Emily Charlotte Edmonds

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• Edmonds, E. C., Thomas, K. R., Rapcsak, S. Z., Lindemer, S. L., Delano-Wood, L., Salmon, D. P., & Bondi, M. W. (2024). Data-driven classification of cognitively normal and mild cognitive impairment subtypes predicts progression in the NACC dataset. Alzheimer's & dementia : the journal of the Alzheimer's Association, 20(5), 3442-3454.
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  Data-driven neuropsychological methods can identify mild cognitive impairment (MCI) subtypes with stronger associations to dementia risk factors than conventional diagnostic methods.
• Edmonds, E. C., Thomas, K. R., Rapcsak, S. Z., Lindemer, S. L., Delano‐Wood, L., Salmon, D. P., & Bondi, M. W. (2024). Data‐driven classification of cognitively normal and mild cognitive impairment subtypes predicts progression in the NACC dataset. Alzheimer's & Dementia. doi:10.1002/alz.13793
• Edmonds, E., Thomas, K., Rapcsak, S., Lindemer, S., Delano-Wood, L., Salmon, D., & Bondi, M. (2024). Data-driven classification of cognitively normal and mild cognitive impairment subtypes predicts progression in the NACC dataset. Alzheimer's and Dementia, 20(5). doi:10.1002/alz.13793
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  INTRODUCTION: Data-driven neuropsychological methods can identify mild cognitive impairment (MCI) subtypes with stronger associations to dementia risk factors than conventional diagnostic methods. METHODS: Cluster analysis used neuropsychological data from participants without dementia (mean age = 71.6 years) in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (n = 26,255) and the “normal cognition” subsample (n = 16,005). Survival analyses examined MCI or dementia progression. RESULTS: Five clusters were identified: “Optimal” cognitively normal (oCN; 13.2%), “Typical” CN (tCN; 28.0%), Amnestic MCI (aMCI; 25.3%), Mixed MCI-Mild (mMCI-Mild; 20.4%), and Mixed MCI-Severe (mMCI-Severe; 13.0%). Progression to dementia differed across clusters (oCN < tCN < aMCI < mMCI-Mild < mMCI-Severe). Cluster analysis identified more MCI cases than consensus diagnosis. In the “normal cognition” subsample, five clusters emerged: High-All Domains (High-All; 16.7%), Low-Attention/Working Memory (Low-WM; 22.1%), Low-Memory (36.3%), Amnestic MCI (16.7%), and Non-amnestic MCI (naMCI; 8.3%), with differing progression rates (High-All < Low-WM = Low-Memory < aMCI < naMCI). DISCUSSION: Our data-driven methods outperformed consensus diagnosis by providing more precise information about progression risk and revealing heterogeneity in cognition and progression risk within the NACC “normal cognition” group.
• Edwards, L., Thomas, K. R., Weigand, A. J., Edmonds, E. C., Clark, A. L., Brenner, E. K., Banks, S. J., Gilbert, P. E., Nation, D. A., Delano-Wood, L., Bondi, M. W., & Bangen, K. J. (2024). Pulse pressure and APOE ε4 dose interact to affect cerebral blood flow in older adults without dementia. Cerebral circulation - cognition and behavior, 6, 100206.
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  This study assessed whether the effect of vascular risk on cerebral blood flow (CBF) varies by gene dose of apolipoprotein (APOE) ε4 alleles. 144 older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative underwent arterial spin labeling and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure (BP) assessment. Vascular risk was assessed using pulse pressure (systolic BP - diastolic BP). CBF was examined in six AD-vulnerable regions: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regressions tested the interaction between APOE ε4 dose and pulse pressure on CBF in each region, adjusting for age, sex, cognitive classification, antihypertensive medication use, FDG-PET, reference CBF region, and AD biomarker positivity. There was a significant interaction between pulse pressure and APOE ɛ4 dose on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex, such that higher pulse pressure was associated with lower CBF only among ε4 homozygous participants. These findings demonstrate that the association between pulse pressure and regional CBF differs by APOE ε4 dose, suggesting that targeting modifiable vascular risk factors may be particularly important for those genetically at risk for AD.
• Edwards, L., Thomas, K., Weigand, A., Edmonds, E., Clark, A., Brenner, E., Banks, S., Gilbert, P., Nation, D., Delano-Wood, L., Bondi, M., & Bangen, K. (2024). Pulse pressure and APOE ε4 dose interact to affect cerebral blood flow in older adults without dementia. Cerebral Circulation - Cognition and Behavior, 6. doi:10.1016/j.cccb.2024.100206
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  This study assessed whether the effect of vascular risk on cerebral blood flow (CBF) varies by gene dose of apolipoprotein (APOE) ε4 alleles. 144 older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative underwent arterial spin labeling and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure (BP) assessment. Vascular risk was assessed using pulse pressure (systolic BP – diastolic BP). CBF was examined in six AD-vulnerable regions: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regressions tested the interaction between APOE ε4 dose and pulse pressure on CBF in each region, adjusting for age, sex, cognitive classification, antihypertensive medication use, FDG-PET, reference CBF region, and AD biomarker positivity. There was a significant interaction between pulse pressure and APOE ɛ4 dose on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex, such that higher pulse pressure was associated with lower CBF only among ε4 homozygous participants. These findings demonstrate that the association between pulse pressure and regional CBF differs by APOE ε4 dose, suggesting that targeting modifiable vascular risk factors may be particularly important for those genetically at risk for AD.
• Kim, H. G., Kim, Y., Edmonds, E. C., & Bondi, M. W. (2024). Comparison of Cognitive Impairment Diagnosis Criteria in Clinical Settings: Conventional vs. Neuropsychological. Alpha psychiatry, 25(2), 212-219.
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  Theories on Alzheimer disease pathogenesis propose a gap between pathological changes and the onset of clinical symptoms. The early detection of cognitive decline is crucial for the implementation of preventive strategies. Mild cognitive impairment is a transitional stage and an accurate diagnosis is vital. However, the diagnosis of mild cognitive impairment varies due to inconsistent diagnostic criteria. This study aims to explore the effectiveness of comprehensive neuropsychological criteria, including all cognitive domains, for diagnosing cognitive impairment in clinical settings.
• Ly, M. T., Adler, J., Ton Loy, A. F., Edmonds, E. C., Bondi, M. W., Delano-Wood, L., & , D. o. (2024). Comparing neuropsychological, typical, and ADNI criteria for the diagnosis of mild cognitive impairment in Vietnam-era veterans. Journal of the International Neuropsychological Society : JINS, 30(5), 439-447.
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  Neuropsychological criteria for mild cognitive impairment (MCI) more accurately predict progression to Alzheimer's disease (AD) and are more strongly associated with AD biomarkers and neuroimaging profiles than ADNI criteria. However, research to date has been conducted in relatively healthy samples with few comorbidities. Given that history of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are risk factors for AD and common in Veterans, we compared neuropsychological, typical (Petersen/Winblad), and ADNI criteria for MCI in Vietnam-era Veterans with histories of TBI or PTSD.
• Ly, M., Adler, J., Ton Loy, A., Edmonds, E., Bondi, M., & Delano-Wood, L. (2024). Comparing neuropsychological, typical, and ADNI criteria for the diagnosis of mild cognitive impairment in Vietnam-era veterans. Journal of the International Neuropsychological Society, 30(5). doi:10.1017/S135561772301144X
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  Objective: Neuropsychological criteria for mild cognitive impairment (MCI) more accurately predict progression to Alzheimer's disease (AD) and are more strongly associated with AD biomarkers and neuroimaging profiles than ADNI criteria. However, research to date has been conducted in relatively healthy samples with few comorbidities. Given that history of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are risk factors for AD and common in Veterans, we compared neuropsychological, typical (Petersen/Winblad), and ADNI criteria for MCI in Vietnam-era Veterans with histories of TBI or PTSD. Method: 267 Veterans (mean age = 69.8) from the DOD-ADNI study were evaluated for MCI using neuropsychological, typical, and ADNI criteria. Linear regressions adjusting for age and education assessed associations between MCI status and AD biomarker levels (cerebrospinal fluid [CSF] p-tau181, t-tau, and Aβ 42) by diagnostic criteria. Logistic regressions adjusting for age and education assessed the effects of TBI severity and PTSD symptom severity simultaneously on MCI classification by each criteria. Results: Agreement between criteria was poor. Neuropsychological criteria identified more Veterans with MCI than typical or ADNI criteria, and were associated with higher CSF p-tau181 and t-tau. Typical and ADNI criteria were not associated with CSF biomarkers. PTSD symptom severity predicted MCI diagnosis by neuropsychological and ADNI criteria. History of moderate/severe TBI predicted MCI by typical and ADNI criteria. Conclusions: MCI diagnosis using sensitive neuropsychological criteria is more strongly associated with AD biomarkers than conventional diagnostic methods. MCI diagnostics in Veterans would benefit from incorporation of comprehensive neuropsychological methods and consideration of the impact of PTSD.
• Membreno, R., Thomas, K. R., Calcetas, A. T., Edwards, L., Bordyug, M., Showell, M., Stanfill, M., Brenner, E. K., Walker, K. S., Rotblatt, L. J., Brickman, A. M., Edmonds, E. C., & Bangen, K. J. (2023). Regional White Matter Hyperintensities Relate to Specific Cognitive Abilities in Older Adults Without Dementia. Alzheimer disease and associated disorders, 37(4), 303-309.
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  White matter hyperintensities (WMHs) are magnetic resonance imaging markers of small vessel cerebrovascular disease that are associated with cognitive decline and clinical Alzheimer disease. Previous studies have often focused on global or total WMH; less is known about associations of regional WMHs and cognitive abilities among older adults without dementia.
• Brenner, E. K., Thomas, K. R., Weigand, A. J., Edwards, L., Edmonds, E. C., Bondi, M. W., Bangen, K. J., & , A. D. (2023). Cognitive reserve moderates the association between cerebral blood flow and language performance in older adults with mild cognitive impairment. Neurobiology of aging, 125, 83-89.
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  Higher cognitive reserve (CR) may offer protection from cognitive changes associated with reduced cerebral blood flow (CBF). We investigated CR as a moderator of the effect of CBF on cognition in older adults with mild cognitive impairment (MCI; N = 46) and those who are cognitively unimpaired (CU; N = 101). Participants underwent arterial spin labeling MRI, which was used to quantify CBF in 4 a priori regions. Estimated verbal intelligence quotient (VIQ) served as a proxy for CR. Multiple linear regressions examined whether VIQ moderated associations between CBF and cognition and whether this differed by cognitive status. Outcomes included memory and language performance. There were 3-way interactions (CBF*VIQ*cognitive status) on category fluency when examining hippocampal, superior frontal, and inferior frontal CBF. Follow-up analyses revealed that, within the MCI but not CU group, there were CBF*VIQ interactions on fluency in all a priori regions examined, where there were stronger, positive associations between CBF and fluency at higher VIQ. Conclusion: In MCI, higher CR plays a role in strengthening CBF-fluency associations.
