Alex Hishaw

Interests

Research

Behavioral Neurology, Neuropsychiatry, Head Injury, Dementia

Courses

Scholarly Contributions

Journals/Publications

• Aksu, S., Indahlastari, A., O'Shea, A., Marsiske, M., Cohen, R., Alexander, G. E., DeKosky, S. T., Hishaw, G. A., Dai, Y., Wu, S. S., & Woods, A. J. (2025). Effect of transcranial direct current stimulation with cognitive training on executive functions in healthy older adults: a secondary analysis from the ACT trial. GeroScience, 47(1), 1361-1380.
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  Cognitive aging has become a public health concern as the mean age of the population is ever-increasing. It is a naturalistic and common process of degenerative and compensatory changes that may result in neurocognitive disorders. While heterogeneous, cognitive aging mostly affects executive functions that may be associated with functional losses during activities of daily living. Cognition-oriented treatments like cognitive training and transcranial direct current stimulation (tDCS) have garnered considerable attention in the past few decades while the exact picture regarding their efficacy in healthy older adults has not been determined yet. The present paper aimed to evaluate the effects of a 3-month intervention of tDCS over the dorsolateral prefrontal cortex (DLPFC) with multimodal cognitive training on the Stroop test and Trail Making Tests A and B performance. One hundred and ninety-three healthy older adults from 2 sites were administered repeated sessions of active/sham tDCS with cognitive training. Baseline, post-intervention, and 1-year performance results between groups were compared using multiple linear regressions. Active tDCS resulted in better Stroop test performance at post-intervention (p = 0.033) but not at 1-year follow-up while no differences between groups were observed in Trail Making Tests A & B performance. The present results may correspond to a modest improvement in conflict monitoring, potentially due to modulation of prefrontal regions, without changing shifting performance. Further investigation is warranted to draw an interference regarding the subdomain-specific impact of repeated tDCS with multimodal cognitive training on executive functions.
• Britton, M. K., Hoogerwoerd, H., Juhasz, J., Johnson, K. J., Stewart, P. D., Bharadwaj, P. K., Merritt, S. S., Jessup, C. J., Wright, C. B., Hishaw, G. A., Raichlen, D. A., Del Bene, V. A., Wadley, V. G., Trouard, T. P., Alperin, N., Levin, B. E., Rundek, T., Visscher, K. M., Alexander, G. E., , Cohen, R. A., et al. (2025). Your brain doesn't look a day past 70! Cross-sectional associations with brain-predicted age in the cognitively-intact oldest-old. GeroScience.
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  The cognitively-intact oldest-old (85 +) may be the most-resilient members of their birth cohort; due to survivorship effects (e.g., depletion of susceptibles), risk factors associated with brain aging biomarkers in younger samples may not generalize to the cognitively-intact oldest-old. We evaluated associations between established aging-related risk factors and brain-predicted age difference (brainPAD) in a cross-sectional cognitively-intact oldest-old sample. Additionally, we evaluated brainPAD-cognition associations to characterize brain maintenance vs. cognitive reserve in our sample. Oldest-old adults (N = 206; 85-99 years; Montreal Cognitive Assessment > 22 or neurologist evaluation) underwent T1-weighted MRI; brainPAD was generated with brainageR, such that more-positive brainPAD reflected more-advanced brain aging. Sex, education, alcohol and smoking history, exercise history, BMI, cardiovascular and metabolic disease history, and anticholinergic medication burden were self-reported. Global cognitive z-score and coefficient of variation were derived from the UDS 3.0 cognitive battery; crystallized-fluid discrepancy was derived from the NIH Toolbox Cognitive Battery. Mean brainPAD was -7.99 (SD: 5.37; range: -24.50, 6.03). Women showed more-delayed brain aging than men (B = -2.9, 95% CI = -4.6, -1.1, p = 0.002). No other exposures were significantly associated with brainPAD. BrainPAD was not associated with any cognitive variable. These findings suggest that cognitively-intact oldest-old adults may be atypically-resistant to risk factors associated with aging in younger samples, consistent with survivorship effects in aging. Furthermore, brainPAD may have limited explanatory value for cognitive performance in cognitively-intact oldest-old adults, potentially due to high cognitive reserve. Overall, our findings highlight the impact of survivorship effects on brain aging research.
