shah, A. R., Alvarez, S., Arbelaez, A., Giraldo, M., Acosta-Baena, N., Sperling, R. A., Dickerson, B., Stern, C. E., Tirado, V., Munoz, C., Reiman, R. A., Huentelman, M. J., , Alexander, G. E., et al. (2012). Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study. The Lancet. Neurology, 11(12), 1048-56.
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  We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease.
• Roberson, E. D., DeFazio, R. A., Barnes, C. A., Alexander, G. E., Bizon, J. L., Bowers, D., Foster, T. C., Glisky, E. L., Levin, B. E., Ryan, L., Wright, C. B., & Geldmacher, D. S. (2012). Challenges and opportunities in characterizing cognitive aging across species. Frontiers in Aging Neuroscience, 4, 6.
• Roberson, E. D., Defazio, R. A., Barnes, C. A., Alexander, G. E., Bizon, J. L., Bowers, D., Foster, T. C., Glisky, E. L., Levin, B. E., Ryan, L., Wright, C. B., & Geldmacher, D. S. (2012). Challenges and opportunities for characterizing cognitive aging across species. Frontiers in aging neuroscience, 4, 6.
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  The gradual decline of cognitive ability with age, even in the absence of overt brain disease, is a growing problem. Although cognitive aging is a common and feared accompaniment of the aging process, its underlying mechanisms are not well understood and there are no highly effective means to prevent it. Additional research on cognitive aging is sorely needed, and methods that enable ready translation between human subjects and animal models stand to provide the most benefit. Here and in the six companion pieces in this special issue, we discuss a variety of challenges and opportunities for studying cognitive aging across species. We identify tests of associative memory, recognition memory, spatial and contextual memory, and working memory and executive function as cognitive domains that are age-sensitive and amenable to testing with parallel means in both humans and animal models. We summarize some of the important challenges in using animal models to test cognition. We describe unique opportunities to study cognitive aging in human subjects, such as those provided by recent large-scale initiatives to characterize cognition in large groups of subjects across the lifespan. Finally, we highlight some of the challenges of studying cognitive aging in human subjects.
• Chen, K., Ayutyanont, N., Langbaum, J. B., Fleisher, A. S., Reschke, C., Lee, W., Liu, X., Bandy, D., Alexander, G. E., Thompson, P. M., Shaw, L., Trojanowski, J. Q., Jack, C. R., Landau, S. M., Foster, N. L., Harvey, D. J., Weiner, M. W., Koeppe, R. A., Jagust, W. J., & Reiman, E. M. (2011). Characterizing Alzheimer's disease using a hypometabolic convergence index. NeuroImage, 56(1), 52-60.
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  PMID: 21276856;PMCID: PMC3066300;Abstract: This article introduces a hypometabolic convergence index (HCI) for the assessment of Alzheimer's disease (AD); compares it to other biological, cognitive and clinical measures; and demonstrates its promise to predict clinical decline in mild cognitive impairment (MCI) patients using data from the AD Neuroimaging Initiative (ADNI). The HCI is intended to reflect in a single measurement the extent to which the pattern and magnitude of cerebral hypometabolism in an individual's fluorodeoxyglucose positron emission tomography (FDG-PET) image correspond to that in probable AD patients, and is generated using a fully automated voxel-based image-analysis algorithm. HCIs, magnetic resonance imaging (MRI) hippocampal volume measurements, cerebrospinal fluid (CSF) assays, memory test scores, and clinical ratings were compared in 47 probable AD patients, 21 MCI patients who converted to probable AD within the next 18. months, 76 MCI patients who did not, and 47 normal controls (NCs) in terms of their ability to characterize clinical disease severity and predict conversion rates from MCI to probable AD. HCIs were significantly different in the probable AD, MCI converter, MCI stable and NC groups (p=9e-17) and correlated with clinical disease severity. Using retrospectively characterized threshold criteria, MCI patients with either higher HCIs or smaller hippocampal volumes had the highest hazard ratios (HRs) for 18-month progression to probable AD (7.38 and 6.34, respectively), and those with both had an even higher HR (36.72). In conclusion, the HCI, alone or in combination with certain other biomarker measurements, has the potential to help characterize AD and predict subsequent rates of clinical decline. More generally, our conversion index strategy could be applied to a range of imaging modalities and voxel-based image-analysis algorithms. © 2011 Elsevier Inc.
• Hua, X., Gutman, B., Boyle, C. P., Rajagopalan, P., Leow, A. D., Yanovsky, I., Kumar, A. R., Toga, A. W., Jack, C. R., Schuff, N., Alexander, G. E., Chen, K., Reiman, E. M., Weiner, M. W., & Thompson, P. M. (2011). Accurate measurement of brain changes in longitudinal MRI scans using tensor-based morphometry. NeuroImage, 57(1), 5-14.
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  PMID: 21320612;PMCID: PMC3394184;Abstract: This paper responds to Thompson and Holland (2011), who challenged our tensor-based morphometry (TBM) method for estimating rates of brain changes in serial MRI from 431 subjects scanned every 6. months, for 2. years. Thompson and Holland noted an unexplained jump in our atrophy rate estimates: an offset between 0 and 6. months that may bias clinical trial power calculations. We identified why this jump occurs and propose a solution. By enforcing inverse-consistency in our TBM method, the offset dropped from 1.4% to 0.28%, giving plausible anatomical trajectories. Transitivity error accounted for the minimal remaining offset. Drug trial sample size estimates with the revised TBM-derived metrics are highly competitive with other methods, though higher than previously reported sample size estimates by a factor of 1.6 to 2.4. Importantly, estimates are far below those given in the critique. To demonstrate a 25% slowing of atrophic rates with 80% power, 62 AD and 129 MCI subjects would be required for a 2-year trial, and 91 AD and 192 MCI subjects for a 1-year trial. © 2011 Elsevier Inc.
• Alexander, G., Bergfield, K. L., Hanson, K. D., Chen, K., Teipel, S. J., Hampel, H., Rapoport, S. I., Moeller, J. R., & Alexander, G. E. (2010). Age-related networks of regional covariance in MRI gray matter: reproducible multivariate patterns in healthy aging. NeuroImage, 49(2).
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  Healthy aging is associated with brain volume reductions that involve the frontal cortex, but also affect other brain regions. We sought to identify an age-related network pattern of MRI gray matter using a multivariate statistical model of regional covariance, the Scaled Subprofile Model (SSM) with voxel based morphometry (VBM) in 29 healthy adults, 23-84 years of age (Group 1). In addition, we evaluated the reproducibility of the age-related gray matter pattern derived from a prior SSM VBM study of 26 healthy adults, 22-77 years of age (Group 2; Alexander et al., 2006) in relation to the current sample and tested the ability of the network analysis to extract an age-related pattern from both cohorts combined. The SSM VBM analysis of Group 1 identified a regional pattern of gray matter atrophy associated with healthy aging (R(2)=0.64, p
• Bergfield, K. L., Hanson, K. D., Chen, K., Teipel, S. J., Hampel, H., Rapoport, S. I., Moeller, J. R., & Alexander, G. E. (2010). Age-related networks of regional covariance in MRI gray matter: Reproducible multivariate patterns in healthy aging. NeuroImage, 49(2), 1750-1759.
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  PMID: 19796692;PMCID: PMC2789892;Abstract: Healthy aging is associated with brain volume reductions that involve the frontal cortex, but also affect other brain regions. We sought to identify an age-related network pattern of MRI gray matter using a multivariate statistical model of regional covariance, the Scaled Subprofile Model (SSM) with voxel based morphometry (VBM) in 29 healthy adults, 23-84 years of age (Group 1). In addition, we evaluated the reproducibility of the age-related gray matter pattern derived from a prior SSM VBM study of 26 healthy adults, 22-77 years of age (Group 2; Alexander et al., 2006) in relation to the current sample and tested the ability of the network analysis to extract an age-related pattern from both cohorts combined. The SSM VBM analysis of Group 1 identified a regional pattern of gray matter atrophy associated with healthy aging (R2 = 0.64, p < 0.000001) that included extensive reductions in bilateral dorsolateral and medial frontal, anterior cingulate, insula/perisylvian, precuneus, parietotemporal, and caudate regions with areas of relative preservation in bilateral cerebellum, thalamus, putamen, mid cingulate, and temporal pole regions. The age-related SSM VBM gray matter pattern, previously reported for Group 2, was highly expressed in Group 1 (R2 = 0.52, p < 0.00002). SSM analysis of the combined cohorts extracted a common age-related pattern of gray matter showing reductions involving bilateral medial frontal, insula/perisylvian, anterior cingulate and, to a lesser extent, bilateral dorsolateral prefrontal, lateral temporal, parietal, and caudate brain regions with relative preservation in bilateral cerebellum, temporal pole, and right thalamic regions. The results suggest that healthy aging is associated with a regionally distributed pattern of gray matter atrophy that has reproducible regional features. Whereas the network patterns of atrophy included parietal, temporal, and subcortical regions, involvement of the frontal brain regions showed the most consistently extensive and reliable reductions across samples. Network analysis with SSM VBM can help detect reproducible age-related MRI patterns, assisting efforts in the study of healthy and pathological aging. © 2009 Elsevier Inc. All rights reserved.
• Chen, K., Langbaum, J. B., Fleisher, A. S., Ayutyanont, N., Reschke, C., Lee, W., Liu, X., Bandy, D., Alexander, G. E., Thompson, P. M., Foster, N. L., Harvey, D. J., J., M., Koeppe, R. A., Jagust, W. J., Weiner, M. W., & Reiman, E. M. (2010). Twelve-month metabolic declines in probable Alzheimer's disease and amnestic mild cognitive impairment assessed using an empirically pre-defined statistical region-of-interest: Findings from the Alzheimer's Disease Neuroimaging Initiative. NeuroImage, 51(2), 654-664.
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  PMID: 20202480;PMCID: PMC2856742;Abstract: Alzheimer's disease (AD) is characterized by specific and progressive reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose (CMRgl), some of which may precede the onset of symptoms. In this report, we describe twelve-month CMRgl declines in 69 probable AD patients, 154 amnestic mild cognitive impairment (MCI) patients, and 79 cognitively normal controls (NCs) from the AD Neuroimaging Initiative (ADNI) using statistical parametric mapping (SPM). We introduce the use of an empirically pre-defined statistical region-of-interest (sROI) to characterize CMRgl declines with optimal power and freedom from multiple comparisons, and we estimate the number of patients needed to characterize AD-slowing treatment effects in multi-center randomized clinical trials (RCTs). The AD and MCI groups each had significant twelve-month CMRgl declines bilaterally in posterior cingulate, medial and lateral parietal, medial and lateral temporal, frontal and occipital cortex, which were significantly greater than those in the NC group and correlated with measures of clinical decline. Using sROIs defined based on training sets of baseline and follow-up images to assess CMRgl declines in independent test sets from each patient group, we estimate the need for 66 AD patients or 217 MCI patients per treatment group to detect a 25% AD-slowing treatment effect in a twelve-month, multi-center RCT with 80% power and two-tailed alpha=0.05, roughly one-tenth the number of the patients needed to study MCI patients using clinical endpoints. Our findings support the use of FDG PET, brain-mapping algorithms and empirically pre-defined sROIs in RCTs of AD-slowing treatments. © 2010 Elsevier Inc.
• Corneveaux, J. J., Liang, W. S., Reiman, E. M., Webster, J. A., Myers, A. J., Zismann, V. L., Joshipura, K. D., Pearson, J. V., Hu-Lince, D., Craig, D. W., Coon, K. D., Dunckley, T., Bandy, D., Lee, W., Chen, K., Beach, T. G., Mastroeni, D., Grover, A., Ravid, R., , Sando, S. B., et al. (2010). Evidence for an association between KIBRA and late-onset Alzheimer's disease. Neurobiology of Aging, 31(6), 901-909.
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  PMID: 18789830;PMCID: PMC2913703;Abstract: We recently reported evidence for an association between the individual variation in normal human episodic memory and a common variant of the KIBRA gene, KIBRA rs17070145 (T-allele). Since memory impairment is a cardinal clinical feature of Alzheimer's disease (AD), we investigated the possibility of an association between the KIBRA gene and AD using data from neuronal gene expression, brain imaging studies, and genetic association tests. KIBRA was significantly over-expressed and three of its four known binding partners under-expressed in AD-affected hippocampal, posterior cingulate and temporal cortex regions (P
• Ho, A. J., Hua, X., Lee, S., Leow, A. D., Yanovsky, I., Gutman, B., Dinov, I. D., Leporé, N., Stein, J. L., Toga, A. W., Jack Jr., C. R., Bernstein, M. A., Reiman, E. M., Harvey, D. J., Kornak, J., Schuff, N., Alexander, G. E., Weiner, M. W., & Thompson, P. M. (2010). Comparing 3 T and 1.5 T MRI for tracking Alzheimer's disease progression with tensor-based morphometry. Human Brain Mapping, 31(4), 499-514.
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  PMID: 19780044;PMCID: PMC2875376;Abstract: A key question in designing MRI-based clinical trials is how the main magnetic field strength of the scanner affects the power to detect disease effects. In 110 subjects scanned longitudinally at both 3.0 and 1.5 T, including 24 patients with Alzheimer's Disease (AD) [74.8 ± 9.2 years, MMSE: 22.6 ± 2.0 at baseline], 51 individuals with mild cognitive impairment (MCI) [74.1 ± 8.0 years, MMSE: 26.6 ± 2.0], and 35 controls [75.9 ± 4.6 years, MMSE: 29.3 ± 0.8], we assessed whether higher-field MR imaging offers higher or lower power to detect longitudinal changes in the brain, using tensor-based morphometry (TBM) to reveal the location of progressive atrophy. As expected, at both field strengths, progressive atrophy was widespread in AD and more spatially restricted in MCI. Power analysis revealed that, to detect a 25% slowing of atrophy (with 80% power), 37 AD and 108 MCI subjects would be needed at 1.5 T versus 49 AD and 166 MCI subjects at 3 T; however, the increased power at 1.5 T was not statistically significant (α = 0.05) either for TBM, or for SIENA, a related method for computing volume loss rates. Analysis of cumulative distribution functions and false discovery rates showed that, at both field strengths, temporal lobe atrophy rates were correlated with interval decline in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), mini-mental status exam (MMSE), and Clinical Dementia Rating sum-of-boxes (CDR-SB) scores. Overall, 1.5 and 3 T scans did not significantly differ in their power to detect neurodegenerative changes over a year. © 2009 Wiley-Liss, Inc.
• Hua, X., Lee, S., Hibar, D. P., Yanovsky, I., Leow, A. D., Toga, A. W., Jack Jr., C. R., Bernstein, M. A., Reiman, E. M., Harvey, D. J., Kornak, J., Schuff, N., Alexander, G. E., Weiner, M. W., & Thompson, P. M. (2010). Mapping Alzheimer's disease progression in 1309 MRI scans: Power estimates for different inter-scan intervals. NeuroImage, 51(1), 63-75.
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  PMID: 20139010;PMCID: PMC2846999;Abstract: Neuroimaging centers and pharmaceutical companies are working together to evaluate treatments that might slow the progression of Alzheimer's disease (AD), a common but devastating late-life neuropathology. Recently, automated brain mapping methods, such as tensor-based morphometry (TBM) of structural MRI, have outperformed cognitive measures in their precision and power to track disease progression, greatly reducing sample size estimates for drug trials. In the largest TBM study to date, we studied how sample size estimates for tracking structural brain changes depend on the time interval between the scans (6-24months). We analyzed 1309 brain scans from 91 probable AD patients (age at baseline: 75.4±7.5 years) and 189 individuals with mild cognitive impairment (MCI; 74.6±7.1 years), scanned at baseline, 6, 12, 18, and 24months. Statistical maps revealed 3D patterns of brain atrophy at each follow-up scan relative to the baseline; numerical summaries were used to quantify temporal lobe atrophy within a statistically-defined region-of-interest. Power analyses revealed superior sample size estimates over traditional clinical measures. Only 80, 46, and 39 AD patients were required for a hypothetical clinical trial, at 6, 12, and 24months respectively, to detect a 25% reduction in average change using a two-sided test (α=0.05, power=80%). Correspondingly, 106, 79, and 67 subjects were needed for an equivalent MCI trial aiming for earlier intervention. A 24-month trial provides most power, except when patient attrition exceeds 15-16%/year, in which case a 12-month trial is optimal. These statistics may facilitate clinical trial design using voxel-based brain mapping methods such as TBM. © 2010 Elsevier Inc.
• Reiman, E. M., Chen, K., Langbaum, J. B., Lee, W., Reschke, C., Bandy, D., Alexander, G. E., & Caselli, R. J. (2010). Higher serum total cholesterol levels in late middle age are associated with glucose hypometabolism in brain regions affected by Alzheimer's disease and normal aging. NeuroImage, 49(1), 169-176.
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  PMID: 19631758;PMCID: PMC2888804;Abstract: Epidemiological studies suggest that higher midlife serum total cholesterol levels are associated with an increased risk of Alzheimer's disease (AD). Using fluorodeoxyglucose positron emission tomography (PET) in the study of cognitively normal late middle-aged people, we demonstrated an association between apolipoprotein E (APOE) e{open}4 gene dose, the major genetic risk factor for late-onset AD, and lower measurements of the cerebral metabolic rate for glucose (CMRgl) in AD-affected brain regions, we proposed using PET as a pre-symptomatic endophenotype to evaluate other putative AD risk modifiers, and we then used it to support an aggregate cholesterol-related genetic risk score in the risk of AD. In the present study, we used PET to investigate the association between serum total cholesterol levels and cerebral metabolic rate for glucose metabolism (CMRgl) in 117 cognitively normal late middle-aged APOE e{open}4 homozygotes, heterozygotes and non-carriers. Higher serum total cholesterol levels were associated with lower CMRgl bilaterally in precuneus, parietotemporal and prefrontal regions previously found to be preferentially affected by AD, and in additional frontal regions previously found to be preferentially affected by normal aging. The associations were greater in APOE e{open}4 carriers than non-carriers in some of the AD-affected brain regions. We postulate that higher midlife serum total cholesterol levels accelerate brain processes associated with normal aging and conspire with other risk factors in the predisposition to AD. We propose using PET in proof-of-concept randomized controlled trials to rapidly evaluate the effects of midlife cholesterol-lowering treatments on the brain changes associated with normal aging and AD. © 2009 Elsevier Inc. All rights reserved.
• Smith, J. F., Alexander, G. E., Chen, K., Husain, F. T., Kim, J., Pajor, N., & Horwitz, B. (2010). Imaging systems level consolidation of novel associate memories: A longitudinal neuroimaging study. NeuroImage, 50(2), 826-836.
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  PMID: 19948227;PMCID: PMC2919751;Abstract: Previously, a standard theory of systems level memory consolidation was developed to describe how memory recall becomes independent of themedial temporal memory system. More recently, an extended consolidation theory was proposed that predicts seven changes in regional neural activity and inter-regional functional connectivity. Using longitudinal event-related functional magnetic resonance imaging of an associate memory task, we simultaneously tested all predictions and additionally tested for consolidation-related changes in recall of associate memories at a sub-trial temporal resolution, analyzing cue, delay and target periods of each trial separately. Results consistent with the theoretical predictions were observed though two inconsistent results were also obtained. In particular, while medial temporal recall related delay period activity decreased with consolidation as predicted, visual cue activity increased for consolidated memories. Though the extended theory of memory consolidation is largely supported by our study, these results suggest that the extended theory needs further refinement and the medial temporal memory system has multiple, temporally distinct roles in associate memory recall. Neuroimaging analysis at a sub-trial temporal resolution, as used here, may further clarify the role of the hippocampal complex in memory consolidation. Published by Elsevier Inc.
• Xia, W. u., Chen, K., Yao, L., Ayutyanont, N., Langbaum, J. B., Fleisher, A., Reschke, C., Lee, W., Liu, X., Alexander, G. E., Bandy, D., Foster, N. L., Thompson, P. M., Harvey, D. J., Weiner, M. W., Koeppe, R. A., Jagust, W. J., & Reiman, E. M. (2010). Assessing the reliability to detect cerebral hypometabolism in probable Alzheimer's disease and amnestic mild cognitive impairment. Journal of Neuroscience Methods, 192(2), 277-285.
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  PMID: 20678521;PMCID: PMC2952503;Abstract: Fluorodeoxyglucose positron emission tomography (FDG-PET) studies report characteristic patterns of cerebral hypometabolism in probable Alzheimer's disease (pAD) and amnestic mild cognitive impairment (aMCI). This study aims to characterize the consistency of regional hypometabolism in pAD and aMCI patients enrolled in the AD neuroimaging initiative (ADNI) using statistical parametric mapping (SPM) and bootstrap resampling, and to compare bootstrap-based reliability index to the commonly used type-I error approach with or without correction for multiple comparisons. Batched SPM5 was run for each of 1000 bootstrap iterations to compare FDG-PET images from 74 pAD and 142 aMCI patients, respectively, to 82 normal controls. Maps of the hypometabolic voxels detected for at least a specific percentage of times over the 1000 runs were examined and compared to an overlap of the hypometabolic maps obtained from 3 randomly partitioned independent sub-datasets. The results from the bootstrap derived reliability of regional hypometabolism in the overall data set were similar to that observed in each of the three non-overlapping sub-sets using family-wise error. Strong but non-linear association was found between the bootstrap-based reliability index and the type-I error. For threshold p= 0.0005, pAD was associated with extensive hypometabolic voxels in the posterior cingulate/precuneus and parietotemporal regions with reliability between 90% and 100%. Bootstrap analysis provides an alternative to the parametric family-wise error approach used to examine consistency of hypometabolic brain voxels in pAD and aMCI patients. These results provide a foundation for the use of bootstrap analysis characterize statistical ROIs or search regions in both cross-sectional and longitudinal FDG-PET studies. This approach offers promise in the early detection and tracking of AD, the evaluation of AD-modifying treatments, and other biologically or clinical important measurements using brain images and voxel-based data analysis techniques. © 2010 Elsevier B.V.
• Caselli, R. J., Dueck, A. C., Osborne, D., Sabbagh, M. N., Connor, D. J., Ahern, G. L., Baxter, L. C., Rapcsak, S. Z., Shi, J., Woodruff, B. K., E., D., Snyder, C. H., Alexander, G. E., Rademakers, R., & Reiman, E. M. (2009). Longitudinal modeling of age-related memory decline and the APOE ε4 effect. New England Journal of Medicine, 361(3), 255-263.
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  PMID: 19605830;PMCID: PMC2928998;Abstract: BACKGROUND: The APOE ε4 allele is associated with the risk of late-onset Alzheimer's disease. The age at which memory decline diverges among persons who are homozygous for the APOE ε4 allele, those who are heterozygous for the allele, and noncarriers is unknown. METHODS: Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOE ε4 status. We then followed the subjects with longitudinal neuropsychological testing. Anyone in whom mild cognitive impairment or dementia developed during follow-up was excluded. We compared the rates of decline in predetermined cognitive measures between carriers and noncarriers of the APOE ε4 allele, using a mixed model for longitudinal change with age. RESULTS: We analyzed 815 subjects: 317 APOE ε4 carriers (79 who were homozygous for the APOE ε4 allele and 238 who were heterozygous) and 498 noncarriers. Carriers, as compared with noncarriers, were generally younger (mean age, 58.0 vs. 61.4 years; P
• Chen, K., Reiman, E. M., Huan, Z., Caselli, R. J., Bandy, D., Ayutyanont, N., & Alexander, G. E. (2009). Linking functional and structural brain images with multivariate network analyses: A novel application of the partial least square method. NeuroImage, 47(2), 602-610.
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  PMID: 19393744;PMCID: PMC2700206;Abstract: In this article, we introduce a multimodal multivariate network analysis to characterize the linkage between the patterns of information from the same individual's complementary brain images, and illustrate its potential by showing its ability to distinguish older from younger adults with greater power than several previously established methods. Our proposed method uses measurements from every brain voxel in each person's complementary co-registered images and uses the partial least square (PLS) algorithm to form a combined latent variable that maximizes the covariance among all of the combined variables. It represents a new way to calculate the singular value decomposition from the high-dimensional covariance matrix in a computationally feasible way. Analyzing fluorodeoxyglucose positron emission tomography (PET) and volumetric magnetic resonance imaging (MRI) images, this method distinguished 14 older adults from 15 younger adults (p = 4e- 12) with no overlap between groups, no need to correct for multiple comparisons, and greater power than the univariate Statistical Parametric Mapping (SPM), multimodal SPM or multivariate PLS analysis of either imaging modality alone. This technique has the potential to link patterns of information among any number of complementary images from an individual, to use other kinds of complementary complex datasets besides brain images, and to characterize individual state- or trait-dependent brain patterns in a more powerful way. © 2009 Elsevier Inc. All rights reserved.
• Hua, X., Lee, S., Yanovsky, I., Leow, A. D., Chou, Y., Ho, A. J., Gutman, B., Toga, A. W., Jack Jr., C. R., Bernstein, M. A., Reiman, E. M., Harvey, D. J., Kornak, J., Schuff, N., Alexander, G. E., Weiner, M. W., & Thompson, P. M. (2009). Optimizing power to track brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based morphometry: An ADNI study of 515 subjects. NeuroImage, 48(4), 668-681.
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  PMID: 19615450;PMCID: PMC2971697;Abstract: Tensor-based morphometry (TBM) is a powerful method to map the 3D profile of brain degeneration in Alzheimer's disease (AD) and mild cognitive impairment (MCI). We optimized a TBM-based image analysis method to determine what methodological factors, and which image-derived measures, maximize statistical power to track brain change. 3D maps, tracking rates of structural atrophy over time, were created from 1030 longitudinal brain MRI scans (1-year follow-up) of 104 AD patients (age: 75.7 ± 7.2 years; MMSE: 23.3 ± 1.8, at baseline), 254 amnestic MCI subjects (75.0 ± 7.2 years; 27.0 ± 1.8), and 157 healthy elderly subjects (75.9 ± 5.1 years; 29.1 ± 1.0), as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). To determine which TBM designs gave greatest statistical power, we compared different linear and nonlinear registration parameters (including different regularization functions), and different numerical summary measures derived from the maps. Detection power was greatly enhanced by summarizing changes in a statistically-defined region-of-interest (ROI) derived from an independent training sample of 22 AD patients. Effect sizes were compared using cumulative distribution function (CDF) plots and false discovery rate methods. In power analyses, the best method required only 48 AD and 88 MCI subjects to give 80% power to detect a 25% reduction in the mean annual change using a two-sided test (at α = 0.05). This is a drastic sample size reduction relative to using clinical scores as outcome measures (619 AD/6797 MCI for the ADAS-Cog, and 408 AD/796 MCI for the Clinical Dementia Rating sum-of-boxes scores). TBM offers high statistical power to track brain changes in large, multi-site neuroimaging studies and clinical trials of AD. © 2009 Elsevier Inc. All rights reserved.
• Huentelman, M. J., Stephan, D. A., Talboom, J., Corneveaux, J. J., Reiman, D. M., Gerber, J. D., Barnes, C. A., Alexander, G. E., Reiman, E. M., & Bimonte-Nelson, H. A. (2009). Peripheral Delivery of a ROCK Inhibitor Improves Learning and Working Memory. Behavioral Neuroscience, 123(1), 218-223.
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  PMID: 19170447;PMCID: PMC2701389;Abstract: Previously, utilizing a series of genome-wide association, brain imaging, and gene expression studies we implicated the KIBRA gene and the RhoA/ROCK pathway in hippocampal-mediated human memory. Here we show that peripheral administration of the ROCK inhibitor hydroxyfasudil improves spatial learning and working memory in the rodent model. This study supports the action of ROCK on learning and memory, suggests the potential value of ROCK inhibition for the promotion of cognition in humans, and highlights the powerful potential of unbiased genome-wide association studies to inform potential novel uses for existing pharmaceuticals. © 2009 American Psychological Association.
• Langbaum, J. B., Chen, K., Lee, W., Reschke, C., Bandy, D., Fleisher, A. S., Alexander, G. E., Foster, N. L., Weiner, M. W., Koeppe, R. A., Jagust, W. J., & Reiman, E. M. (2009). Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer's Disease Neuroimaging Initiative (ADNI). NeuroImage, 45(4), 1107-1116.