• Brenner, E. K., Weigand, A. J., Edwards, L., Thomas, K. R., Edmonds, E. C., Bondi, M. W., Bangen, K. J., & , A. D. (2023). Brain Derived Neurotrophic Factor Interacts with White Matter Hyperintensities to Influence Processing Speed and Hippocampal Volume in Older Adults. Journal of Alzheimer's disease : JAD, 93(1), 141-149.
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  Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in regulating synaptic activity and plasticity.
• Edwards, L., Thomas, K. R., Weigand, A. J., Edmonds, E. C., Clark, A. L., Walker, K. S., Brenner, E. K., Nation, D. A., Maillard, P., Bondi, M. W., Bangen, K. J., & , A. D. (2023). White Matter Hyperintensity Volume and Amyloid-PET Synergistically Impact Memory Independent of Tau-PET in Older Adults Without Dementia. Journal of Alzheimer's disease : JAD, 94(2), 695-707.
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  Alzheimer's disease (AD) and cerebrovascular disease are common, co-existing pathologies in older adults. Whether the effects of cerebrovascular disease and AD biomarkers on cognition are additive or synergistic remains unclear.
• Holmqvist, S. L., Thomas, K. R., Edmonds, E. C., Calcetas, A., Edwards, L., Bangen, K. J., & , A. D. (2023). Cognitive dispersion is elevated in amyloid-positive older adults and associated with regional hypoperfusion. Journal of the International Neuropsychological Society : JINS, 29(7), 621-631.
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  Cognitive dispersion across neuropsychological measures within a single testing session is a promising marker predictive of cognitive decline and development of Alzheimer's disease (AD). However, little is known regarding brain changes underlying cognitive dispersion, and the association of cognitive dispersion with in vivo AD biomarkers and regional cerebral blood flow (CBF) has received limited study. We therefore examined associations among cognitive dispersion, amyloid-beta (Aβ) positivity, and regional CBF among older adults free of dementia.
• Calcetas, A. T., Thomas, K. R., Edmonds, E. C., Holmqvist, S. L., Edwards, L., Bordyug, M., Delano-Wood, L., Brickman, A. M., Bondi, M. W., Bangen, K. J., & For The Alzheimer's Disease Neuroimaging Initiative, . (2022). Increased regional white matter hyperintensity volume in objectively-defined subtle cognitive decline and mild cognitive impairment. Neurobiology of aging, 118, 1-8.
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  White matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase risk of developing mild cognitive impairment (MCI) and Alzheimer's disease (AD). Less is known about the extent and pattern of WMH in pre-MCI stages, such as among those with objectively-defined subtle cognitive decline (Obj-SCD). Five hundred and fifty-nine Alzheimer's Disease Neuroimaging Initiative participants (170 cognitively unimpaired [CU]; 83 Obj-SCD; 306 MCI) free of clinical dementia or stroke completed neuropsychological testing and MRI exams. ANCOVA models compared cognitive groups on regional WMH adjusting for age, sex, and apolipoprotein E (APOE) ɛ4 frequency. Compared with the CU group, those with Obj-SCD had greater temporal, occipital, and frontal WMH whereas those with MCI had higher WMH volume across all regions (p's < 0.01). No differences in WMH volume were observed between the Obj-SCD and MCI groups (p's > 0.05). Findings add to growing evidence of associations between Obj-SCD and imaging biomarkers, providing support for utility of these criteria to capture subtle cognitive changes that are biologically based.
• Graves, L. V., Edmonds, E. C., Thomas, K. R., Weigand, A. J., Cooper, S., Stickel, A. M., Zlatar, Z. Z., Clark, A. L., & Bondi, M. W. (2022). Diagnostic accuracy and differential associations between ratings of functioning and neuropsychological performance in non-Hispanic Black and White older adults. The Clinical neuropsychologist, 36(2), 287-310.
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  We recently demonstrated that relative to consensus-based methods, actuarial methods may improve diagnostic accuracy across the continuum of cognitively normal (CN), mild cognitive impairment (MCI), and dementia in the overall National Alzheimer's Coordinating Center (NACC) cohort. However, the generalizability and comparative utility of current methods of diagnosing MCI and dementia due to Alzheimer's disease and related disorders (ADRD) are significantly understudied in non-Hispanic Black (NHB) older adults. Thus, we extended our previous investigation to more specifically explore the utility of consensus-based and actuarial diagnostic methods in NHB older adults. We compared baseline consensus and actuarial diagnostic rates, and associations of ratings of functioning with neuropsychological performance and diagnostic outcomes, in NHB (n = 963) and non-Hispanic White (NHW; n = 4577) older adults in the NACC cohort. 60.0% of the NHB subsample, versus 29.2% of the NHW subsample, included participants who met actuarial criteria for MCI despite being classified as CN or impaired-not-MCI per consensus. Additionally, associations between ratings of functioning and neuropsychological performance were less consistent in NHB participants than in NHW participants. Our results provide evidence of differential degrees of association between reported functioning and neuropsychological performance in NHB and NHW older adults, which may contribute to racial group differences in diagnostic rates, and prompt consideration of the strengths and weaknesses of consensus-based and actuarial diagnostic approaches in assessing neurocognitive functioning in NHB older adults.
• Holmqvist, S. L., Thomas, K. R., Brenner, E. K., Edmonds, E. C., Calcetas, A., Edwards, L., Bordyug, M., & Bangen, K. J. (2022). Longitudinal Intraindividual Cognitive Variability Is Associated With Reduction in Regional Cerebral Blood Flow Among Alzheimer's Disease Biomarker-Positive Older Adults. Frontiers in aging neuroscience, 14, 859873.
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  Intraindividual variability (IIV) across neuropsychological measures within a single testing session is a promising marker predictive of cognitive decline and development of Alzheimer's disease (AD). We have previously shown that greater IIV is cross-sectionally associated with reduced cerebral blood flow (CBF), but not with cortical thickness or brain volume, in older adults without dementia who were amyloid beta (Aβ) positive. However, there is little known about the association between change in IIV and CBF over time. Therefore, we examined 12-month longitudinal change in IIV and interactions of IIV and AD biomarker status on changes in regional CBF. Fifty-three non-demented Alzheimer's Disease Neuroimaging Initiative (ADNI) participants underwent lumbar puncture to obtain cerebrospinal fluid (CSF) at baseline and neuropsychological testing and magnetic resonance imaging (MRI) exams at baseline and 12-month follow-up evaluation. IIV was calculated as the intraindividual standard deviation across 6 demographically-corrected neuropsychological measures. Pulsed arterial spin labeling (ASL) MRI was acquired to quantify CBF and FreeSurfer-derived CBF regions of interest (ROIs) were examined. AD biomarker positivity was determined using a published CSF p-tau/Aβ ratio cut-score. Change scores were calculated for IIV, CBF, and mean neuropsychological performance from baseline to 12 months. Hierarchical linear regression models showed that after adjusting for age and gender, there was a significant interaction between IIV change and biomarker-positivity (p-tau/Aβ+) for change in entorhinal and hippocampal CBF but not for the other ROIs. Specifically, increases in IIV were associated with reductions in entorhinal and hippocampal CBF among individuals who were biomarker-positive ( = 21). In contrast, there were no significant associations between change in IIV and CBF among those who were biomarker-negative ( = 32). Findings remained similar when analyses were performed adjusting for change in mean level of neuropsychological performance. Changes in IIV may be sensitive to changes in regional hypoperfusion in AD-vulnerable regions among AD biomarker-positive individuals, above and beyond demographics and mean neuropsychological performance. These findings provide further evidence supporting IIV as a potential marker of cerebrovascular brain changes in individuals at risk for dementia.
• Sanderson-Cimino, M., Elman, J. A., Tu, X. M., Gross, A. L., Panizzon, M. S., Gustavson, D. E., Bondi, M. W., Edmonds, E. C., Eglit, G. M., Eppig, J. S., Franz, C. E., Jak, A. J., Lyons, M. J., Thomas, K. R., Williams, M. E., Kremen, W. S., & , A. D. (2022). Cognitive practice effects delay diagnosis of MCI: Implications for clinical trials. Alzheimer's & dementia (New York, N. Y.), 8(1), e12228.
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  Practice effects (PEs) on cognitive tests obscure decline, thereby delaying detection of mild cognitive impairment (MCI). Importantly, PEs may be present even when there are performance declines, if scores would have been even lower without prior test exposure. We assessed how accounting for PEs using a replacement-participants method impacts incident MCI diagnosis.
• Sanderson-Cimino, M., Elman, J. A., Tu, X. M., Gross, A. L., Panizzon, M. S., Gustavson, D. E., Bondi, M. W., Edmonds, E. C., Eppig, J. S., Franz, C. E., Jak, A. J., Lyons, M. J., Thomas, K. R., Williams, M. E., & Kremen, W. S. (2022). Practice Effects in Mild Cognitive Impairment Increase Reversion Rates and Delay Detection of New Impairments. Frontiers in aging neuroscience, 14, 847315.
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  Cognitive practice effects (PEs) can delay detection of progression from cognitively unimpaired to mild cognitive impairment (MCI). They also reduce diagnostic accuracy as suggested by biomarker positivity data. Even among those who decline, PEs can mask steeper declines by inflating cognitive scores. Within MCI samples, PEs may increase reversion rates and thus impede detection of further impairment. Within an MCI sample at baseline, we evaluated how PEs impact prevalence, reversion rates, and dementia progression after 1 year.
• Thomas, K. R., Bangen, K. J., Weigand, A. J., Ortiz, G., Walker, K. S., Salmon, D. P., Bondi, M. W., & Edmonds, E. C. (2022). Cognitive Heterogeneity and Risk of Progression in Data-Driven Subtle Cognitive Decline Phenotypes. Journal of Alzheimer's disease : JAD, 90(1), 323-331.
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  There is increasing recognition of cognitive and pathological heterogeneity in early-stage Alzheimer's disease and other dementias. Data-driven approaches have demonstrated cognitive heterogeneity in those with mild cognitive impairment (MCI), but few studies have examined this heterogeneity and its association with progression to MCI/dementia in cognitively unimpaired (CU) older adults.