• Britton, M. K., Hoogerwoerd, H., Juhasz, J., Johnson, K. J., Stewart, P. D., Merritt, S. S., Jessup, C. J., Wright, C. B., Raichlen, D. A., Hishaw, G. A., Del Bene, V. A., Wadley, V. G., Trouard, T. P., Alperin, N., Levin, B. E., Rundek, T., Visscher, K. M., Alexander, G. E., Cohen, R. A., , Porges, E. C., et al. (2025). Your Brain Doesn't Look a Day Past 70! Cross-Sectional Associations with Brain-Predicted Age in the Cognitively-Intact Oldest-Old. bioRxiv : the preprint server for biology.
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  The cognitively-intact oldest-old (85+) may be the most-resilient members of their birth cohort; due to survivorship effects (e.g., depletion of susceptibles), risk factors associated with brain aging biomarkers in younger samples may not generalize to the oldest-old. We evaluated associations between established aging-related risk factors and brain-predicted age difference (brainPAD) in a cross-sectional cognitively-intact oldest-old sample. Additionally, we evaluated brainPAD-cognition associations to characterize brain maintenance vs. cognitive reserve in our sample. Oldest-old adults (N = 206; 85-99 years; MoCA > 22 or neurologist evaluation) underwent T1-weighted MRI; brainPAD was generated with brainageR, such that more-positive brainPAD reflected relatively advanced brain aging. Sex, educational attainment, alcohol and smoking history, exercise history, BMI, cardiovascular and metabolic disease history, and anticholinergic medication burden were self-reported. Global cognitive z-score and coefficient of variation were derived from the NACC UDS 3.0 cognitive battery; crystallized-fluid discrepancy was derived from the NIH Toolbox Cognitive Battery. Mean brainPAD was -7.99 (SD: 5.37; range: -24.50, 6.03). Women showed more-delayed brain aging than men (B = -2.35, 95% CI = -4.28, -0.41, p = 0.018). No other exposures were associated with brainPAD. BrainPAD was not associated with any cognitive variable. These findings suggest that cognitively-intact oldest-old adults may be atypically-resistant to risk factors associated with aging in younger samples, consistent with survivorship effects in aging. Furthermore, brainPAD may have limited explanatory value for cognitive performance in cognitively-intact oldest-old adults, potentially due to high cognitive reserve. Overall, our findings highlight the impact of survivorship effects on brain aging research.
• Britton, M. K., Jensen, G., Edden, R. A., Puts, N. A., Nolin, S. A., Merritt, S. S., Rezaei, R. F., Forbes, M., Johnson, K. J., Bharadwaj, P. K., Franchetti, M. K., Raichlen, D. A., Jessup, C. J., Hishaw, G. A., Van Etten, E. J., Gudmundson, A. T., Murali-Manohar, S., Cowart, H., Trouard, T. P., , Geldmacher, D. S., et al. (2025). "Surviving and Thriving": evidence for cortical GABA stabilization in cognitively-intact oldest-old adults. Translational psychiatry, 15(1), 79.
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  Age-related alterations in GABAergic function, including depletion of cortical GABA concentrations, is likely associated with declining cognitive performance in normative aging. However, the extent to which GABAergic function is perturbed in the highest-functioning stratum of the oldest-old (85+) population is unknown. For the first time, we report the stability of cortical GABA in this population. We extend our previously-reported Individual Participant Data Meta-Analysis of GABA levels across the lifespan, integrating four large cross-sectional datasets sampling cognitively-intact oldest-old adults. Within our lifespan model, the slope of age-related GABA differences in cognitively-intact oldest-old adults flattens after roughly age 80; within oldest-old adults only, inclusion of age does not improve the fit of models predicting GABA. We interpret these findings as an effect of survivorship: inclusion in the study required intact cognition, and too great a reduction of GABA levels may not be compatible with neurophysiological function needed for intact cognition. This work contributes to a growing body of evidence suggesting that successful cognitive aging may require intact GABAergic function, as well as further characterizing successful aging amongst oldest-old adults and emphasizing GABA as a potential target for interventions to prolong cognitive health in aging.