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  PMID: 19349228;PMCID: PMC2886795;Abstract: In mostly small single-center studies, Alzheimer's disease (AD) is associated with characteristic and progressive reductions in fluorodeoxyglucose positron emission tomography (PET) measurements of the regional cerebral metabolic rate for glucose (CMRgl). The AD Neuroimaging Initiative (ADNI) is acquiring FDG PET, volumetric magnetic resonance imaging, and other biomarker measurements in a large longitudinal multi-center study of initially mildly affected probable AD (pAD) patients, amnestic mild cognitive impairment (aMCI) patients, who are at increased AD risk, and cognitively normal controls (NC), and we are responsible for analyzing the PET images using statistical parametric mapping (SPM). Here we compare baseline CMRgl measurements from 74 pAD patients and 142 aMCI patients to those from 82 NC, we correlate CMRgl with categorical and continuous measures of clinical disease severity, and we compare apolipoprotein E (APOE) e{open}4 carriers to non-carriers in each of these subject groups. In comparison with NC, the pAD and aMCI groups each had significantly lower CMRgl bilaterally in posterior cingulate, precuneus, parietotemporal and frontal cortex. Similar reductions were observed when categories of disease severity or lower Mini-Mental State Exam (MMSE) scores were correlated with lower CMRgl. However, when analyses were restricted to the pAD patients, lower MMSE scores were significantly correlated with lower left frontal and temporal CMRgl. These findings from a large, multi-site study support previous single-site findings, supports the characteristic pattern of baseline CMRgl reductions in AD and aMCI patients, as well as preferential anterior CMRgl reductions after the onset of AD dementia. © 2009 Elsevier Inc. All rights reserved.
• Leow, A. D., Yanovsky, I., Parikshak, N., Hua, X., Lee, S., Toga, A. W., Jack Jr., C. R., Bernstein, M. A., Britson, P. J., Gunter, J. L., Ward, C. P., Borowski, B., Shaw, L. M., Trojanowski, J. Q., Fleisher, A. S., Harvey, D., Kornak, J., Schuff, N., Alexander, G. E., , Weiner, M. W., et al. (2009). Alzheimer's Disease Neuroimaging Initiative: A one-year follow up study using tensor-based morphometry correlating degenerative rates, biomarkers and cognition. NeuroImage, 45(3), 645-655.
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  PMID: 19280686;PMCID: PMC2696624;Abstract: Tensor-based morphometry can recover three-dimensional longitudinal brain changes over time by nonlinearly registering baseline to follow-up MRI scans of the same subject. Here, we compared the anatomical distribution of longitudinal brain structural changes, over 12 months, using a subset of the ADNI dataset consisting of 20 patients with Alzheimer's disease (AD), 40 healthy elderly controls, and 40 individuals with mild cognitive impairment (MCI). Each individual longitudinal change map (Jacobian map) was created using an unbiased registration technique, and spatially normalized to a geometrically-centered average image based on healthy controls. Voxelwise statistical analyses revealed regional differences in atrophy rates, and these differences were correlated with clinical measures and biomarkers. Consistent with prior studies, we detected widespread cerebral atrophy in AD, and a more restricted atrophic pattern in MCI. In MCI, temporal lobe atrophy rates were correlated with changes in mini-mental state exam (MMSE) scores, clinical dementia rating (CDR), and logical/verbal learning memory scores. In AD, temporal atrophy rates were correlated with several biomarker indices, including a higher CSF level of p-tau protein, and a greater CSF tau/beta amyloid 1-42 (ABeta42) ratio. Temporal lobe atrophy was significantly faster in MCI subjects who converted to AD than in non-converters. Serial MRI scans can therefore be analyzed with nonlinear image registration to relate ongoing neurodegeneration to a variety of pathological biomarkers, cognitive changes, and conversion from MCI to AD, tracking disease progression in 3-dimensional detail. © 2009 Elsevier Inc. All rights reserved.
• Patel, R., Liu, J., Chen, K., Reiman, E., Alexander, G., & Jieping, Y. e. (2009). Sparse inverse covariance analysis of human brain for Alzheimer's disease study. 2009 ICME International Conference on Complex Medical Engineering, CME 2009.
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  Abstract: Analysis of functional neuroimaging data in the studies of human brain has become very critical in understanding neuro-degenerative diseases such as Alzheimer's disease (AD). The most common approach in AD neuroimaging studies has been of univariate nature, where individual brain regions/voxels are analyzed separately. In many cases these techniques prove to be effective. However, they could not shed light on inter brain region connectivity associated with the brain function or disease of interest. Indeed, human brain is a very complex organ anatomically and the functional interactions between its regions are even more. As a result, there is a need to understand this interdependency or inter-connection of brain regions. There are several existing techniques to address this issue. They include principal component analysis (PCA), PCA based scaled subprofile modeling (SSM), Bayesian network approach and independent component analysis (ICA). In this study, we propose a machine learning technique called "Sparse Inverse Covariance Analysis" to learn the brain region interactivity, with minimal computational cost and appropriate degree of sparsity. Under Gaussian assumption, each element of the inverse covariance matrix represents conditional dependence between the constituent pair of variables, given all other variables. By introducing sparsity constraint, unnecessary/noisy functional dependencies are eliminated by setting the constituent element to zero, resulting into conditional independence between the variable pairs. Using functional FDG-PET data acquired from 49 AD and 67 normal subjects from the Alzheimer's disease neuroimaging initiative (ADNI) project, we evaluate this technique in terms of distinct brain region connectivity pattern in patients with AD compared to that in normal control subjects. It was found that the patients with AD had disconnections that are not present in the normal controls. This different connectivity pattern is potentially usable for clinical diagnosis and for establishing sensitive markers for the disease progression and treatment evaluation. ©2009 IEEE.
• Reiman, E. M., Chen, K., Liu, X., Bandy, D., Meixiang, Y. u., Lee, W., Ayutyanont, N., Keppler, J., Reeder, S. A., B., J., Alexander, G. E., Klunk, W. E., Mathis, C. A., Price, J. C., Aizensteini, H. J., DeKosky, S. T., & Caselli, R. J. (2009). Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 106(16), 6820-6825.
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  PMID: 19346482;PMCID: PMC2665196;Abstract: Fibrillar amyloid-beta (Aβ) is found in the brains of many cogni-tively normal older people. Whether or not this reflects a predisposition to Alzheimer's disease (AD) is unknown. We used Pittsburgh Compound B (PiB) PET to characterize the relationship between fibrillar Aβ burden and this predisposition in cognitively normal older people at 3 mean levels of genetic risk for AD. Dynamic PiB PET scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest (ROIs) were used to characterize and compare cerebral-to-cerebellar PIB distribution volume ratios, reflecting fibrillar Aβ burden, in 28 cognitively normal persons (mean age, 64 years) with a reported family history of AD and 2 copies, 1 copy, and no copies of the apolipoprotein E (APOE) ε4 allele. The 8 ε4 homozygotes, 8 heterozygotes, and 12 noncarriers did not differ significantly in terms of age, sex, or cognitive scores. Fibrillar Aβ was significantly associated with APOE ε4 carrier status and ε4 gene dose in AD-affected mean cortical, frontal, temporal, posterior cingulate-precuneus, parietal, and basal ganglia ROIs, and was highest in an additional homozygote who had recently developed mild cognitive impairment. These findings suggest that fibrillar Aβ burden in cognitively normal older people is associated with APOE ε4 gene dose, the major genetic risk factor for AD. Additional studies are needed to track fibrillar Aβ accumulation in persons with different kinds and levels of AD risk; to determine the extent to which fibrillar Aβ, alone or in combination with other biomarkers and risk factors, predicts rates of cognitive decline and conversion to clinical AD; and to establish the role of fibrillar Aβ imaging in primary prevention trials.
• Alexander, G. E., Boyes, R. G., Gunter, J. L., Frost, C., Janke, A. L., Yeatman, T., Hill, D. L., Bernstein, M. A., Thompson, P. M., Weiner, M. W., Schuff, N., Killiany, R. J., Decarli, C., Jack, C. R., & Fox, N. C. (2008). Intensity non-uniformity correction using N3 on 3-T scanners with multichannel phased array coils. Neuroimage.
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  Study as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI) project;Your Role: Co-author involved in the study design, analysis, and critical review of manuscript;Full Citation: Boyes RG, Gunter JL, Frost C, Janke AL, Yeatman T, Hill DL, Bernstein MA, Thompson PM, Weiner MW, Schuff N, Alexander GE, Killiany RJ, Decarli C, Jack CR, & Fox NC; for the ADNI study. (2008). Intensity non-uniformity correction using N3 on 3-T scanners with multichannel phased array coils. Neuroimage, 39, 1752-62.;Other collaborative: Yes;Specify other collaborative: Multi-institutional collaborative study as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI), including UCSF, Mayo Clinic, University College London, UCLA, Boston University, and UC Davis;
• Alexander, G. E., Caselli, R. J., Chen, K., Lee, W., & EM., R. (2008). Correlating cerebral hypometabolism with future memory decline in subsequent converters to amnestic pre-mild cognitive impairment. Archives of Neuology.
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  Article on findings in subjects with the very early age-related cognitive impairment in relation to PET cerebral metabolism. Figure from paper selected for the cover of the journal issue.;Your Role: Co-author involved in study design, analysis, and critical review of manuscript;Full Citation: Caselli RJ, Chen K, Lee W, Alexander GE, & Reiman EM. (2008). Correlating cerebral hypometabolism with future memory decline in subsequent converters to amnestic pre-mild cognitive impairment. Archives of Neurology, 65, 1231-6.;Other collaborative: Yes;Specify other collaborative: Part of ongoing collaboration with Banner Good Samaritan Medical Center and Mayo Clinic Scottsdale;
• Alexander, G. E., Chen, K., Aschenbrenner, M., Merkley, T. L., LE, S., Shamy, J. L., Skaggs, W. E., Buonocore, M. H., Rapp, P., & C.A., B. (2008). Age-related regional network pattern of MRI gray matter in the rhesus macaque. Journal of Neuroscience.
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  Article providing findings on the first application of regional network analysis to non-human primate model of healthy aging.;Your Role: First author.;Full Citation: Alexander GE, Chen K, Aschenbrenner M, Merkley TL, Santerre-Lemmon LE, Shamy JL, Skaggs WE, Buonocore MH, Rapp P, & Barnes C.A. (2008). Age-related regional network pattern of MRI gray matter in the rhesus macaque. Journal of Neuroscience, 28, 2710-8.;Collaborative with faculty member in unit: Yes;
• Alexander, G. E., Chen, K., Aschenbrenner, M., Merkley, T. L., Santerre-Lemmon, L. E., Shamy, J. L., Skaggs, W. E., Buonocore, M. H., Rapp, P. R., & Barnes, C. A. (2008). Age-related regional network of magnetic resonance imaging gray matter in the rhesus macaque. Journal of Neuroscience, 28(11), 2710-2718.
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  PMID: 18337400;Abstract: Humanstructural neuroimaging studies have supported the preferential effects of healthy aging on frontal cortex, but reductions in other brain regions have also been observed. We investigated the regional network pattern of gray matter using magnetic resonance imaging (MRI) in young adult and old rhesus macaques (RMs) to evaluate age effects throughout the brain in a nonhuman primate model of healthy aging in which the full complement of Alzheimer's disease (AD) pathology does not occur. Volumetric T1 MRI scans were spatially normalized and segmented for gray matter using statistical parametric mapping (SPM2) voxel-based morphometry. Multivariate network analysis using the scaled subprofile model identified a linear combination of two gray matter patterns that distinguished the young from old RMs. The combined pattern included reductions in bilateral dorsolateral and ventrolateral prefrontal and orbitofrontal and superior temporal sulcal regions with areas of relative preservation in vicinities of the cerebellum, globus pallidus, visual cortex, and parietal cortex in old compared with young RMs. Higher expression of this age-related gray matter pattern was associated with poorer performance in working memory. In the RM model of healthy aging, the major regionally distributed effects of advanced age on the brain involve reductions in prefrontal regions and in the vicinity of the superior temporal sulcus. The age-related differences in gray matter reflect the effects of healthy aging that cannot be attributed to AD pathology, providing support for the targeted effects of aging on the integrity of frontal lobe regions and selective temporal lobe areas and their associated cognitive functions. Copyright © 2008 Society for Neuroscience.
• Alexander, G. E., Hua, X., Leow, A. D., Lee, S., Klunder, A. D., Toga, A. W., Lepore, N., Chou, Y. Y., Brun, C., Chiang, M. C., Barysheva, M., Jr, J. C., Bernstein, M. A., Britson, P. J., Ward, C. P., Whitwell, J. L., Borowski, B., Fleisher, A. S., Fox, N. C., , Boyes, R. G., et al. (2008). 3D characterization of brain atrophy in Alzheimer's disease and mild cognitive impairment using tensor-based morphometry. Neuroimage.
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  Article providing findings from the ADNI project using tensor based morphometry in patients with Alzheimer's disease and those at risk for dementia;Your Role: Co-author involved in the analysis, study design, and critical review of manuscript;Full Citation: Hua X, Leow AD, Lee S, Klunder AD, Toga AW, Lepore N, Chou YY, Brun C, Chiang MC, Barysheva M, Jack CR Jr, Bernstein MA, Britson PJ, Ward CP, Whitwell JL, Borowski B, Fleisher AS, Fox NC, Boyes RG, Barnes J, Harvey D, Kornak J, Schuff N, Boreta L, Alexander GE, Weiner MW, & Thompson PM, Alzheimer's Disease Neuroimaging Initiative. (2008). 3D characterization of brain atrophy in Alzheimer's disease and mild cognitive impairment using tensor-based morphometry. Neuroimage, 4, 19-34.;Other collaborative: Yes;Specify other collaborative: ;
• Alexander, G. E., Jr, a. C., Bernstein, M. A., Fox, N. C., Thompson, P., Harvey, D., Borowski, B., Britson, P. J., J, L. W., Ward, C., Dale, A. M., Felmlee, J. P., Gunter, J. L., Hill, D. L., Killiany, R., Schuff, N., S, F., Lin, C., Studholme, C., , DeCarli, C. S., et al. (2008). The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods.. Journal of Magnetic Resonance Imaging.
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  Article outlining the methods and procedures developed as part of the ADNI MRI Core.;Your Role: Co-author in the development of the study and plan for analysis. Member of the steering committee for the MRI Core of the ADNI project.;Full Citation: Jack CR Jr, Bernstein MA, Fox NC, Thompson P, Alexander G, Harvey D, Borowski B, Britson PJ, L Whitwell J, Ward C, Dale AM, Felmlee JP, Gunter JL, Hill DL, Killiany R, Schuff N, Fox-Bosetti S, Lin C, Studholme C, DeCarli CS, Krueger G, Ward HA, Metzger GJ, Scott KT, Mallozzi R, Blezek D, Levy J, Debbins JP, Fleisher AS, Albert M, Green R, Bartzokis G, Glover G, Mugler J, & Weiner MW. (2008). The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods. Journal of Magnetic Resonance Imaging, 27, 685-91.;Other collaborative: Yes;Specify other collaborative: Multi-institutional collaborative study as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI), including UCSF, Mayo Clinic, University College London, UCLA, Boston University, and UC Davis, Johns Hopkins University, UCSD;
• Alexander, G. E., Reiman, E. M., Chen, K., Caselli, R. J., Bandy, D., Adamson, J. L., Lee, W., Cannon, A., Stephan, E. A., Stephan, D. A., & Papassotiropoulos, A. (2008). Cholesterol-related genetic risk scores are associated with hypometabolism in Alzheimer's-affected brain regions. Neuroimage.
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  Study identifying the relation between genetic factors associated with cholesterol and cerebral metabolism assessed by positron emission tomography;Your Role: Co-author involved in analysis, study design, and critical review of manuscript;Full Citation: Reiman EM, Chen K, Caselli RJ, Alexander GE, Bandy D, Adamson JL, Lee W, Cannon A, Stephan EA, Stephan DA, & Papassotiropoulos A. (2008). Cholesterol-related genetic risk scores are associated with hypometabolism in Alzheimer's-affected brain regions. Neuroimage,40, 1214-21.;Other collaborative: Yes;Specify other collaborative: Part of ongoing collaboration with Banner Good Samaritan Medical Center, Phoenix, AZ;
• Boyes, R. G., Gunter, J. L., Frost, C., Janke, A. L., Yeatman, T., Hill, D. L., Bernstein, M. A., Thompson, P. M., Weiner, M. W., Schuff, N., Alexander, G. E., Killiany, R. J., DeCarli, C., Jack, C. R., & Fox, N. C. (2008). Intensity non-uniformity correction using N3 on 3-T scanners with multichannel phased array coils. NeuroImage, 39(4), 1752-1762.
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  PMID: 18063391;PMCID: PMC2562663;Abstract: Measures of structural brain change based on longitudinal MR imaging are increasingly important but can be degraded by intensity non-uniformity. This non-uniformity can be more pronounced at higher field strengths, or when using multichannel receiver coils. We assessed the ability of the non-parametric non-uniform intensity normalization (N3) technique to correct non-uniformity in 72 volumetric brain MR scans from the preparatory phase of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Normal elderly subjects (n = 18) were scanned on different 3-T scanners with a multichannel phased array receiver coil at baseline, using magnetization prepared rapid gradient echo (MP-RAGE) and spoiled gradient echo (SPGR) pulse sequences, and again 2 weeks later. When applying N3, we used five brain masks of varying accuracy and four spline smoothing distances (d = 50, 100, 150 and 200 mm) to ascertain which combination of parameters optimally reduces the non-uniformity. We used the normalized white matter intensity variance (standard deviation/mean) to ascertain quantitatively the correction for a single scan; we used the variance of the normalized difference image to assess quantitatively the consistency of the correction over time from registered scan pairs. Our results showed statistically significant (p < 0.01) improvement in uniformity for individual scans and reduction in the normalized difference image variance when using masks that identified distinct brain tissue classes, and when using smaller spline smoothing distances (e.g., 50-100 mm) for both MP-RAGE and SPGR pulse sequences. These optimized settings may assist future large-scale studies where 3-T scanners and phased array receiver coils are used, such as ADNI, so that intensity non-uniformity does not influence the power of MR imaging to detect disease progression and the factors that influence it. © 2007 Elsevier Inc. All rights reserved.
• Caselli, R. J., Chen, K., Lee, W., Alexander, G. E., & Reiman, E. M. (2008). Correlating cerebral hypometabolism with future memory decline in subsequent converters to amnestic pre-mild cognitive impairment. Archives of Neurology, 65(9), 1231-1236.
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  PMID: 18779428;Abstract: Background: Before symptomatic memory loss, healthy apolipoprotein E ε4 (APOE ε4) (OMIM 104310) carriers demonstrate accelerated longitudinal decline on memory tests, suggesting the existence of a transitional state between normal aging and mild cognitive impairment (MCI), which we have called amnestic pre-MCI. Objective: To support our neuropsychological construct of pre-MCI by characterizing and comparing the relationship between measurements of baseline regional hypometabolism and subsequent rates of memory decline in a group of individuals with neuropsychologically defined asymptomatic memory decline (pre-MCI group) and in nondecliners after controlling for APOE ε4 gene dose. Design: Longitudinal study. Setting: Academic medical center. Participants: Of 139 healthy individuals in the Arizona APOE Cohort aged 50 to 69 years who underwent longitudinal neuropsychological testing and fludeoxyglucose F 18-positron emission tomography (FDG-PET) since 1994, 10 met our criteria for amnestic pre-MCI, and 15 showed no decline. Main Outcome Measures: Correlations between lower regional cerebral metabolic rates for glucose (CMRgl) and rates of verbal memory test decline that occurred at a mean of 41 months after baseline FDG-PET using an automated brain mapping algorithm (SPM5). Results: The pre-MCI and nondecliner groups did not differ in mean (SD) age (56.8 [4.8] years), education (16.5 [2.3] years), sex (19 women [76%]), or APOE ε4 carrier status (12 ε4 carriers [48%)]. After controlling for APOE ε4 gene dose, the pre-MCI group had significant correlations between lower baseline CMRgl in the posterior cingulate, bilateral parietal, and left prefrontal regions (known to be preferentially affected by Alzheimer disease) and subsequent verbal memory decline. Nondecliners had significant correlations bilaterally in the posterior and midcingulate cortices. Correlations in the left parietal, left temporal, and bilateral frontal regions were significantly greater in the pre-MCI group than those in the nondecliner group. Conclusion: Individuals with amnestic pre-MCI showed significantly greater correlations between cerebral hypometabolism and subsequent long-term memory decline than nondecliners in Alzheimer disease-affected brain regions. ©2008 American Medical Association. All rights reserved.
• Hua, X., Leow, A. D., Lee, S., Klunder, A. D., Toga, A. W., Lepore, N., Chou, Y., Brun, C., Chiang, M., Barysheva, M., Jack Jr., C. R., Bernstein, M. A., Britson, P. J., Ward, C. P., Whitwell, J. L., Borowski, B., Fleisher, A. S., Fox, N. C., Boyes, R. G., , Barnes, J., et al. (2008). 3D characterization of brain atrophy in Alzheimer's disease and mild cognitive impairment using tensor-based morphometry. NeuroImage, 41(1), 19-34.
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  PMID: 18378167;PMCID: PMC2556222;Abstract: Tensor-based morphometry (TBM) creates three-dimensional maps of disease-related differences in brain structure, based on nonlinearly registering brain MRI scans to a common image template. Using two different TBM designs (averaging individual differences versus aligning group average templates), we compared the anatomical distribution of brain atrophy in 40 patients with Alzheimer's disease (AD), 40 healthy elderly controls, and 40 individuals with amnestic mild cognitive impairment (aMCI), a condition conferring increased risk for AD. We created an unbiased geometrical average image template for each of the three groups, which were matched for sex and age (mean age: 76.1 years+/- 7.7 SD). We warped each individual brain image (N = 120) to the control group average template to create Jacobian maps, which show the local expansion or compression factor at each point in the image, reflecting individual volumetric differences. Statistical maps of group differences revealed widespread medial temporal and limbic atrophy in AD, with a lesser, more restricted distribution in MCI. Atrophy and CSF space expansion both correlated strongly with Mini-Mental State Exam (MMSE) scores and Clinical Dementia Rating (CDR). Using cumulative p-value plots, we investigated how detection sensitivity was influenced by the sample size, the choice of search region (whole brain, temporal lobe, hippocampus), the initial linear registration method (9- versus 12-parameter), and the type of TBM design. In the future, TBM may help to (1) identify factors that resist or accelerate the disease process, and (2) measure disease burden in treatment trials. © 2008 Elsevier Inc. All rights reserved.
• Jack Jr., C. R., Bernstein, M. A., Fox, N. C., Thompson, P., Alexander, G., Harvey, D., Borowski, B., Britson, P. J., Whitwell, J. L., Ward, C., Dale, A. M., Felmlee, J. P., Gunter, J. L., L., D., Killiany, R., Schuff, N., Fox-Bosetti, S., Lin, C., Studholme, C., , DeCarli, C. S., et al. (2008). The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods. Journal of Magnetic Resonance Imaging, 27(4), 685-691.
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  PMID: 18302232;PMCID: PMC2544629;Abstract: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a longitudinal multisite observational study of healthy elders, mild cognitive impairment (MCI), and Alzheimer's disease. Magnetic resonance imaging (MRI), (18F)-fluorodeoxyglucose positron emission tomography (FDG PET), urine serum, and cerebrospinal fluid (CSF) biomarkers, as well as clinical/psychometric assessments are acquiredat multiple time points. All data will be cross-linked and made available to the general scientific community. The purpose of this report is to describe the MRI methods employed in ADNI. The ADNI MRI core established specifications thatguided protocol development. A major effort was devoted toevaluating 3D T1-weighted sequences for morphometric analyses. Several options for this sequence were optimized for the relevant manufacturer platforms and then compared in a reduced-scale clinical trial. The protocol selected for the ADNI study includes: back-to-back 3D magnetization prepared rapid gradient echo (MP-RAGE) scans; B1-calibration scans when applicable; and an axial proton density-T2 dual contrast (i.e., echo) fast spin echo/turbo spin echo (FSE/TSE) for pathology detection. ADNI MRI methods seek to maximize scientific utility while minimizing the burden placed on participants. The approach taken in ADNI to standardization across sites and platforms of the MRI protocol, postacquisition corrections, and phantom-based monitoring of all scanners could be used as a model for other multisite trials. © 2008 Wiley-Liss, Inc.
• Jieping, Y. e., Chen, K., Teresa, W. u., Jing, L. i., Zhao, Z., Patel, R., Bae, M., Janardan, R., Liu, H., Alexander, G., & Reiman, E. (2008). Heterogeneous data fusion for alzheimer's disease study. Proceedings of the ACM SIGKDD International Conference on Knowledge Discovery and Data Mining, 1025-1033.
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  Abstract: Effective diagnosis of Alzheimer's disease (AD) is of primary importance in biomedical research. Recent studies have demonstrated that neuroimaging parameters are sensitive and consistent measures of AD. In addition, genetic and demographic information have also been successfully used for detecting the onset and progression of AD. The research so far has mainly focused on studying one type of data source only. It is expected that the integration of heterogeneous data (neuroimages, demographic, and genetic measures) will improve the prediction accuracy and enhance knowledge discovery from the data, such as the detection of biomarkers. In this paper, we propose to integrate heterogeneous data for AD prediction based on a kernel method. We further extend the kernel framework for selecting features (biomarkers) from heterogeneous data sources. The proposed method is applied to a collection of MRI data from 59 normal healthy controls and 59 AD patients. The MRI data are pre-processed using tensor factorization. In this study, we treat the complementary voxel-based data and region of interest (ROI) data from MRI as two data sources, and attempt to integrate the complementary information by the proposed method. Experimental results show that the integration of multiple data sources leads to a considerable improvement in the prediction accuracy. Results also show that the proposed algorithm identifies biomarkers that play more significant roles than others in AD diagnosis. © 2008 ACM.
• Reiman, E. M., Chen, K., Caselli, R. J., Alexander, G. E., Bandy, D., Adamson, J. L., Lee, W., Cannon, A., Stephan, E. A., Stephan, D. A., & Papassotiropoulos, A. (2008). Cholesterol-related genetic risk scores are associated with hypometabolism in Alzheimer's-affected brain regions. NeuroImage, 40(3), 1214-1221.
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  PMID: 18280754;PMCID: PMC2441925;Abstract: We recently implicated a cluster of nine single nucleotide polymorphisms from seven cholesterol-related genes in the risk of Alzheimer's disease (AD) in a European cohort, and we proposed calculating an aggregate cholesterol-related genetic score (CREGS) to characterize a person's risk. In a separate study, we found that apolipoprotein E (APOE) e{open}4 gene dose, an established AD risk factor, was correlated with fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of hypometabolism in AD-affected brain regions in a cognitively normal American cohort, and we proposed using PET as a presymptomatic endophenotype to help assess putative modifiers of AD risk. Thus, the objective in the present study is to determine whether CREGS is related to PET measurements of hypometabolism in AD-affected brain regions. DNA and PET data from 141 cognitively normal late middle-aged APOE e{open}4 homozygotes, heterozygotes and noncarriers were analyzed to evaluate the relationship between CREGS and regional PET measurements. Cholesterol-related genetic risk scores were associated with hypometabolism in AD-affected brain regions, even when controlling for the effects of APOE e{open}4 gene dose. The results support the role of cholesterol-related genes in the predisposition to AD and support the value of neuroimaging in the presymptomatic assessment of putative modifiers of AD risk. © 2008 Elsevier Inc. All rights reserved.
• Alexander, G. E., Caselli, R. J., Reiman, E. M., Locke, D. E., Hutton, M. L., Hentz, J. G., C, H., Woodruff, B. K., Alexander, G. E., & D., O. (2007). Cognitive domain decline in healthy apolipoprotein E epsilon4 homozygotes before the diagnosis of mild cognitive impairment.. Archives of Neurology.