• Thomas, K. R., Weigand, A. J., Cota, I. H., Edmonds, E. C., Wierenga, C. E., Bondi, M. W., Bangen, K. J., & , A. D. (2022). Intrusion errors moderate the relationship between blood glucose and regional cerebral blood flow in cognitively unimpaired older adults. Brain imaging and behavior, 16(1), 219-227.
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  Regional cerebral blood flow (CBF) has a complex relationship with cognitive functioning such that cognitively unimpaired individuals at risk for Alzheimer's disease (AD) may show regional hyperperfusion, while those with cognitive impairment typically show hypoperfusion. Diabetes and word-list intrusion errors are both linked to greater risk of cognitive decline and dementia. Our study examined associations between fasting blood glucose, word-list intrusion errors, and regional CBF. 113 cognitively unimpaired older adults had arterial spin labeling MRI to measure CBF in a priori AD vulnerable regions: medial temporal lobe (MTL), inferior parietal lobe (IPL), precuneus, medial orbitofrontal cortex (mOFC), and pericalcarine (control region). Hierarchical linear regressions, adjusting for demographics, vascular risk, and reference CBF region, examined the main effect of blood glucose on regional CBF as well as whether intrusions moderated this relationship. Higher glucose was associated with higher CBF in the precuneus (β = .134, 95% CI = .007 to .261, p = .039), IPL (β = .173, 95% CI = .072 to .276, p = .001), and mOFC (β = .182, 95% CI = .047 to .320, p = .009). There was no main effect of intrusions on CBF across regions. However, the glucose x intrusions interaction was significant such that having higher glucose levels and more intrusion errors was associated with reduced CBF in the MTL (β = -.186, 95% CI = -.334 to -.040, p = .013) and precuneus (β = -.146, 95% CI = -.273 to -.022, p = .022). These findings may reflect early neurovascular dysregulation, whereby higher CBF is needed to maintain unimpaired cognition in individuals with higher glucose levels. However, lower regional CBF in unimpaired participants with both higher glucose and more intrusions suggests a failure in this early compensatory mechanism that may signal a decrease in neural activity in AD vulnerable regions.
• Thomas, K. R., Weigand, A. J., Edwards, L. C., Edmonds, E. C., Bangen, K. J., Ortiz, G., Walker, K. S., Bondi, M. W., & , A. D. (2022). Tau levels are higher in objective subtle cognitive decline but not subjective memory complaint. Alzheimer's research & therapy, 14(1), 114.
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  The 2018 NIA-AA Alzheimer's Disease (AD) Research Framework states that subtle cognitive decline in cognitively unimpaired individuals can be measured by subjective reports or evidence of objective decline on neuropsychological measures. Both subjective memory complaint (SMC) and objective subtle cognitive decline (Obj-SCD) have been shown to be associated with future cognitive decline and AD biomarkers. We examined whether there are differences in tau PET levels between (a) SMC- vs. SMC+ participants, (b) Obj-SCD- vs. Obj-SCD+ participants, and (c) participants with overlapping vs. discrepant SMC and Obj-SCD classifications.
• Bangen, K. J., Thomas, K. R., Sanchez, D. L., Edmonds, E. C., Weigand, A. J., Delano-Wood, L., Bondi, M. W., & , A. D. (2021). Entorhinal Perfusion Predicts Future Memory Decline, Neurodegeneration, and White Matter Hyperintensity Progression in Older Adults. Journal of Alzheimer's disease : JAD, 81(4), 1711-1725.
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  Altered cerebral blood flow (CBF) has been linked to increased risk for Alzheimer's disease (AD). However, whether altered CBF contributes to AD risk by accelerating cognitive decline remains unclear. It also remains unclear whether reductions in CBF accelerate neurodegeneration and development of small vessel cerebrovascular disease.
• Bangen, K. J., Thomas, K. R., Weigand, A. J., Edmonds, E. C., Clark, A. L., Solders, S., Delano-Wood, L., Galasko, D. R., Bondi, M. W., & , A. D. (2021). Elevated plasma neurofilament light predicts a faster rate of cognitive decline over 5 years in participants with objectively-defined subtle cognitive decline and MCI. Alzheimer's & dementia : the journal of the Alzheimer's Association, 17(10), 1756-1762.
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  Neurofilament light (NFL) reflects neuroaxonal damage and is implicated in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Little is known about NFL in pre-MCI stages, such as in individuals with objectively-defined subtle cognitive decline (Obj-SCD).
• Edmonds, E. C., Smirnov, D. S., Thomas, K. R., Graves, L. V., Bangen, K. J., Delano-Wood, L., Galasko, D. R., Salmon, D. P., & Bondi, M. W. (2021). Data-Driven vs Consensus Diagnosis of MCI: Enhanced Sensitivity for Detection of Clinical, Biomarker, and Neuropathologic Outcomes. Neurology, 97(13), e1288-e1299.
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  Given prior work demonstrating that mild cognitive impairment (MCI) can be empirically differentiated into meaningful cognitive subtypes, we applied actuarial methods to comprehensive neuropsychological data from the University of California San Diego Alzheimer's Disease Research Center (ADRC) in order to identify cognitive subgroups within ADRC participants without dementia and to examine cognitive, biomarker, and neuropathologic trajectories.
• Reyes, A., Kaestner, E., Edmonds, E. C., Christina Macari, A., Wang, Z. I., Drane, D. L., Punia, V., Busch, R. M., Hermann, B. P., McDonald, C. R., & , A. D. (2021). Diagnosing cognitive disorders in older adults with epilepsy. Epilepsia, 62(2), 460-471.
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  To characterize the nature and prevalence of cognitive disorders in older adults with temporal lobe epilepsy (TLE) and compare their cognitive profiles to patients with amnestic mild cognitive impairment (ie, aMCI).
• Sundermann, E. E., Thomas, K. R., Bangen, K. J., Weigand, A. J., Eppig, J. S., Edmonds, E. C., Wong, C. G., Bondi, M. W., & Delano-Wood, L. (2021). Prediabetes Is Associated With Brain Hypometabolism and Cognitive Decline in a Sex-Dependent Manner: A Longitudinal Study of Nondemented Older Adults. Frontiers in neurology, 12, 551975.
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  Although type 2 diabetes is a well-known risk factor for Alzheimer's disease (AD), little is known about how its precursor-prediabetes-impacts neuropsychological function and brain health. Thus, we examined the relationship between prediabetes and AD-related biological and cognitive/clinical markers in a well-characterized sample drawn from the Alzheimer's Disease Neuroimaging Initiative. Additionally, because women show higher rates of AD and generally more atherogenic lipid profiles than men, particularly in the context of diabetes, we examined whether sex moderates any observed associations. The total sample of 911 nondemented and non-diabetic participants [normal control = 540; mild cognitive impairment (MCI) = 371] included 391 prediabetic (fasting blood glucose: 100-125 mg/dL) and 520 normoglycemic individuals (age range: 55-91). Linear mixed effects models, adjusted for demographics and vascular and AD risk factors, examined the independent and interactive effects of prediabetes and sex on 2-6 year trajectories of FDG-PET measured cerebral metabolic glucose rate (CMRglu), hippocampal/intracranial volume ratio (HV/IV), cerebrospinal fluid phosphorylated tau-/amyloid-β ratio (p-tau/Aβ), cognitive function (executive function, language, and episodic memory) and the development of dementia. Analyses were repeated in the MCI subsample. In the total sample, prediabetic status had an adverse effect on CMRglu across time regardless of sex, whereas prediabetes had an adverse effect on executive function across time in women only. Within the MCI subsample, prediabetic status was associated with lower CMRglu and poorer executive function and language performance across time within women, whereas these associations were not seen within men. In the total sample and MCI subsample, prediabetes did not relate to HV/IV, p-tau/Aβ, memory function or dementia risk regardless of sex; however, among incident dementia cases, prediabetic status related to earlier age of dementia onset in women but not in men. Results suggest that prediabetes may affect cognition through altered brain metabolism, and that women may be more vulnerable to the negative effects of glucose intolerance.
• Thomas, K. R., Bangen, K. J., Edmonds, E. C., Weigand, A. J., Walker, K. S., Bondi, M. W., Galasko, D. R., & , A. D. (2021). Objective subtle cognitive decline and plasma phosphorylated tau181: Early markers of Alzheimer's disease-related declines. Alzheimer's & dementia (Amsterdam, Netherlands), 13(1), e12238.
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  Objectively-defined subtle cognitive decline (Obj-SCD) and plasma phosphorylated-tau181 (p-tau181) are promising early Alzheimer's disease (AD) markers. However, associations between Obj-SCD and p-tau181, and their combined prognostic potential, are unknown.
• Thomas, K. R., Osuna, J. R., Weigand, A. J., Edmonds, E. C., Clark, A. L., Holmqvist, S., Cota, I. H., Wierenga, C. E., Bondi, M. W., Bangen, K. J., & , A. D. (2021). Regional hyperperfusion in older adults with objectively-defined subtle cognitive decline. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 41(5), 1001-1012.
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  Although cerebral blood flow (CBF) alterations are associated with Alzheimer's disease (AD), CBF patterns across prodromal stages of AD remain unclear. Therefore, we investigated patterns of regional CBF in 162 Alzheimer's Disease Neuroimaging Initiative participants characterized as cognitively unimpaired (CU;  = 80), objectively-defined subtle cognitive decline (Obj-SCD;  = 31), or mild cognitive impairment (MCI;  = 51). Arterial spin labeling MRI quantified regional CBF in a priori regions of interest: hippocampus, inferior temporal gyrus, inferior parietal lobe, medial orbitofrontal cortex, and rostral middle frontal gyrus. Obj-SCD participants had increased hippocampal and inferior parietal CBF relative to CU and MCI participants and increased inferior temporal CBF relative to MCI participants. CU and MCI groups did not differ in hippocampal or inferior parietal CBF, but CU participants had increased inferior temporal CBF relative to MCI participants. There were no CBF group differences in the two frontal regions. Thus, we found an inverted-U pattern of CBF signal across prodromal AD stages in regions susceptible to early AD pathology. Hippocampal and inferior parietal hyperperfusion in Obj-SCD may reflect early neurovascular dysregulation, whereby higher CBF is needed to maintain cognitive functioning relative to MCI participants, yet is also reflective of early cognitive inefficiencies that distinguish Obj-SCD from CU participants.
• Werhane, M. L., Thomas, K. R., Bangen, K. J., Weigand, A. J., Edmonds, E. C., Nation, D. A., Sundermann, E. E., Bondi, M. W., & Delano-Wood, L. (2021). Arterial Stiffening Moderates the Relationship Between Type-2 Diabetes Mellitus and White Matter Hyperintensity Burden in Older Adults With Mild Cognitive Impairment. Frontiers in aging neuroscience, 13, 716638.