• Nolin, S. A., Faulkner, M. E., Stewart, P., Fleming, L. L., Merritt, S., Rezaei, R. F., Bharadwaj, P. K., Franchetti, M. K., Raichlen, D. A., Jessup, C. J., Edwards, L., Hishaw, G. A., Van Etten, E. J., Trouard, T. P., Geldmacher, D., Wadley, V. G., Alperin, N., Porges, E. S., Woods, A. J., , Cohen, R. A., et al. (2025). Network segregation is associated with processing speed in the cognitively healthy oldest-old. eLife, 14.
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  The brain is organized into systems and networks of interacting components. The functional connections among these components give insight into the brain's organization and may underlie some cognitive effects of aging. Examining the relationship between individual differences in brain organization and cognitive function in older adults who have reached oldest-old ages with healthy cognition can help us understand how these networks support healthy cognitive aging. We investigated functional network segregation in 146 cognitively healthy participants aged 85+ in the McKnight Brain Aging Registry (MBAR). We found that the segregation of the association system and the individual networks within the association system (the fronto-parietal network , cingulo-opercular network, and default mode network), has strong associations with overall cognition and processing speed. We also provide a healthy oldest-old (85+) cortical parcellation that can be used in future work in this age group. This study shows that network segregation of the oldest-old brain is closely linked to cognitive performance. This work adds to the growing body of knowledge about differentiation in the aged brain by demonstrating that cognitive ability is associated with differentiated functional networks in very old individuals representing successful cognitive aging.
• Smith, S. G., Bharadwaj, P. K., Raichlen, D. A., Grilli, M. D., Andrews-Hanna, J. R., Hishaw, G. A., Huentelman, M. J., Trouard, T. P., & Alexander, G. E. (2025). Regional network covariance patterns of white matter integrity related to cardiorespiratory fitness in healthy aging. Frontiers in aging neuroscience, 17, 1542458.
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  Cardiorespiratory fitness (CRF), measured by VOmax, is an indicator of vascular functioning that can influence the integrity of brain microstructural white matter tracts in aging. How CRF is related to regional patterns of white matter bundles for magnetic resonance imaging (MRI) diffusion metrics (axial diffusivity, AD; radial diffusivity, RD; mean diffusivity, MD; fractional anisotropy, FA) has been less studied. We used a multivariate analysis method, the Scaled Subprofile Model (SSM), to identify network patterns of MRI tract-specific white matter integrity (WMI) for AD, RD, MD, and FA related to VOmax and to evaluate their relation to demographic, vascular health, and dementia risk factors in 167 cognitively unimpaired older adults, ages 50 to 88. We identified four CRF-related regional patterns of WMI characterized by enhanced integrity in commissural pathways that connect areas within anterior brain regions (prefrontal body of the corpus callosum), connect subcortical regions to one another (fornix), and include selected association tracts (arcuate fasciculus, superior longitudinal fasciculus). Greater white matter lesion load, in addition to age, was associated with reduced expression of all four CRF-WMI patterns, while high vascular risk level was further associated with reduced expression of the RD, MD, and FA patterns. The regional patterns of RD and FA were most strongly associated with CRF. The results suggest that in healthy older adults, enhanced CRF is differentially associated with regional patterns of WMI, which are related to age and further impacted by macrostructural white matter lesion load and vascular risk. These findings support the use of the multivariate SSM in identifying regional patterns of white matter tracts that may provide markers of brain aging and cerebrovascular health.
• Song, H., Bharadwaj, P. K., Grilli, M. D., Raichlen, D. A., Habeck, C. G., Huentelman, M. J., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2025). Subcortical brain volumetric differences related to white matter lesion volume and cognition in healthy aging. npj aging, 11(1), 44.
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  White matter hyperintensity (WMH) lesions associated with small vessel cerebrovascular disease (CVD) are common structural neuroimaging findings in older adults. Greater global brain WMH burden related to aging has been implicated in dementia but has also been linked to brain atrophy and cognitive dysfunction in old age. We sought to investigate the regionally distributed association of global WMH lesion load with subcortical gray matter (SGM) volumes using a multivariate network analysis method in 178 community-dwelling, healthy older adults (mean age = 69.77 ± 10.22 years). We additionally applied mediation models with WMH-related subcortical volumetric differences as a mediator to evaluate a potential global WMH-related vascular risk pathway leading to cognitive aging. Global WMH burden was associated with a regionally distributed pattern of SGM atrophy involving bilateral putamen and left nucleus accumbens, with relative volume increases in bilateral caudate nucleus. Mediation analyses revealed that increasing age predicted greater WMH-SGM pattern expression, which then predicted slowed processing speed that was, in turn, associated with decrements in other age-sensitive cognitive domains of memory, executive functioning, and fine motor function. These results suggest that the multivariate WMH-SGM pattern and its association with processing speed may provide an important early indicator of age-related decrements in higher-order cognitive processes, reflecting a potential link between CVD and broader cognitive dysfunction across multiple domains in healthy aging.