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  Study investigating the pre-mild cognitive impairment effects of Alzheiemer's disease.;Your Role: Contributed to analysis, aspects of study design, and revision of manuscript;Full Citation: Caselli RJ, Reiman EM, Locke DE, Hutton ML, Hentz JG, Hoffman-Snyder C, Woodruff BK, Alexander GE, Osborne D. Cognitive domain decline in healthy apolipoprotein E epsilon4 homozygotes before the diagnosis of mild cognitive impairment.Arch Neurol. 2007 Sep;64(9):1306-11.;Collaborative with faculty member at UA: Yes;
• Alexander, G. E., Chen, K., Chen, X., Renaut, R., Alexander, G. E., Bandy, D., Guo, H., & EM., R. (2007). Characterization of the image-derived carotid artery input function using independent component analysis for the quantitation of [18F] fluorodeoxyglucose positron emission tomography images.. Phys Med Biol..
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  Development of new method to fully quantify 18FDG PET non-invasively.;Your Role: Contributed to analysis, aspects of study design, and revision of manuscript.;Full Citation: Chen K, Chen X, Renaut R, Alexander GE, Bandy D, Guo H, Reiman EM. Characterization of the image-derived carotid artery input function using independent component analysis for the quantitation of [18F] fluorodeoxyglucose positron emission tomography images. Phys Med Biol. 2007 Dec 7;52(23):7055-71.;Collaborative with faculty member at UA: Yes;
• Alexander, G. E., Etnier, J. L., Caselli, R. J., Reiman, E. M., Alexander, G. E., Sibley, B. A., Tessier, D., & EC., M. (2007). Cognitive performance in older women relative to ApoE-epsilon4 genotype and aerobic fitness.. Med Sci Sports Exerc..
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  Study demonstrating the beneficial effect of aerobic fitness on cognitive function in older women with increased risk for Alzheimer's disease.;Your Role: Contributed to analysis, aspects of study design, and revision of manuscript.;Full Citation: Etnier JL, Caselli RJ, Reiman EM, Alexander GE, Sibley BA, Tessier D, McLemore EC. Cognitive performance in older women relative to ApoE-epsilon4 genotype and aerobic fitness. Med Sci Sports Exerc. 2007 39(1):199-207.;Collaborative with faculty member at UA: Yes;
• Alexander, G. E., Reiman, E. M., Webster, J. A., Myers, A. J., Hardy, J., Dunckley, T., Zismann, V. L., Joshipura, K. D., Pearson, J. V., Hu-Lince, D., Huentelman, M. J., Craig, D. W., Coon, K. D., Liang, W. S., Herbert, R. H., Beach, T., Rohrer, K. C., Zhao, A. S., Leung, D., & Bryden, L. (2007). GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.. Neuron.
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  ;Your Role: Contributed to analysis, aspects of study design, and revision of manuscript.;Full Citation: Reiman, E.M., Webster, J.A., Myers, A.J., Hardy, J., Dunckley, T., Zismann, V.L., Joshipura, K.D., Pearson, J.V., Hu-Lince, D., Huentelman, M.J., Craig, D.W., Coon, K.D., Liang, W.S., Herbert, R.H., Beach, T., Rohrer, K.C., Zhao, A.S., Leung, D., Bryden, L., Marlowe, L., Kaleem, M., Mastroeni, D., Grover, A., Heward, C.B., Ravid, R., Rogers, J., Hutton, M.L., Melquist, S., Petersen, R.C., Alexander, G.E., Caselli, R.J., Kukull, W., Papassotiropoulos, A., Stephan, D.A. (2007). GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. Neuron, 54, 713-20.;Collaborative with faculty member at UA: Yes;
• Caselli, R. J., Reiman, E. M., E., D., Hutton, M. L., Hentz, J. G., Hoffman-Snyder, C., Woodruff, B. K., Alexander, G. E., & Osborne, D. (2007). Cognitive domain decline in healthy apolipoprotein E ε4 homozygotes before the diagnosis of mild cognitive impairment. Archives of Neurology, 64(9), 1306-1311.
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  PMID: 17846270;Abstract: Background: Memory declines more rapidly with age in apolipoprotein E (APOE) ε4 carriers than in APOE ε4 noncarriers, and APOE ε4 homozygotes' cognitive performances correlate with stressors. These changes could represent presymptomatic disease in some, despite their youth. Objective: To show that presymptomatic APOE ε4 homozygotes experience greater psychometric decline at a younger age than APOE ε4 heterozygotes and noncarriers before the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD). Design: Prospective observational study Setting: Academic medical center. Participants: A total of 43 APOE ε4 homozygotes, 59 APOE ε4 heterozygotes, and 112 APOE ε4 noncarriers aged 50 to 69 years were cognitively healthy and matched at entry according to age, educational level, and sex. Intervention: Neuropsychological battery given every 2 years. Main Outcome Measures: Predefined test and cognitive domain decline criteria applied to consecutive epochs. Results: Of 214 participants, 48 showed no decline on any test, 126 showed decline on only 1 test in 1 or more domains, and 40 showed decline on 2 or more tests in 1 or more domains. Cognitive domain decline occurred in 4 of 10 APOE ε4 homozygotes 60 years and older at entry (40.0%) compared with 5 of 66 APOE ε4 heterozygotes and noncarriers (7.6%) (P=.02) and was more predictive of subsequent decline than nondomain decline (17 of 24 [70.8%] vs 29 of 70 [41.4%]; P=.01). Decline on any memory test was predictive of further decline (P
• Chen, K., Chen, X., Renaut, R., Alexander, G. E., Bandy, D., Guo, H., & Reiman, E. M. (2007). Characterization of the image-derived carotid artery input function using independent component analysis for the quantitation of [18F] fluorodeoxyglucose positron emission tomography images. Physics in Medicine and Biology, 52(23), 7055-7071.
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  PMID: 18029993;Abstract: We previously developed a noninvasive technique for the quantification of fluorodeoxyglucose (FDG) positron emission tomography (PET) images using an image-derived input function obtained from a manually drawn carotid artery region. Here, we investigate the use of independent component analysis (ICA) for more objective identification of the carotid artery and surrounding tissue regions. Using FDG PET data from 22 subjects, ICA was applied to an easily defined cubical region including the carotid artery and neighboring tissue. Carotid artery and tissue time activity curves and three venous samples were used to generate spillover and partial volume-corrected input functions and to calculate the parametric images of the cerebral metabolic rate for glucose (CMRgl). Different from a blood-sampling-free ICA approach, the results from our ICA approach are numerically well matched to those based on the arterial blood sampled input function. In fact, the ICA-derived input functions and CMRgl measurements were not only highly correlated (correlation coefficients >0.99) to, but also highly comparable (regression slopes between 0.92 and 1.09), with those generated using arterial blood sampling. Moreover, the reliability of the ICA-derived input function remained high despite variations in the location and size of the cubical region. The ICA procedure makes it possible to quantify FDG PET images in an objective and reproducible manner. © 2007 IOP Publishing Ltd.
• Chen, K., Reiman, E. M., & Alexander, G. E. (2007). A Monte-Carlo simulation package, multiple comparison corrections and power estimation incorporating secondary supportive evidence. 2007 IEEE/ICME International Conference on Complex Medical Engineering, CME 2007, 907-913.
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  Abstract: Various approaches have been proposed to account for the family-wise type-I errors in neuroimaging studies. This study introduces new global features as alternatives to address the multiple-comparison issue. These global features can serve as alternative brain indices whose type-I error theoretical calculations are unknown. A Monte-Carlo simulation package was used to calculate the family-wise type-I error of the newly introduced global features, as well as the conventional multiple comparison corrected p-values related to the height of the statistic (and cluster size) of interest in situations where random field theorem based p-values might be validated. In addition, this package was designed to perform statistical power analyses, taking multiple comparisons into consideration for the conventional statistics and the new global features. The behaviors of the global index type-I error thresholds as a function of the degrees of freedom (D) of t-distribution were investigated. Data from an oxygen-15 water PET study of right hand movement was used to illustrate the use of the global features and their type-I error and statistical power. With this PET example, we showed the superior statistical power of some global indices in cases where there were moderate changes over a relatively large brain volume. We believe that the global features and the calculation of type-I errors/statistical powers by the computer simulation package provide researchers alternative ways to account for multiple comparisons in neuroimaging studies. © 2007 IEEE.
• Chen, K., Reiman, E. M., Alexander, G. E., Caselli, R. J., Gerkin, R., Bandy, D., Domb, A., Osborne, D., Fox, N., Crum, W. R., Saunders, A. M., & Hardy, J. (2007). Correlations between apolipoprotein E epsilon4 gene dose and whole brain atrophy rates.. American Journal of Psychiatry.
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  Study demonstrating a gene dose relationship between APOE e4 and brain atrophy in cognitive normal late middle aged adults.;Your Role: Contributed to analysis, aspects of study design, and revision of manuscript.;Full Citation: Chen, K., Reiman, E.M., Alexander, G.E., Caselli, R.J., Gerkin, R., Bandy, D., Domb, A., Osborne, D., Fox, N., Crum, W.R., Saunders, A.M., Hardy, J. (2007). Correlations between apolipoprotein E epsilon4 gene dose and whole brain atrophy rates. American Journal of Psychiatry, 164, 916-21.;Collaborative with faculty member at UA: Yes;
• Chen, K., Reiman, E. M., Alexander, G. E., Caselli, R. J., Gerkin, R., Bandy, D., Domb, A., Osborne, D., Fox, N., Crum, W. R., Saunders, A. M., & Hardy, J. (2007). Correlations between apolipoprotein E ε4 gene dose and whole brain atrophy rates. American Journal of Psychiatry, 164(6), 916-921.
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  PMID: 17541051;Abstract: Objective: The purpose of this study was to characterize the relationship between whole brain atrophy rates and three levels of genetic risk for Alzheimer's disease in cognitively normal persons. The authors previously found accelerated whole brain atrophy rates in patients with probable Alzheimer's disease by computing changes in brain volume from sequential magnetic resonance images (MRIs). Methods: The authors assessed 36 late-middle-aged persons from three genetic groups: those with two, one, and no copies of the apolipoprotein E (APOE) ε4 allele, a common Alzheimer's disease susceptibility gene. The participants had clinical ratings, neuropsychological tests, and volumetric T1-weighted MRIs during a baseline visit and again approximately 2 years later. Two different image-analysis techniques, brain boundary shift integration and iterative principal component analysis, were used to compute whole brain atrophy rates. Results: While there were no baseline, follow-up, or between-visit differences in the clinical ratings or neuropsychological test scores among the three subject groups, whole brain atrophy rates were significantly greater in the ε4 homozygote group than in noncarriers and were significantly correlated with ε4 gene dose (i.e., the number of ε4 alleles in a person's APOE genotype). Conclusion: Since APOE ε4 gene dose is associated with an increased risk of Alzheimer's disease and a younger median age at dementia onset, this study suggests an association between the risk of Alzheimer's disease and accelerated brain atrophy rates before the onset of cognitive impairment.
• Etnier, J. L., Caselli, R. J., Reiman, E. M., Alexander, G. E., Sibley, B. A., Tessier, D., & Mclemore, E. C. (2007). Cognitive performance in older women relative to ApoE-ε4 genotype and aerobic fitness. Medicine and Science in Sports and Exercise, 39(1), 199-207.
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  PMID: 17218903;Abstract: INTRODUCTION: Apolipoprotein E (ApoE) genotype and aerobic fitness are each associated with cognitive performance in older adults. However, their potentially interactive effects on cognitive performance have not been examined. PURPOSE: The primary purpose of this study was to determine whether ApoE genotype and aerobic fitness interact to uniquely impact memory performance and executive functioning. A secondary purpose was to examine the interactive effects on other measures of cognition to provide a more comprehensive assessment of cognitive abilities across a broad range of functions. METHODS: Community-dwelling, cognitively normal older women (N = 90) provided blood samples to allow for assessment of ApoE genotype, completed cognitive tests, and performed a maximal aerobic fitness test. Primary outcome variables were the auditory verbal learning test (AVLT), the complex figures test (CFT), and the Wisconsin card-sorting task (WCST). Secondary outcome variables were the block design test and the paced auditory serial addition task (PASAT). RESULTS: Regression analyses indicated that aerobic fitness was associated with significantly better performance on measures of the AVLT, the CFT, and the PASAT for the ApoE-ε4 homozygotes. CONCLUSION: The preliminary findings from this study support the possibility that aerobic fitness is positively associated with the memory performance of those individuals at most genetic risk for Alzheimer disease. ©2007The American College of Sports Medicine.
• Liang, W. S., Dunckley, T., Beach, T. G., Grover, A., Mastroeni, D., Walker, D. G., Caselli, R. J., Kukull, W. A., McKeel, D., Morris, J. C., Hulette, C., Schmechel, D., Alexander, G. E., Reiman, E. M., Rogers, J., & Stephan, D. A. (2007). Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain. Physiological Genomics, 28(3), 311-322.
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  PMID: 17077275;PMCID: PMC2259385;Abstract: In this article, we have characterized and compared gene expression profiles from laser capture microdissected neurons in six functionally and anatomically distinct regions from clinically and histopathologically normal aged human brains. These regions, which are also known to be differentially vulnerable to the histopathological and metabolic features of Alzheimer's disease (AD), include the entorhinal cortex and hippocampus (limbic and paralimbic areas vulnerable to early neurofibrillary tangle pathology in AD), posterior cingulate cortex (a paralimbic area vulnerable to early metabolic abnormalities in AD), temporal and prefrontal cortex (unimodal and heteromodal sensory association areas vulnerable to early neuritic plaque pathology in AD), and primary visual cortex (a primary sensory area relatively spared in early AD). These neuronal profiles will provide valuable reference information for future studies of the brain, in normal aging, AD and other neurological and psychiatric disorders. Copyright © 2007 the American Physiological Society.
• Liang, W. S., Dunckley, T., Beach, T. G., Grover, A., Mastroeni, D., Walker, D. G., Caselli, R. J., Kukull, W., McKeel, D., Morris, J. C., Hulette, C., Schmechel, D., Alexander, G. E., Reiman, E. M., Rogers, J., & Stephan, D. A. (2007). Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain.. Physiological Genomics..
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  Study investigating the regional brain differences in gene expression related to healthy aging.;Your Role: Contributed to analysis, aspects of study design, and revision of manuscript.;Full Citation: Liang, W.S., Dunckley, T., Beach, T.G., Grover, A., Mastroeni, D., Walker, D.G., Caselli, R.J., Kukull, W., McKeel, D., Morris, J.C., Hulette, C., Schmechel, D., Alexander, G.E., Reiman, E.M., Rogers, J., Stephan, D.A. (2007). Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain. Physiological Genomics, 28, 311-22.;Collaborative with faculty member at UA: Yes;
• Reiman, E. M., Webster, J. A., Myers, A. J., Hardy, J., Dunckley, T., Zismann, V. L., Joshipura, K. D., Pearson, J. V., Hu-Lince, D., Huentelman, M., Craig, D. W., Coon, K. D., Liang, W. S., Herbert, R. H., Beach, T., Rohrer, K. C., Zhao, A. S., Leung, D., Bryden, L., , Marlowe, L., et al. (2007). GAB2 Alleles Modify Alzheimer's Risk in APOE ε4 Carriers. Neuron, 54(5), 713-720.
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  PMID: 17553421;PMCID: PMC2587162;Abstract: The apolipoprotein E (APOE) ε4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In ε4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 × 10-11) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE ε4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE ε4 carriers and influences Alzheimer's neuropathology. © 2007 Elsevier Inc. All rights reserved.
• Alexander, G. E., Chen, K., Merkley, T. L., Reiman, E. M., Caselli, R. J., Aschenbrenner, M., Santerre-Lemmon, L., Lewis, D. J., Pietrini, P., Teipel, S. J., Hampel, H., Rapoport, S. I., & Moeller, J. R. (2006). Regional network of magnetic resonance imaging gray matter volume in healthy aging. NeuroReport, 17(10), 951-956.
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  PMID: 16791083;Abstract: Healthy aging has been associated with brain volume reductions preferentially affecting the frontal cortex, but also involving other regions. We used a network model of regional covariance, the Scaled Subprofile Model, with magnetic resonance imaging voxel-based morphometry to identify the regional distribution of gray matter associated with aging in 26 healthy adults, 22-77 years old. Scaled Subprofile Model analysis identified a pattern that was highly correlated with age (R2=0.66, P≤0.0001). Older age was associated with less gray matter in the bilateral frontal, temporal,thalamic, and right cerebellar regions. Gender differences suggested more advanced brain aging in the men. In this healthy adult sample, aging was associated with a regional pattern of gray matter atrophy most prominently involving the frontal and temporal cortices. Scaled Subprofile Model network analysis may aid in the detection and tracking of brain aging and in the evaluation of putative antiaging therapies. © 2006 Lippincott Williams & Wilkins.
• Caselli, R. J., Chen, K., Bandy, D., Smilovici, O., Boeve, B. F., Osborne, D., Alexander, G. E., Parish, J. M., Krahn, L. E., & Reiman, E. M. (2006). A preliminary fluorodeoxyglucose positron emission tomography study in healthy adults reportinq dream-enactment behavior. Sleep, 29(7), 927-933.
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  PMID: 16895260;Abstract: Study Objectives: To test the hypothesis that healthy adults reporting dream-enactment behavior (DEB+) have reduced cerebral metabolic rate for glucose (CMRgI) in regions preferentially affected in patients with dementia with Lewy bodies (DLB). Design: Automated brain-mapping algorithms were used to compare regional fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements from previously evaluated DEB cases and controls. Setting: Tertiary-care academic medical centers. Participants: Seventeen cognitively normal patients with DEB+ and 17 control subjects (DEB-) who were individually matched for age (59 ± 11 years), education level (16 ± 4 years), sex (67% women), body mass index (26 ± 4.8 kg/m2), first-degree relative with dementia (85%), and proportion of apolipoprotein E (APOE) e4 carriers (13 e4 carriers, 4 noncarriers). Interventions: FDG-PET. Measurements and Results: DEB was associated with significantly lower CMRgI in several brain regions known to be preferentially affected in both DLB and Alzheimer disease (parietal, temporal, and posterior cingulate cortexes) and in several other regions, including the anterior cingulate cortex (p < .001, uncorrected for multiple comparisons). The DEB-associated CMRgI reductions were significantly greater in the APOE e4 noncarriers than in the carriers. Conclusions: These preliminary findings suggest that cognitively normal persons with DEB have reduced CMRgI in brain regions known to be metabolically affected by DLB, supporting further study of DEB as a possible risk factor for the development of DLB.
• Chen, K., Xiaolin, G. e., Yao, L., Bandy, D., Alexander, G. E., Prouty, A., Burns, C., Zhao, X., Wen, X., Korn, R., Lawson, M., & Reiman, E. M. (2006). An automated, normative-based fluorodeoxyglucose positron emission tomography image-analysis procedure to aid Alzheimer disease diagnosis using statistical parametric mapping and interactive image display. Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 6144 III.
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  Abstract: Having approved fluorodeoxyglucose positron emission tomography (FDG PET) for the diagnosis of Alzheimer's disease (AD) in some patients, the Centers for Medicare and Medicaid Services suggested the need to develop and test analysis techniques to optimize diagnostic accuracy. We developed an automated computer package comparing an individual's FDG PET image to those of a group of normal volunteers. The normal control group includes FDG-PET images from 82 cognitively normal subjects, 61.89±5.67 years of age, who were characterized demographically, clinically, neuropsychologically, and by their apolipoprotein E genotype (known to be associated with a differential risk for AD). In addition, AD-affected brain regions functionally defined as based on a previous study (Alexander, et al, Am J Psychiatr, 2002) were also incorporated. Our computer package permits the user to optionally select control subjects, matching the individual patient for gender, age, and educational level. It is fully streamlined to require minimal user intervention. With one mouse click, the program runs automatically, normalizing the individual patient image, setting up a design matrix for comparing the single subject to a group of normal controls, performing the statistics, calculating the glucose reduction overlap index of the patient with the AD-affected brain regions, and displaying the findings in reference to the AD regions. In conclusion, the package automatically contrasts a single patient to a normal subject database using sound statistical procedures. With further validation, this computer package could be a valuable tool to assist physicians in decision making and communicating findings with patients and patient families.
• Johnson, S. C., Schmitz, T. W., Moritz, C. H., Meyerand, M. E., Rowley, H. A., Alexander, A. L., Hansen, K. W., Gleason, C. E., Carlsson, C. M., Ries, M. L., Asthana, S., Chen, K., Reiman, E. M., & Alexander, G. E. (2006). Activation of brain regions vulnerable to Alzheimer's disease: The effect of mild cognitive impairment. Neurobiology of Aging, 27(11), 1604-1612.
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  PMID: 16226349;PMCID: PMC2627778;Abstract: This study examined the functionality of the medial temporal lobe (MTL) and posterior cingulate (PC) in mild cognitive impairment amnestic type (MCI), a syndrome that puts patients at greater risk for developing Alzheimer disease (AD). Functional MRI (fMRI) was used to identify regions normally active during encoding of novel items and recognition of previously learned items in a reference group of 77 healthy young and middle-aged adults. The pattern of activation in this group guided further comparisons between 14 MCI subjects and 14 age-matched controls. The MCI patients exhibited less activity in the PC during recognition of previously learned items, and in the right hippocampus during encoding of novel items, despite comparable task performance to the controls. Reduced fMRI signal change in the MTL supports prior studies implicating the hippocampus for encoding new information. Reduced signal change in the PC converges with recent research on its role in recognition in normal adults as well as metabolic decline in people with genetic or cognitive risk for AD. Our results suggest that a change in function in the PC may account, in part, for memory recollection failure in AD. © 2005 Elsevier Inc. All rights reserved.
• Leow, A. D., Klunder, A. D., Jack Jr., C. R., Toga, A. W., Dale, A. M., Bernstein, M. A., Britson, P. J., Gunter, J. L., Ward, C. P., Whitwell, J. L., Borowski, B. J., Fleisher, A. S., Fox, N. C., Harvey, D., Kornak, J., Schuff, N., Studholme, C., Alexander, G. E., Weiner, M. W., & Thompson, P. M. (2006). Longitudinal stability of MRI for mapping brain change using tensor-based morphometry. NeuroImage, 31(2), 627-640.
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  PMID: 16480900;PMCID: PMC1941663;Abstract: Measures of brain change can be computed from sequential MRI scans, providing valuable information on disease progression, e.g., for patient monitoring and drug trials. Tensor-based morphometry (TBM) creates maps of these brain changes, visualizing the 3D profile and rates of tissue growth or atrophy, but its sensitivity depends on the contrast and geometric stability of the images. As part of the Alzheimer's Disease Neuroimaging Initiative (ADNI), 17 normal elderly subjects were scanned twice (at a 2-week interval) with several 3D 1.5 T MRI pulse sequences: high and low flip angle SPGR/FLASH (from which Synthetic T1 images were generated), MP-RAGE, IR-SPGR (N = 10) and MEDIC (N = 7) scans. For each subject and scan type, a 3D deformation map aligned baseline and follow-up scans, computed with a nonlinear, inverse-consistent elastic registration algorithm. Voxelwise statistics, in ICBM stereotaxic space, visualized the profile of mean absolute change and its cross-subject variance; these maps were then compared using permutation testing. Image stability depended on: (1) the pulse sequence; (2) the transmit/receive coil type (birdcage versus phased array); (3) spatial distortion corrections (using MEDIC sequence information); (4) B1-field intensity inhomogeneity correction (using N3). SPGR/FLASH images acquired using a birdcage coil had least overall deviation. N3 correction reduced coil type and pulse sequence differences and improved scan reproducibility, except for Synthetic T1 images (which were intrinsically corrected for B1-inhomogeneity). No strong evidence favored B0 correction. Although SPGR/FLASH images showed least deviation here, pulse sequence selection for the ADNI project was based on multiple additional image analyses, to be reported elsewhere. © 2006 Elsevier Inc. All rights reserved.
• Smith, J. F., Chen, K., Johnson, S., Morrone-Strupinsky, J., Reiman, E. M., Nelson, A., Moeller, J. R., & Alexandera, G. E. (2006). Network analysis of single-subject fMRI during a finger opposition task. NeuroImage, 32(1), 325-332.
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  PMID: 16733091;Abstract: The analysis of functional magnetic resonance imaging (fMRI) data has typically relied on univariate methods to identify areas of brain activity related to cognitive and behavioral task performance. We investigated the ability of multivariate network analysis using a modified form of principal component analysis, the Scaled Subprofile Model (SSM), applied to single-subject fMRI data to identify patterns of interactions among brain regions over time during an anatomically well-characterized simple motor task. We hypothesized that each subject would exhibit correlated patterns of brain activation in several regions known to participate in the regulation of movement including the contralateral motor cortex and the ipsilateral cerebellum. EPI BOLD images were acquired in six healthy participants as they performed a visually and auditorally paced finger opposition task. SSM analysis was applied to the fMR time series on a single-subject basis. Linear combinations of the major principal components that predicted the expected hemodynamic response to the order of experimental conditions were identified for each participant. These combinations of SSM patterns were highly associated with the expected hemodynamic response, an indicator of local neuronal activity, in each participant (0.84 ≤ R2 ≤ 0.97, all P's < 0.0001). As predicted, the combined pattern in each subject was characterized most prominently by relatively increased activations in contralateral sensorimotor cortex and ipsilateral cerebellum. Additionally, all subjects showed areas of relatively decreased activation in the ipsilateral sensorimotor cortex and contralateral cerebellum. The application of network analysis methods, such as SSM, to singlesubject fMRI data can identify patterns of task-specific, functionally interacting brain areas in individual subjects. This approach may helpidentify individual differences in the task-related functional connectivity, track changes in task-related patterns of activity within or between fMRI sessions, and provide a method to identify individual differences in response to treatment.
• Valla, J., Schneider, L., Niedzielko, T., Coon, K. D., Caselli, R., Sabbagh, M. N., Ahern, G. L., Baxter, L., Alexander, G., Walker, D. G., & Reiman, E. M. (2006). Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment. Mitochondrion, 6(6), 323-330.
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  PMID: 17123871;PMCID: PMC1864936;Abstract: Mitochondrial abnormalities are found in Alzheimer's disease (AD), but previous reports have not examined at-risk groups. In subjects with AD, mild cognitive impairment (MCI), and non-demented aged controls, platelet and lymphocyte mitochondria were isolated and analyzed for Complexes I, III, and IV of the electron transport chain. Western blots were used to control for differential enrichment of samples. Results demonstrated significant declines in Complexes III and IV in AD, and a significant decline in Complex IV in MCI. This report confirms mitochondrial deficiencies in AD, extends them to MCI, and suggests they are present at the earliest symptomatic stages of disease. © 2006 Mitochondria Research Society.
• Lin, L., Chen, K., Valla, J., Jiping, H. e., Reiman, E. M., Galons, J., Hauss-Wegrzyniak, B., & Alexander, G. E. (2005). MRI template and atlas toolbox for the C57BL/6J mouse brain. 2nd International IEEE EMBS Conference on Neural Engineering, 2005, 6-8.
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  Abstract: In order to compare brain-imaging measurements from different subjects, brain-mapping algorithms are commonly used to register individual brain onto a standardized brain atlas. In this study, SPM99 was used to linearly and nonlinearly coregister a spatially standardized T2-weighted template of C57BL/6J to the atlas by Paxinos and Franklin (2001), local accuracy of between atlas and template was evaluated, and a toolbox was developed. This study provides a foundation for the region of interest analysis for mouse brain images. © 2005 IEEE.
• Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., Saunders, A. M., & Hardy, J. (2005). Correlations between apolipoprotein E ε4 gene dose and brain-imaging measurements of regional hypometabolism. Proceedings of the National Academy of Sciences of the United States of America, 102(23), 8299-8302.
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  PMID: 15932949;PMCID: PMC1149416;Abstract: Patients with Alzheimer's disease (AD) have abnormally low positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgI) in regions of the precuneus and the posterior cingulate, parietotemporal, and frontal cortex. Apolipoprotein E (APOE) ε4 gene dose (i.e., the number of ε4 alleles in a person's APOE genotype) is associated with a higher risk of AD and a younger age at dementia onset. We previously found that cognitively normal late-middle-aged APOE ε4 carriers have abnormally low CMRgl in the same brain regions as patients with probable Alzheimer's dementia. In a PET study of 160 cognitively normal subjects 47-68 years of age, including 36 ε4 homozygotes, 46 heterozygotes, and 78 ε4 noncarriers who were individually matched for their gender, age, and educational level, we now find that ε4 gene dose is correlated with lower CMRgl in each of these brain regions. This study raises the possibility of using PET as a quantitative presymptomatic endophenotype to help evaluate the individual and aggregate effects of putative genetic and nongenetic modifiers of AD risk. © 2005 by The National Academy of Sciences of the USA.
• Alexander, G., Caselli, R. J., Reiman, E. M., Hentz, J. G., Osborne, D., & Alexander, G. E. (2004). A distinctive interaction between chronic anxiety and problem solving in asymptomatic APOE e4 homozygotes. The Journal of neuropsychiatry and clinical neurosciences, 16(3).
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  We correlated measures of problem solving (Wisconsin Card Sorting Test [WCST] categories, total errors, and perseverative errors) and chronic anxiety (Personality Assessment Inventory Anxiety Scale [ANX]) in asymptomatic apolipoprotein E (APOE) e4 homozygotes (HMZs), heterozygotes, and noncarriers (NC) (n = 42 in each group) matched for age, education, and gender. Differences between HMZ and NC in the slope of the regression of WCST scores on ANX reached statistical significance on all three WCST measures. Chronic anxiety adversely affects cognitive skills in all groups, and is associated with significantly greater decline in problem solving skills in cognitively normal APOE e4 HMZ.
• Caselli, R. J., Reiman, E. M., Hentz, J. G., Osborne, D., & Alexander, G. E. (2004). A distinctive interaction between chronic anxiety and problem solving in asymptomatic APOE e4 homozygotes. Journal of Neuropsychiatry and Clinical Neurosciences, 16(3), 320-329.
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  PMID: 15377739;Abstract: We correlated measures of problem solving (Wisconsin Card Sorting Test [WCST] categories, total errors, and perseverative errors) and chronic anxiety (Personality Assessment Inventory Anxiety Scale [ANX]) in asymptomatic apolipoprotein E (APOE) e4 homozygotes (HMZs), heterozygotes, and noncarriers (NC) (n = 42 in each group) matched for age, education, and gender. Differences between HMZ and NC in the slope of the regression of WCST scores on ANX reached statistical significance on all three WCST measures. Chronic anxiety adversely affects cognitive skills in all groups, and is associated with significantly greater decline in problem solving skills in cognitively normal APOE e4 HMZ.
• Caselli, R. J., Reiman, E. M., Osborne, D., Hentz, J. G., Baxter, L. C., Hernandez, J. L., & Alexander, G. G. (2004). Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology, 62(11), 1990-1995.
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  PMID: 15184602;Abstract: Objective: To determine whether memory loss is detectable before the symptomatic presentation of mild cognitive impairment (MCI) in those at greater genetic risk for Alzheimer disease (AD) based upon presence or absence of the e4 allele of APOE. Methods: Participants were age 50 years or older who responded to newspaper advertisements. A total of 212 cognitively normal individuals of known APOE genotype were initially enrolled in a match paradigm that included e4 homozygotes, e3/4 heterozygotes, and e4 noncarriers in a 1:1:2 ratio (53 sets). Of the original 212 individually matched participants, 180 completed at least two epochs of testing including 45 APOE e4/4 homozygotes, 42 APOE e3/4 heterozygotes, and 93 APOE e4 noncarriers, mean age 60 (±6.2) years. Of these, four developed MCI or AD during the follow-up period and were excluded from analysis. Longitudinal neuropsychological study included two verbal (Auditory Verbal Learning Test [AVLT], Selective Reminding Test [SRT]) and two visual (Complex Figure Test [CFT], Visual Retention Test) memory tests. Results: Multiple measures on both verbal memory tests showed poorer performance over a mean interval of 33 months in e4 carriers than noncarriers: AVLT total learning, long term delayed recall; SRT free and cued recall. Among those age 50 to 59 years, AVLT long term delayed recall, SRT free and cued recall, and CFT recall declined more in APOE e4 carriers. No differences were found in the domains of language, spatial skills, or executive function. Conclusions: Memory declined in APOE e4 carriers before the symptomatic presentation of MCI in a cohort whose mean age was 60 years over a median period of 33 months. The decline began prior to age 60.
• Chen, K., Reiman, E. M., Alexander, G. E., Bandy, D., Renaut, R., Crum, W. R., Fox, N. C., & Rossor, M. N. (2004). An automated algorithm for the computation of brain volume change from sequential MRIs using an iterative principal component analysis and its evaluation for the assessment of whole-brain atrophy rates in patients with probable Alzheimer's disease. NeuroImage, 22(1), 134-143.
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  PMID: 15110003;Abstract: This article introduces an automated method for the computation of changes in brain volume from sequential magnetic resonance images (MRIs) using an iterative principal component analysis (IPCA) and demonstrates its ability to characterize whole-brain atrophy rates in patients with Alzheimer's disease (AD). The IPCA considers the voxel intensity pairs from coregistered MRIs and identifies those pairs a sufficiently large distance away from the iteratively determined PCA major axis. Analyses of simulated and real MRI data support the underlying assumption of a linear relationship in paired voxel intensities, identify an outlier distance threshold that optimizes the trade-off between sensitivity and specificity in the detection of small volume changes while accounting for global intensity changes, and demonstrate an ability to detect changes as small as 0.04% of brain volume without confounding effects of between-scan shifts in voxel intensity. In eight patients with probable AD and eight age-matched normal control subjects, the IPCA was comparable to the established but partly manual digital subtraction (DS) method in characterizing annual rates of whole-brain atrophy: resulting rates were correlated (Spearman rank correlation = 0.94, P < 0.0005) and comparable in distinguishing probable AD from normal aging (IPCA-detected atrophy rates: 2.17 ± 0.52% per year in the patients vs. 0.41 ± 0.22% per year in the controls [Wilcoxon-Mann-Whitney test P = 7.8 × 10-4]; DS-detected atrophy rates: 3.51 ± 1.31% per year in the patients vs. 0.48 ± 0.29% per year in the controls [P = 7.8 × 10-4]). The IPCA could be used in tracking the progression of AD, evaluating the disease-modifying effects of putative treatments, and investigating the course of other normal and pathological changes in brain morphology. © 2004 Elsevier Inc. All rights reserved.
• Ibáñez, V., Pietrini, P., Furey, M. L., Alexander, G. E., Millet, P., Bokde, A. L., Teichberg, D., Schapiro, M. B., Horwitz, B., & Rapoport, S. I. (2004). Resting state brain glucose metabolism is not reduced in normotensive healthy men during aging, after correction for brain atrophy. Brain Research Bulletin, 63(2), 147-154.
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  PMID: 15130704;Abstract: Studies using positron emission tomography (PET) have reported that global and regional values for cerebral blood flow and metabolic rates for glucose (CMRglc and rCMRglc) decline with age in humans. We wished to determine if such decreases could have reflected a partial volume effect (PVE) of cerebral atrophy in the elderly, rather than "intrinsic" reductions per gram brain. We used PET to compare rCMRglc, before and after correcting for the PVE, between 13 healthy older men (aged: 55-82 years) and 11 healthy young men (aged: 22-34 years). PET was performed with 18F-fluoro-2-deoxy-D-glucose while the subjects were in the "resting" state (eyes covered and ears plugged with cotton). The PET scans were normalized to a common brain volume after superimposing them on the subjects' tissue segmented magnetic resonance scans. Analysis showed that rCMRglc in the absence of a PVE correction was significantly less in the older group in insular, frontal, superior temporal cortical, and thalamic regions. Statistical significant differences in rCMRglc, however, were absent after the PVE correction. Thus, statistically significant age reductions in regional brain glucose metabolism, corrected for brain atrophy, are not detectable in healthy normotensive men scanned while in the resting state. © 2004 Elsevier Inc. All rights reserved.
• Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., Saunders, A. M., & Hardy, J. (2004). Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proceedings of the National Academy of Sciences of the United States of America, 101(1), 284-289.
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  PMID: 14688411;PMCID: PMC314177;Abstract: Fluorodeoxyglucose positron emission tomography (PET) studies have found that patients with Alzheimer's dementia (AD) have abnormally low rates of cerebral glucose metabolism in posterior cingulate, parietal, temporal, and prefrontal cortex, We previously found that cognitively normal, late-middle-aged carriers of the apolipoprotein E ε4 allele, a common susceptibility gene for late-onset Alzheimer's dementia, have abnormally low rates of glucose metabolism in the same brain regions as patients with probable AD. We now consider whether ε4 carriers have these regional brain abnormalities as relatively young adults. Apolipoprotein E genotypes were established in normal volunteers 20-39 years of age. Clinical ratings, neuropsychological tests, magnetic resonance imaging, and PET were performed in 12 ε4 heterozygotes, all with the ε3/ε4 genotype, and 15 noncarriers of the ε4 allele, 12 of whom were individually matched for sex, age, and educational level. An automated algorithm was used to generate an aggregate surface-projection map that compared regional PET measurements in the two groups. The young adult ε4 carriers and noncarriers did not differ significantly in their sex, age, educational level, clinical ratings, or neuropsychological test scores. Like previously studied patients with probable AD and late-middle-aged ε4 carriers, the young ε4 carriers had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex. Carriers of a common Alzheimer's susceptibility gene have functional brain abnormalities in young adulthood, several decades before the possible onset of dementia.
• Teipel, S. J., Alexander, G. E., Schapiro, M. B., Möller, H., Rapoport, S. I., & Hampel, H. (2004). Age-related cortical grey matter reductions in non-demented Down's syndrome adults determined by MRI with voxel-based morphometry. Brain, 127(4), 811-824.
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  PMID: 14985261;Abstract: Ageing in Down's syndrome is accompanied by amyloid and neurofibrillary pathology the distribution of which replicates pathological features of Alzheimer's disease. With advancing age, an increasing proportion of Down's syndrome subjects >40 years old develop progressive cognitive impairment, resembling the cognitive profile of Alzheimer's disease. Based on these findings, Down's syndrome has been proposed as a model to study the predementia stages of Alzheimer's disease. Using an interactive anatomical segmentation technique and volume-of-interest measurements of MRI, we showed recently that non-demented Down's syndrome adults had significantly reduced hippocampus, entorhinal cortex and corpus callosum sizes with increasing age. In this study, we applied the automated and objective technique of voxel-based morphometry, implemented in SPM99, to the analysis of structural MRI from 27 non-demented Down's syndrome adults (mean age 41.1 years, 15 female). Regional grey matter volume was decreased with advancing age in bilateral parietal cortex (mainly the precuneus and inferior parietal lobule), bilateral frontal cortex with left side predominance (mainly middle frontal gyrus), left occipital cortex (mainly lingual cortex), right precentral and left postcentral gyrus, left transverse temporal gyrus, and right parahippocampal gyrus. The reductions were unrelated to gender, intracranial volume or general cognitive function. Grey matter volume was relatively preserved in subcortical nuclei, periventricular regions, the basal surface of the brain (bilateral orbitofrontal and anterior temporal) and the anterior cingulate gyrus. Our findings suggest grey matter reductions in allocortex and association neocortex in the predementia stage of Down's syndrome. The most likely substrate of these changes is alterations or loss of allocortical and neocortical neurons due to Alzheimer's disease-type pathology.
• Teipel, S. J., Bayer, W., Alexander, G. E., Bokde, A. L., Zebuhr, Y., Teichberg, D., Müller-Spahn, F., Schapiro, M. B., Möller, H., Rapoport, S. I., & Hampel, H. (2003). Regional pattern of hippocampus and corpus callosum atrophy in Alzheimer's disease in relation to dementia severity: Evidence for early neocortical degeneration. Neurobiology of Aging, 24(1), 85-94.
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  PMID: 12493554;Abstract: We used volumetric MRI and analysis of areas under receiver operating characteristic (ROC) curves to directly compare the extent of hippocampus-amygdala formation (HAF) and corpus callosum atrophy in patients with Alzheimer's disease (AD) in different clinical stages of dementia. Based on neuropathological studies, we hypothesized that HAF atrophy, representing allocortical neuronal degeneration, would precede atrophy of corpus callosum, representing loss of neocortical association neurons, in early AD. HAF and corpus callosum sizes were significantly reduced in 27 AD patients (37% and 16%, respectively) compared to 28 healthy controls. In mildly- and moderately-demented AD patients, the ROC derived index of atrophy was greater for HAF volume than for total corpus callosum area. The index of atrophy of posterior corpus callosum was not significantly different from HAF at mild, moderate or severe stages of dementia. In conclusion, these findings suggest a characteristic regional pattern of allocortical and neocortical neurodegeneraton in AD. Our data indicate that neuronal loss in parietotemporal cortex (represented by atrophy of corpus callosum splenium) may occur simultaneously with allocortical neurodegeneration in mild AD. Moreover, ROC analysis may provide a statistical framework to determine atrophy patterns of different brain structures in neurodegenerative diseases in vivo. © 2002 Elsevier Science Inc. All rights reserved.
• Teipel, S. J., Schapiro, M. B., Alexander, G. E., Krasuski, J. S., Horwitz, B., Hoehne, C., Möller, H., Rapoport, S. I., & Hampel, H. (2003). Relation of corpus callosum and hippocampal size to age in nondemented adults with Down's syndrome. American Journal of Psychiatry, 160(10), 1870-1878.
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  PMID: 14514503;Abstract: Objective: Aging in Down's syndrome is accompanied by amyloid and neurofibrillary pathology, the regional and laminar distribution of which resembles pathological changes seen in Alzheimer's disease. Previous studies using magnetic resonance imaging (MRI) demonstrated age-related atrophy of medial temporal lobe structures in nondemented older subjects with Down's syndrome, reflecting early allocortical pathology. Corpus callosum atrophy has been established as a marker of neocortical neuronal loss in Alzheimer's disease. This study investigated whether atrophy of the corpus callosum and hippocampus occurs in nondemented subjects with Down's syndrome and compared the degree of age-related atrophy between these structures. Method: Hippocampus and corpus callosum measures were obtained from volumetric T1-weighted MRI scans of 34 non-demented Down's syndrome adults (mean age=41.6 years, 17 women) and 31 healthy comparison subjects (mean age= 41.8 years, 14 women). Results: Down's syndrome subjects had smaller corpus callosum areas and hippocampal volumes relative to age-matched healthy comparison subjects, even after age and total intracranial volume were controlled. There was an age-related decrease of corpus callosum area (most prominent in posterior regions) and hippocampal volume in the Down's syndrome group. The degree of the age effect was comparable between the total corpus callosum and hippocampus, and corpus callosum size was correlated with cognitive performance in the Down's syndrome subjects. There was no correlation between age and corpus callosum or hippocampal size in the comparison group. Conclusions: Comparable decrease of corpus callosum and hippocampal size with age in nondemented subjects with Down's syndrome suggests that neocortical neuronal alterations accompany allocortical changes in the predementia phase of Down's syndrome.
• Alexander, G. E., Chen, K., Pietrini, P., Rapoport, S. I., & Reiman, E. M. (2002). Longitudinal PET evaluation of cerebral metabolic decline in dementia: A potential outcome measure in Alzheimer's disease treatment studies. American Journal of Psychiatry, 159(5), 738-745.
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  PMID: 11986126;Abstract: Objective: It is well established that regional cerebral metabolic rates for glucose assessed by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in patients with Alzheimer's disease in the mental resting state (eyes and ears covered) provide a sensitive, in vivo metabolic index of Alzheimer's disease dementia. Few studies, however, have evaluated longitudinal declines in regional cerebral glucose metabolism in patients with dementia caused by Alzheimer's disease. In addition, the available studies have not used recently developed brain mapping algorithms to characterize the progression of Alzheimer's disease throughout the brain, and none considered the statistical power of regional cerebral glucose metabolism in testing the ability of treatments to attenuate the progression of dementia. Method: The authors used FDG PET and a brain mapping algorithm to investigate cross-sectional reductions in regional cerebral glucose metabolism, longitudinal decline in regional cerebral glucose metabolism after a 1-year follow-up, and the power of this method to evaluate treatments for Alzheimer's disease in patients with mild to moderate dementia. PET scans were initially acquired in 14 patients with Alzheimer's disease and 34 healthy comparison subjects of similar age and sex. Repeat scans were obtained in the patients 1 year later. Power analyses for voxels showing maximal decline over the 1-year period in regional cerebral glucose metabolism (mg/100 g per minute) were computed to estimate the sample sizes needed to detect a significant treatment response in a 1-year, double-blind, placebo-controlled treatment study. Results: The patients with Alzheimer's disease had significantly lower glucose metabolism than healthy comparison subjects in parietal, temporal, occipital, frontal, and posterior cingulate cortices. One year later, the patients with Alzheimer's disease had significant declines in glucose metabolism in parietal, temporal, frontal, and posterior cingulate cortices. Using maximal glucose metabolism reductions in the left frontal cortex, we estimated that as few as 36 patients per group would be needed to detect a 33% treatment response with one-tailed significance of p≤0.005 and 80% power in a 1-year, double-blind, placebo-controlled treatment study. Conclusions: These findings indicate that brain metabolism as assessed by FDG PET during mental rest is a sensitive marker of disease progression in Alzheimer's disease over a 1-year period. These findings also support the feasibility of using FDG PET as an outcome measure to test the ability of treatments to attenuate the progression of Alzheimer's disease.
• Caselli, R. J., Hentz, J. G., Osborne, D., Graff-Radford, N. R., Barbieri, C. J., Alexander, G. E., Hall, G. R., Reiman, E. M., Hardy, J., & Saunders, A. M. (2002). Apolipoprotein E and intellectual achievement. Journal of the American Geriatrics Society, 50(1), 49-54.
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  PMID: 12028246;Abstract: OBJECTIVES: To determine whether apolipoprotein E (apo E) genotype influences intellectual achievement in cognitively normal individuals. DESIGN: Between 1994 and 1999 we performed apo E testing on 1,000 self-described cognitively normal residents of Maricopa County and detailed neuropsychological testing on a subset of 250. SETTING: Tertiary care academic medical center. PARTICIPANTS: Cognitively normal adults genotyped for apo E. MEASUREMENTS: Measures of intellectual background included years of education and a demographically based estimate of intellectual capacity (demographic intellectual quotient (DIQ)). Measures of intellectual achievement, which included Wechsler Adult Intelligence Scale revised (WAIS-R), information (WAISI), and vocabulary (WAISV) scores, occupational intellectual requirements (OIR), and census-derived estimates of household income, were compared between apo E genetic subgroups while adjusting for intellectual background and demographic variables. RESULTS: WAISI, WAISV, OIR, and income correlated with age, sex, education, and DIQ, but after controlling for these variables there were no clinically significant differences between apo E-e4 homozygotes and noncarriers on any measure. CONCLUSIONS: No clinically significant differences between genotypes were observed for the effects of education and DIQ on WAISI, WAISV, OIR, or income, although a larger sample size would be required to exclude smaller, clinically insignificant differences.
• Caselli, R. J., Reiman, E. M., Hentz, J. G., Osborne, D., Alexander, G. E., & Boeve, B. F. (2002). A distinctive interaction between memory and chronic daytime somnolence in asymptomatic APOE e4 homozygotes. Sleep, 25(4), 447-453.
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  PMID: 12071547;Abstract: Study Objectives: To correlate memory measures with a trait measure of chronic daytime somnolence in cognitively normal individuals with different gene doses of the apolipoprotein E (APOE) e4 allele, a common Alzheimer's disease susceptibility gene. Design: Cross-sectional, exploratory study of cognitive abilities in APOE e4 homozygotes (HMZ) (n=42), heterozygotes (HTZ), (n=42) and noncarriers (NC) (n=42) who are matched for age, gender, educational level, and family history of dementia. Setting: Tertiary care academic medical center Participants: Cognitively normal residents of Maricopa County, Arizona who are 30-70 years of age, genotyped for APOE, and have no history of a sleep disorder Interventions: N/A Measurements: Epworth Sleepiness Scale (ESS) and a battery of neuropsychological tests Results: Age, education, gender, and insomnia complaints did not significantly differ among groups. Despite normal baseline memory scores, memory declined with increasing ESS on all eight memory measures in the HMZ, two of eight in the HTZ, and one of eight in the NC. Differences between HMZ and NC on the slope of memory decline with increasing ESS reached statistical significance on two verbal memory measures, AVLT Long-Term Memory (p=0.048) and Percent Delayed Recall (p=0.035). Conclusions: Chronic daytime somnolence is associated with a distinctive decline in verbal memory in cognitively normal APOE e4 HMZ, a group at particularly high risk of Alzheimer's disease. Additional studies are needed to confirm these exploratory findings and to determine the effects of acute somnolence on cognition in these genetic subgroups.
• Hampel, H., Teipel, S. J., Alexander, G. E., Pogarell, O., Rapoport, S. I., & Möller, H. (2002). In vivo imaging of region and cell type specific neocortical neurodegeneration in Alzheimer's disease: Perspectives of MRI derived corpus callosum measurement for mapping disease progression and effects of therapy. Evidence from studies with MRI, EEG and PET. Journal of Neural Transmission, 109(5-6), 837-855.
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  PMID: 12111472;Abstract: Neuropathological studies in Alzheimer's disease (AD) indicate specific loss of layer III and V large pyramidal neurons in association cortex. These neurons give rise to long cortico-cortical connections, projecting through the corpus callosum, in an anterior-posterior topology. Based on these findings we hypothesized that regional corpus callosum atrophy may be a potential in vivo marker for neocortical neuronal loss in AD. To evaluate this hypothesis, we developed a method to measure cross-sectional area of the corpus callosum and of five corpus callosum subregions on midsagittal magnetic resonance imaging scans (MRI). In a subsequent series of six experimental studies using MRI, 18FDG-PET and EEG, we investigated the relation of white matter hyperintensities (WMH) to corpus callosum size and correlated regional pattern of corpus callosum atrophy with regional cortical metabolic decline as well as intracortical coherencies. Mean total corpus callosum area was reduced significantly in AD patients compared to healthy age-matched controls, with the greatest changes in the rostrum and the splenium and relative sparing of the truncus. The regional pattern of corpus callosum atrophy was independent of WMH load and correlated significantly with pattern of regional metabolic decline measured with 18FDG-PET, the degree of cognitive impairment and regional decline of bilateral intracortical-coherency in EEG in AD patients. We further found that hippocampus atrophy, as a marker of early allocortical degeneration, was more pronounced than total corpus callosum atrophy in mild stages of AD. Regional corpus callosum atrophy in mild disease, however, suggested early neocortical degeneration in AD. In a longitudinal study, AD patients showed significantly greater rates of corpus callosum atrophy than controls. Rates of atrophy correlated with progression of clinical dementia severity in AD. Our results indicate that regional corpus callosum atrophy in AD patients represents the loss of callosal efferent neurons in corresponding regions of the neocortex. As these neurons are a subset of cortico-cortical projecting neurons, region-specific corpus callosum atrophy may serve as a marker of progressive neocortical disconnection in AD. In combination with measurement of hippocampal atrophy, assessment of corpus callosum atrophy over time in individual patients is useful to evaluate effects on brain structure of currently developed drugs, thought to slow or modify AD progression.
• Hampel, H., Teipel, S. J., Bayer, W., Alexander, G. E., Schwarz, R., Schapiro, M. B., Rapoport, S. I., & Möller, H. (2002). Age transformation of combined hippocampus and amygdala volume improves diagnostic accuracy in Alzheimer's disease. Journal of the Neurological Sciences, 194(1), 15-19.
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  PMID: 11809161;Abstract: Objective: The specificity of magnetic resonance imaging (MRI)-based hippocampal measurements in detecting Alzheimer's disease (AD) pathology is reduced by an age-related reduction of the hippocampus volume. We propose an adjustment for this age effect to increase the diagnostic accuracy of hippocampal volumes in AD. Method: Using an orthogonal rotational transformation of the coordinate system, values of MRI-determined volumes of hippocampus-amygdala formation (HAF) were transformed according to the age effect in 27 AD patients and 28 age- and sex-matched healthy control subjects. Results: The age transformation increased the diagnostic accuracy of HAF volumes in the study sample and in an independent sample from the literature. The age-transformed HAF volume predicted AD in a subject with mild cognitive impairment (MCI) with later biopsy-confirmed AD. Conclusion: Age transformation may provide an easily applicable method to increase the clinical diagnostic accuracy of hippocampal measurements by considering the effect of aging on hippocampus volume. Copyright © 2002 Elsevier Science B.V.
• Krasuski, J. S., Alexander, G. E., Horwitz, B., Rapoport, S. I., & Schapiro, M. B. (2002). Relation of medial temporal lobe volumes to age and memory function in nondemented adults with Down's syndrome: Implications for the prodromal phase of Alzheimer's disease. American Journal of Psychiatry, 159(1), 74-81.
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  PMID: 11772693;Abstract: Objective: In Down's syndrome (trisomy 21), a dementia syndrome occurs that is phenotypically similar to Alzheimer's disease; the initial phase is characterized by memory loss. The authors used an in vivo structural technique in the predementia stage of Alzheimer's disease in adults with Down's syndrome to investigate whether atrophy of medial temporal lobe structures occurs in these subjects and whether volumes of these structures correlate specifically with performance on memory tests. Method: The subjects were 34 nondemented Down's syndrome adults (mean age=41.6 years, 17 women and 17 men) and 33 healthy comparison subjects (mean age=41.3, 15 women and 18 men). By using T 1-weighted magnetic resonance imaging slices taken perpendicular to the Sylvian fissure, volumes of the hippocampus, amygdala, anterior and posterior parahippocampal gyrus, and temporal pole CSF were measured in both hemispheres. These data were normalized to the total intracranial volume. Results: For Down's syndrome, smaller volumes of the right and left amygdala, hippocampus, and posterior parahippocampal gyrus were significantly associated with greater age; this association was not seen in the anterior parahippocampal gyrus. The amygdala and hippocampus volumes were positively correlated with memory measures. For the comparison group, there was no relationship between volume and age in any region. Conclusions: In the predementia phase of Down's syndrome, significant volume changes in medial temporal lobe structures occur with age and are related to memory. These structures are affected early in Alzheimer's disease in Down's syndrome, and their evaluation may help identify people in the preclinical stages of Alzheimer's disease.
• Lin, L., Chen, K., Alexander, G. E., Jiping, H. e., & Reiman, E. M. (2002). Adaptive smoothing strategies to eliminate the scalp/ventricle artifact in statistical parametric mapping. Annual International Conference of the IEEE Engineering in Medicine and Biology - Proceedings, 2, 1039-1040.
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  Abstract: In positron emission tomographic (PET) or magnetic resonance imaging (MRI) neuroimaging studies, spatial smoothing technique is commonly applied to increase the signal to noise ratio and to condition neoroimaging data for subsequent statistical analysis, and to reduce errors associated with registration or spatial normalizations. Usually, the smoothing step is applied to the images without any masking. Thus, some artifacts adjacent but outside of the brain will enter the brain volume. Masking the brain volume before smoothing has been suggested as one way to eliminate the introduced artifact, but it will introduce zero-in (intensities within-mask voxels are reduced) and nonzero-out (intensities outside the mask become non-zero) artifacts. Here we proposed an adaptive smoothing method to reduce the influence of such artifacts. Unlike the conventional smoothing method, the adaptive strategy did not introduce artificial addition (due to nonzero-out artifact) and deletion (due to zero-in), suggesting that such adaptive smoothing methods may be helpful in reducing the influence of non-brain tissue in the analysis of neuroimaging data.
• Teipel, S. J., Bayer, W., Alexander, G. E., Zebuhr, Y., Teichberg, D., Kulic, L., Schapiro, M. B., Möller, H., Rapoport, S. I., & Hampel, H. (2002). Progression of corpus callosum atrophy in Alzheimer disease. Archives of Neurology, 59(2), 243-248.
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  PMID: 11843695;Abstract: Background: Atrophy of the corpus callosum in the absence of primary white matter degeneration reflects loss of intracortical projecting neocortical pyramidal neurons in Alzheimer disease (AD). Objectives: To determine individual rates of atrophy progression of the corpus callosum in patients with AD and to correlate rates of atrophy progression with clinical disease severity and subcortical disease. Methods: Magnetic resonance imaging-derived measurements of corpus callosum size were studied longitudinally in 21 patients clinically diagnosed as having AD (mean observation time, 17.0 ± 8.5 months) and 10 age-and sex-matched healthy controls (mean observation time, 24.1 ± 6.8 months). Results: Corpus callosum size was significantly reduced in AD patients at baseline. Annual rates of atrophy of total corpus callosum, splenium, and rostrum were significantly larger in AD patients (-7.7%, -12.1%, and -7.3%, respectively) than in controls (-0.9%, -1.5%, and 0.6%, respectively). Rates of atrophy of the corpus callosum splenium were correlated with progression of dementia severity in AD patients (p = 0.52, P
• Bokde, A. L., Pietrini, P., Ibáñez, V., Furey, M. L., Alexander, G. E., Graff-Radford, N., Rapoport, S. I., Schapiro, M. B., & Horwitz, B. (2001). The effect of brain atrophy on cerebral hypometabolism in the visual variant of Alzheimer disease. Archives of Neurology, 58(3), 480-486.
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  PMID: 11255453;Abstract: Background: Brain glucose metabolic rates measured by positron emission tomography can be more affected by partial volume effects in Alzheimer disease (AD) than in healthy aging because of disease-associated brain atrophy. Objective: To determine whether the distinct distribution of cerebral metabolic lesions in patients with the visual variant of AD (AD + VS) represents a true index of neuronal/synaptic dysfunction or is the consequence of brain atrophy. Setting: Government research hospital. Design: Resting cerebral metabolic rate for glucose was measured with positron emission tomography in a cross-sectional study of AD and AD + VS groups and in healthy control subjects. Segmented magnetic resonance images were used to correct for brain atrophy. Patients: Patients with AD + VS had prominent visual and visuospatial symptoms. There were 15 patients with AD, 10 with AD + VS, and 37 age-matched control subjects. Main Outcome Measure: Measurement of the rate of cerebral glucose metabolism. Results: Before atrophy correction, the AD + VS group, compared with the control subjects, showed hypometabolism in primary and extrastriate visual areas and in parietal and superior temporal cortical areas. Compared with the AD group, the AD + VS group showed hypometabolism in visual association areas. After atrophy correction, hypometabolism remained significantly different between patients and controls and between the 2 AD groups. Conclusions: The reductions in cerebral hypometabolism represent a true loss of functional activity and are not simply an artifact caused by brain atrophy. The different patterns of hypometabolism indicate the differential development of the lesions between the AD and AD + VS groups.
• Caselli, R. J., Osborne, D., Reiman, E. M., Hentz, J. G., Barbieri, C. J., Saunders, A. M., Hardy, J., Graff-Radford, N. R., Hall, G. R., & Alexander, G. E. (2001). Preclinical cognitive decline in late middle-aged asymptomatic apolipoprotein E-e4/4 homozygotes: A replication study. Journal of the Neurological Sciences, 189(1-2), 93-98.
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  PMID: 11535238;Abstract: In a previous cross-sectional study of 100 asymptomatic individuals aged 49-69, we reported age-related decline in immediate and delayed memory that was steeper in apolipoprotein E (apoE)-e4/4 homozygotes than in members of other genetic subgroups. These findings were preliminarily based upon the statistical problem of multiple comparisons. We therefore sought to replicate these findings in a new cohort. From 1998 to 2000, 80 asymptomatic residents of Maricopa County, AZ were recruited through newspaper ads. 20 apoE-e4/4 homozygotes, 20 e3/4 heterozygotes, and 40 e4 noncarriers were matched (1:1:2) by age, gender, and years of education. All had normal neurologic and psychiatric examinations, including Folstein minimental status exam (MMSE) and Hamilton depression scale, and underwent a battery of neuropsychological tests identical to those in our previous study. The groups were well-matched for age (55.9±5.9 years), gender (60% women), and education (15.9±2.2 years), and were demographically similar to our previous cohort. Complex figure test recall was lower in e3/4 heterozygotes than noncarriers, but there was no significant difference between e4/4 homozygotes and noncarriers. There were no other significant differences in mean test scores between groups, but Wechsler adult intelligence scale-revised (WAIS-R) digit span showed a significant negative correlation with age in the e4/4 homozygote group relative to e4 noncarriers (p=0.008) as we had found in our previous study. In conclusion, we found a significant negative correlation of WAIS-R digit span with age in apoE-e4/4 homozygotes relative to e4 noncarriers in two separate cohorts, possibly reflecting an age-related effect on frontal lobe function in this genetic subgroup. Copyright © 2001 Elsevier Science B.V.
• Huang, W., Alexander, G. E., Chang, L., Shetty, H. U., Krasuski, J. S., Rapoport, S. I., & Schapiro, M. B. (2001). Brain metabolite concentration and dementia severity in Alzheimer's disease: A ¹H MRS study. Neurology, 57(4), 626-632.
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  PMID: 11524470;Abstract: Objective: 1H-MRS studies have shown abnormalities in brain levels of myo-inositol (mI) and N-acetyl aspartate (NAA) in AD, but the relation of these abnormalities with dementia severity was not examined. The authors sought to determine whether altered brain levels of mI and other metabolites occur in mild AD and whether they change as dementia severity worsens. Methods: The authors used 1H-MRS with external standards to measure absolute brain concentrations of mI, NAA, total creatine (Cr), and choline (Cho)-containing compounds in 21 subjects with AD and 17 age- and sex-matched controls in occipital and left and right parietal regions. Results: Concentrations of NAA were significantly decreased, whereas mI and Cr concentrations were significantly increased in all three brain regions in subjects with AD compared with controls. Higher concentrations of mI and Cr occurred even in mild AD. A discriminant analysis of the 1H-MRS data combined with CSF volume measurements distinguished subjects with AD, ranging from mild to severe dementia, from controls with 100% correct classification. NAA concentration, though not other metabolites, was positively correlated with Mini-Mental State Examination score. Conclusion: The measurements with 1H-MRS of absolute metabolite concentrations in the neocortex showed abnormal concentrations of brain metabolites in AD; these metabolite concentrations do not necessarily correlate with disease severity. Although changes in myo-inositol and creatine occur in the early stages of AD, abnormalities of N-acetyl aspartate do not occur in mild AD but progressively change with dementia severity. Further, subjects with mild AD can be differentiated from controls with 1H-MRS.
• Reiman, E. M., Caselli, R. J., Alexander, G. E., & Chen, K. (2001). Tracking the decline in cerebral glucose metabolism in persons and laboratory animals at genetic risk for Alzheimer's disease. Clinical Neuroscience Research, 1(3), 194-206.
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  Abstract: Brain imaging methods can be used to track declines in the cerebral metabolic rate for glucose (CMRgl) in the absence of symptoms in persons and laboratory animals at risk for Alzheimer's disease (AD). In fluorodeoxyglucose (FDG) positron emission tomography studies, late middle-aged, cognitively normal carriers of a common Alzheimer's susceptibility gene (the apolipoprotein E ε4 allele) had progressively reduced CMRgl in the same regions of the brain as patients with Alzheimer's dementia. In an FDG autoradiography study, transgenic mice carrying two copies of an Alzheimer's gene (a mutation in the amyloid precursor protein gene) had a similar CMRgl pattern, including progressively reduced CMRgl in the posterior cingulate cortex. Functional brain imaging techniques could be used to help bridge the gap between studies of patients with Alzheimer's dementia, cognitively normal persons at genetic risk for AD, and suitable laboratory animals. By providing a potential indicator of AD, these techniques could help clarify disease mechanisms and screen candidate treatments in at least some transgenic mice, and they could efficiently test the potential of candidate Alzheimer's prevention therapies in persons at genetic risk for the disorder. © 2001 Association for Research in Nervous and Mental Disease. Published by Elsevier Science B.V. All rights reserved.
• Reiman, E. M., Caselli, R. J., Chen, K., Alexander, G. E., Bandy, D., & Frost, J. (2001). Declining brain activity in cognitively normal apolipoprotein E ε4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 98(6), 3334-3339.
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  PMID: 11248079;PMCID: PMC30654;Abstract: Cross-sectional positron emission tomography (PET) studies find that cognitively normal carriers of the apolipoprotein E (APOE) ε4 allele, a common Alzheimer's susceptibility gene, have abnormally low measurements of the cerebral metabolic rate for glucose (CMRgl) in the same regions as patients with Alzheimer's dementia. In this article, we characterize longitudinal CMRgl declines in cognitively normal ε4 heterozygotes, estimate the power of PET to test the efficacy of treatments to attenuate these declines in 2 years, and consider how this paradigm could be used to efficiently test the potential of candidate therapies for the prevention of Alzheimer's disease. We studied 10 cognitively normal ε4 heterozygotes and 15 ε4 noncarriers 50-63 years of age with a reported family history of Alzheimer's dementia before and after an interval of approximately 2 years. The ε4 heterozygotes had significant CMRgl declines in the vicinity of temporal, posterior cingulate, and prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus, and these declines were significantly greater than those in the ε4 noncarriers. In testing candidate primary prevention therapies, we estimate that between 50 and 115 cognitively normal ε4 heterozygotes are needed per active and placebo treatment group to detect a 25% attenuation in these CMRgl declines with 80% power and P = 0.005 in 2 years. Assuming these CMRgl declines are related to the predisposition to Alzheimer's dementia, this study provides a paradigm for testing the potential of treatments to prevent the disorder without having to study thousands of research subjects or wait many years to determine whether or when treated individuals develop symptoms.
• Silverman, D. H., Small, G. W., Chang, C. Y., Lu, C. S., Kung, M., Chen, W., Czernin, J., Rapoport, S. I., Pietrini, P., Alexander, G. E., Schapiro, M. B., Jagust, W. J., Hoffman, J. M., Welsh-Bohmer, K., Alavi, A., Clark, C. M., Salmon, E., Leon, M. D., Mielke, R., , Cummings, J. L., et al. (2001). Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome. Journal of the American Medical Association, 286(17), 2120-2127.
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  PMID: 11694153;Abstract: Context: Deficits in cerebral glucose utilization have been identified in patients with cognitive dysfunction attributed to various disease processes, but their prognostic and diagnostic value remains to be defined. Objective: To assess the sensitivity and specificity with which cerebral metabolic patterns at a single point in time forecast subsequent documentation of progressive dementia. Design, Setting, and Patients: Positron emission tomography (PET) studies of [18F]fluorodeoxyglucose in 146 patients undergoing evaluation for dementia with at least 2 years' follow-up for disease progression at the University of California, Los Angeles, from 1991 to 2000, and PET studies in 138 patients undergoing evaluation for dementia at an international consortium of facilities, with histopathological diagnoses an average of 2.9 years later, conducted from 1984 to 2000. Main Outcome Measures: Regional distribution of [18F]fluorodeoxyglucose in each patient, classified by criteria established a priori as positive or negative for presence of a progressive neurodegenerative disease in general and of Alzheimer disease (AD) specifically, compared with results of longitudinal or neuropathologic analyses. Results: Progressive dementia was detected by PET with a sensitivity of 93% (191/ 206) and a specificity of 76% (59/78). Among patients with neuropathologically based diagnoses, PET identified patients with AD and patients with any neurodegenerative disease with a sensitivity of 94% and specificities of 73% and 78%, respectively. The negative likelihood ratio of experiencing a progressive vs nonprogressive course over the several years following a single negative brain PET scan was 0.10 (95% confidence interval, 0.06-0.16), and the initial pattern of cerebral metabolism was significantly associated with the subsequent course of progression overall (P
• Carlin, D., Bonerba, J., Phipps, M., Alexander, G., Shapiro, M., & Grafman, J. (2000). Planning impairments in frontal lobe dementia and frontal lobe lesion patients. Neuropsychologia, 38(5), 655-665.
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  PMID: 10689042;Abstract: Patients with frontal lobe brain damage are reportedly impaired on tasks that require plan development and execution. In this study, we examined the performance of 15 patients diagnosed with frontal lobe dementia and 14 patients with focal frontal lobe lesions on the Tower of London planning task. Patients with frontal lobe dementia committed a significantly higher number of rule violations, made more moves, and demonstrated longer solution time latencies compared to their matched controls. Patients with frontal lobe lesions demonstrated significantly delayed solution times and also made more moves compared to their matched controls. Frontal lobe lesion patient performance suggests an impairment in execution-related processes, while frontal lobe dementia patients appear to be impaired in both plan development and execution. Despite these findings, the identification of a specific cognitive impairment that induces these planning problems remains elusive. (C) 2000 Elsevier Science Ltd.
• Furey, M. L., Pietrini, P., Alexander, G. E., Mentis, M. J., Szczepanik, J., Shetty, U., Greig, N. H., Holloway, H. W., Schapiro, M. B., & Freo, U. (2000). Time course of pharmacodynamic and pharmacokinetic effects of physostigmine assessed by functional brain imaging in humans. Pharmacology Biochemistry and Behavior, 66(3), 475-481.
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  PMID: 10899358;Abstract: In imaging studies of brain functions using pharmacological probes, identification of the time point at which central effects of intravenously infused drugs become stable is crucial to separate the effects of experimental variables from the concomitant changes in drug effects over time. We evaluated the time courses of the pharmacokinetics and pharmacodynamics, including butyrylcholinesterase inhibition and central neural responses, of physostigmine in healthy young subjects. Ten positron emission tomography (PET) scans that alternated between a rest condition (eyes open, ears unplugged) and a working memory for faces (WM) task were acquired in healthy subjects. Subjects in the drug group received a saline infusion for the first two scans, providing a baseline measure, then received an infusion of physostigmine for all subsequent scans. Subjects in the control group received a placebo infusion of saline for all scans. Physostigmine plasma levels and percent butyrylcholinesterase inhibition increased over time (p < 0.0001), and both became stable by 40 min. Physostigmine decreased reaction time (RT) (p = 0.0005), and this effect was detected after 20 min of infusion and stable thereafter. Physostigmine also decreased regional cerebral blood flow (rCBF) in right prefrontal cortex during task (p = 0.0002), and this effect was detected after 40 min of infusion and stable thereafter. No change in RT or rCBF was observed in the control group. These results indicate that a 40-min infusion of physostigmine was necessary to obtain stable central effects. More generally, we have demonstrated that experimental effects can vary with time, especially during the initial phases of a drug infusion, indicating that it is critical that these changes are controlled. Copyright (C) 2000 Elsevier Science Inc.
• Furey, M. L., Pietrini, P., Alexander, G. E., Schapiro, M. B., & Horwitz, B. (2000). Cholinergic enhancement improves performance on working memory by modulating the functional activity in distinct brain regions: A positron emission tomography regional cerebral blood flow study in healthy humans. Brain Research Bulletin, 51(3), 213-218.
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  PMID: 10718513;Abstract: Previously, we have shown that physostigmine, an acetylcholinesterase inhibitor, improved performance on a working memory for faces task, as reflected by reduced reaction time (RT), and reduced task-specific regional cerebral blood flow (rCBF) in right prefrontal cortex and, further, that these reductions in RT and right frontal rCBF were significantly correlated. Here we investigated the relation between the effects of physostigmine on task performance and task-specific functional brain response throughout the cortex by examining correlations between physostigmine-related changes in rCBF in all brain areas and changes in RT. In subjects who received an infusion of physostigmine, reduced RT correlated (p < 0.001) positively with reduced rCBF in right frontal cortex, left temporal cortex, anterior cingulate, and left hippocampus; and correlated with increased rCBF in medial occipital visual cortex. In subjects who received a placebo infusion of saline, no significant correlations between changes in RT and cortical rCBF were observed. The results show that cholinergically induced improvements in working memory performance are related to alterations in neural activity in multiple cortical regions, including increased neural activity in regions associated with early perceptual processing and decreased neural activity in regions associated with attention, memory encoding, and memory maintenance. Copyright (C) 2000 Elsevier Science Inc.
• Hampel, H., Teipel, S. J., Alexander, G. E., Horwitz, B., Pietrini, P., Hippius, H., Möller, H., Schapiro, M. B., & Rapoport, S. I. (2000). Corpus callosum measurement as an in vivo indicator for neocortical neuronal integrity, but not white matter pathology, in Alzheimer's disease. Annals of the New York Academy of Sciences, 903, 470-476.
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  PMID: 10818540;
• Levine, B. K., Beason-Held, L., Purpura, K. P., Aronchick, D. M., Optican, L. M., Alexander, G. E., Horwitz, B., Rapoport, S. I., & Schapiro, M. B. (2000). Age-related differences in visual perception: A PET study. Neurobiology of Aging, 21(4), 577-584.
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  PMID: 10924775;Abstract: To assess age-related differences in cortical activation during form perception, two classes of visual textures were shown to young and older subjects undergoing positron emission tomography (PET). Subjects viewed even textures that were rich in rectangular blocks and extended contours and random textures that lacked these organized form elements. Within-group significant increases in regional cerebral blood flow (rCBF) during even stimulation relative to random stimulation in young subjects were seen in occipital, inferior and medial temporal regions, and cerebellum, and in older subjects, in posterior occipital and frontal regions. Group by texture type interactions revealed significantly smaller rCBF increases in older subjects relative to young in occipital and medial temporal regions. These results indicate that young subjects activate the occipitotemporal pathway during form perception, whereas older subjects activate occipital and frontal regions. The between-group differences suggest that age-related reorganization of cortical activation occur during early visual processes in humans. (C) 2000 Elsevier Science Inc.
• Parasuraman, R., Greenwood, P. M., & Alexander, G. E. (2000). Alzheimer disease constricts the dynamic range of spatial attention in visual search. Neuropsychologia, 38(8), 1126-1135.
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  PMID: 10838147;Abstract: A cued visual search task was used to examine the dynamic range over which spatial attention affects target identification during visual search. Precues varied in validity (valid, invalid, or neutral) and in precision (cue size) of target localization. Participants were 'young-old' (65-74 years) and 'old-old' (75-85 years) elderly adults and individuals in the mild stage of dementia of the Alzheimer type (DAT). For all participants, search was speeded as the precision with which a precue surrounding the location of a subsequently appearing target increased (precue size decreased). The cue size effect was evident in both feature and conjunction search, but was greatly reduced in both old-old and DAT groups compared to the young-old. However, whereas all non-demented adults showed a progressive modulation of search efficiency over the entire range of cue sizes, the dynamic range of spatial attention was restricted to the most precise cue in the DAT group. The restriction in the dynamic range of spatial attention may represent an underlying component of the impairment in perceptual and memory functioning found in early-stage DAT. Copyright (C) 2000 Elsevier Science Ltd.
• Pietrini, P., Alexander, G. E., Furey, M. L., Dani, A., Mentis, M. J., Horwitz, B., Guazzelli, M., Schapiro, M. B., & Rapoport, S. I. (2000). Cerebral metabolic response to passive audiovisual stimulation in patients with Alzheimer's disease and healthy volunteers assessed by PET. Journal of Nuclear Medicine, 41(4), 575-583.
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  PMID: 10768555;Abstract: Alzheimer's disease is associated with reductions in resting-state brain metabolism, as measured by PET, progressing with dementia severity. The purpose of this study was to see to what extent brain regions with reduced resting-state metabolic rates in Alzheimer patients could be activated by a passive audiovisual stimulation test and to compare the result with activation in age-matched healthy volunteers. The extent of activation in Alzheimer's disease is considered to reflect the integrity of synaptic function, or inherent viability, and the potential responsiveness of the Alzheimer brain to drug therapy. Methods: Regional cerebral metabolic rates for glucose (rCMR(gic), in mg/100 g tissue/min) were measured in the resting state (eyes and ears covered) and during passive audiovisual stimulation (watching a movie) in 15 otherwise healthy Alzheimer patients of differing dementia severity (Mattis Dementia Rating Scale score, 23-128) and in 14 age- matched healthy volunteers (score, 141 ± 3) using PET with 2 sequential injections of FDG. Results: In the volunteers, audiovisual stimulation caused significant rCMR(glc) increases in visual and auditory cortical areas but significant decreases in frontal areas. In the mildly demented patients, rCMR(glc) responses were within 2 SDs of the mean in volunteers. However, the magnitude of the rCMR(glc) responses during stimulation declined significantly with dementia severity in the right occipitotemporal, right and left occipital association, and left calcarine cortical regions. Conclusion: Functional brain responsiveness, evaluated by a passive audiovisual stimulation paradigm with PET, is within normal limits in mildly demented Alzheimer patients but fails with worsening dementia severity. Declining responsiveness may account for the limited success of neurotransmitter replacement therapy in Alzheimer patients with moderate-to-severe dementia.
• Pietrini, P., Alexander, G. E., Furey, M. L., Hampel, H., & Guazzelli, M. (2000). The neurometabolic landscape of cognitive decline: In vivo studies with positron emission tomography in Alzheimer's disease. International Journal of Psychophysiology, 37(1), 87-98.
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  PMID: 10828377;Abstract: Alzheimer's disease, the most common form of dementia in the elderly, is characterized by the progressive, global and irreversible deterioration of cognitive abilities. The development of positron emission tomography (PET) methodologies has made it possible to study the in vivo brain metabolic correlates of human cognitive and behavioral functions. Moreover, as PET scan examinations can be repeated, the progression of the neuropathological process and its relation to cognitive dysfunction can be followed over time. In an effort to understand the changes in neural function that precede and accompany onset of dementia and their relation to clinical manifestations, in the last several years, we have conducted clinical, neuropsychological and brain metabolic studies in groups of Alzheimer's disease patients at different stages of dementia severity or with distinct clinical pictures and in populations at risk for developing the disease. Here, we discuss the main findings and implications obtained from these studies. Copyright (C) 2000 Elsevier Science B.V.
• Alexander, G. E., Mentis, M. J., D., J., Grady, C. L., Berman, K. F., Furey, M. L., Pietrini, P., Rapoport, S. I., Schapiro, M. B., & Moeller, J. R. (1999). Individual differences in PET activation of object perception and attention systems predict face matching accuracy. NeuroReport, 10(9), 1965-1971.
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  PMID: 10501542;Abstract: We sought to investigate how individual differences in the regional patterns of cerebral blood flow (rCBF) relate to task performance during the perceptual matching of faces. We analyzed rCBF data obtained by PET and H215O from nine young healthy, right-handed, adult males (mean age 29 ± 3 years) using a statistical model of regional covariance, the Sealed Subprofile Model (SSM). SSM analysis performed on a voxel-basis for scan substractions comparing face-matching and control tasks extracted two patterns whose subject expression in a multiple regression analysis was highly predictive of task accuracy (R2 = 0.87, p < 0.002). The pattern reflecting this linear combination was principally characterized by higher rCBF in regions of bilateral occipital and occipitotemporal cortex, right orbitofrontal cortex, left thalamus, basal ganglia, midbrain, and cerebellum with relatively lower rCBF in anterior cingulate, regions in bilateral prefrontal and temporal cortex, right thalamus, and right inferior parietal cortex. The results indicate that individual subject differences in face matching performance are specifically associated with the functional interaction of cortical and subcortical brain regions previously implicated in aspects of object perception and visual attentional processing.
• Dimitrov, M., Granetz, J., Peterson, M., Hollnagel, C., Alexander, G., & Grafman, J. (1999). Associative learning impairments in patients with frontal lobe damage. Brain and Cognition, 41(2), 213-230.
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  PMID: 10590820;Abstract: The performance of 18 frontal lobe lesion (FL) and 10 frontal lobe dementia (FLD) patients on an associative memory test was compared with the performance of their matched normal controls. The FL group was severely impaired on cued and free recall and was moderately impaired on a recognition condition. Left FL patients performed the poorest on the cued and free recall conditions. The FLD patients were moderately impaired on the free recall condition only but there was a subgroup of FLD patients with additional left temporal atrophy who appeared severely impaired on both cued and free recall. These findings indicate that both left frontal and temporal lobe damage can impair associative learning and that this impairment is more strikingly seen with free rather than cued recall.
• Giovacchini, G., Alexander, G. E., Furey, M. L., Ricciardi, E., Horwitz, B., Solaini, G., Guazzelli, M., Schapiro, M. B., Rapoport, S. I., & Pietrini, P. (1999). Brain metabolism at rest and during passive audiovisual stimulation in young and older healthy human subjects. NeuroImage, 9(6 PART II), S262.
• Huang, W., Alexander, G. E., Daly, E. M., Shetty, H. U., Krasuski, J. S., Rapoport, S. I., & Schapiro, M. B. (1999). High brain myo-inositol levels in the predementia phase of Alzheimer's disease in adults with Down's syndrome: A ¹H MRS study. American Journal of Psychiatry, 156(12), 1879-1886.
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  PMID: 10588400;Abstract: Objective: An extra portion of chromosome 21 in Down's syndrome leads to a dementia in later life that is phenotypically similar to Alzheimer's disease. Down's syndrome therefore represents a model for studying preclinical stages of Alzheimer's disease. Markers that have been investigated in symptomatic Alzheimer's disease are myo-inositol and N- acetylaspartate. The authors investigated whether abnormal brain levels of myo-inositol and other metabolites occur in the preclinical stages of Alzheimer's disease associated with Down's syndrome. Method: The authors used 1H magnetic resonance spectroscopy (MRS) with external standards to measure absolute brain metabolite concentrations in 19 nondemented adults with Down's syndrome and 17 age- and sex-matched healthy comparison subjects. Results: Concentrations of myo-inositol and choline-containing compounds were significantly higher in the occipital and parietal regions of the adults with Down's syndrome than in the comparison subjects. Within the Down's syndrome group, older subjects (42-62 years, N=11) had higher myo-inositol levels than younger subjects (28-39 years, N=8). Older subjects in both groups had lower N-acetylaspartate levels than the respective younger subjects, although this old-young difference was not greater in the Down's syndrome group. Conclusions: The approximately 50% higher level of myo-inositol in Down's syndrome suggests a gene dose effect of the extra chromosome 21, where the human osmoregulatory sodium/myo-inositol cotransporter gene is located. The even higher myoinositol level in older adults with Down's syndrome extends to the predementia phase earlier findings of high myo-inositol levels in symptomatic Alzheimer's disease.
• Keilp, J. G., Gorlyn, M., Alexander, G. E., Stern, Y., & Prohovnik, I. (1999). Cerebral blood flow patterns underlying the differential impairment in category vs letter fluency in Alzheimer's disease. Neuropsychologia, 37(11), 1251-1261.
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  PMID: 10530725;Abstract: Verbal fluency tasks are used to assess language functioning in Alzheimer's disease (AD), and performance typically declines as the disease progresses. However, several studies have shown that Category Fluency performance (produce words from a category) declines faster than Letter Fluency performance (produce words beginning with a certain letter), which is not the case for other dementias. The purpose of this study was to determine if each of these two types of fluency tasks was associated with different patterns of cerebral blood flow abnormality in AD. A resting, Xenon-inhalation regional cerebral blood flow measurement (133Xe rCBF) and neuropsychological evaluation was administered to 25 patients with probable AD and 24 healthy elderly controls. Stepwise regression using rCBF measures as predictor variables was used to predict Category and Letter Fluency performance, in both a combined group of patients and controls, and in the patient group alone. Correlations were also computed between rCBF variables and the difference between normatively corrected scores on each task for each subject, which characterized the extent of the discrepancy between them. In full sample regressions, both Category and Letter Fluency were predicted by education and the decline in left inferior parietal flow, a focal AD-related deficit. Additional variance in Category fluency, however, was predicted by global mean flow, while additional variance in Letter Fluency was predicted by frontal flow. Within the patient sample, in turn, the primary predictor of Category Fluency was mean flow; the primary predictor of Letter Fluency was left-sided frontal flow. Analysis of the fluency difference score revealed that relatively greater impairment of Category Fluency was associated with more typical, AD-related deficits in posterior temporal and parietal perfusion. When the two were equivalently impaired, typical AD-related deficits were accompanied by marked deficits in frontal perfusion. These findings are consistent with the underlying neuropsychology of these tasks, and suggest that Category Fluency's stronger association to the most typical CBF deficits of AD account for its greater sensitivity to this disease. Letter Fluency deficits, on the other hand, carry significant information about the degree to which perfusion deficits have spread to frontal cortex. Copyright (C) 1999 Elsevier Science Ltd.
• Pietrini, P., Furey, M. L., Alexander, G. E., Mentis, M. J., Dani, A., Guazzelli, M., Rapoport, S. I., & Schapiro, M. B. (1999). Association between brain functional failure and dementia severity in Alzheimer's disease: Resting versus stimulation PET study. American Journal of Psychiatry, 156(3), 470-473.
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  PMID: 10080567;Abstract: Objective: This study tested the hypothesis that regional cerebral glucose metabolism during neuronal activation is a more sensitive index of neuronal dysfunction and clinical severity in Alzheimer's disease than is glucose metabolism at rest. Method: The subjects were 15 Alzheimer's disease patients with a wide range of Mattis Dementia Rating Scale scores (23-128). By using positron emission tomography, absolute glucose metabolism was measured in the parietal, occipital (visual areas), and temporal (auditory areas) cortical regions during rest (eyes/ears covered) and audiovisual stimulation. Results: In the parietal cortex, glucose metabolism correlated with dementia severity in both conditions. In contrast, in the relatively preserved visual and auditory cortical regions, glucose metabolism predicted dementia severity during stimulation but not at rest. Conclusions: These findings suggest that regional cerebral glucose metabolism during stimulation is a more sensitive index of the functional/metabolic failure of neuronal systems than is metabolism at rest.
• Ricciardi, E., Alexander, G. E., Furey, M. L., Giovacchini, G., Horwitz, B., Dani, A., Guazzelli, M., Rapoport, S. I., Schapiro, M. B., & Pietrini, P. (1999). Coupling between regional cerebral glucose metabolism and blood flow at rest in young and older healthy subjects. NeuroImage, 9(6 PART II), S265.
• Schapiro, M. B., Berman, K. F., Alexander, G. E., Weinberger, D. R., & Rapoport, S. I. (1999). Regional cerebral blood flow in Down syndrome adults during the Wisconsin Card Sorting Test: Exploring cognitive activation in the context of poor performance. Biological Psychiatry, 45(9), 1190-1196.
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  PMID: 10331111;Abstract: Background: Prior studies have indicated abnormal frontal lobes in Down syndrome (DS). The Wisconsin Card Sorting Test (WCST) has been used during functional brain imaging studies to activate the prefrontal cortex. Whether this activation is dependent on successful performance remains unclear. To determine frontal lobe regional cerebral blood flow (rCBF) response in DS and to further understand the effect of performance on rCBF during the WCST, we studied DS adults who perform poorly on this task. Methods: Initial slope (IS), an rCBF index, was measured with the 133Xe inhalation technique during a Numbers Matching Control Task and the WCST. Ten healthy DS subjects (mean age 28.3 years) and 20 sex-matched healthy volunteers (mean age 28.7 years) were examined. Results: Performance of DS subjects was markedly impaired compared to controls. Both DS and control subjects significantly increased prefrontal IS indices compared to the control task during the WCST. Conclusions: Prefrontal activation in DS during the WCST was not related to performance of that task, but may reflect engagement of some components involved in the task, such as effort. Further, these results show that failure to activate prefrontal cortex during WCST in schizophrenia is unlikely to be due to poor performance alone.
• Teipel, S. J., Bartenstein, P., Alexander, G. E., Moller, H. -., Rapoport, S. I., & Hampel, H. (1999). In vivo neuroreceptor imaging and applications for Alzheimer's disease. Drug News and Perspectives, 12(6), 341-350.
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  Abstract: A large body of evidence from neuropathological studies in Alzheimer's disease (AD) on postmortem brains has demonstrated impairment of specific neurotransmitter systems, especially of the cholinergic system. These studies, however, reflect end stages of the disease and permit only limited inference of the temporal sequence and cognitive and behavioral effects of deficits in neurotransmission. Since 1979, positron emission tomography (PET) has evolved into a powerful tool to visualize neuroreceptor binding in the living human brain and to quantify neuroreceptor density and ligand-receptor binding kinetics. Assessment of binding characteristics and receptor availability is essentially based on compartment models or saturation kinetic analysis derived from autoradiographic studies. This article describes the mathematical assumptions underlying these models and the biochemical characteristics that have to be met by a ligand to allow mapping of specific binding in PET. From this methodological basis, we review the present state of in vivo neuroreceptor imaging in AD. The majority of studies have focused on the cholinergic system, showing a decrease of nicotinic binding sites in frontal and temporal cortex in AD that was partially reversible through administration of central cholinergic drugs. As will be shown, interpretation of these results is severely limited by methodological difficulties. Recent studies have further demonstrated alterations of serotonin and opioid receptor availability in AD. We conclude with a discussion of the requirements that should be met by future studies on neurotransmission alterations in AD and outline possible future perspectives for these studies with respect to differential diagnosis and selective assessment of drug action and efficacy.
• Teipel, S. J., Hampel, H., Pietrini, P., Alexander, G. E., Horwitz, B., Daley, E., Möller, H., Schapiro, M. B., & Rapoport, S. I. (1999). Region-specific corpus callosum atrophy correlates with the regional pattern of cortical glucose metabolism in Alzheimer disease. Archives of Neurology, 56(4), 467-473.
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  PMID: 10199337;Abstract: Background: Positron emission tomographic studies of patients with Alzheimer disease (AD) suggest a loss of metabolic functional interactions between different cortical regions. Atrophy of the corpus callosum as the major tract of intracortical connective fibers may reflect decreased cortical functional integration in AD. Objectives: To investigate whether regional atrophy of the corpus callosum is correlated with regional reductions of cortical glucose metabolism, as shown by positron emission tomography, and whether primary white matter degeneration is a possible cofactor of corpus callosum atrophy in AD. Patients and Methods: We measured total and regional cross-sectional areas of the corpus callosum on midsagittal magnetic resonance imaging scans from 12 patients with AD and 15 age-matched control subjects. Regional cerebral metabolic rates for glucose in cortical lobes were measured by positron emission tomography using fludeoxyglucose F 18. White matter hyperintensities were rated in T2-weighted magnetic resonance imaging scans. Results: The total cross-sectional area of corpus callosum was significantly reduced in patients with AD, with the most prominent changes in the rostrum and splenium and relative sparing of the body of the corpus callosum. Frontal and parietal lobe metabolism was correlated with the truncal area of the corpus callosum in AD. The ratios of frontal to parietal and of frontal to occipital metabolism were correlated with the ratio of anterior to posterior corpus callosum area in the group with AD. White matter hyperintensities did not correlate with corpus callosum atrophy in the patients with AD. Conclusion: The regional pattern of corpus callosum atrophy correlated with reduced regional glucose metabolism independently of primary white matter degeneration in the patients with AD.
• Alexander, G. E., Greenwood, P. M., Parasuraman, R., Mentis, M. J., Furey, M. L., Desmond, R. E., Szczepanik, J., Levine, B., Pietrini, P., Schapiro, M. B., & Rapoport, S. I. (1998). Functional brain response in right prefrontal cortex with increasing distraction during visual selective attention. NeuroImage, 7(4 PART II), S77.
• Beason-Held, L. L., Purpura, K. P., W., J., Azari, N. P., Mangot, D. J., Optican, L. M., Mentis, M. J., Alexander, G. E., Grady, C. L., Horwitz, B., Rapoport, S. I., & Schapiro, M. B. (1998). PET reveals occipitotemporal pathway activation during elementary form perception in humans. Visual Neuroscience, 15(3), 503-510.
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  PMID: 9685203;Abstract: To define brain regions involved in feature extraction or elementary form perception, regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) in subjects viewing two classes of achromatic textures. Textures composed of local features (e.g. extended contours and rectangular blocks) produced activation or increased rCBF along the occipitotemporal pathway relative to textures with the same mean luminance, contrast, and spatial-frequency content but lacking organized form elements or local features. Significant activation was observed in striate, extrastriate, lingual, and fusiform cortices as well as the hippocampus and brain stem. On a scan-by-scan basis, increases in rCBF shifted from the occipitotemporal visual cortices to medial temporal (hippocampus) and frontal lobes with increased exposure to only those textures containing local features. These results suggest that local feature extraction occurs throughout the occipitotemporal (ventral) pathway during extended exposure to visually salient stimuli, and may indicate the presence of similar receptive-field mechanisms in both occipital and temporal visual areas of the human brain.
• Bokde, A. L., Ibáñez, V., Pietrini, P., Furey, M. L., Alexander, G. E., Graff-Radford, N., Rapoport, S. I., Schapiro, M. B., & Horwitz, B. (1998). Cerebral glucose hypometabolism in the visual variant of Alzheimer's disease after correcting for brain atrophy. NeuroImage, 7(4 PART II), S628.
• Furey, M. L., Pietrini, P., Courtney, S. M., Alexander, G. E., Schapiro, M. B., & Haxby, J. V. (1998). Cholinergic modulation enhances visual processing during working memory. NeuroImage, 7(4 PART II), S872.
• Hampel, H., Teipel, S. J., Alexander, G. E., Horwitz, B., Teichberg, D., Schapiro, M. B., & Rapoport, S. I. (1998). Corpus callosum atrophy is a possible indicator of region- and cell type-specific neuronal degeneration in Alzheimer disease: A magnetic resonance imaging analysis. Archives of Neurology, 55(2), 193-198.
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  PMID: 9482361;Abstract: Background: Pathological studies in Alzheimer disease indicate the specific loss of layer III and V large pyramidal neurons in association cortex. These neurons give rise to long corticocortical connections within and between the cerebral hemispheres. Objectives: To evaluate the corpus callosum as an in vivo marker for cortical neuronal loss. Method: Using a new imaging technique, we measured region-specific corpus callosum atrophy in patients with Alzheimer disease and correlated the changes with neuropsychological functioning. Total cross-sectional area of the corpus callosum and areas of 5 callosal subregions were measured on mid-sagittal magnetic resonance imaging scans of 14 patients with Alzheimer disease (mean age, 64.4 years; Mini-Mental State Examination score, 11.4) and 22 healthy age- and sex-matched control subjects (mean age, 66.6 years; Mini-Mental State Examination score, 29.8). All subjects had minimal white matter changes. Results: The total callosal area was significantly reduced in the patients with Alzheimer disease, with the greatest changes in the rostrum and splenium and relative sparing of the callosal body. Regional callosal atrophy correlated significantly with cognitive impairment in the patients with Alzheimer disease, but not with age or the white matter hyperintensities score. Conclusions: Callosal atrophy in patients with Alzheimer disease with only minimal white matter changes may indicate loss of callosal efferent neurons in corresponding regions of the cortex. Because these neurons are a subset of corticocortical projecting neurons, region-specific callosal atrophy may serve as a marker of progressive neo-cortical disconnection in Alzheimer disease.
• Ibáñez, V., Pietrini, P., Alexander, G. E., Furey, M. L., Teichberg, D., Rajapakse, J. C., Rapoport, S. I., Schapiro, M. B., & Horwitz, B. (1998). Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer's disease. Neurology, 50(6), 1585-1593.
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  PMID: 9633698;Abstract: Objective: To determine whether the hypometabolism observed in PET images of patients with Alzheimer's disease (AID) is due entirely to brain atrophy. Background: Reduced brain glucose metabolism in AD patients measured using PET has been reported by numerous authors. Actual glucose metabolic values in AD may be reduced artificially because of brain atrophy, which accentuates the partial volume effect (PVE) on data collected by PET. Methods: Using segmented MR images, we corrected regional cerebral metabolic rates for glucose for PVEs to evaluate the effect of atrophy on uncorrected values for brain metabolism in AD patients and healthy control subjects. Results: Global glucose metabolism was reduced significantly before and after correction in AD patients compared with controls. Before PVE correction, glucose metabolic values in patients were lower than in control subjects in the inferior parietal, frontal, and lateral temporal cortex; in the posterior cingulate; and in the precuneus. These reductions remained significantly lower after PVE correction, although in the posterior cingulate the difference in metabolism between AD patients and control subjects lessened. Regional glucose metabolism of these areas with PVE correction was lower in moderately-severely demented patients than in mildly demented patients. Conclusion: Reduced glucose metabolism measured by PET in AD is not simply an artifact due to an increase in CSF space induced by atrophy, but reflects a true metabolic reduction per gram of tissue.
• Krasuski, J. S., Alexander, G. E., Horwitz, B., Daly, E. M., Murphy, D. G., Rapoport, S. I., & Schapiro, M. B. (1998). Volumes of medial temporal lobe structures in patients with Alzheimer's disease and mild cognitive impairment (and in healthy controls). Biological Psychiatry, 43(1), 60-68.
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  PMID: 9442345;Abstract: Background: The clinical diagnosis of Alzheimer's disease (AD) can be difficult to make in early stages of disease. Structural neuroimaging offers a potential tool in the clinical diagnosis of AD with mild cognitive impairment. Postmortem studies indicate that early neuropathology in AD occurs in medial temporal lobe limbic structures. Magnetic resonance imaging (MRI) studies that assessed these volumes in mildly impaired AD patients remain inconclusive. Methods: Using MRI, we measured volumes of left and right hippocampus, amygdala, and anterior and posterior parahippocampal gyrus (PHG) in 13 AD patients with mild cognitive impairment, defined as ≤ 20 on the Mini-Mental State Exam, and in 21 healthy age- and sex-matched controls. Results: The AD patients had smaller medial temporal lobe volumes, except for the right anterior PHG. Discriminant function analysis using MRI volumes produced 94% correct group classification. Conclusions: These results show that in mildly impaired AD patients atrophy is present in medial temporal lobe structures; that MRI volumes of the anterior PHG, which contains entorhinal cortex, are reduced, but the amygdala and hippocampal volumes show greater reduction; and that discriminant function analysis using all volumes as predictors can correctly classify a high proportion of individuals.
• Mentis, M. J., Alexander, G. E., Krasuski, J., Pietrini, P., Furey, M. L., Schapiro, M. B., & Rapoport, S. I. (1998). Increasing required neural response to expose abnormal brain function in mild versus moderate or severe Alzheimer's disease: PET study using parametric visual stimulation. American Journal of Psychiatry, 155(6), 785-794.
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  PMID: 9619151;Abstract: Objective: The authors examined the interaction of Alzheimer's disease severity and visual stimulus complexity in relation to regional brain function. Method: Each subject had five positron emission tomography [15]H20 scans while wearing goggles containing a grid of red lights embedded into each lens. Regional cerebral blood flow (CBF) was measured at 0 Hz and while lights were flashed alternately into the two eyes at 1, 4, 7, and 14 Hz. Changes in regional CBF from the 0-Hz baseline were measured at each frequency in 19 healthy subjects (mean age=65 years, SD=11), 10 patients with mild Alzheimer's disease (mean age=69, SD=5; Mini-Mental State score ≤20), and 11 patients with moderate to severe Alzheimer's disease (mean age=73, SD=12; Mini-Mental State score ≤19). Results: As pattern-flash frequency increased, CBF responses in the comparison group included biphasic rising then falling in the striate cortex, linear increase in visual association areas, linear decrease in many anterior areas, and a peak at 1 Hz in V5/MT. Despite equivalent resting CBF and CBF responses to low frequencies among all groups, the groups with Alzheimer's disease had significantly smaller CBF responses than the comparison group at the frequency producing the largest response in the comparison group in many brain regions. Also, patients with moderate/severe dementia had smaller responses at frequencies producing intermediate responses in comparison subjects. Conclusions: Functional failure was demonstrated in patients with mild dementia when large neural responses were required and in patients with moderate/severe dementia when large and intermediate responses were required.
• Teipel, S. J., Hampel, H., Alexander, G. E., Schapiro, M. B., Horwitz, B., Teichberg, D., Daley, E., Hippius, H., Möller, H., & Rapoport, S. I. (1998). Dissociation between corpus callosum atrophy and white matter pathology in Alzheimer's disease. Neurology, 51(5), 1381-1385.
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  PMID: 9818864;Abstract: Objective: To determine whether the size of the corpus callosum is related to the extent of white matter pathology in patients with AD and age- matched healthy control subjects. Methods: White matter hyperintensity load and corpus callosum size were compared between 20 clinically diagnosed AD patients and 21 age-matched healthy control subjects. We investigated the effect of age and disease severity on corpus callosum size and white matter hyperintensity, in addition to the relation between corpus callosum areas and white matter hyperintensity load. Results: We found significant regional atrophy of the corpus callosum in AD when compared with control subjects, although the groups did not differ in their white matter hyperintensity load. We further showed a region-specific correlation between corpus callosum size and white matter hyperintensity in the control group but not in AD patients. In the AD group, corpus callosum size correlated with age and dementia severity, whereas white matter hyperintensity correlated only with age. Conclusion: Corpus callosum atrophy in AD can occur independent of white matter degeneration, likely reflecting specific AD pathology in projecting neurons.
• Alexander, G. E., Furey, M. L., Grady, C. L., Pietrini, P., Brady, D. R., Mentis, M. J., & Schapiro, M. B. (1997). Association of premorbid intellectual function with cerebral metabolism in Alzheimer's disease: Implications for the cognitive reserve hypothesis. American Journal of Psychiatry, 154(2), 165-172.
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  PMID: 9016263;Abstract: Objective: Clinical heterogeneity in Alzheimer's disease has been widely observed. One factor that may influence the expression of dementia in Alzheimer's disease is premorbid intellectual ability. It has been hypothesized that premorbid ability, as measured by educational experience, reflects a cognitive reserve that can affect the clinical expression of Alzheimer's disease. The authors investigated the relation between estimates of premorbid intellectual function and cerebral glucose metabolism in patients with Alzheimer's disease to test the effect of differing levels of premorbid ability on neurophysiological dysfunction. Method: In a resting state with eyes closed and ears occluded, 46 patients with Alzheimer's disease were evaluated with positron emission tomography and [ 18F]-2- fluoro-2-deoxy-D-glucose to determine cerebral metabolism. Premorbid intellectual ability was assessed by a demographics-based IQ estimate and performance on a measure of word-reading ability. Results: After the authors controlled for demographic characteristics and dementia severity, both estimates of premorbid intellectual ability were inversely correlated with cerebral metabolism in the prefrontal, premotor, and left superior parietal association regions. In addition, the performance-based estimate (i.e., reading ability) was inversely correlated with metabolism in the anterior cingulate, paracentral, right orbitofrontal, anti left thalamic regions, after demographic and clinical variables were controlled for. Conclusions: The results suggest that higher levels of premorbid ability are associated with greater pathophysiological effects of Alzheimer's disease among patients of similar dementia severity levels. These findings provide support for a cognitive reserve that can alter the clinical expression of dementia and influence the neurophysiological heterogeneity observed in Alzheimer's disease.
• Alexander, G. E., Mentis, M. J., Horn, J. V., Grady, C. L., Berman, K. F., Furey, M. L., Pietrini, P., & Moeller, J. R. (1997). Association of task performance with regional PET activation patterns during face-matching: A "pixelated" scaled subprofile model (SSM) analysis. NeuroImage, 5(4 PART II), S118.
• Alexander, G. E., Saunders, A. M., Szczepanik, J., Strassburger, T. L., Pietrini, P., Dani, A., Furey, M. L., Mentis, M. J., Roses, A. D., Rapoport, S. I., & Schapiro, M. B. (1997). Relation of age and apolipoprotein E to cognitive function in Down syndrome adults. NeuroReport, 8(8), 1835-1840.
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  PMID: 9223061;Abstract: TO test the cognitive effects of aging and apolipoprotein E (APOE) in individuals at high risk for Alzheimer's disease (AD), we assessed APOE genotypes and performance on a battery of neuropsychological tests in 41 non- demented, Down syndrome (DS) adults. Old DS subjects (ages 41-61 years) showed poorer memory and orientation scores than young DS adults (ages 22-38 years), but the groups did not differ in other measures after we controlled for intellectual function. Language ability was inversely related to APOE genotype, even after age was controlled for, with the presence of the ε2 allele corresponding to better language skills than ε4. Age-related cognitive changes in non-demented DS adults are consistent with the early effects of AD. The relationship between basic linguistic skills and APOE genotype supports this genetic factor in influencing the development of dementia and AD neuropathology in DS.
• Dani, A., Pietrini, P., Furey, M. L., Alexander, G. E., Horwitz, B., Mentis, M. J., & Schapiro, M. B. (1997). Cerebral glucose metabolic dysfunction in relation to dementia in down syndrome: Potential implications for therapeutic intervention. NeuroImage, 5(4 PART II), S337.
• Furey, M. L., Horwitz, B., Pietrini, P., Alexander, G. E., Mentis, M. J., Dani, A., Shetty, U., Freo, U., Rapoport, S. I., & Schapiro, M. B. (1997). Improved performance on working memory is related to regional cerebral blood flow changes induced by pharmacological modulation of the cholinergic system. NeuroImage, 5(4 PART II), S623.
• Furey, M. L., Pietrini, P., Haxby, J. V., Alexander, G. E., Lee, H. C., Vanmeter, J., Grady, C. L., Shetty, U., Rapoport, S. I., Schapiro, M. B., & Freo, U. (1997). Cholinergic stimulation alters performance and task-specific regional cerebral blood flow during working memory. Proceedings of the National Academy of Sciences of the United States of America, 94(12), 6512-6516.
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  PMID: 9177249;PMCID: PMC21081;Abstract: Modulation of the cholinergic neurotransmitter system results in changes in memory performance, including working memory (WM), in animals and in patients with Alzheimer disease. To identify associated changes in the functional brain response, we studied performance measures and regional cerebral blood flow (rCBF) using positron emission tomography (PET) in healthy subjects during performance of a WM task. Eight control subjects received an infusion of saline throughout the study and 13 experimental subjects received a saline infusion for the first 2 scans followed by a continuous infusion of physostigmine, an acetylcholinesterase inhibitor, for the subsequent 8 scans. rCBF was measured using H215O and PET in a sequence of 10 PET scans that alternated between rest and task scans. During task scans, subjects performed the WM task for faces. Physostigmine both improved WM efficiency, as indicated by faster reaction times, and reduced WM task-related activity in anterior and posterior regions of right midfrontal gyrus, a region shown previously to be associated with WM. Furthermore, the magnitudes of physostigmine-induced change in reaction time and right midfrontal rCBF correlated. These results suggest that enhancement of cholinergic function can improve processing efficiency and thus reduce the effort required to perform a WM task, and that activation of right prefrontal cortex is associated with task effort.
• Greenwood, P. M., Parasuraman, R., & Alexander, G. E. (1997). Controlling the focus of spatial attention during visual search: Effects of advanced aging and Alzheimer disease. Neuropsychology, 11(1), 3-12.
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  PMID: 9055265;Abstract: It was hypothesized that slowed visual search in healthy adult aging arises from reduced ability to adjust the size of the attentional focus. A novel, cued-visual search task manipulated the scale of spatial attention in a complex field in healthy elderly individuals and patients with dementia of the Alzheimer type (DAT). Precues indicated with varying validity the size and location of the area to be searched. Location precues exerted the strongest effects on conjunction search and the weakest effects on feature search. As the size of valid location cues decreased, conjunction search was facilitated. These effects declined progressively with advanced age and the onset of DAT. As the size of invalid cues increased, conjunction search was first facilitated, then slowed, but neither age nor DAT altered this effect. These results indicate that both Alzheimer's disease and, to a lesser degree, advanced aging, reduce control of the spatial focus of attention.
• Mentis, M. J., Alexander, G. E., Furey, M. L., Levine, B., Prasad, K., Krasuski, J., Pietrini, P., Schapiro, M. B., & Rapoport, S. I. (1997). Effect of dementia severity on the functional response to parametric visual stimulation during PET in Alzheimer disease. NeuroImage, 5(4 PART II), S343.
• Mentis, M. J., Alexander, G. E., Grady, C. L., Horwitz, B., Krasuski, J., Pietrini, P., Strassburger, T., Hampel, H., Schapiro, M. B., & Rapoport, S. I. (1997). Frequency variation of a pattern-flash visual stimulus during PET differentially activates brain from striate through frontal cortex. NeuroImage, 5(2), 116-128.
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  PMID: 9345542;Abstract: We evaluated regional cerebral blood flow (rCBF) in 19 healthy elderly subjects, mean age 64 ± 11 (SD, years), during a passive visual stimulus in which pattern-flash frequency was parametrically manipulated. Using goggles with a grid of red lights imbedded into each lens, we performed five positron emission tomography (PET) H215O water scans on each subject at alternating (left to right eye) flash frequencies of 0, 1, 4, 7, and 14 Hz. We found a biphasic rising and falling rCBF response in the striate cortex (7 Hz peak) and left anterior cingulate (4 Hz peak), 1 Hz activation in left middle temporal gyrus (V5), monotonically increasing rCBF in posterior areas (lateral and inferior visual association areas, Brodmann 18 and 19), and monotonically decreasing rCBF in anterior areas (frontal, cingulate, and superior temporal) predominantly in right hemisphere. We suggest the striate rCBF changes at all frequencies primarily reflect lateral geniculate input, the middle temporal activation at 1 Hz reflects perception of apparent motion, and the posterior extrastriate rCBF monotonic increase represents a neural response to increasing luminance intensity and form and color complexity that occur as pattern-flash frequency increases. The anterior monotonic rCBF decrease may represent active cross-modal functional suppression of brain areas irrelevant for processing the passive visual stimulus. Pattern-flash rCBF responses were highly reproducible (no series effect), more so in posterior than in anterior brain regions. The reproducibility and systematically changing rCBF responses to this passive stimulus suggest that it could be successfully used as a disease probe to evaluate neural function and drug effects in cognitively impaired patients.
• Pietrini, P., Dani, A., Furey, M. L., Alexander, G. E., Freo, U., Grady, C. L., Mentis, M. J., Mangot, D., Simon, E. W., Horwitz, B., Haxby, J. V., & Schapiro, M. B. (1997). Low glucose metabolism during brain stimulation in older Down's syndrome subjects at risk for Alzheimer's disease prior to dementia. American Journal of Psychiatry, 154(8), 1063-1069.
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  PMID: 9247390;Abstract: Objective: Down' s syndrome is characterized by the genetically programmed accumulation of substantial Alzheimer's disease neuropathology after age 40 and the development of early dementia years later, providing a unique human model to investigate the preclinical phases of Alzheimer's disease. Older nondemented adults with Down's syndrome show normal rates of regional cerebral glucose metabolism at rest before the onset of dementia, indicating that their neurons maintain function at rest. The authors hypothesized that an audiovisual stimulation paradigm, acting as a stress test, would reveal abnormalities in cerebral glucose metabolism before dementia in the neocortical parietal and temporal areas most vulnerable to Alzheimer' s disease. Method: Regional cerebral glucose metabolism was assessed by means of positron emission tomography (PET) with [18F]fluorodeoxyglucose in eight younger (mean age=35 years, SD=2) and eight older (mean age=50, SD=7) healthy, nondemented adults with trisomy 21 Down's syndrome. PET scans were performed at rest and during audiovisual stimulation in the same scanning session. Levels of general intellectual functioning and compliance were similar in the two groups. Results: At rest the two groups showed no difference in glucose metabolism in any cerebral region. In contrast, during audiovisual stimulation the older subjects with Down' s syndrome had significantly lower glucose metabolic rates in the parietal and temporal cortical areas. Conclusions: Abnormalities in cerebral metabolism during stimulation appeared in the first cortical regions typically affected in Alzheimer's disease. These results indicate that a stress test paradigm can detect metabolic abnormalities in the preclinical stages of Alzheimer's disease despite normal cerebral metabolism at rest.
• Pietrini, P., Furey, M. L., Dani, A., Alexander, G. E., Mentis, M. J., Freo, U., Rapoport, S. I., & Schapiro, M. B. (1997). Brain synaptic efficiency is preserved in early but not in late stages of Alzheimer's disease: A PET-FDG stimulation study. NeuroImage, 5(4 PART II), S344.
• Strassburger, T. L., Lee, H., Daly, E. M., Szczepanik, J., Krasuski, J. S., Mentis, M. J., Salerno, J. A., DeCarli, C., Schapiro, M. B., & Alexander, G. E. (1997). Interactive effects of age and hypertension on volumes of brain structures. Stroke, 28(7), 1410-1417.
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  PMID: 9227693;Abstract: Background and Purpose: Advanced age and hypertension have each been associated with changes in brain morphology and cognitive function. To investigate the interaction of age and hypertension with structural brain changes and neuropsychological performance in otherwise healthy patients with essential hypertension, we compared young-old (ages 56 to 69 years) and old- old (ages 70 to 84 years) hypertensive patients (n=27) with 20 age-matched normotensive healthy control subjects, using quantitative volumetric MRI and a battery of neuropsychological tests. Methods: Quantitative regions of interest and segmentation analyses were applied to MRI scans of brain to measure volumes of different brain structures and of cerebrospinal fluid (CSF). Severity of white matter hyperintensities (WMHs) was qualitatively rated in the MRI scans. A battery of neuropsychological tests was administered to each subject. Results: The combined hypertensive group (young-old and old-old) had smaller volumes of thalamic nuclei and larger volumes of CSF in the cerebellum and temporal lobes and showed poorer performance in memory and language tests than did the control subjects. Main effects for age were significant in multiple brain regions of interest. The old-old hypertensive patients and age-matched control subjects demonstrated volume reductions in brain structures and increases in ventricular and peripheral CSF volumes compared with the younger subjects. There was a significant group x age-group interaction in temporal and occipital CSF, not related to WMH, with the old-old hypertensive patients having significantly larger CSF volumes in these regions than the young-old hypertensives and both healthy control groups. Conclusions: Hypertension exacerbates the morphological changes accompanying advanced age. Temporal and occipital regions appear most vulnerable to brain atrophy due to the interactive effects of age and hypertension.
• Dani, A., Pietrini, P., Furey, M. L., McIntosh, A. R., Grady, C. L., Horwitz, B., Freo, U., Alexander, G. E., & Schapiro, M. B. (1996). Brain cognition and metabolism in Down syndrome adults in association with development of dementia. NeuroReport, 7(18), 2933-2936.
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  PMID: 9116213;Abstract: To identify changes in brain functions associated with the development of dementia, brain metabolism and cognition were assessed repeatedly in 12 adults with Down syndrome (DS) using positron emission tomography and neuropsychological tests. Ten subjects remained non-demented (ND) and showed no significant changes over time in cognitive measures or in cerebral metabolism. Two subjects developed dementia after 7 years. Brain functions were relatively stable prior to the onset of dementia; after the onset of dementia, both cognitive function and glucose metabolism in parietal and temporal brain regions known to be vulnerable to Alzheimer disease (AD) showed a rapid linear decline. These findings support the concept that brain functions are stable over time in ND individuals with DS and that decline of brain functions in DS subjects with dementia follows two distinct phases that correspond to the clinical progression of AD. This may have implications for timing of new therapeutic strategies.
• Furey-Kurkjian, M. L., Pietrini, P., Graff-Radford, N. R., Alexander, G. E., Freo, U., Szczepanik, J., & Schapiro, M. B. (1996). Visual variant of Alzheimer disease: Distinctive neuropsychological features. Neuropsychology, 10(2), 294-300.
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  Abstract: A subgroup of patients with probable Alzheimer disease (AD) reported a history of isolated visual disturbances (VS) early in the course of disease, without the characteristic memory complaints. Brain imaging and neuropathologic studies indicated that this subgroup had larger involvement of visual cortical areas and relative sparing of temporal, frontal, and limbic structures compared with classic AD. Consistent with these Endings, the authors hypothesized that the cognitive deficits in this subgroup would be distinctly different from those seen in more typical AD patients. The authors studied 10 probable AD patients with VS (AD+VS), 22 patients without VS (AD-), and 25 healthy controls with a neuropsychological test battery. Compared with AD-, AD+VS patients performed significantly better on tests of verbal memory and had greater impairment on tests of visuospatial skills, suggesting a distinct pattern of cognitive dysfunction consistent with metabolic and neuropathologic reports.
• Goldman, R. G., Alexander, G. E., Zemishlany, Z., Mukherjee, S., Sackeim, H., & Prohovnik, I. (1996). Acute effects of haloperidol on cerebral cortex blood flow in normal and schizophrenic subjects. Biological Psychiatry, 40(7), 604-608.
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  PMID: 8886293;Abstract: To evaluate the effects of neuroleptic medications on cerebral blood flow (CBF), cortical perfusion was quantified by the 133xenon technique in 8 unmedicated schizophrenics and 9 healthy controls before, and 1 and 3 hours after, administration of haloperidol (5 mg per os). At 3 hours, the normal subjects, but not schizophrenic patients, showed a significant increase in global mean perfusion (17 ± 13%). Changes in CBF were not associated with plasma haloperidol levels or the presence of extrapyramidal side effects, and remained significant after controlling for pCO2. The lack of change in CBF in schizophrenic patients following acute haloperidol administration may be due to prior neuroleptic exposure, absence of anxiety, or other nonspecific factors, or may reflect a more fundamental feature of underlying pathophysiology in schizophrenia.
• Keilp, J. G., Alexander, G. E., Stern, Y., & Prohovnik, I. (1996). Interior parietal perfusion, lateralization, and neuropsychological dysfunction in Alzheimer's disease. Brain and Cognition, 32(3), 365-383.
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  PMID: 8975677;Abstract: The severity of inferior parietal perfusion deficits in Alzheimer's disease (AD) is strongly associated with global intellectual decline. The relationship to specific losses of neuropsychological functioning, however, is less clear, as is the relative importance of the side (left vs. right) of hemispheric deficit. In this study, 53 patients with probable AD and 35 elderly controls received both a resting 133Xe rCBF measurement and neuropsychological examination. AD patients demonstrated the expected bilateral deficits in inferior parietal perfusion, as well as impairment on measures of mental status, intelligence, verbal and visual memory, attention, language, and construction abilities. The severity of this bilateral parietal deficit, in turn, was associated with virtually all of these AD-related neuropsychological impairments, most strongly with declining Performance IQ. Left-sided deficits correlated better with overall declines in IQ, as well as with declining attention and language fluency. Right-sided deficit, on the other hand, correlated best with declines in mental status and- paradoxically - verbal memory and contributed independently to declines in Full Scale and Performance IQ. In terms of the number and strength of their association to neuropsychological measures, left-sided deficits appear much more predictive of cognitive decline in AD. Right-sided deficits, however, may be most important for predicting aspects of performance skill that are only indirectly assessed in standard paper-and-pencil format. Overall, it appears that both sides make significant, but independent contributions to general functional decline in AD, but that left-sided deficits are more closely associated with cognitive decline as measured by most standard neuropsychological measures.
• Mentis, M. J., Horwitz, B., Grady, C. L., Alexander, G. E., VanMeter, J. W., Maisog, J. M., Pietrini, P., Schapiro, M. B., & Rapoport, S. I. (1996). Visual cortical dysfunction in Alzheimer's disease evaluated with a temporally graded "stress test" during PET. American Journal of Psychiatry, 153(1), 32-40.
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  PMID: 8540589;Abstract: Objective: Visual-processing abnormalities commonly contribute to typical Alzheimer's disease symptoms, but their detailed pathophysiology remains unknown. To investigate why patients with Alzheimer's disease have greater difficulty performing visuoconstructive (magnocellular-dominated) tasks than face- or color-perception (parvocellular-dominated) tasks, the authors measured brain activation in response to a temporally graded visual stimulus (neural stress test) during positron emission tomography. Method: The stress test measured regional cerebral blood flow (CBF) in response to a patterned flash stimulus in the resting state (0 Hz in the dark) and at frequencies of 1, 2, 4, 7, and 14 Hz. Ten patients with Alzheimer's disease and 12 age- and sex-matched comparison subjects were studied. Results: The striate response at 7 Hz and 14 Hz (the degree of regional CBF increase from that at 0 Hz) was significantly less in the patients than in the comparison subjects, whereas the change in regional CBF at the lower frequencies did not differ between groups. In bilateral middle temporal association areas activated by motion and dominated by magnocellular input, regional CBF at 1 Hz (the frequency with maximal apparent motion) was significantly greater than at 0 Hz in the comparison subjects but not in the patients. Conclusions: The magnocellular visual system normally responds to high-frequency input and motion; the failure of response in the striate cortex at high but not low frequencies in the Alzheimer's patients suggests greater magnocellular than parvocellular dysfunction at these levels. Activation failure in the middle temporal areas in the patients supports magnocellular dysfunction. The finding that the Alzheimer's disease group had abnormal visual cortical function emphasizes the importance of clinical visuospatial evaluation of patients with Alzheimer's disease to fully understand symptom production and to plan interventions.
• Moeller, J. R., Ishikawa, T., Dhawan, V., Spetsieris, P., Mandel, F., Alexander, G. E., Grady, C., Pietrini, P., & Eidelberg, D. (1996). The metabolic topography of normal aging. Journal of Cerebral Blood Flow and Metabolism, 16(3), 385-398.
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  PMID: 8621743;Abstract: Normal aging is associated with the degeneration of specific neural systems. We used [18F]fluorodeoxyglucose (FDG)/positron emission tomography (PET) and a statistical model of regional covariation to explore the metabolic topography of this process. We calculated global and regional metabolic rates for glucose (GMR and rCMR(glc)) in two groups of normal subjects studied independently on different tomographs: Group 1-130 normal subjects (62 men and 68 women; range 21-90 years); Group 2-20 normal subjects (10 men and 10 women; range 24-78 years). In each of the two groups, the Scaled Subprofile Model (SSM) was applied to rCMR(glc) data to identify specific age-related profiles. The validity of these profiles as aging markers was assessed by correlating the associated subject scores with chronological age in both normal populations. SSM analysis disclosed two significant topographic profiles associated with aging. The first topographic profile, extracted in an analysis of group 1 normals, was characterized by relative frontal hypometabolism associated with covariate metabolic increases in the parietooccipital association areas, basal ganglia, midbrain, and cerebellum. Subject scores for this profile correlated significantly with age in both normal groups (R2 = 0.48 and 0.33, p < 0.0001 for groups 1 and 2, respectively). Because of clinical similarities between normal motoric aging and parkinsonism, we explored the possibility of shared elements in the metabolic topography of both processes. We performed a combined group SSM analysis of the 20 group 2 normals and 22 age-matched Parkinson's disease patients, and identified another aging-related topographic profile. This profile was characterized by relative basal ganglia hypermetabolism associated with covariate decreases in frontal premotor cortex. Subject scores for this profile also correlated significantly with age in both normal groups (group 1: R2 = 0.30, p < 0.00001; group 2: R2 = 0.59, p < 0.01). Healthy aging is associated with reproducible topographic covariation profiles associated with specific neural systems. FDG/PET may provide a useful metabolic marker of the normal aging process.
• Pietrini, P., Furey, M. L., Graff-Radford, N., Freo, U., Alexander, G. E., Grady, C. L., Dani, A., Mentis, M. J., & Schapiro, M. B. (1996). Preferential metabolic involvement of visual cortical areas in a subtype of Alzheimer's disease: Clinical implications. American Journal of Psychiatry, 153(10), 1261-1268.
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  PMID: 8831432;Abstract: Objective: A subgroup of patients with Alzheimer's disease present with visual disturbances at onset. This study investigated whether specific cortical networks associated with visual processes are preferentially affected in this subgroup and determined the clinical implications of such abnormalities. Method: Regional cerebral glucose metabolic rates were assessed with positron emission tomography and [18F]2-fluoro-2-deoxy-D- glucose, and general intellectual functions, memory, and visual skilled were measured with cognitive tests in patients with probable Alzheimer's disease - 10 with and 22 without prominent visual symptoms - and in 25 healthy comparison subjects. Results: Both patient groups showed reduced glucose metabolism in parietal regions and in middle and superior temporal regions in comparison with the healthy subjects. The Alzheimer's disease patients without visual symptoms also showed reductions in inferior temporal, frontal, and limbic structures, as is typical of Alzheimer's disease. In contrast, the patients with visual symptoms had larger metabolic deficits than the patients without visual symptoms in the parietal and occipital cortices (including the primary visual cortex), with a relative sparing of inferior temporal, frontal, and limbic regions. Consistently, the patients with visual symptoms had significantly greater visuospatial deficits and less severe memory impairments than the patients without visual symptoms. Conclusions: Alzheimer's disease patients with visuospatial deficits who are studied while alive have a distinctive regional distribution of cerebral metabolic impairment that is related to specific cognitive deficits and that distinguishes them from patients with typical Alzheimer's disease. These findings imply that regional variations in brain function can occur in Alzheimer's disease, with differential involvement of cortical systems resulting in distinctive clinical subgroups.
• Zemishlany, Z., Alexander, G. E., Prohovnik, I., Goldman, R. G., Mukherjee, S., & Sackeim, H. (1996). Cortical blood flow and negative symptoms in schizophrenia. Neuropsychobiology, 33(3), 127-131.
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  PMID: 8776740;Abstract: An association between negative symptoms and frontal cortex abnormalities has been suggested in schizophrenic patients. We tested whether this association can be found when patients' task performance is good and while controlling for possible cortical atrophy. We investigated regional cerebral blood flow with the xenon-133 inhalation method in 9 unmedicated schizophrenic patients at rest and during performance of the Continuous Performance Test. Negative symptoms were quantified with the Scale for Assessment of Negative Symptoms. All patients could attend to the test and performed it successfully with mean accuracy of 91 ± 8%. Changes of the left hemisphere hyperfrontality ratio were significantly correlated with severity of negative symptoms, especially for the subscales of attention (r = -0.83) and anhedonia (r = -0.70). These results lend further support to the putative association between negative symptoms and physiological abnormalities of the frontal cortex in schizophrenic patients.
• Alexander, G. E., Prohovnik, I., Sackeim, H. A., Stern, Y., & Mayeux, R. (1995). Cortical perfusion and gray matter weight in frontal lobe dementia. Journal of Neuropsychiatry and Clinical Neurosciences, 7(2), 188-196.
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  PMID: 7626962;Abstract: To evaluate the pathophysiology of frontal lobe dementia (FLD), the authors compared regional cerebral blood flow (rCBF) in matched groups of FLD, probable Alzheimer's disease (AD), and major depression patients and normal control subjects (n = 7 each). The planar xenon-133 technique allowed full quantification of cortical perfusion and estimates of the relative weight of gray matter (wg). FLD patients showed lower blood flow and wg in the frontal cortex than the other groups. Mean cortical perfusion was correlated with cortical wg in the FLD group only. These findings 1) suggest that matched reductions of frontal gray matter weight and perfusion occur in FLD and 2) support the use of rCBF in distinguishing FLD from AD and severe depression.
• Keilp, J. G., Waniek, C., Goldman, R. G., Zemishlany, Z., Alexander, G. E., Gibbon, M., Amy, W. u., Susser, E., & Prohovnik, I. (1995). Reliability of post-mortem chart diagnoses of schizophrenia and dementia. Schizophrenia Research, 17(2), 221-228.
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  PMID: 8562497;Abstract: The reliability of psychiatric diagnosis has a direct effect on the validity of post-mortem analyses of neuropathological data, yet little is known about the reliability of retrospective diagnostic procedures which rely on review of medical records. In this paper, we report on the reliability of DSM-III-R psychiatric diagnoses assigned by a pool of 8 raters to a set of 106 state hospital charts of elderly, chronic patients who had died while institutionalized and were autopsied. Diagnoses were grouped by general diagnostic class, and Kappa coefficients computed for agreement among raters, as well as for agreement between ultimate consensus diagnoses and those made while subjects were living. Interrater agreement for those diagnoses that occurred most frequently in this sample (e.g. Schizophrenia and Dementia) was excellent, and comparable to the the agreement observed for ratings of live patients. Interrater agreement for less frequently occurring diagnoses (e.g. Mental Retardation, Mood Disorders, other non-Schizophrenic Psychoses) ranged from excellent to poor. We found high agreement between our raters diagnoses and those assigned by state hospital personnel while patients were living, although post-mortem review produced lower rates of diagnosis of both schizophrenia and Alzheimer-type dementias. Overall, results suggest that the reliability of chart review diagnosis is comparable to that obtained from interviews of live patients when experienced raters are used and diagnostic base rates are high enough to produce stable estimates of reliability. © 1995.
• Mentis, M. J., Weinstein, E. A., Horwitz, B., McIntosh, A. R., Pietrini, P., Alexander, G. E., Furey, M., & Murphy, D. G. (1995). Abnormal brain glucose metabolism in the delusional misidentification syndromes: A positron emission tomography study in Alzheimer disease. Biological Psychiatry, 38(7), 438-441,443-449.
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  PMID: 8672604;Abstract: Brain lesions have been reported with increasing frequency in the delusional misidentification syndromes (DMS). This is the first controlled study to describe DMS regional cerebral metabolic rates of glucose (rCMRglc). We compared rCMRglc (using positron emission tomography) and neuropsychological data in 9 patients with DMS and Alzheimer dementia (AD), 15 AD patients without DMS, and 17 healthy controls. The DMS group differed from the AD group without DMS in having significant hypometabolism in paralimbic (orbitofrontal and cingulate areas bilaterally) and left medial temporal areas, and significant bilateral normalized hypermetabolism in sensory association cortices (superior temporal and inferior parietal) without right left asymmetry. Compared to healthy controls, both AD groups had significant dorsolateral frontal hypometabolism bilaterally. No specific DMS neuropsychological profile was identified. Dysfunctional connections among multimodal association areas, paralimbic structures, and dorsolateral frontal cortex are proposed as the predisposing neural deficit underlying DMS, causing cognitive-perceptual-affective dissonance, which under specific conditions results in "positive" delusion formation. © 1995 Society of Biological Psychiatry.
• Schapiro, M. B., Murphy, D. G., Hagerman, R. J., Azari, N. P., Alexander, G. E., Miezejeski, C. M., Hinton, V. J., Horwitz, B., Haxby, J. V., Kumar, A., White, B., & Grady, C. L. (1995). Adult fragile X syndrome: Neuropsychology, brain anatomy, and metabolism. American Journal of Medical Genetics - Neuropsychiatric Genetics, 60(6), 480-493.
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  PMID: 8825884;Abstract: To understand the implications of suboptimal gene expression in fragile X syndrome [fra(X)], we sought to define the central nervous abnormalities in fra(X) syndrome to determine if abnormalities in specific brain regions or networks might explain the cognitive and behavioral abnormalities in this syndrome. Cranial and ventricular volumes were measured with quantitative computed tomography (CT), regional cerebral metabolic rates for glucose (rCMRglc) were measured with [18-F]-2-fluoro-2-deoxy-D-glucose (18FDG), and patterns of cognition were determined with neuropsychological testing in ten healthy, male patients with karyotypically proven fra(X) syndrome (age range 20-30 yr). Controls for the CT studies were 20 healthy males (age range 21- 37 yr), controls for the PET studies were 9 healthy males (age range 22-31 yr), and controls for the neuropsychological tests were 10 young adult, male Down syndrome (DS) subjects (age range 22-31 yr). The mean mental age of the fra(X) syndrome group was 5.3 yr (range 3.5-7.5 yr; Stanford-Binet Intelligence Scale). Despite comparable levels of mental retardation, the fra(X) subjects showed poorer attention/short term memory in comparison to the DS group. Further, the fra(X) subjects showed a relative strength in verbal compared to visuospatial attention/short term memory. As measured with quantitative CT, 8 fra(X) subjects had a significant (P < 0.05) 12% greater intracranial volume (1,410 ± 86 cm3) as compared to controls(1,254 ± 122 cm3). Volumes of the right and left lateral ventricles and the third ventricle did not differ between groups. Seven of eight patients had greater right lateral ventricle volumes than left, as opposed to 9 out of 20 controls (P < 0.05). Global gray matter CMR-glc in nine fra(X) patients was 9.79 ± 1.28 mg/100 g/minute and did not differ from 8.84 ± 1.31 mg/100 g/minute in the controls. R/L asymmetry in metabolism of the superior parietal lobe was significantly higher in the patients than controls. A preliminary principal component analysis of metabolic data showed that the fra(X) subjects tended to form a separate subgroup that is characterized by relative elevation of normalized metabolism in the lenticular nucleus, thalamus, and premotor regions. Further, a discriminant function, that reflected rCMRglc interactions of the right lenticular and left premotor regions, distinguished the fra(X) subjects from controls. These regions are part of a major group of functionally and anatomically related brain regions and appear disturbed as well in autism with which fra(X) has distinct behavioral similarities. These results show a cognitive profile in fra(X) syndrome that is distinct from that of Down syndrome, that the larger brains in fragile X syndrome are not accompanied by generalized cerebral cortical atrophy or hypoplasia, and that distinctive alterations in resting regional glucose metabolism, measured with 18 FDG and PET, occur in fra(X) syndrome.
• Stern, Y., Alexander, G. E., Prohovnik, I., Stricks, L., Link, B., Lennon, M. C., & Mayeux, R. (1995). Relationship between lifetime occupation and parietal flow: Implications for a reserve against Alzheimer's disease pathology. Neurology, 45(1), 55-60.
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  PMID: 7824135;Abstract: We previously reported an inverse relation between parietal cerebral blood flow and years of education in Alzheimer's disease (AD) patients matched for clinical severity. This suggested that the clinical manifestation of advancing AD pathology is delayed in patients with higher educational attainment. Other aspects of life experience may also provide a reserve against the clinical expression of AD. To test this hypothesis, we classified the primary lifetime occupations of 51 AD patients using the Dictionary of Occupational Titles, published by the US Department of Labor, and derived six factor scores describing intellectual, interpersonal, and physical job demands. Regional cerebral blood flow was measured using the xenon-133 inhalation method. After controlling for age, clinical dementia severity, and education, there was less relative perfusion in the parietal region in subjects whose occupations were associated with higher interpersonal skills and physical demands factor scores. We conclude that independent of education, aspects of occupational experience may provide a reserve that delays the clinical manifestation of AD.
• Alexander, G. E., & Moeller, J. R. (1994). Application of the scaled subprofile model to functional imaging in neuropsychiatric disorders: A principal component approach to modeling brain function in disease. Human Brain Mapping, 2(1-2), 79-94.
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  Abstract: Recent advances in functional neuroimaging have presented a challenge to traditional statistical methods in characterizing the effects of neuropsychiatric illness on brain function. The most common approach for analyzing regional group differences has relied on t-tests with significance thresholds selected to reduce the potential effect of multiple statistical tests. Regional covariance analysis offers an alternative to this threshold-based, group difference approach by identifying the functional interactions among brain regions that can be spatially distributed throughout the brain. The Scaled Subprofile Model (SSM) is one form of regional covariance analysis that has been applied to the study of patient groups. Based on a modified principal component analysis, the SSM offers a method for modeling regionally specific patterns of brain function whose expression can be evaluated between groups and validated against clinical measures of patient disease severity and neuropsychological test scores. We review the application of the SSM, to date, in studies of the effects of neurological and psychiatric illness on brain function, including a discussion of SSM methodology and its application to the study of resting state functional neuroimaging in patient groups. SSM analyses applied to studies of Alzheimer's disease, Parkinson's disease, major depressive disorder, AIDS dementia complex, and neoplastic disease each identified functionally specific topographic effects that were associated with clinical disease severity. The results of the SSM analyses suggest that neuropsychiatric disorders may alter functional networks or systems of neural activity in ways that can be expressed as regional covariance patterns in resting functional imaging data. © 1994 Wiley-Liss, Inc.
• Alexander, G. E., Prohovnik, I., Stern, Y., & Mayeux, R. (1994). WAIS-R subtest profile and cortical perfusion in Alzheimer's disease. Brain and Cognition, 24(1), 24-43.
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  PMID: 8123262;
• Alexander, G., Gmitro, A. F., & Alexander, G. E. (1993). Use of a projection reconstruction method to decrease motion sensitivity in diffusion-weighted MRI. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine, 29(6).
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  Diffusion-weighted MRI is a clinically useful technique, but its utility is compromised by high sensitivity to patient motion. Use of radial-scan data acquisition and projection reconstruction, rather than the conventional Fourier imaging method, can substantially reduce the sensitivity to global translational motion of the object. The basis of this concept and a demonstration of the technique in an animal imaging experiment are presented.
• Stern, Y., Alexander, G. E., Prohovnik, I., & Mayeux, R. (1992). Inverse relationship between education and parietotemporal perfusion deficit in Alzheimer's disease. Annals of Neurology, 32(3), 371-375.
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  PMID: 1416806;Abstract: A higher prevalence of dementia in individuals with fewer years of education has suggested that education may protect against Alzheimer's disease (AD). We tested whether individuals with more years of education have a more advanced AD before it is clinically evident. As a measure of pathophysiological severity, we quantified regional cerebral blood flow (rCBF), by the 133Xenon inhalation technique; a specific pattern of flow reduction in the parietotemporal cortex corresponds to AD pathology. In 3 groups of patients with probable AD, matched for clinical measures of dementia severity but with varying levels of education, whole-cortex mean flows were comparable. However, the parietotemporal perfusion deficit was significantly greater in the group with the highest level of education, indicating that AD was more advanced in this group. We conclude that education or its covariates or both may provide a reserve that compensates for the neuropathological changes of AD and delays the onset of its clinical manifestations.
• Acklin, M. W., Sauer, A., Alexander, G., & Dugoni, B. (1989). Predicting depression using earliest childhood memories. Journal of Personality Assessment, 53(1), 51-59.
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  PMID: 2918458;
• Acklin, M. W., & Alexander, G. (1988). Alexithymia and somatization. A Rorschach study of four psychosomatic groups. Journal of Nervous and Mental Disease, 176(6), 343-350.
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  PMID: 2967348;Abstract: The construct of alexithymia has been postulated as a predisposing factor in psychosomatic illness. The alexithymia construct has achieved wide currency in psychosomatic research and theorizing despite its doubtful psychometric foundations. Also, the question of between-group variability in alexithymia has not been addressed. In this study we proposed and tested a Rorschach measure of alexithymia on four groups of psychosomatic patients (back pain, gastrointestinal, dermatology, migraine headache). It was hypothesized that psychosomatic groups would be more alexithymic than nonpatients. To examine the question of between-group variability in alexithymia, it was hypothesized that back pain patients would be more alexithymic than other psychosomatic groups. Both hypotheses were supported. Additionally, exploratory comparisons between psychosomatic groups revealed a number of differences between the groups in basic personality processes. The findings show promise for the use of the Rorschach test as an alexithymia measure. Based on the current study, heterogenous grouping of psychosomatic patients in research designs and treatment programs appear to be a highly questionable procedure.

Presentations

• Alexander, G. E. (2021, April). Influence of Modifiable Health and Lifestyle Factors on Brain Aging. Loma Linda Medical Center.
• Alexander, G. E. (2021, April). Physical Activity and Brain Health in the Oldest Old: Findings from the McKnight Brain Aging Registry. McKnight Interinstitutional Meeting.
• Alexander, G. E. (2021, May). Application of Multivariate Network Covariance for Neuroimaging Biomarkers of Aging and Alzheimer's Disease Risk. NACC Data Core Webinar.
• Alexander, G. E. (2021, November). Modifiable Health and Lifestyle Factors on Cognitive and Brain Aging. Clinical Student Brown Bag.
• Alexander, G. E. (2021, September). Arizona ADRC Biomarker Core. Arizona Alzheimer's Consortium Meeting.
• Alexander, G. E. (2020, August). Taking a look at the aging brain: Effects of lifestyle and health risk factors. Invited virtual talk for APA election to Fellow, Div. 20, Adult Development and Aging.
• Alexander, G. E. (2020, January). Exercise, cognition, and brain health in aging and Alzheimer’s Risk. Arizona Alzheimer’s Consortium Retreat. Lake Havasu, AZ.
• Alexander, G. E. (2019, April). Patterns of daily activity in the oldest old: Findings from the McKnight Brain Aging Registry. McKnight Brain Institute Inter-Institutional Meeting. Gainesville, FL.
• Alexander, G. E. (2019, April). Relation of daily activity patterns to cortical gray matter maps in the healthy oldest old: Findings from the McKnight Brain Aging Registry. McKnight Brain Institute Inter-Institutional Meeting. Gainesville, FL.
• Alexander, G. E. (2019, May). Measuring physical activity in older adults: Associations with brain atrophy and white matter hyperintensities. Arizona Alzheimer’s Consortium Annual Conference. Tempe, AZ.
• Alexander, G. E. (2019, May). Why your brain needs exercise: Lessons from evolutionary neuroscience. American College of Sports Medicine Annual Meeting. Orlando, FL.
• Alexander, G. E. (2018, April). Modifiable Risk Factors in Cognitive Aging: Influence of Vascular Health and Physical Activity. McKnight Inter-Institutional Meeting. Birmingham, AL.
• Alexander, G. E. (2018, August). Viewing the aging brain: Looking at lifestyle, health & cognition. Invited talk for APA Election to Fellow, Div. 40, Society for Clinical Neuropsychology. San Francisco, CA.
• Alexander, G. E. (2018, January). MRI Core Summary/Update. McKnight Arizona Site Visit. Tucson, AZ.
• Alexander, G. E. (2018, November). Exercise and Brain Aging: The surprising Links Between Your Brain and Body. Sun City Oro Valley. Tucson, AZ.
• Alexander, G. E. (2018, October). Modifiable health & lifestyle factors in brain aging and Alzheimer’s disease. University of Arizona Alzheimer’s Consortium meeting. Tucson, AZ.
• Alexander, G. E. (2018, October). Neuroimaging of the aging brain: Implications for successful aging and the risk for Alzheimer’s disease. Clinical Psychology Program Brown Bag. Tucson, AZ.
• Alexander, G. E. (2017, April). The Brain-Exercise Connection. Tucson Medical Center Brain Week.
• Alexander, G. E. (2017, August). Neuroimaging in brain aging, vascular health, and the risk of Alzheimer’s disease. Neruoscience Community Data Blitz. University of Arizona.
• Alexander, G. E. (2017, September). Neuroimaging of the aging brain: Implications for successful aging and the risk for Alzheimer’s disease. Psychiatry Grand Rounds.
• Alexander, G. E., & Ryan, L. (2017, February). The Science of decision making and aging. Joan Kaye Cauthorn Annual Conference on Successful Aging.
• Alexander, G. E. (2016, April). Imaging the aging brain: Implications for clinical-translational research. Arizona Research Institute for Biomedical Imaging Spring Workshop, Tucson, AZ.
• Alexander, G. E. (2016, April). Staying mentally fit by being cognitively active. Kinghorn Law Group, Tucson, AZ.
• Alexander, G. E. (2016, March). Can technology enhance healthy lifestyles and brain fitness?. Annual Conference on Successful Aging, Tucson, AZ.
• Alexander, G. E. (2016, May). Imaging the aging brain: Implications for healthy aging and the risk for Alzheimer’s disease. Human Magnetic Resonance Imaging Center, Institute for Applied Life Sciences, University of Massachusetts, Amherst, MA.
• Alexander, G. E. (2016, May). Neuroimaging of the aging brain: Implications for clinical-translational research. Department of Psychiatry, Oregon Health & Science University, Portland, OR.
• Alexander, G. E. (2016, May, 2016). Roadmap to healthy aging: Building connections through advancing research. Columbine Health Systems Center for Healthy Aging, Colorado State University, Fort Collins, CO..
• Alexander, G. E. (2015, April). Influence of health factors on cognitive and brain aging. McKnight Brain Institute Inter-Institutional Meeting, Miami, FL.
• Alexander, G. E. (2015, August). Research Activity: Where we are now and opportunities for growth. Psychology Faculty Retreat, University of Arizona, Tucson, AZ.
• Alexander, G. E. (2015, March). Research studies on healthy and pathological brain aging. Alzheimer's Disease Consortium Retreat, Winslow, AZ.
• Alexander, G. E. (2015, May). Individual differences in aerobic fitness influence the regional pattern of brain volume in healthy aging. Arizona Alzheimer's Consortium Annual Meeting, Phoenix, AZ.
• Alexander, G. E. (2015, October). The Brain and Aging. The Spirit of the Senses, Phoenix, AZ.
• Alexander, G. E., & Ryan, L. (2015, February). Staying mentally fit by being cognitively active. Annual Conference on Successful Aging, Tucson, AZ.
• Alexander, G. E., Bharadwaj, P. K., Haws, K. A., Nguyen, L. A., Fitzhugh, M. C., Trouard, T. P., & Hishaw, G. A. (2015, October). Impact of white matter hyperintensity volume on cortical brain morphology in healthy cognitive aging. Society for Neuroscience Annual Meeting, Chicago, IL.
• Alexander, G. E. (2014). Brain Imaging Individual Differences in Cognitive Aging. McKnight Brain Institute Inter-Institutional meeting. Gainesville, FL.
• Alexander, G. E. (2014). Neuroimaging of the Aging Brain: Implications for Successful Aging and the Risk for Alzheimer’s Disease. Cognitive Science Colloquium, University of Arizona. Tucson, AZ.
• Alexander, G. E. (2014). Neuroimaging of the Aging Brain: Implications for Successful Aging and the Risk for Alzheimer’s Disease. Vanderbilt Memory & Alzheimer’s Center Lecture Series. Nashville, TN.
• Alexander, G. E. (2014). Studies of healthy and pathological aging. Alzheimer's Disease Consortium Retreat. Tucson, AZ.
• Alexander, G. E., Fitzhugh, M. C., Raichlen, D. A., Haws, K. A., Torre, G. A., Trouard, T. P., & Hishaw, G. A. (2014, November). Individual differences in aerobic fitness influence the regional pattern of brain volume in healthy aging. Society for Neuroscience Annual Meeting, Washington, DC.
• Alexander, G. E. (2013). Applications of neuroimaging in the study of brain aging. Neuroscience Community Data Blitz, University of Arizona. Tucson, AZ.
• Alexander, G. E. (2013). Exercise: The surprising links between your brain and body. Annual Conference on Successful Aging. Tucson, AZ.
• Alexander, G. E. (2013). Exercise: The surprising links between your brain and body. Pima Council on Aging Living Well Series. Green Valley, AZ.
• Alexander, G. E. (2013). MRI Workgroup Update. McKnight Brain Institute Inter-Institutional meeting. Tucson, AZ.
• Alexander, G. E. (2013). Opportunities and challenges: Multi-site MRI studies of cognitive aging. McKnight Brain Institute Inter-Institutional Meeting. Birmingham, AL.
• Alexander, G. E. (2013). Plans for studies of healthy and pathological aging. Alzheimer's Disease Consortium Retreat. AZ.
• Alexander, G. E. (2013). Viewing the Aging Brain: New Findings from Neuroimaging Research. Jewish Community Center. Tucson, AZ.
• Alexander, G. E. (2012). Characterizing cognitive aging in humans with links to animal models. McKnight Brain Institute Inter-Institutional Meeting. Tucson, AZ.
• Alexander, G. E., Alexander, G. E., Hanson, K. D., Chen, K., Reiman, E. M., Bernstein, M. A., Kornak, J., Schuff, N., Fox, N. C., Thompson, P. M., Weiner, M. W., & Jack, C. R. (2008, 2008-07-01). Six month MRI gray matter declines in Alzheimer's dementia evaluated by voxel based morphometry with multivariate network analysis: Preliminary findings from the ADNI Study. Alzheimer's Imaging Consortium Meeting. Chicago, IL.
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  ;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Other collaborative: Yes;Specify other collaborative: Part of the ADNI collaborative project.;Type of Presentation: Academic Conference;
• Alexander, G. E., Ayutyanont, N., Chen, K., Liu, X., Reschke, C., Lee, W., Bandy, D., Alexander, G. E., Jagust, W. J., Koeppe, R. A., Foster, N. L., & Reiman, E. M. (2008, 2008-07-01). Differentiating amnestic MCI converting to probable AD from stable amnestic MCI using FDG-PET and an AD-related hypometabolism overlap index. Alzheimer's Imaging Consortium Meeting. Chicago, IL.
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  ;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Other collaborative: Yes;Specify other collaborative: Part of the ADNI collaborative project.;Type of Presentation: Academic Conference;
• Alexander, G. E., Bergfield, K. L., Hanson, K. D., Chen, K., Teipel, S. J., Hampel, H., Rapoport, S. I., Moeller, J. R., & Alexander, G. E. (2008, 2008-11-01). Age-related regional MRI gray matter network pattern in healthy aging: A replication study.. Society for Neuroscience. Washington, DC.
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  ;Your Role: Senior author supervising study design, analysis, and abstract revision;Refereed: Yes;Interdisciplinary: Yes;Collaborative with graduate student: Yes;Other collaborative: Yes;Specify other collaborative: Collaboration with colleagues at the NIH, Columbia University, and the Ludwig Maximilian University;Type of Presentation: Academic Conference;
• Alexander, G. E., Brickman, A. M., Muraskin, J., Shamy, J. L., Steffener, J., Buonocore, M. H., Rapp, P. R., Alexander, G. E., Barnes, C. A., & Small, S. A. (2008, 2008-11-01). Cerebral blood volume magnetic resonance imaging reveals localized correlates of age-associated cognitive decline in rhesus monkeys. Society for Neuroscience. Washington, DC.
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  ;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Collaborative with faculty member in unit: Yes;Other collaborative: Yes;Specify other collaborative: Part of collaboration with Columbia University and UC Davis;Type of Presentation: Academic Conference;
• Alexander, G. E., Chen, K., Lee, W., Liu, X., Alexander, G. E., Bandy, D., Reschke, C., Foster, N., Weiner, M., Koeppe, R., Jagust, W., & E., R. (2008, 2009-03-01). The consistency of hypometabolic brain voxels in probable Alzheimer's disease and amnestic mild cognitive impairment patients from the Alzheimer's Disease Neuroimaging Initiative. Alzheimer's Imaging Consortium Meeting. Chicago, IL.
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  ;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Other collaborative: Yes;Specify other collaborative: Part of the ADNI collaborative project.;Type of Presentation: Academic Conference;
• Alexander, G. E., Edgin, J. O., Hanson, K. D., Chen, K., Bergfield, K. L., Nadel, L., Teipel, S. J., Hampel, H., Rapoport, S. I., Schapiro, M. B., & Alexander, G. E. (2008, 2008-11-01). Regional network of MRI gray matter reductions associated with aging in non-demented adults with Down Syndrome. Society for Neuroscience. Washington, DC.
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  ;Your Role: Senior author supervising study design, analysis, and abstract revision;Refereed: Yes;Interdisciplinary: Yes;Collaborative with graduate student: Yes;Collaborative with faculty member in unit: Yes;Other collaborative: Yes;Specify other collaborative: Collaboration with colleagues at the NIH and Ludwig Maximilian University;Type of Presentation: Academic Conference;
• Alexander, G. E., Hanson, K. D., Bergfield, K. L., Chen, K., Reiman, E. M., Bernstein, M. A., Kornak, J., Harvey, D. J., Schuff, N. W., Thompson, P. M., Weiner, M. W., Jack, C. R., & Alexander, G. E. (2008, 2008-11-01). Twelve month MRI gray matter declines in Alzheimer's dementia evaluated by voxel-based morphometry with multivariate network analyses: Findings from the Alzheimer's Disease Neuroimaging Initiative. Society for Neuroscience. Washington, DC.
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  ;Your Role: Senior author supervising study design, analysis, and abstract revision;Refereed: Yes;Interdisciplinary: Yes;Collaborative with graduate student: Yes;Other collaborative: Yes;Specify other collaborative: Part of the ADNI collaborative project.;Type of Presentation: Academic Conference;
• Alexander, G. E., JBS, L., Chen, K., Lee, W., Recshke, C., Reeder, S., Bandy, D., Alexander, G. E., Caselli, R. J., & Reiman, E. M. (2008, 2008-11-01). Hypertension is associated with hypometabolism in brain regions affected by Alzheimer's disease and normal aging: preliminary results. Society for Neuroscience. Washington, DC.
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  ;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Other collaborative: Yes;Specify other collaborative: Part of a collaboration with Banner Good Samaritan and Mayo Clinic;Type of Presentation: Academic Conference;
• Alexander, G. E., Lee, W., Langbaum, J., Chen, K., Recshke, C., Bandy, D., Alexander, G. E., Foster, N. L., Weiner, M. W., Koeppe, R. A., Jagust, W., & EM., R. (2008, 2008-07-01). Categorical and correlational analysis of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer's Disease Neuroimaging Initiative.. Alzheimer's Imaging Consortium Meeting. Chicago, IL.
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  ;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Other collaborative: Yes;Specify other collaborative: Part of the ADNI collaborative project.;Type of Presentation: Academic Conference;
• Alexander, G. E., Smith, J. F., Alexander, G. E., Chen, K., Braun, A. R., & Horwitz, B. (2008, 2008-11-01). Assessing the functional organization of visual-semantic memory: An fMRI study of linguistic and non-linguistic visual-to-auditory associations. Society for Neuroscience. Washington, DC.
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  ;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Other collaborative: Yes;Specify other collaborative: Collaboration with colleagues at the NIH Intramural Research Program.;Type of Presentation: Academic Conference;
• Alexander, G. E., Zhang, H., Wu, T., M-H, B., Reiman, E. M., Alexander, G. E., Thompson, P. M., CR, J. J., & Chen, K. (2008, 2008-07-01). Use of the support vector machine and sensitivity of an Alzheimer's disease-related region-of-interest gray matter classifier in identifying amnestic mild cognitive impairment subjects who convert to Alzheimer's disease: Preliminary findings from the Alzh. Alzheimer's Neuroimaging Consortium Meeting. Chicago, IL.
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  ;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Other collaborative: Yes;Specify other collaborative: Zhang H, Wu T, Bae M-H, Reiman EM, Alexander GE, Thompson PM, Jack Jr CR, & Chen K. (2008) Use of the support vector machine and sensitivity of an Alzheimer's disease-related region-of-interest gray matter classifier in identifying amnestic mild cognitive impairment subjects who convert to Alzheimer's disease: Preliminary findings from the Alzheimer's Disease Neuroimaging Initiative. Abstract for presentation at the Alzheimer's Imaging Consortium meeting, Chicago, IL.;Type of Presentation: Academic Conference;
• Alexander, G. E., angbaum, J., Reiman, E. M., Chen, K., Alexander, G. E., Bandy, D., Smilovici, O., Lee, W., Reschke, C., & Caselli, R. (2008, 2008-07-01). Regional hypometabolism in cognitively normal Hispanic carriers of the apolipoprotein E epsilon4 allele. Alzheimer's Imaging Consortium Meeting. Chicago, IL.
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  ;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Other collaborative: Yes;Specify other collaborative: Collaboration with Mayo Clinic and Banner Good Samaritan Medical Center;Type of Presentation: Academic Conference;
• Alexander, G. E., Alexander, G. E., Chen, K., Reiman, E. M., Merkley, T. L., Aschenbrenner, M., Bandy, D., Caselli, R. J., & JR., M. (2007, 2007-11-01). Regional network of gray matter reductions associated with APOE ε4 in cognitive normal young to middle-aged adults.. Society for Neuroscience. San Diego, CA.
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  Accepted as paper presentation.;Refereed: Yes;Interdisciplinary: Yes;Collaborative with faculty member at UA: Yes;Type of Presentation: Academic Conference;
• Alexander, G. E., Caselli, R. J., Chen, K., Lee, W., Alexander, G. E., & EM., R. (2007, 2007-11-01). FDG-PET imaging of amnestic pre-MCI.. Society for Neuroscience. San Diego, CA.
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  Acccepted for paper presentation.;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Collaborative with faculty member at UA: Yes;Type of Presentation: Academic Conference;
• Alexander, G. E., Chen, K., Reiman, E. M., Alexander, G. E., Caselli, R. J., Smilovici, O., Lee, W., Reschke, C., & D., B. (2007, 2007-11-01). Linkage between cerebral glucose metabolism pattern and APOE4 gene dose predicts 4-year long term memory decline.. Society for Neuroscience. San Diego, CA.
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  Acccepted for paper presentation.;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Collaborative with faculty member at UA: Yes;Type of Presentation: Academic Conference;
• Alexander, G. E., Engler, E. B., Alexander, G. E., Zay, C. A., & HA., B. (2007, 2007-11-01). Age-related change in the ability to handle an increased working memory load: Associations with gonadotropins and ovarian hormones.. Society for Neuroscience. San Diego, CA.
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  Poster presentation.;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Other collaborative: Yes;Specify other collaborative: Collaboration with Arizona Alzheimer Research Center investigator.;Type of Presentation: Academic Conference;
• Alexander, G. E., Reiman, E. M., Chen, K., Caselli, R. J., Bandy, D., Lee, W., Smilovici, C., Reschke, C., & GE., A. (2007, 2007-11-01). Higher mid-life cholesterol levels are associated with hypometabolism in brain regions affected by Alzheimer's disease and normal aging.. Society for Neuroscience. San Diego, CA.
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  Accepted for paper presentation.;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Collaborative with faculty member at UA: Yes;Type of Presentation: Academic Conference;
• Alexander, G. E., Smith, J. F., Husain, F. T., Pajor, N. M., Goldinger, S., Chen, K., Alexander, G. E., & B., H. (2007, 2007-11-01). Functional Neuroimaging of Immediate, Remote, and Linguistic Visual-to-Auditory Paired Associates Memory.. Society for Neuroscience. San Diego, CA.
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  Accepted for paper presentation.;Your Role: Contributed to analysis, aspects of study design, and abstract revision.;Refereed: Yes;Interdisciplinary: Yes;Other collaborative: Yes;Specify other collaborative: Collaborative project with investigators at the Intramural Research Program at NIH.;Type of Presentation: Academic Conference;

Poster Presentations

• Bharadwaj, P. K., Andrews Hanna, J. R., & Alexander, G. E. (2022, February). Association of Gray Matter Network Covariance Related to Cerebrospinal Fluid pTau 181 /Aβ 42 Biomarker Clusters of Alzheimer's Disease Risk with Cognitive Function in Healthy Older Adults. International Neuropsychological Society. New Orleans, LA.
• Smith, S. G., Bharadwaj, P. K., Van Etten, E. J., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2022, February). Association of Age with Gray to White Matter Contrast Differences is Mediated by White Matter Integrity in Healthy Older Adults. International Neuropsychological Society. New Orleans, LA.
• Song, H., Bharadwaj, P. K., Raichlen, D. A., Habeck, C. G., Huentelman, M. J., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2022, February). Homocysteine-Related Network Covariance Pattern of Subcortical Gray Matter Volumes in Healthy Aging. International Neuropsychological Society. New Orleans, LA.
• Van Etten, E. J., Bharadwaj, P. K., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2022, February). Influence of age and apolipoprotein E ε4 status on regional white matter hyperintensity volume and cognition in healthy aging. International Neuropsychological Society. New Orleans, LA.
• Smith, S. G., Bharadwaj, P. K., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2021, February). Age-Related Regional Network Covariance Pattern of Gray to White Matter Contrast in Healthy Middle-Aged to Older Adults. International Neuropsychological Society. San Diego, CA.
• Van Etten, E. J., Bharadwaj, P. K., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2021, February). BMI-related regional covariance patterns of white matter microstructure in healthy older adults.. International Neuropsychological Society. San Diego, CA.
• Smith, S. G., Bharadwaj, P. K., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2020, February). Age-Related Regional Network Pattern of Cortical Thickness in Healthy Middle-Aged to Older Adults. Abstract presented at the International Neuropsychological Society Annual Meeting. Denver, Co.
• Song, H., Raichlen, D. A., Klimentidis, Y. C., Bharadwaj, P. K., & Alexander, G. E. (2020, February). Interactive Effects of WMH Volume and Sex on Heart Rate Response to Aerobic Exercise in Healthy Middle-Aged to Older Adults. Abstract presented at the International Neuropsychological Society Annual Meeting. Denver, CO.
• Van Etten, E. J., Bharadwaj, P. K., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2020, February). White matter integrity mediates the relationship between Body Mass Index and executive function in healthy older adults. Abstract presented at the International Neuropsychological Society Annual Meeting. Denver, CO.
• Bharadwaj, P., Andrews-Hanna, J., Kuo, P., & Alexander, G. E. (2019, November). Alzheimer's disease fluid biomarkers related gray matter covariance patterns in healthy older adults. Abstract presented at the Society for Neuroscience Annual Meeting. Chicago, IL.
• Raichlen, D., Bharadwaj, P., Franchetti, M. K., Sims, S., Rezaei, R., Merritt, S., Jessup, C., Porges, E., Geldmacher, D., Hishaw, G., Alperin, N., Trouard, T., Wadley, V., Levin, B., Woods, A., Rundek, T., Visscher, K., Cohen, R., & Alexander, G. E. (2019, November). Relation of daily activity patterns to cortical gray matter maps in the healthy oldest old: Findings from the McKnight Brain Aging Registry. Abstract presented at the Society for Neuroscience Annual Meeting. Chicago, IL.
• Van Etten, E., Bharadwaj, P., Hishaw, G. A., Trouard, T., & Alexander, G. E. (2019, November). Mediation of age and hippocampal volume by temporal lobe white matter hyperintensities differ in relation to APOE e4 status in healthy older adults. Abstract presented at the Society for Neuroscience Annual Meeting. Chicago, IL.
• Bharadwaj, P. K., Nguyen, L. A., Moeller, T. P., Haybeck, C. G., & Alexander, G. E. (2018, November). Relation of white matter lesion load to cortical gray matter thickness in healthy aging. Abstract presented at the Society for Neuroscience Annual Meeting. San Diego, CA.
• Franchetti, M. K., Bharadwaj, P. K., Nguyen, L. A., Klimentidis, Y. C., Hishaw, G. A., Trouard, T. P., Raichlen, D. A., & Alexander, G. E. (2018, November). Relation between physical sport activity and white matter hyperintensity volume in older adults. Abstract presented at the Society for Neuroscience Annual Meeting. San Diego, CA.
• Furlong, M., Alexander, G. E., Klimentidis, Y., & Raichlen, D. (2018, August). Physical Activity may Modify the Association between Air Pollution and Brain Structure in the UK Biobank. Abstract presented at the International Society for Environmental Epidemiology Annual Meeting. Ottawa, Canada.
• Mizell, J., Franchetti, M., Keung, W., Sundman, M., Chou, Y., Alexander, G. E., & Wilson, R. D. (2018, November). Differential effects of healthy aging on directed and random exploration. Abstract presented at the Society for Neuroscience Annual Meeting. San Diego, CA.
• Van Etten, E., Bharadwaj, P. K., Nguyen, L., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2018, November). Hippocampal mediation of subjective memory complaints differs by hypertension status in healthy older adults. Abstract presented at the Society for Neuroscience Annual Meeting. San Diego, CA.
• Alexander, G. E., Bharadwaj, P. K., Raichlen, D. A., Klimentidis, Y. C., Fitzhugh, M. C., Nguyen, L. A., Haws, K. A., Hishaw, G. A., Moeller, J. R., Habeck, C. G., & Trouard, T. P. (2017, November). Network covariance of hippocampal subfield volumes associated with healthy aging and the risk for Alzheimer’s disease. Society for Neuroscience Annual Meeting.
• Bharadwaj, P. K., Fitzhugh, M. C., Nguyen, L. A., Haws, K. A., Hishaw, G. A., Trouard, T. P., Moeller, J. R., Habeck, C. G., & Alexander, G. E. (2017, November). Multimodal neuroimaging reveals white matter microstructure related covariance networks of subcortical gray matter volumes in healthy aging. Society For Neuroscience Annual Meeting.
• Do, L., Bernstein, A., Bharadwaj, P. K., Alexander, G. E., Barnes, C. A., & Trouard, T. P. (2017, November). Advanced techniques for characterizing rodent brains with diffusion MRI. Society for Neuroscience Annual Meeting.
• Franchetti, M., Bharadwaj, P. K., Nguyen, L. A., Klimentidis, Y. C., Haws, K. A., Fitzhugh, M. C., Hishaw, G. A., Trouard, T. P., Raichlen, D. A., & Alexander, G. E. (2017, November). Relation of physical sport activity to regional white matter integrity in older adults. Society for Neuroscience Annual Meeting.
• Nguyen, L. A., Bharadwaj, P. K., Fitzhugh, M. C., Haws, K. A., Moeller, J. R., Habeck, C. G., Trouard, T. P., & Alexander, G. E. (2017, Nov.). Regional covariance patterns of white matter microstructure in healthy aging. Society for Neuroscience Annual Meeting.
• Bharadwaj, P., Nguyen, L., Haws, K., Hishaw, G., Trouard, T., & Alexander, G. E. (2016, November). Differential regional alterations of white matter integrity in healthy cognitive aging.. Society for Neuroscience Annual Meeting.
• Franchetti, M., Bharadwaj, P., Nguyen, L., Haws, K., Fitzhugh, M., Hishaw, G., Raichlen, D., & Alexander, G. E. (2016, November). Relation of physical sport activity to cognitive performance in older adults. Society for Neuroscience Annual Meeting.
• Nguyen, L., Bharadwaj, P., Haws, K., Hishaw, G., Trouard, T., & Alexander, G. E. (2016, November). Differential effects of hypertension status and white matter hyperintensity volume on white matter integrity in older adults. Society for Neuroscience Annual Meeting.
• Bharadwaj, P. K., Burke, S. N., Trouard, T. P., Chen, K., Moeller, J. R., Barnes, C. A., & Alexander, G. E. (2015, October). Age-associated regional network pattern of MRI gray matter in the bonnet macaque. Society for Neuroscience Annual Meeting.
• Kuo, P. H., Bharadwaj, P. K., Krafft, W. P., Fitzhugh, M. C., Alexander, G. E., & Zubal, G. (2015, October). Rapid, fully automated method for quantitative analysis of PET amyloid scans in Alzheimer’s disease. Society for Neuroscience Annual Meeting.
• Nguyen, L. A., Bharadwaj, P. K., Haws, K. A., Fitzhugh, M. C., Trouard, T. P., Hishaw, G. A., & Alexander, G. E. (2015, October). Relation of white matter hyperintensity volume to cognitive performance in older adults. Society for Neuroscience Annual Meeting.
• Raichlen, D., Bharadwaj, P. K., Fitzhugh, M. C., Haws, K. A., Torre, G. A., Trouard, T. P., & Alexander, G. E. (2015, October). Differences in resting state functional connectivity between aerobic athletes and sedentary young adults. Society for Neuroscience Annual Meeting.
• Haws, K., Hishaw, G. A., Totenhagen, J. W., Torre, G. A., Gillespie, W. L., Reid, B. A., Nguyen, L. A., Fitzhugh, M. C., Lines, J. W., & Alexander, G. E. (2013, November). Relation of MRI white matter hyperintensity severity to nocturnal blood pressure variation and hypertension in healthy cognitive aging. Society for Neuroscience Annual Meeting.
• Lines, J. W., Totenhagen, J. W., Haws, K. A., Fitzhugh, M. C., Hishaw, G. A., Torre, G. A., Gillespie, W. L., Chen, K., Reiman, E. M., Trouard, T. P., Moeller, J. R., & Alexander, G. E. (2013, November). Multivariate regional network of gray matter volume associated with healthy cognitive aging. Society for Neuroscience Annual Meeting.
• Nguyen, L. A., Haws, K. A., Totenhagen, J. W., Torre, G. A., Gillespie, W. L., Fitzhugh, M. C., Hishaw, G. A., & Alexander, G. E. (2013, November). Effects of memory complaints and hypertension status on cognitive performance in the elderly. Society for Neuroscience Annual Meeting.
• Reid, B. A., Haws, K. A., Totenhagen, J. W., Torre, G. A., Gillespie, W. L., Fitzhugh, M. C., Lines, J. W., Hishaw, G. A., & Alexander, G. E. (2013, November). Effects of self-reported sleep quality on cognitive functioning in healthy older adults. Society for Neuroscience Annual Meeting.
• Totenhagen, J., Lines, J. W., Bergfield, K. L., Torre, G. A., Gillespie, W. L., Haws, K. A., Fitzhugh, M. C., Reid, B. A., Nguyen, L. A., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2013, November). Resting state MRI functional connectivity differences in healthy middle-aged to elderly adults. Society for Neuroscience Annual Meeting.

Others

• Alexander, G., Lui, C. Y., & Alexander, G. E. (2008). Prolonged survival in 2 nonagenarians with heart failure and severe aortic stenosis. Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital.
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  The prevalence of severe aortic stenosis is 6% in persons 85 to 86 years of age according to a Finnish population-based report. In the United States, the population over 80 years old is projected to rise from the current 7 million to 25 million by the year 2050. Thus, aortic stenosis in aging adults, and the management questions it poses, will be increasingly common. We report herein the cases of 2 nonagenarian patients with severe symptomatic aortic stenosis who far outlived the natural history of this disease. We suspect that we are seeing a change in the prognosis of senile aortic stenosis as a result of advances in the geriatric care and management of advanced heart failure. Furthermore, the unusual longevity of these patients was made possible by the remarkable holistic care given by a dedicated, altruistic caregiver who had training in psychology, theology, and nursing.