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  Cerebrovascular dysfunction has been proposed as a possible mechanism underlying cognitive impairment in the context of type 2 diabetes mellitus (DM). Although magnetic resonance imaging (MRI) evidence of cerebrovascular disease, such as white matter hyperintensities (WMH), is often observed in DM, the vascular dynamics underlying this pathology remain unclear. Thus, we assessed the independent and combined effects of DM status and different vascular hemodynamic measures (i.e., systolic, diastolic, and mean arterial blood pressure and pulse pressure index [PPi]) on WMH burden in cognitively unimpaired (CU) older adults and those with mild cognitive impairment (MCI). 559 older adults (mean age: 72.4 years) from the Alzheimer's Disease Neuroimaging Initiative were categorized into those with diabetes (DM+; CU = 43, MCI = 34) or without diabetes (DM-; CU = 279; MCI = 203). Participants underwent BP assessment, from which all vascular hemodynamic measures were derived. T2-FLAIR MRI was used to quantify WMH burden. Hierarchical linear regression, adjusting for age, sex, BMI, intracranial volume, CSF amyloid, and APOE ε4 status, examined the independent and interactive effects of DM status and each vascular hemodynamic measure on total WMH burden. The presence of DM ( = 0.046), but not PPi values ( = 0.299), was independently associated with greater WMH burden overall after adjusting for covariates. Analyses stratified by cognitive status revealed a significant DM status x PPi interaction within the MCI group ( = 0.001) such that higher PPi values predicted greater WMH burden in the DM + but not DM- group. No significant interactions were observed in the CU group (all s > 0.05). Results indicate that higher PPi values are positively associated with WMH burden in diabetic older adults with MCI, but not their non-diabetic or CU counterparts. Our findings suggest that arterial stiffening and reduced vascular compliance may have a role in development of cerebrovascular pathology within the context of DM in individuals at risk for future cognitive decline. Given the specificity of these findings to MCI, future exploration of the sensitivity of earlier brain markers of vascular insufficiency (i.e., prior to macrostructural white matter changes) to the effects of DM and arterial stiffness/reduced vascular compliance in CU individuals is warranted.
• Bangen, K. J., Thomas, K. R., Weigand, A. J., Sanchez, D. L., Delano-Wood, L., Edmonds, E. C., Carmichael, O. T., Schwarz, C. G., Brickman, A. M., Bondi, M. W., & , A. D. (2020). Pattern of regional white matter hyperintensity volume in mild cognitive impairment subtypes and associations with decline in daily functioning. Neurobiology of aging, 86, 134-142.
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  White matter hyperintensities (WMHs), a marker of small-vessel cerebrovascular disease, increase risk for mild cognitive impairment (MCI). Less is known about whether regional WMHs distinguish MCI subtypes and predict decline in everyday functioning. About 618 Alzheimer's Disease Neuroimaging Initiative participants (301 cognitively normal [CN]; 232 amnestic MCI [aMCI]; 85 nonamnestic MCI [naMCI]) underwent neuropsychological testing, MRI, and assessment of everyday functioning. aMCI participants showed greater temporal (p = 0.002) and occipital WMHs (p = 0.030) relative to CN whereas naMCI participants had greater frontal (p = 0.045), temporal (p = 0.003), parietal (p = 0.018), and occipital (p < 0.001) WMH compared with CN. Relative to those with aMCI, individuals with naMCI showed greater occipital WMH (p = 0.013). Greater WMH in temporal (p = 0.001) and occipital regions (p = 0.006) was associated with faster decline in everyday functioning across the sample. Temporal lobe WMHs were disproportionately associated with accelerated functional decline among naMCI (p = 0.045). Regional WMH volumes vary across cognitive groups and predict functional decline. Cerebrovascular markers may help identify individuals at risk for decline and distinguish subtypes of cognitive impairment.
• Blanken, A. E., Jang, J. Y., Ho, J. K., Edmonds, E. C., Han, S. D., Bangen, K. J., & Nation, D. A. (2020). Distilling Heterogeneity of Mild Cognitive Impairment in the National Alzheimer Coordinating Center Database Using Latent Profile Analysis. JAMA network open, 3(3), e200413.
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  This cohort study uses latent profile analysis to examine the variation in mild cognitive impairment among participants in the National Alzheimer Coordinating Center (NACC) database.
• Edmonds, E. C., Weigand, A. J., Hatton, S. N., Marshall, A. J., Thomas, K. R., Ayala, D. A., Bondi, M. W., McDonald, C. R., & , A. D. (2020). Patterns of longitudinal cortical atrophy over 3 years in empirically derived MCI subtypes. Neurology, 94(24), e2532-e2544.
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  We previously identified 4 empirically derived mild cognitive impairment (MCI) subtypes via cluster analysis within the Alzheimer's Disease Neuroimaging Initiative (ADNI) and demonstrated high correspondence between patterns of cortical thinning at baseline and each cognitive subtype. We aimed to determine whether our MCI subtypes demonstrate unique longitudinal atrophy patterns.
• Graves, L. V., Edmonds, E. C., Thomas, K. R., Weigand, A. J., Cooper, S., & Bondi, M. W. (2020). Evidence for the Utility of Actuarial Neuropsychological Criteria Across the Continuum of Normal Aging, Mild Cognitive Impairment, and Dementia. Journal of Alzheimer's disease : JAD, 78(1), 371-386.
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  Research suggests that actuarial neuropsychological criteria improve the accuracy of mild cognitive impairment (MCI) diagnoses relative to conventional diagnostic methods.
• Sanchez, D. L., Thomas, K. R., Edmonds, E. C., Bondi, M. W., Bangen, K. J., & , A. D. (2020). Regional Hypoperfusion Predicts Decline in Everyday Functioning at Three-Year Follow-Up in Older Adults without Dementia. Journal of Alzheimer's disease : JAD, 77(3), 1291-1304.
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  Increasing evidence indicates that cerebrovascular dysfunction may precede cognitive decline in aging and Alzheimer's disease (AD). Reduced cerebral blood flow (CBF) is associated with cognitive impairment in older adults. However, less is known regarding the association between CBF and functional decline, and whether CBF predicts functional decline beyond cerebrovascular and metabolic risk factors.
• Sanderson-Cimino, M., Elman, J. A., Tu, X. M., Gross, A. L., Panizzon, M. S., Gustavson, D. E., Bondi, M. W., Edmonds, E. C., Eglit, G. M., Eppig, J. S., Franz, C. E., Jak, A. J., Lyons, M. J., Thomas, K. R., Williams, M. E., Kremen, W. S., & , A. D. (2020). Cognitive Practice Effects Delay Diagnosis; Implications for Clinical Trials. medRxiv : the preprint server for health sciences.
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  Practice effects on cognitive tests obscure decline, thereby delaying detection of mild cognitive impairment (MCI). This reduces opportunities for slowing Alzheimer's disease progression and can hinder clinical trials. Using a novel method, we assessed the ability of practice-effect-adjusted diagnoses to detect MCI earlier, and tested the validity of these diagnoses based on AD biomarkers.
• Thomas, K. R., Bangen, K. J., Weigand, A. J., Edmonds, E. C., Sundermann, E., Wong, C. G., Eppig, J., Werhane, M. L., Delano-Wood, L., Bondi, M. W., & , A. D. (2020). Type 2 Diabetes Interacts With Alzheimer Disease Risk Factors to Predict Functional Decline. Alzheimer disease and associated disorders, 34(1), 10-17.
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  The current study examined the interactive effect of type 2 diabetes and Alzheimer disease (AD) risk factors on the rate of functional decline in cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative.
• Thomas, K. R., Bangen, K. J., Weigand, A. J., Edmonds, E. C., Wong, C. G., Cooper, S., Delano-Wood, L., Bondi, M. W., & , A. D. (2020). Objective subtle cognitive difficulties predict future amyloid accumulation and neurodegeneration. Neurology, 94(4), e397-e406.
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  To determine the temporal sequence of objectively defined subtle cognitive difficulties (Obj-SCD) in relation to amyloidosis and neurodegeneration, the current study examined the trajectories of amyloid PET and medial temporal neurodegeneration in participants with Obj-SCD relative to cognitively normal (CN) and mild cognitive impairment (MCI) groups.
• Bangen, K. J., Weigand, A. J., Thomas, K. R., Delano-Wood, L., Clark, L. R., Eppig, J., Werhane, M. L., Edmonds, E. C., & Bondi, M. W. (2019). Cognitive dispersion is a sensitive marker for early neurodegenerative changes and functional decline in nondemented older adults. Neuropsychology, 33(5), 599-608.
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  Intraindividual cognitive variability (IIV), a measure of within-person variability across cognitive measures at a single time point, is associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Little is known regarding brain changes underlying IIV, or the relationship between IIV and functional ability. Therefore, we investigated the association between IIV and cerebral atrophy in AD-vulnerable regions and everyday functioning in nondemented older adults.
• Edmonds, E. C., McDonald, C. R., Marshall, A., Thomas, K. R., Eppig, J., Weigand, A. J., Delano-Wood, L., Galasko, D. R., Salmon, D. P., Bondi, M. W., & , A. D. (2019). Early versus late MCI: Improved MCI staging using a neuropsychological approach. Alzheimer's & dementia : the journal of the Alzheimer's Association, 15(5), 699-708.
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  The Alzheimer's Disease Neuroimaging Initiative (ADNI) separates "early" and "late" mild cognitive impairment (MCI) based on a single memory test. We compared ADNI's MCI classifications to our neuropsychological approach, which more broadly assesses cognitive abilities.
• Thomas, K. R., Edmonds, E. C., Eppig, J. S., Wong, C. G., Weigand, A. J., Bangen, K. J., Jak, A. J., Delano-Wood, L., Galasko, D. R., Salmon, D. P., Edland, S. D., Bondi, M. W., & , A. D. (2019). MCI-to-normal reversion using neuropsychological criteria in the Alzheimer's Disease Neuroimaging Initiative. Alzheimer's & dementia : the journal of the Alzheimer's Association, 15(10), 1322-1332.
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  The low mild cognitive impairment (MCI) to cognitively normal (CN) reversion rate in the Alzheimer's Disease Neuroimaging Initiative (2-3%) suggests the need to examine reversion by other means. We applied comprehensive neuropsychological criteria (NP criteria) to determine the resulting MCI to CN reversion rate.
• Thomas, K. R., Eppig, J. S., Weigand, A. J., Edmonds, E. C., Wong, C. G., Jak, A. J., Delano-Wood, L., Galasko, D. R., Salmon, D. P., Edland, S. D., Bondi, M. W., & , A. D. (2019). Artificially low mild cognitive impairment to normal reversion rate in the Alzheimer's Disease Neuroimaging Initiative. Alzheimer's & dementia : the journal of the Alzheimer's Association, 15(4), 561-569.