• Zhu, G., Jiang, B., Chen, H., Heit, J. J., Etter, M., Hishaw, G. A., Faizy, T. D., Steinberg, G., & Wintermark, M. (2025). Using generative adversarial deep learning networks to synthesize cerebrovascular reactivity imaging from pre-acetazolamide arterial spin labeling in moyamoya disease. Neuroradiology, 67(5), 1251-1262.
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  Cerebrovascular reactivity (CVR) assesses vascular health in various brain conditions, but CVR measurement requires a challenge to cerebral perfusion such as the administration of acetazolamide(ACZ), thus limiting widespread use. We determined whether generative adversarial networks (GANs) can create CVR images from baseline pre-ACZ arterial spin labeling (ASL) MRI.
• Aksu, S., Indahlastari, A., O'Shea, A., Marsiske, M., Cohen, R., Alexander, G. E., DeKosky, S. T., Hishaw, G. A., Dai, Y., Wu, S. S., & Woods, A. J. (2024). Facilitation of working memory capacity by transcranial direct current stimulation: a secondary analysis from the augmenting cognitive training in older adults (ACT) study. GeroScience, 46(5), 4075-4110.
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  Aging is a public health concern with an ever-increasing magnitude worldwide. An array of neuroscience-based approaches like transcranial direct current stimulation (tDCS) and cognitive training have garnered attention in the last decades to ameliorate the effects of cognitive aging in older adults. This study evaluated the effects of 3 months of bilateral tDCS over the frontal cortices with multimodal cognitive training on working memory capacity. Two hundred ninety-two older adults without dementia were allocated to active or sham tDCS paired with cognitive training. These participants received repeated sessions of bilateral tDCS over the bilateral frontal cortices, combined with multimodal cognitive training. Working memory capacity was assessed with the digit span forward, backward, and sequencing tests. No baseline differences between active and sham groups were observed. Multiple linear regressions indicated more improvement of the longest digit span backward from baseline to post-intervention (p = 0.021) and a trend towards greater improvement (p = 0.056) of the longest digit span backward from baseline to 1 year in the active tDCS group. No significant between-group changes were observed for digit span forward or digit span sequencing. The present results provide evidence for the potential for tDCS paired with cognitive training to remediate age-related declines in working memory capacity. These findings are sourced from secondary outcomes in a large randomized clinical trial and thus deserve future targeted investigation in older adult populations.
• Hardcastle, C., Kraft, J. N., Hausman, H. K., O'Shea, A., Albizu, A., Evangelista, N. D., Boutzoukas, E. M., 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. (2024). Learning ratio performance on a brief visual learning and memory test moderates cognitive training gains in Double Decision task in healthy older adults. GeroScience, 46(4), 3929-3943.
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  Cognitive training using a visual speed-of-processing task, called the Useful Field of View (UFOV) task, reduced dementia risk and reduced decline in activities of daily living at a 10-year follow-up in older adults. However, there was variability in the achievement of cognitive gains after cognitive training across studies, suggesting moderating factors. Learning trials of visual and verbal learning tasks recruit similar cognitive abilities and have overlapping neural correlates with speed-of-processing/working memory tasks and therefore could serve as potential moderators of cognitive training gains. This study explored the association between the Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT-R) learning with a commercial UFOV task called Double Decision. Through a secondary analysis of a clinical trial, we assessed the moderation of HVLT-R and BVMT-R learning on Double Decision improvement after a 3-month speed-of-processing/attention and working memory cognitive training intervention in a sample of 75 cognitively healthy older adults. Multiple linear regressions showed that better baseline Double Decision performance was significantly associated with better BVMT-R learning (β =  - .303). This association was not significant for HVLT-R learning (β =  - .142). Moderation analysis showed that those with poorer BVMT-R learning improved the most on the Double Decision task after cognitive training. This suggests that healthy older adults who perform below expectations on cognitive tasks related to the training task may show the greatest training gains. Future cognitive training research studying visual speed-of-processing interventions should account for differing levels of visuospatial learning at baseline, as this could impact the magnitude of training outcomes and efficacy of the intervention.