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  We examined reasons for low mild cognitive impairment (MCI)-to-cognitively normal (CN) reversion rates in the Alzheimer's Disease Neuroimaging Initiative (ADNI).
• Wong, C., Thomas, K., Edmonds, E., Weigand, A., Bangen, K., Eppig, J., Jak, A., Devine, S., Delano-Wood, L., Libon, D., Edland, S., Au, R., & Bondi, M. (2019). Neuropsychological criteria for mild cognitive impairment in the framingham heart study's old-old. Dementia and Geriatric Cognitive Disorders, 46(5-6). doi:10.1159/000493541
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  Background/Aims: Mild cognitive impairment (MCI) lacks a "gold standard" operational definition. The Jak/Bondi actuarial neuropsychological criteria for MCI are associated with improved diagnostic stability and prediction of progression to dementia compared to conventional MCI diagnostic approaches, although its utility in diagnosing MCI in old-old individuals (age 75+) is unknown. Therefore, we investigated the applicability of neuropsychological MCI criteria among old-old from the Framingham Heart Study. Methods: A total of 347 adults (ages 79-102) were classified as cognitively normal or MCI via Jak/Bondi and conventional Petersen/Winblad criteria, which differ on cutoffs for cognitive impairment and number of impaired scores required for a diagnosis. Cox models examined MCI status in predicting risk of progression to dementia. Results: MCI diagnosed by both the Jak/Bondi and Petersen/Winblad criteria was associated with incident dementia; however, when both criteria were included in the regression model together, only the Jak/Bondi criteria remained statistically significant. At follow-up, the Jak/Bondi criteria had a lower MCI-to-normal reversion rate than the Petersen/Winblad criteria. Conclusions: Our findings are consistent with previous research on the Jak/Bondi criteria and support the use of a comprehensive neuropsychological diagnostic approach for MCI among old-old individuals.
• Bangen, K. J., Werhane, M. L., Weigand, A. J., Edmonds, E. C., Delano-Wood, L., Thomas, K. R., Nation, D. A., Evangelista, N. D., Clark, A. L., Liu, T. T., & Bondi, M. W. (2018). Reduced Regional Cerebral Blood Flow Relates to Poorer Cognition in Older Adults With Type 2 Diabetes. Frontiers in aging neuroscience, 10, 270.
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  Type 2 diabetes mellitus (T2DM) increases risk for dementia, including Alzheimer's disease (AD). Many previous studies of brain changes underlying cognitive impairment in T2DM have applied conventional structural magnetic resonance imaging (MRI) to detect macrostructural changes associated with cerebrovascular disease such as white matter hyperintensities or infarcts. However, such pathology likely reflects end-stage manifestations of chronic decrements in cerebral blood flow (CBF). MRI techniques that measure CBF may (1) elucidate mechanisms that precede irreversible parenchymal damage and (2) serve as a marker of risk for cognitive decline. CBF measured with arterial spin labeling (ASL) MRI may be a useful marker of perfusion deficits in T2DM and related conditions. We examined associations among T2DM, CBF, and cognition in a sample of 49 well-characterized nondemented older adults. Along with a standard T1-weighted scan, a pseudocontinuous ASL sequence optimized for older adults (by increasing post-labeling delays to allow more time for the blood to reach brain tissue) was obtained on a 3T GE scanner to measure regional CBF in FreeSurfer derived regions of interest. Participants also completed a neuropsychological assessment. Results showed no significant differences between individuals with and without T2DM in terms of cortical thickness or regional brain volume. However, adjusting for age, sex, comorbid vascular risk factors, and reference CBF (postcentral gyrus) older adults with T2DM demonstrated reduced CBF in the hippocampus, and inferior temporal, inferior parietal, and frontal cortices. Lower CBF was associated with poorer memory and executive function/processing speed. When adjusting for diabetes, the significant associations between lower regional CBF and poorer executive function/processing speed remained. Results demonstrate that CBF is reduced in older adults with T2DM, and suggest that CBF alterations likely precede volumetric changes. Notably, relative to nondiabetic control participants, those with T2DM showed lower CBF in predilection sites for AD pathology (medial temporal lobe and inferior parietal regions). Findings augment recent research suggesting that perfusion deficits may underlie cognitive decrements frequently observed among older adults with T2DM. Results also suggest that CBF measured with ASL MRI may reflect an early and important marker of risk of cognitive impairment in T2DM and related conditions.
• Edmonds, E. C., Ard, M. C., Edland, S. D., Galasko, D. R., Salmon, D. P., & Bondi, M. W. (2018). Unmasking the benefits of donepezil via psychometrically precise identification of mild cognitive impairment: A secondary analysis of the ADCS vitamin E and donepezil in MCI study. Alzheimer's & dementia (New York, N. Y.), 4, 11-18.
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  Criteria for mild cognitive impairment (MCI) used in many clinical trials are susceptible to "false-positive (FP)" errors that can be avoided by an actuarial psychometric approach.
• Edmonds, E. C., Martin, A. S., Palmer, B. W., Eyler, L. T., Rana, B. K., & Jeste, D. V. (2018). Positive mental health in schizophrenia and healthy comparison groups: relationships with overall health and biomarkers. Aging & mental health, 22(3), 354-362.
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  Positive psychological factors (PPFs) have been reported to have a significant impact on health in the general population. However, little is known about the relationship of these factors with mental and physical health in schizophrenia.
• Edmonds, E. C., Weigand, A. J., Thomas, K. R., Eppig, J., Delano-Wood, L., Galasko, D. R., Salmon, D. P., & Bondi, M. W. (2018). Increasing Inaccuracy of Self-Reported Subjective Cognitive Complaints Over 24 Months in Empirically Derived Subtypes of Mild Cognitive Impairment. Journal of the International Neuropsychological Society : JINS, 24(8), 842-853.
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  Although subjective cognitive complaints (SCC) are an integral component of the diagnostic criteria for mild cognitive impairment (MCI), previous findings indicate they may not accurately reflect cognitive ability. Within the Alzheimer's Disease Neuroimaging Initiative, we investigated longitudinal change in the discrepancy between self- and informant-reported SCC across empirically derived subtypes of MCI and normal control (NC) participants.
• Montross-Thomas, L. P., Joseph, J., Edmonds, E. C., Palinkas, L. A., & Jeste, D. V. (2018). Reflections on wisdom at the end of life: qualitative study of hospice patients aged 58-97 years. International psychogeriatrics, 30(12), 1759-1766.
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  ABSTRACTObjective:Wisdom is a complex trait, and previous research has identified several components of wisdom. This study explored the possible impact of a diagnosis of a terminal illness on the conceptualization and evolution of wisdom while facing the end of life.
• Sundermann, E. E., Edmonds, E. C., Delano-Wood, L., Galasko, D. R., Salmon, D. P., Rubin, L. H., Bondi, M. W., & , A. D. (2018). Sex Influences the Accuracy of Subjective Memory Complaint Reporting in Older Adults. Journal of Alzheimer's disease : JAD, 61(3), 1163-1178.
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  Subjective memory complaints (SMC) are required when diagnosing amnestic mild cognitive impairment (aMCI), although their relationship with objective memory performance and Alzheimer's disease (AD) pathology remains unclear. We investigated whether the sex of the patient/participant moderates these associations. Participants were 940 normal control (NC) and aMCI participants from the Alzheimer's Disease Neuroimaging Initiative. SMC were assessed via the memory scale of the Everyday Cognition questionnaire. Discrepancy scores were calculated between self- and informant-reports and categorized into "overestimates," "comparable estimates", and "underestimates" of SMC. We conducted linear and logistic regressions to examine the interaction of sex with self- and informant-reported SMC and discrepancy group on the Rey Auditory Verbal Learning Test (RAVLT) Immediate and Delayed Recall and on PET measures of amyloid-β (Aβ) positivity. Diagnosis-stratified analyses were also conducted. Overall, there were sex by self- and informant-reported SMC interactions for Immediate and Delayed Recall. Despite a higher proportion of "overestimates" in women, greater self- and informant-reported SMC showed a stronger relationship to poorer RAVLT scores in women versus men. Diagnosis-stratified analyses revealed that results were driven by aMCI participants. Conversely, overall, greater self- and informant-reported SMC related to greater odds of Aβ positivity regardless of sex. In diagnosis-stratified analyses, only informant-reported SMC related to Aβ positivity in aMCI. Relative to "comparable estimates," "underestimates" of SMC were associated with poorer RAVLT scores across sexes in the overall sample and in aMCI. The predictive utility of self-report SMC may be limited to women in aMCI. Sex differences should be considered when evaluating SMC.
• Thomas, K. R., Edmonds, E. C., Eppig, J., Salmon, D. P., Bondi, M. W., & , A. D. (2018). Using Neuropsychological Process Scores to Identify Subtle Cognitive Decline and Predict Progression to Mild Cognitive Impairment. Journal of Alzheimer's disease : JAD, 64(1), 195-204.
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  We previously operationally-defined subtle cognitive decline (SCD) in preclinical Alzheimer's disease (AD) using total scores on neuropsychological (NP) tests. NP process scores (i.e., provide information about how a total NP score was achieved) may be a useful tool for identifying early cognitive inefficiencies prior to objective impairment seen in mild cognitive impairment (MCI) and dementia.
• Thomas, K. R., Eppig, J., Edmonds, E. C., Jacobs, D. M., Libon, D. J., Au, R., Salmon, D. P., Bondi, M. W., & , A. D. (2018). Word-list intrusion errors predict progression to mild cognitive impairment. Neuropsychology, 32(2), 235-245.
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  Preclinical Alzheimer's disease (AD) defined by a positive AD biomarker in the presence of normal cognition is presumed to precede mild cognitive impairment (MCI). Subtle cognitive deficits and cognitive inefficiencies in preclinical AD may be detected through process and error scores on neuropsychological tests in those at risk for progression to MCI.
• Werhane, M. L., Thomas, K. R., Edmonds, E. C., Bangen, K. J., Tran, M., Clark, A. L., Nation, D. A., Gilbert, P. E., Bondi, M. W., Delano-Wood, L., & , A. D. (2018). Differential Effect of APOE ɛ4 Status and Elevated Pulse Pressure on Functional Decline in Cognitively Normal Older Adults. Journal of Alzheimer's disease : JAD, 62(4), 1567-1578.
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  The APOE ɛ4 allele and increased vascular risk have both been independently linked to cognitive impairment and dementia. Since few studies have characterized how these risk factors affect everyday functioning, we investigated the relationship between APOE ɛ4 genotype and elevated pulse pressure (PP) on functional change in cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI).
• Wong, C. G., Thomas, K. R., Edmonds, E. C., Weigand, A. J., Bangen, K. J., Eppig, J. S., Jak, A. J., Devine, S. A., Delano-Wood, L., Libon, D. J., Edland, S. D., Au, R., & Bondi, M. W. (2018). Neuropsychological Criteria for Mild Cognitive Impairment in the Framingham Heart Study's Old-Old. Dementia and geriatric cognitive disorders, 46(5-6), 253-265.
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  Mild cognitive impairment (MCI) lacks a "gold standard" operational definition. The Jak/Bondi actuarial neuropsychological criteria for MCI are associated with improved diagnostic stability and prediction of progression to dementia compared to conventional MCI diagnostic approaches, although its utility in diagnosing MCI in old-old individuals (age 75+) is unknown. Therefore, we investigated the applicability of neuropsychological MCI criteria among old-old from the Framingham Heart Study.
• Bangen, K. J., Clark, A. L., Edmonds, E. C., Evangelista, N. D., Werhane, M. L., Thomas, K. R., Locano, L. E., Tran, M., Zlatar, Z. Z., Nation, D. A., Bondi, M. W., & Delano-Wood, L. (2017). Cerebral Blood Flow and Amyloid-β Interact to Affect Memory Performance in Cognitively Normal Older Adults. Frontiers in aging neuroscience, 9, 181.
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  Cerebral blood flow (CBF) alterations and amyloid-β (Aβ) accumulation have been independently linked to cognitive deficits in older adults at risk for dementia. Less is known about how CBF and Aβ may interact to affect cognition in cognitively normal older adults. Therefore, we examined potential statistical interactions between CBF and Aβ status in regions typically affected in Alzheimer's disease (AD) within a sample of older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Sixty-two cognitively normal participants (mean age = 72 years) underwent neuroimaging and memory testing. Arterial spin labeling magnetic resonance imaging was used to quantify CBF and florbetapir PET amyloid imaging was used to measure Aβ deposition. Aβ status (i.e., positivity versus negativity) was determined based on established cutoffs (Landau et al., 2013). The Rey Auditory Verbal Learning Test was used to assess memory. Linear regression models adjusted for age, education, and sex, demonstrated significant interactions between CBF and Aβ status on memory performance. Among Aβ positive older adults, there were significant negative associations between higher CBF in hippocampus, posterior cingulate, and precuneus and poorer memory performance. In contrast, among Aβ negative older adults, there were no significant associations between CBF and cognition. Our findings extend previous CBF studies of dementia risk by reporting interactions between Aβ status and CBF on memory performance in a sample of well-characterized, cognitively normal older adults. Results suggest that differential CBF-cognition associations can be identified in healthy, asymptomatic Aβ positive older adults relative to Aβ negative individuals. Associations between higherCBF and poorer memory among Aβ positive older adults may reflect a cellular and/or vascular compensatory response to pathologic processes whereby higher CBF is needed to maintain normal memory abilities. Findings indicate that CBF and its associations with cognition may have utility as a reliable marker of brain function early in the AD process when interventions are likely to be beneficial.
• Bondi, M. W., Edmonds, E. C., & Salmon, D. P. (2017). Alzheimer's Disease: Past, Present, and Future. Journal of the International Neuropsychological Society : JINS, 23(9-10), 818-831.
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  Although dementia has been described in ancient texts over many centuries (e.g., "Be kind to your father, even if his mind fail him." - Old Testament: Sirach 3:12), our knowledge of its underlying causes is little more than a century old. Alzheimer published his now famous case study only 110 years ago, and our modern understanding of the disease that bears his name, and its neuropsychological consequences, really only began to accelerate in the 1980s. Since then we have witnessed an explosion of basic and translational research into the causes, characterizations, and possible treatments for Alzheimer's disease (AD) and other dementias. We review this lineage of work beginning with Alzheimer's own writings and drawings, then jump to the modern era beginning in the 1970s and early 1980s and provide a sampling of neuropsychological and other contextual work from each ensuing decade. During the 1980s our field began its foundational studies of profiling the neuropsychological deficits associated with AD and its differentiation from other dementias (e.g., cortical vs. subcortical dementias). The 1990s continued these efforts and began to identify the specific cognitive mechanisms affected by various neuropathologic substrates. The 2000s ushered in a focus on the study of prodromal stages of neurodegenerative disease before the full-blown dementia syndrome (i.e., mild cognitive impairment). The current decade has seen the rise of imaging and other biomarkers to characterize preclinical disease before the development of significant cognitive decline. Finally, we suggest future directions and predictions for dementia-related research and potential therapeutic interventions. (JINS, 2017, 23, 818-831).
• Eppig, J. S., Edmonds, E. C., Campbell, L., Sanderson-Cimino, M., Delano-Wood, L., Bondi, M. W., & , A. D. (2017). Statistically Derived Subtypes and Associations with Cerebrospinal Fluid and Genetic Biomarkers in Mild Cognitive Impairment: A Latent Profile Analysis. Journal of the International Neuropsychological Society : JINS, 23(7), 564-576.
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  Research demonstrates heterogeneous neuropsychological profiles among individuals with mild cognitive impairment (MCI). However, few studies have included visuoconstructional ability or used latent mixture modeling to statistically identify MCI subtypes. Therefore, we examined whether unique neuropsychological MCI profiles could be ascertained using latent profile analysis (LPA), and subsequently investigated cerebrospinal fluid (CSF) biomarkers, genotype, and longitudinal clinical outcomes between the empirically derived classes.
• Thomas, K. R., Edmonds, E. C., Delano-Wood, L., & Bondi, M. W. (2017). Longitudinal Trajectories of Informant-Reported Daily Functioning in Empirically Defined Subtypes of Mild Cognitive Impairment. Journal of the International Neuropsychological Society : JINS, 23(6), 521-527.
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  Within the Alzheimer's Disease Neuroimaging Initiative (ADNI)'s mild cognitive impairment (MCI) cohort, we previously identified MCI subtypes as well as participants initially diagnosed with MCI but found to have normal neuropsychological, biomarker, and neuroimaging profiles. We investigated the functional change over time in these empirically derived MCI subgroups.
• Ahmed, S., Brennan, L., Eppig, J., Price, C. C., Lamar, M., Delano-Wood, L., Bangen, K. J., Edmonds, E. C., Clark, L., Nation, D. A., Jak, A., Au, R., Swenson, R., Bondi, M. W., & Libon, D. J. (2016). Visuoconstructional Impairment in Subtypes of Mild Cognitive Impairment. Applied neuropsychology. Adult, 23(1), 43-52.
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  Clock Drawing Test performance was examined alongside other neuropsychological tests in mild cognitive impairment (MCI). We tested the hypothesis that clock-drawing errors are related to executive impairment. The current research examined 86 patients with MCI for whom, in prior research, cluster analysis was used to sort patients into dysexecutive (dMCI, n = 22), amnestic (aMCI, n = 13), and multidomain (mMCI, n = 51) subtypes. First, principal components analysis (PCA) and linear regression examined relations between clock-drawing errors and neuropsychological test performance independent of MCI subtype. Second, between-group differences were assessed with analysis of variance (ANOVA) where MCI subgroups were compared to normal controls (NC). PCA yielded a 3-group solution. Contrary to expectations, clock-drawing errors loaded with lower performance on naming/lexical retrieval, rather than with executive tests. Regression analyses found increasing clock-drawing errors to command were associated with worse performance only on naming/lexical retrieval tests. ANOVAs revealed no differences in clock-drawing errors between dMCI versus mMCI or aMCI versus NCs. Both the dMCI and mMCI groups generated more clock-drawing errors than the aMCI and NC groups in the command condition. In MCI, language-related skills contribute to clock-drawing impairment.
• Bangen, K. J., Clark, A. L., Werhane, M., Edmonds, E. C., Nation, D. A., Evangelista, N., Libon, D. J., Bondi, M. W., Delano-Wood, L., & , A. D. (2016). Cortical Amyloid Burden Differences Across Empirically-Derived Mild Cognitive Impairment Subtypes and Interaction with APOE ɛ4 Genotype. Journal of Alzheimer's disease : JAD, 52(3), 849-61.
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  We examined cortical amyloid-β (Aβ) levels and interactions with apolipoprotein (APOE) ɛ4 genotype status across empirically-derived mild cognitive impairment (MCI) subgroups and cognitively normal older adults. Participants were 583 ADNI participants (444 MCI, 139 normal controls [NC]) with baseline florbetapir positron emission tomography (PET) amyloid imaging and neuropsychological testing. Of those with ADNI-defined MCI, a previous cluster analysis [1] classified 51% (n = 227) of the current sample as amnestic MCI, 8% (n = 37) as dysexecutive/mixed MCI, and 41% (n = 180) as cluster-derived normal (cognitively normal). Results demonstrated that the dysexecutive/mixed and amnestic MCI groups showed significantly greater levels of amyloid relative to the cluster-derived normal and NC groups who did not differ from each other. Additionally, 78% of the dysexecutive/mixed, 63% of the amnestic MCI, 42% of the cluster-derived normal, and 34% of the NC group exceeded the amyloid positivity threshold. Finally, a group by APOE genotype interaction demonstrated that APOE ɛ4 carriers within the amnestic MCI, cluster-derived normal, and NC groups showed significantly greater amyloid accumulation compared to non-carriers of their respective group. Such an interaction was not revealed within the dysexecutive/mixed MCI group which was characterized by both greater cognitive impairment and amyloid accumulation compared to the other participant groups. Our results from the ADNI cohort show considerable heterogeneity in Aβ across all groups studied, even within a group of robust NC participants. Findings suggest that conventional criteria for MCI may be susceptible to false positive diagnostic errors, and that onset of Aβ accumulation may occur earlier in APOE ɛ4 carriers compared to non-carriers.
• Edmonds, E. C., Bangen, K. J., Delano-Wood, L., Nation, D. A., Furst, A. J., Salmon, D. P., Bondi, M. W., & , A. D. (2016). Patterns of Cortical and Subcortical Amyloid Burden across Stages of Preclinical Alzheimer's Disease. Journal of the International Neuropsychological Society : JINS, 22(10), 978-990.
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  We examined florbetapir positron emission tomography (PET) amyloid scans across stages of preclinical Alzheimer's disease (AD) in cortical, allocortical, and subcortical regions. Stages were characterized using empirically defined methods.
• Edmonds, E. C., Delano-Wood, L., Jak, A. J., Galasko, D. R., Salmon, D. P., Bondi, M. W., & , A. D. (2016). "Missed" Mild Cognitive Impairment: High False-Negative Error Rate Based on Conventional Diagnostic Criteria. Journal of Alzheimer's disease : JAD, 52(2), 685-91.
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  Mild cognitive impairment (MCI) is typically diagnosed using subjective complaints, screening measures, clinical judgment, and a single memory score. Our prior work has shown that this method is highly susceptible to false-positive diagnostic errors. We examined whether the criteria also lead to "false-negative" errors by diagnostically reclassifying 520 participants using novel actuarial neuropsychological criteria. Results revealed a false-negative error rate of 7.1%. Participants' neuropsychological performance, cerebrospinal fluid biomarkers, and rate of decline provided evidence that an MCI diagnosis is warranted. The impact of "missed" cases of MCI has direct relevance to clinical practice, research studies, and clinical trials of prodromal Alzheimer's disease.
• Edmonds, E. C., Eppig, J., Bondi, M. W., Leyden, K. M., Goodwin, B., Delano-Wood, L., McDonald, C. R., & , A. D. (2016). Heterogeneous cortical atrophy patterns in MCI not captured by conventional diagnostic criteria. Neurology, 87(20), 2108-2116.
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  We investigated differences in regional cortical thickness between previously identified empirically derived mild cognitive impairment (MCI) subtypes (amnestic MCI, dysnomic MCI, dysexecutive/mixed MCI, and cluster-derived normal) in order to determine whether these cognitive subtypes would show different patterns of cortical atrophy.
• Jeste, D. V., & Edmonds, E. C. (2016). Evolution of the Care of the Dying: From Paternalistic to Palliative Care. Psychiatry, 79(3), 227-232.
• Edmonds, E. C., Delano-Wood, L., Clark, L. R., Jak, A. J., Nation, D. A., McDonald, C. R., Libon, D. J., Au, R., Galasko, D., Salmon, D. P., Bondi, M. W., & , A. D. (2015). Susceptibility of the conventional criteria for mild cognitive impairment to false-positive diagnostic errors. Alzheimer's & dementia : the journal of the Alzheimer's Association, 11(4), 415-24.
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  We assessed whether mild cognitive impairment (MCI) subtypes could be empirically derived within the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort and examined associated biomarkers and clinical outcomes.
• Edmonds, E. C., Delano-Wood, L., Galasko, D. R., Salmon, D. P., Bondi, M. W., & , A. D. (2015). Subtle Cognitive Decline and Biomarker Staging in Preclinical Alzheimer's Disease. Journal of Alzheimer's disease : JAD, 47(1), 231-42.
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  The NIA-AA criteria for "preclinical" Alzheimer's disease (AD) propose a staging method in which AD biomarkers follow an invariable temporal sequence in accordance with the amyloid cascade hypothesis. However, recent findings do not align with the proposed temporal sequence and "subtle cognitive decline," which has not been definitively operationalized, may occur earlier than suggested in preclinical AD. We aimed to define "subtle cognitive decline" using sensitive and reliable neuropsychological tests, and to examine the number and sequence of biomarker abnormalities in the Alzheimer's Disease Neuroimaging Initiative (ADNI). 570 cognitively normal ADNI participants were classified based on NIA-AA criteria and separately based on the number of abnormal biomarkers/cognitive markers associated with preclinical AD that each individual possessed. Results revealed that neurodegeneration alone was 2.5 times more common than amyloidosis alone at baseline. For those who demonstrated only one abnormal biomarker at baseline and later progressed to mild cognitive impairment/AD, neurodegeneration alone was most common, followed by amyloidosis alone or subtle cognitive decline alone, which were equally common. Findings suggest that most individuals do not follow the temporal order proposed by NIA-AA criteria. We provide an operational definition of subtle cognitive decline that captures both cognitive and functional decline. Additionally, we offer a new approach for staging preclinical AD based on number of abnormal biomarkers, without regard to their temporal order of occurrence. This method of characterizing preclinical AD is more parsimonious than the NIA-AA staging system and does not presume that all patients follow a singular invariant expression of the disease.
• Nation, D. A., Edmonds, E. C., Bangen, K. J., Delano-Wood, L., Scanlon, B. K., Han, S. D., Edland, S. D., Salmon, D. P., Galasko, D. R., Bondi, M. W., & , A. D. (2015). Pulse pressure in relation to tau-mediated neurodegeneration, cerebral amyloidosis, and progression to dementia in very old adults. JAMA neurology, 72(5), 546-53.
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  Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear.
• Bondi, M. W., Edmonds, E. C., Jak, A. J., Clark, L. R., Delano-Wood, L., McDonald, C. R., Nation, D. A., Libon, D. J., Au, R., Galasko, D., & Salmon, D. P. (2014). Neuropsychological criteria for mild cognitive impairment improves diagnostic precision, biomarker associations, and progression rates. Journal of Alzheimer's disease : JAD, 42(1), 275-89.
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  We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winblad criteria as operationalized by the Alzheimer's Disease Neuroimaging Initiative (ADNI) and an actuarial neuropsychological method put forward by Jak and Bondi designed to balance sensitivity and reliability. 1,150 ADNI participants were diagnosed at baseline as cognitively normal (CN) or MCI via ADNI criteria (MCI: n = 846; CN: n = 304) or Jak/Bondi criteria (MCI: n = 401; CN: n = 749), and the two MCI samples were submitted to cluster and discriminant function analyses. Resulting cluster groups were then compared and further examined for APOE allelic frequencies, cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker levels, and clinical outcomes. Results revealed that both criteria produced a mildly impaired Amnestic subtype and a more severely impaired Dysexecutive/Mixed subtype. The neuropsychological Jak/Bondi criteria uniquely yielded a third Impaired Language subtype, whereas conventional Petersen/Winblad ADNI criteria produced a third subtype comprising nearly one-third of the sample that performed within normal limits across the cognitive measures, suggesting this method's susceptibility to false positive diagnoses. MCI participants diagnosed via neuropsychological criteria yielded dissociable cognitive phenotypes, significant CSF AD biomarker associations, more stable diagnoses, and identified greater percentages of participants who progressed to dementia than conventional MCI diagnostic criteria. Importantly, the actuarial neuropsychological method did not produce a subtype that performed within normal limits on the cognitive testing, unlike the conventional diagnostic method. Findings support the need for refinement of MCI diagnoses to incorporate more comprehensive neuropsychological methods, with resulting gains in empirical characterization of specific cognitive phenotypes, biomarker associations, stability of diagnoses, and prediction of progression. Refinement of MCI diagnostic methods may also yield gains in biomarker and clinical trial study findings because of improvements in sample compositions of 'true positive' cases and removal of 'false positive' cases.
• Edmonds, E. C., Delano-Wood, L., Galasko, D. R., Salmon, D. P., Bondi, M. W., & , A. D. (2014). Subjective cognitive complaints contribute to misdiagnosis of mild cognitive impairment. Journal of the International Neuropsychological Society : JINS, 20(8), 836-47.
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  Subjective cognitive complaints are a criterion for the diagnosis of mild cognitive impairment (MCI), despite their uncertain relationship to objective memory performance in MCI. We aimed to examine self-reported cognitive complaints in subgroups of the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort to determine whether they are a valuable inclusion in the diagnosis of MCI or, alternatively, if they contribute to misdiagnosis. Subgroups of MCI were derived using cluster analysis of baseline neuropsychological test data from 448 ADNI MCI participants. Cognitive complaints were assessed via the Everyday Cognition (ECog) questionnaire, and discrepancy scores were calculated between self- and informant-report. Cluster analysis revealed Amnestic and Mixed cognitive phenotypes as well as a third Cluster-Derived Normal subgroup (41.3%), whose neuropsychological and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker profiles did not differ from a "robust" normal control group. This cognitively intact phenotype of MCI participants overestimated their cognitive problems relative to their informant, whereas Amnestic MCI participants with objective memory impairment underestimated their cognitive problems. Underestimation of cognitive problems was associated with positive CSF AD biomarkers and progression to dementia. Overall, there was no relationship between self-reported cognitive complaints and objective cognitive functioning, but significant correlations were observed with depressive symptoms. The inclusion of self-reported complaints in MCI diagnostic criteria may cloud rather than clarify diagnosis and result in high rates of misclassification of MCI. Discrepancies between self- and informant-report demonstrate that overestimation of cognitive problems is characteristic of normal aging while underestimation may reflect greater risk for cognitive decline.
• Bauer, A., Timpe, J., Edmonds, E. C., Bechara, A., Tranel, D., & Denburg, N. L. (2013). Myopia for the future or hypersensitivity to reward? Age-related changes in decision-making on the Iowa Gambling Task.. Emotion, 13, 19-24.
• Edmonds, E. C., Glisky, E. L., Bartlett, J. C., & Rapcsak, S. Z. (2012). Cognitive mechanisms of false facial recognition in older adults. Psychology and aging, 27(1), 54-60.
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  Older adults show elevated false alarm rates on recognition memory tests involving faces in comparison to younger adults. It has been proposed that this age-related increase in false facial recognition reflects a deficit in recollection and a corresponding increase in the use of familiarity when making memory decisions. To test this hypothesis, we examined the performance of 40 older adults and 40 younger adults on a face recognition memory paradigm involving three different types of lures with varying levels of familiarity. A robust age effect was found, with older adults demonstrating a markedly heightened false alarm rate in comparison to younger adults for "familiarized lures" that were exact repetitions of faces encountered earlier in the experiment, but outside the study list, and therefore required accurate recollection of contextual information to reject. By contrast, there were no age differences in false alarms to "conjunction lures" that recombined parts of study list faces, or to entirely new faces. Overall, the pattern of false recognition errors observed in older adults was consistent with excessive reliance on a familiarity-based response strategy. Specifically, in the absence of recollection older adults appeared to base their memory decisions on item familiarity, as evidenced by a linear increase in false alarm rates with increasing familiarity of the lures. These findings support the notion that automatic memory processes such as familiarity remain invariant with age, while more controlled memory processes such as recollection show age-related decline.
• Han, S. D., Arfanakis, K., Fleischman, D. A., Leurgans, S. E., Tuminello, E. R., Edmonds, E. C., & Bennett, D. A. (2012). Functional connectivity variations in mild cognitive impairment: associations with cognitive function. Journal of the International Neuropsychological Society : JINS, 18(1), 39-48.
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  Participants with mild cognitive impairment (MCI) have a higher likelihood of developing Alzheimer's disease (AD) compared to those without MCI, and functional magnetic resonance neuroimaging (fMRI) used with MCI participants may prove to be an important tool in identifying early biomarkers for AD. We tested the hypothesis that functional connectivity differences exist between older adults with and without MCI using resting-state fMRI. Data were collected on over 200 participants of the Rush Memory and Aging Project, a community-based, clinical-pathological cohort study of aging. From the cohort, 40 participants were identified as having MCI, and were compared to 40 demographically matched participants without cognitive impairment. MCI participants showed lesser functional connectivity between the posterior cingulate cortex and right and left orbital frontal, right middle frontal, left putamen, right caudate, left superior temporal, and right posterior cingulate regions; and greater connectivity with right inferior frontal, left fusiform, left rectal, and left precentral regions. Furthermore, in an alternate sample of 113, connectivity values in regions of difference correlated with episodic memory and processing speed. Results suggest functional connectivity values in regions of difference are associated with cognitive function and may reflect the presence of AD pathology and increased risk of developing clinical AD.
• Han, S. D., Boyle, P. A., Arfanakis, K., Fleischman, D. A., Yu, L., Edmonds, E. C., & Bennett, D. A. (2012). Neural intrinsic connectivity networks associated with risk aversion in old age. Behavioural brain research, 227(1), 233-40.
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  Risk aversion is associated with several important real world outcomes. Although the neurobiological correlates of risk aversion have been studied in young persons, little is known of the neurobiological correlates of risk aversion among older persons. Resting-state functional MRI data were collected on 134 non-demented participants of the Rush Memory and Aging Project, a community-based cohort study of aging. Risk aversion was measured using a series of standard questions in which participants were asked to choose between a certain monetary payment ($15) versus a gamble in which they could gain more than $15 or gain nothing, with potential gains varied across questions. Participants determined to be "high" (n=27) and "low" (n=27) in risk aversion were grouped accordingly. Using a spherical seed region of interest in the anterior cingulate cortex, voxel-wise functional connectivity network similarities were observed in bilateral frontal, anterior and posterior cingulate, insula, basal ganglia, temporal, parietal, and thalamic regions. Differences in functional connectivity were observed such that those low in risk aversion had greater connectivity to clusters in the superior, middle, and medial frontal regions, as well as cerebellar, parietal, occipital, and inferior temporal regions. Those high in risk aversion had greater connectivity to clusters in the inferior and orbital frontal, parahippocampal, and insula regions, as well as thalamic, parietal, precentral gyrus, postcentral gyrus, and middle temporal regions. Similarities and differences in functional connectivity patterns may reflect the historical recruitment of specific brain regions as a network in the active processing of risk in older adults.
• Ruppert, P., Edmonds, E. C., Brook, M., Musil, S., & Han, S. D. (2012). Neuropsychological assessment in a case of adult-onset hemophagocytic lymphohistiocytosis (HLH). The Clinical neuropsychologist, 26(6), 1038-52.
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  We present a case of an individual diagnosed with hemophagocytic lymphohistiocytosis (HLH), an extremely rare and commonly fatal disorder characterized by rapid dysregulation of immune system processes. Typical age of onset is in childhood, with adult-onset occurring less frequently. The pathophysiology of this condition is characterized by a hyperinflammatory response with infiltration of visceral organs, lymph nodes, bone marrow, and the central nervous system. The clinical presentation has been documented in the extant medical literature. However, there appear to be no published reports of neuropsychological functioning in HLH patients. The patient we present here is a 28-year-old woman with 16 years of education who developed HLH subsequent to systemic lupus erythematosus flare-up. She was initially comatose for 3 weeks. Acute MRI reported multiple subcortical abnormalities, including the brainstem. The patient underwent chemotherapy, immunosuppresant, and steroid treatments. She underwent a neuropsychological evaluation at 2.5 and 7 months post initial presentation. Preliminary neuropsychological evaluation found impairments in motor abilities and aspects of executive functions. Subsequent evaluation showed improved executive function and relative sparing of higher-order cognitive abilities, but continued impairment on motor tests. To our knowledge this is the first study to report neuropsychological data for an adult diagnosed with HLH.
• Edmonds, E. C., & Rapcsak, S. Z. (2011).

  The Executive Control of Face Memory

  . Behavioural Neurology, 24(4), 285-298. doi:10.1155/2011/692460
• Rapcsak, S. Z., & Edmonds, E. C. (2011). The executive control of face memory. Behavioural neurology, 24(4), 285-98.
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  Patients with frontal lobe damage and cognitively normal elderly individuals demonstrate increased susceptibility to false facial recognition. In this paper we review neuropsychological evidence consistent with the notion that the common functional impairment underlying face memory distortions in both subject populations is a context recollection/source monitoring deficit, coupled with excessive reliance on relatively preserved facial familiarity signals in recognition decisions. In particular, we suggest that due to the breakdown of strategic memory retrieval, monitoring, and decision operations, individuals with frontal lobe impairment caused by focal damage or age-related functional decline do not have a reliable mechanism for attributing the experience of familiarity to the correct context or source. Memory illusions are mostly apparent under conditions of uncertainty when the face cue does not directly elicit relevant identity-specific contextual information, leaving the source of familiarity unspecified or ambiguous. Based on these findings, we propose that remembering faces is a constructive process that requires dynamic interactions between temporal lobe memory systems that operate in an automatic or bottom-up fashion and frontal executive systems that provide strategic top-down control of recollection. Executive memory control functions implemented by prefrontal cortex play a critical role in suppressing false facial recognition and related source memory misattributions.
• Brand, M., Recknor, E. C., Grabenhorst, F., & Bechara, A. (2007). Decisions under ambiguity and decisions under risk: correlations with executive functions and comparisons of two different gambling tasks with implicit and explicit rules. Journal of clinical and experimental neuropsychology, 29(1), 86-99.
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  We conducted two experiments with healthy subjects to investigate the possible relationships between Iowa Gambling Task (IGT) performance and executive functions as well as IGT performance and decision-making in a task with explicit rules, the Game of Dice Task (GDT). Results indicated that only the last trials of the IGT were correlated with executive functions and GDT performance. We suggest that the IGT taps into two mechanisms of decision-making: decisions under ambiguity in the first trials and decisions under risk in the latter trials. Results have impact on the interpretation of deficient IGT performance in patients with frontal lobe dysfunctions.
• Verdejo-García, A., Bechara, A., Recknor, E. C., & Pérez-García, M. (2007). Negative emotion-driven impulsivity predicts substance dependence problems. Drug and alcohol dependence, 91(2-3), 213-9.
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  Impulsivity is predominant among users of several drugs of abuse including alcohol, cocaine, and amphetamines, and it is considered a risk factor for later development of alcohol and substance abuse and dependence. However, there is little consensus on how impulsivity should be defined and measured, and there are few studies on the relationship between separate dimensions of impulsivity and substance dependence. We used a multidimensional measure of impulsivity (the UPPS scale) to examine differences between 36 individuals with substance dependence (ISD) and 36 drug-free controls on the dimensions of urgency, lack of premeditation, lack of perseverance, and sensation seeking. In addition, we examined which dimensions of impulsivity better predicted addiction-related problems as measured with the addiction severity index. Results revealed that ISD show high scores on dimensions of urgency, lack of perseverance, and lack of premeditation (effect sizes ranging from 1.10 to 1.96), but not on sensation seeking. Among the different impulsivity dimensions, urgency was the best predictor of severity of medical, employment, alcohol, drug, family/social, legal and psychiatric problems in ISD, explaining 13-48% of the total variance of these indices. Furthermore, urgency scores alone correctly classified 83% of the participants in the ISD group. Urgency is characterized by a tendency to act impulsively in response to negative emotional states. Thus, our results could have important implications for novel treatment approaches for substance dependence focused on emotional regulation.
• Denburg, N. L., Recknor, E. C., Bechara, A., & Tranel, D. (2006). Psychophysiological anticipation of positive outcomes promotes advantageous decision-making in normal older persons. International journal of psychophysiology : official journal of the International Organization of Psychophysiology, 61(1), 19-25.
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  Previous studies have demonstrated that aging has an adverse effect on laboratory decision-making in some older adults, and such findings have important implications for real-world reasoning and judgment. Emotion, and its accompanying somatic responses, is thought to contribute significantly to decision-making. In the present study, we had two objectives: 1) to investigate decision-making in a new sample of elderly participants, using the Iowa Gambling Task (IGT); and 2) to investigate psychophysiological correlates of decision-making, focusing on anticipatory skin conductance responses (SCRs) that participants produce immediately prior to their behavioral response. We hypothesized that the previous behavioral findings would be replicated, and further, that the older adult participants with IGT impairments would show a lack of discriminatory anticipatory SCRs during the IGT. The results supported both predictions. First, a subgroup of the new elderly sample demonstrated impaired decision-making on the IGT, replicating our previous findings. Second, the participants with impaired IGT performance failed to demonstrate discriminatory anticipatory SCRs for advantageous versus disadvantageous choices, whereas participants with normal IGT performance did demonstrate such discrimination; in the latter case, however, SCR magnitude was higher for advantageous decisions (unlike the pattern in young normal adults). Our data lead to the suggestion that strong decision-making abilities among older adults may be a function of positive somatic markers, whereas poor decision-making abilities may arise from an abnormal somatic response generated in anticipation of a future event.
• Verdejo-García, A., Bechara, A., Recknor, E. C., & Pérez-García, M. (2006). Executive dysfunction in substance dependent individuals during drug use and abstinence: an examination of the behavioral, cognitive and emotional correlates of addiction. Journal of the International Neuropsychological Society : JINS, 12(3), 405-15.
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  Increasing evidence indicates that substance-dependent individuals (SDI) are impaired in executive control tasks relying on different systems within the prefrontal cortex (PFC). Three different functional systems have been described: the dorsolateral prefrontal cortex (DLPC), orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC) circuits. Dysfunction within each PFC system is associated with different behavioral, cognitive, and emotional abnormalities. Few studies have conducted an exhaustive examination of all these different factors in SDI. In this study, SDI (including alcohol, cocaine, and methamphetamine polysubstance users, n=35) were compared with healthy controls (n=36) on a series of behavioral (Frontal Systems Behaviour Scale, FrSBe), cognitive (N-back, Go-No Go, and Wisconsin Card Sorting Tasks), and emotional (International Affective Picture System, IAPS) tasks, each of which was thought to tax a different component of these PFC functional systems. SDI showed greater behavioral problems in the apathy, disinhibition, and executive dysfunction subscales of the FrSBe. Behavioral deficits were significantly associated with several real-life domains in which SDI typically have problems. SDI also showed poorer performance on cognitive tests of working memory, response inhibition and mental flexibility, and abnormal processing of affective images from the IAPS. Cognitive, behavioral, and emotional measures were moderately correlated.