• Song, H., Bharadwaj, P. K., Raichlen, D. A., Habeck, C. G., Grilli, M. D., Huentelman, M. J., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2024). Cortical lobar volume reductions associated with homocysteine-related subcortical brain atrophy and poorer cognition in healthy aging. Frontiers in aging neuroscience, 16, 1406394.
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  Homocysteine (Hcy) is a cardiovascular risk factor implicated in cognitive impairment and cerebrovascular disease but has also been associated with Alzheimer's disease. In 160 healthy older adults (mean age = 69.66 ± 9.95 years), we sought to investigate the association of cortical brain volume with white matter hyperintensity (WMH) burden and a previously identified Hcy-related multivariate network pattern showing reductions in subcortical gray matter (SGM) volumes of hippocampus and nucleus accumbens with relative preservation of basal ganglia. We additionally evaluated the potential role of these brain imaging markers as a series of mediators in a vascular brain pathway leading to age-related cognitive dysfunction in healthy aging. We found reductions in parietal lobar gray matter associated with the Hcy-SGM pattern, which was further associated with WMH burden. Mediation analyses revealed that slowed processing speed related to aging, but not executive functioning or memory, was mediated sequentially through increased WMH lesion volume, greater Hcy-SGM pattern expression, and then smaller parietal lobe volume. Together, these findings suggest that volume reductions in parietal gray matter associated with a pattern of Hcy-related SGM volume differences may be indicative of slowed processing speed in cognitive aging, potentially linking cardiovascular risk to an important aspect of cognitive dysfunction in healthy aging.
• Van Etten, E. J., Bharadwaj, P. K., Grilli, M. D., Raichlen, D. A., Hishaw, G. A., Huentelman, M. J., Trouard, T. P., & Alexander, G. E. (2024). Impact of age and apolipoprotein E ε4 status on regional white matter hyperintensity volume and cognition in healthy aging. Journal of the International Neuropsychological Society : JINS, 30(6), 553-563.
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  White matter hyperintensity (WMH) volume is a neuroimaging marker of lesion load related to small vessel disease that has been associated with cognitive aging and Alzheimer's disease (AD) risk.
• Van Etten, E. J., Bharadwaj, P. K., Grilli, M. D., Raichlen, D. A., Hishaw, G. A., Huentelman, M. J., Trouard, T. P., & Alexander, G. E. (2024). Regional covariance of white matter hyperintensity volume patterns associated with hippocampal volume in healthy aging. Frontiers in aging neuroscience, 16, 1349449.
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  Hippocampal volume is particularly sensitive to the accumulation of total brain white matter hyperintensity volume (WMH) in aging, but how the regional distribution of WMH volume differentially impacts the hippocampus has been less studied. In a cohort of 194 healthy older adults ages 50-89, we used a multivariate statistical method, the Scaled Subprofile Model (SSM), to (1) identify patterns of regional WMH differences related to left and right hippocampal volumes, (2) examine associations between the multimodal neuroimaging covariance patterns and demographic characteristics, and (3) investigate the relation of the patterns to subjective and objective memory in healthy aging. We established network covariance patterns of regional WMH volume differences associated with greater left and right hippocampal volumes, which were characterized by reductions in left temporal and right parietal WMH volumes and relative increases in bilateral occipital WMH volumes. Additionally, we observed lower expression of these hippocampal-related regional WMH patterns were significantly associated with increasing age and greater subjective memory complaints, but not objective memory performance in this healthy older adult cohort. Our findings indicate that, in cognitively healthy older adults, left and right hippocampal volume reductions were associated with differences in the regional distribution of WMH volumes, which were exacerbated by advancing age and related to greater subjective memory complaints. Multivariate network analyses, like SSM, may help elucidate important early effects of regional WMH volume on brain and cognitive aging in healthy older adults.
• 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.
• 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.
• 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.
• Lane, R. D., Solms, M., Weihs, K. L., Hishaw, A., & Smith, R. (2021). Is the concept of affective agnosia a useful addition to the alexithymia literature?. Neuroscience and biobehavioral reviews, 127, 747-748.
• 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, 31(5), 469-480.
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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.
• 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. (2020). Independent Contributions of Dorsolateral Prefrontal Structure and Function to Working Memory in Healthy Older Adults. Cerebral cortex (New York, N.Y. : 1991).
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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.
• 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.
• 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.
• Mendoza, N. S., Moreno, F. A., Hishaw, G. A., Gaw, A. C., Fortuna, L. R., Skubel, A., Porche, M. V., Roessel, M. H., Shore, J., & Gallegos, A. (2020). Affirmative Care Across Cultures: Broadening Application. Focus (American Psychiatric Publishing), 18(1), 31-39.
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  Affirmative practice is an approach to health and behavioral health care that validates and supports the identities stated or expressed by those served. Affirmative care requires the practitioner to actively honor and celebrate identity while at the same time validating the oppression felt by individuals seeking services. Validation and empathy fundamentally result from increased understanding of individuals' history, cultural context, and lived experiences. Origins of the approach honored the experience of those in LGBTQ+ communities; however, affirmative care should be valued across cultures, systems, and settings in which health and behavioral health care are offered. Affirmative care principles should be applied across cultures and communities while recognizing the worth of the individual and avoiding stereotyping. Along with delineating historical and demographic contexts, the authors offer recommendations for affirmative care in practice with African American, Asian, Indigenous, and Latinx individuals, as well as those living in rural communities.
• Mendoza, N. S., Moreno, F. A., Hishaw, G. A., Saw, A. C., Fortuna, L. R., Skubel, A., Porche, M. V., Roessel, M. H., Shore, J., & Gallegos, A. (2020). Affirmative Care Across Cultures: Broadening Application. FOCUS, 18(1), 31-39.
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  Affirmative practice is an approach to health and behavioral health care that validates and supports the identities stated or expressed by those served. Affirmative care requires the practitioner to actively honor and celebrate identity while at the same time validating the oppression felt by individuals seeking services. Validation and empathy fundamentally result from increased understanding of individuals’ history, cultural context, and lived experiences. Origins of the approach honored the experience of those in LGBTQ+ communities; however, affirmative care should be valued across cultures, systems, and settings in which health and behavioral health care are offered. Affirmative care principles should be applied across cultures and communities while recognizing the worth of the individual and avoiding stereotyping. Along with delineating historical and demographic contexts, the authors offer recommendations for affirmative care in practice with African American, Asian, Indigenous, and Latinx individuals, as well as those living in rural communities.
• 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.
• 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.
• Lane, R. D., Weihs, K. L., Herring, A., Hishaw, A., & Smith, R. (2015). Affective agnosia: Expansion of the alexithymia construct and a new opportunity to integrate and extend Freud's legacy. Neuroscience and biobehavioral reviews, 55, 594-611.
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  We describe a new type of agnosia consisting of an impairment in the ability to mentally represent or know what one is feeling. Freud the neurologist coined the term "agnosia" in 1891 before creating psychoanalysis in 1895 but the term has not been previously applied to the domain of affective processing. We propose that the concept of "affective agnosia" advances the theory, measurement and treatment of what is now called "alexithymia," meaning "lack of words for emotion." We trace the origin of the alexithymia construct and discuss the strengths and limitations of extant research. We review evidence that the ability to represent and put emotions into words is a developmental achievement that strongly influences one's ability to experience, recognize, understand and use one's own emotional responses. We describe the neural substrates of emotional awareness and affective agnosia and compare and contrast these with related conditions. We then describe how this expansion of the conceptualization and measurement of affective processing deficits has important implications for basic emotion research and clinical practice.
• Salloway, S., Sperling, R., Fox, N. C., Blennow, K., Klunk, W., Raskind, M., Sabbagh, M., Honig, L. S., Porsteinsson, A. P., Ferris, S., Reichert, M., Ketter, N., Nejadnik, B., Guenzler, V., Miloslavsky, M., Wang, D., Lu, Y., Lull, J., Tudor, I. C., , Liu, E., et al. (2014). Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. The New England journal of medicine, 370(4), 322-33.
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  Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease.