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Dr. Sarah Chen
Stanford · NLP & interpretability
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Professor Rosemary Toomey is involved in research focused on Gulf War Illness (GWI), a chronic health condition affecting veterans of the First Gulf War. Her work centers on addressing the cognitive symptoms of GWI, which include poor attention, concentration, and memory function—symptoms that significantly impact the quality of life of affected veterans. Recognizing the lack of effective treatments for these cognitive impairments, Professor Toomey is engaged in a pilot study investigating the use of d-cycloserine (DCS), a medication previously shown to improve memory, attention, and mood in other cognitive disorders. This study compares the effects of DCS treatment against a placebo over a four-week period, aiming to evaluate improvements in verbal memory, focused and sustained attention, and selective attention, alongside assessments of physical health and mood.
Journal of the International Neuropsychological Society · 2025-06-01
articleSenior authorCorresponding
OBJECTIVE: Developmental Gerstmann's Syndrome (DGS) is a proposed neurological disorder characterized by finger agnosia, acalculia, right-left disorientation, agraphia, and in some cases, constructional dyspraxia. Case studies of DGS are limited, particularly those reporting on assessments in adults. The present case study demonstrates the presence of DGS symptoms in a young female adult with an autoimmune disorder but no clear history of neurological damage. METHOD: This client sought academic accommodations for her undergraduate math classes. She was administered a comprehensive neuropsychological assessment, during which she demonstrated difficulties with mathematical concepts, right-left disorientation, inverted writing, mild finger agnosia, andimpairments in fine motor abilities and visual motor coordination. RESULTS: The client's symptoms were consistent with DGS, though variability in her performance on assessments suggests compensatory strategies she may have developed throughout her life. CONCLUSION: Our client demonstrated similarities with previously reported accounts of DGS as assessed in adults. This case proposes further evidence for DGS as a syndrome and presents challenges to assessing DGS in high-functioning adults. The case highlights a need for a standardized testing battery to assess DGS.
BACKGROUND: Subjective memory decline (SMD) is a putative early indicator of Alzheimer's disease (AD). However, its association with changes in objective memory and AD-related brain structure is mixed, which may be partly due to reliance on single-item measures of subjective decline. The Everyday Cognition scale (ECog) was developed to improve detection of early AD risk by leveraging multiple items, focusing on behaviors rather than general perceptions, and including informant ratings. METHOD: Data were collected from cognitively unimpaired men at waves 3 and 4 (mean ages 68 and 74) of the Vietnam Era Twin Study of Aging (VETSA). The ECog memory subscale, assessing SMD over 10 years, was completed by participants (wave 3: n = 904; wave 4: n = 516) and informants (wave 3: n = 811; wave 4: n = 473). Participants also completed objective memory testing, summarized as latent factor scores. For a subset completing MRI (wave 3: n = 388; wave 4: n = 191), AD brain signature scores were derived from hippocampal volume and cortical thickness in seven AD-related regions. Structural equation models estimated associations of ECog-SMD with objective memory and AD brain signature scores at wave 3, and predictive associations between ECog-SMD at wave 3 and changes in objective memory and AD brain signature scores by wave 4. Associations between changes in ECog-SMD and changes in objective memory and AD brain signature scores were also examined. Covariates included age 20 cognitive ability, depressive symptoms, and state anxiety. RESULT: Shown in Figures 1 and 2, ECog-SMD at wave 3 was associated with worse objective memory (participant: b=-.59, p < .001; informant: b=10.99, p = .001) and lower AD brain signature scores (participant: b=-1.86, p = .007; informant: b=-1.71, p = .018). ECog-SMD also predicted declines in objective memory (participant: b=-.33, p < .001; informant: -5.50, ps<.001) and reductions in AD brain signature (participant :b=-1.10, p < .001) by wave 4. At wave 4, increases in ECog-SMD correlated with declines in objective memory (participant: b=-.08, p = .007; informant: b=-.12, p = .013) but were not associated with changes in AD brain signatures (participant and informant: ps>.05). CONCLUSION: Participant and informant ECog ratings of SMD reflected concurrent differences in objective memory decline and AD-related neurodegeneration. Participant-reported SMD were associated with future AD-related neurodegeneration, potentially capturing risk undetected by neuropsychological testing or informant reports.
Brain atrophy is a key factor behind episodic memory loss in aging, but the nature and ubiquity of this relationship remains poorly understood. This study leverages 13 longitudinal datasets, including 3737 cognitively healthy adults (10,343 MRI scans; 13,460 memory assessments), to determine whether brain change-memory change associations are more pronounced with age and genetic risk for Alzheimer's Disease. Both factors are associated with accelerated brain decline, yet it remains unclear whether memory loss is exacerbated beyond what atrophy alone would predict. Additionally, we assess whether memory decline aligns with a global pattern of atrophy or stems from distinct regional contributions. Our mega-analysis reveals a nonlinear relationship between memory decline and brain atrophy, primarily affecting individuals with above-average brain structural decline. The associations are stronger in the hippocampus but also spread across diverse cortical and subcortical regions. The associations strengthen with age, reaching moderate associations in participants in their eighties. While APOE ε4 carriers exhibit steeper brain and memory loss, genetic risk has no effect on the change-change associations. These findings support the presence of common biological macrostructural substrates underlying memory function in older age which are vulnerable to multiple age-related factors, even in the absence of overt pathological changes.
Concerns about memory often increase with age and have been suggested as a precursor to impending memory impairment or dementia. However, subjective memory concern (SMC) has also been shown to reflect an individual's trait-like tendency to worry about memory, which is more strongly linked to negative affect than to objective memory performance. Despite behavioral evidence supporting a trait-like dimension of SMC, its neuroanatomical underpinnings remain underexplored. In 477 community-dwelling dementia-free men (56-72 years old), we investigated the association between SMC and cortical mean diffusivity (cMD)-a diffusion MRI-based metric of gray matter microstructural integrity-generating a brain-wide map of their association. Self-report trait anxiety and depressive symptoms were collected, along with objective memory scores based on three neuropsychological tasks for which brain maps of their association with cMD were also generated. Finally, we conducted spatial correlational analyses to compare the spatial patterns of these brain association maps to assess whether there were significant spatial resemblances between each. We found that the gray matter integrity correlates of SMC spatially resembled those of depressive symptoms and trait anxiety but not those of objective memory. The spatial correspondences between gray matter integrity correlates of negative affect measures and SMC were significantly stronger than those between SMC and objective memory. Together, these results suggest a neuroanatomical basis of trait-like SMC, which should be distinguished from state-related SMC that may be a precursor of objective memory deficits in research and clinical settings.
BACKGROUND: Subjective memory decline (SMD) is a putative early indicator of Alzheimer's disease (AD). However, its association with changes in objective memory and AD-related brain structure is mixed, which may be partly due to reliance on single-item measures of subjective decline. The Everyday Cognition scale (ECog) was developed to improve detection of early AD risk by leveraging multiple items, focusing on behaviors rather than general perceptions, and including informant ratings. METHOD: Data were collected from cognitively unimpaired men at waves 3 and 4 (mean ages 68 and 74) of the Vietnam Era Twin Study of Aging (VETSA). The ECog memory subscale, assessing SMD over 10 years, was completed by participants (wave 3: n = 904; wave 4: n = 516) and informants (wave 3: n = 811; wave 4: n = 473). Participants also completed objective memory testing, summarized as latent factor scores. For a subset completing MRI (wave 3: n = 388; wave 4: n = 191), AD brain signature scores were derived from hippocampal volume and cortical thickness in seven AD-related regions. Structural equation models estimated associations of ECog-SMD with objective memory and AD brain signature scores at wave 3, and predictive associations between ECog-SMD at wave 3 and changes in objective memory and AD brain signature scores by wave 4. Associations between changes in ECog-SMD and changes in objective memory and AD brain signature scores were also examined. Covariates included age 20 cognitive ability, depressive symptoms, and state anxiety. RESULT: Shown in Figures 1 and 2, ECog-SMD at wave 3 was associated with worse objective memory (participant: b=-.59, p < .001; informant: b=10.99, p = .001) and lower AD brain signature scores (participant: b=-1.86, p = .007; informant: b=-1.71, p = .018). ECog-SMD also predicted declines in objective memory (participant: b=-.33, p < .001; informant: -5.50, ps < .001) and reductions in AD brain signature (participant :b=-1.10, p < .001) by wave 4. At wave 4, increases in ECog-SMD correlated with declines in objective memory (participant: b=-.08, p = .007; informant: b=-.12, p = .013) but were not associated with changes in AD brain signatures (participant and informant: ps > .05). CONCLUSION: Participant and informant ECog ratings of SMD reflected concurrent differences in objective memory decline and AD-related neurodegeneration. Participant-reported SMD were associated with future AD-related neurodegeneration, potentially capturing risk undetected by neuropsychological testing or informant reports.
BACKGROUND: Visual short-term memory binding (VSTMB) requires efficient functional connectivity between cortical regions and is a sensitive behavioral marker of Alzheimer's disease (AD). VSTMB impairments have been detected in individuals with subjective cognitive decline (SCD) who perform normally on standard neuropsychological tests. Research has linked SCD to reduced integrity of the rostral-middle locus coeruleus (LC), an area that accumulates tau in early preclinical AD. Since the LC plays a crucial role in maintaining cortical efficiency, VSTMB may be similarly associated with LC integrity, particularly among those with SCD. METHOD: Data were from cognitively unimpaired men in the Vietnam Era Twin Study of Aging (N = 350; mean age=72.9, SD=2.4) who completed a test of VSTMB, an LC-sensitive MRI scan, and the 39-item Everyday Cognition (ECog) scale; 274 participants also had informant ECog ratings. The VSTMB task employs a change detection paradigm and compares performance in shape-color binding (SCB) versus shape-only (SO) conditions (see Figure 1). Rostral-middle and caudal LC integrity was calculated as a contrast-to-noise ratio (LC-CNR) using a pontine tegmentum reference region. Mixed models regressed VSTMB accuracy across condition (SO, SCB) and set size (2, 3) within person, while testing main effects and interactions with LC-CNR and ECog. Models adjusted for age 20 cognitive ability, current age, depressive symptoms, and state anxiety. Sensitivity analyses adjusted for global performance on standard neuropsychological measures. RESULT: VSTMB accuracy was lower on the SCB than SO condition (b=-1.08, p = .001), especially at higher set sizes (b=-1.90, p < .001). Higher participant-rated, but not informant-rated, SCD was associated with decreasing accuracy on SCB relative to the SO condition (b=-.253, p = .007). Lower rostral-middle, but not caudal, LC-CNR was associated with poorer SCB accuracy relative to SO condition accuracy (b=7.10, p = .010). Results remained significant after adjusting for global neuropsychological performance. CONCLUSION: Subtle losses in cognitive efficiency detected in cognitively unimpaired older adults on a VSTMB task were associated with SCD and LC integrity, even after accounting for performance on traditional neuropsychological tests. Given its role in modulating cortical efficiency through cognitive effort, reduced LC integrity may be associated with SCD when capacity for increasing compensatory effort to perform tasks is exceeded.
Background: Repeated cognitive testing can boost scores due to practice effects (PEs), yet it remains unclear whether PEs persist across multiple follow-ups and long durations. We examined PEs across multiple assessments from midlife to old age in a nonclinical sample. Method: Men (N=1,608) in the Vietnam Era Twin Study of Aging (VETSA) underwent neuropsychological assessment comprising 30 measures across 4 waves (~6-year testing intervals) spanning up to 20 years. We leveraged age-matched replacement participants to estimate PEs at each wave. We compared cognitive trajectories and MCI prevalence using unadjusted versus PE-adjusted scores. Results: Across follow-ups, a range of 7-12 tests (out of 30) demonstrated significant PEs, especially in episodic memory and visuospatial domains. Adjusting for PEs resulted in improved detection of cognitive decline and MCI, with up to 20% higher MCI prevalence. Conclusion: PEs persist across multiple assessments and decades underscoring the importance of accounting for PEs in longitudinal studies.
BACKGROUND: Repeated cognitive testing can boost performance due to practice effects (PEs). Follow-up scores are rarely adjusted for PEs, but such correction can be highly important as it has been shown to result in earlier detection of MCI and increased validity based on concordance with Alzheimer's biomarkers. However, it remains unclear to what extent PEs persist across multiple follow-ups and long durations, which are further complicated by normative age-related decline. We examined PEs across 17 years from midlife to old age in a nonclinical sample. METHOD: Men (N = 1,608) in the longitudinal Vietnam Era Twin Study of Aging (VETSA) completed neuropsychological batteries over 4 waves: wave 1(N = 1,290, mean age=56); wave 2, mean ages=62); wave 3 (mean age=68); wave 4 (mean age=73). Waves 2 and 3 also included age-matched attrition replacements. By comparing returnees' performance to replacements being assessed for the first time, we estimated PEs for 30 tests at each wave using generalized estimating equations, accounting for normative age effects and differential patterns of missingness. We calculated unadjusted and PE-adjusted cognitive scores (episodic memory, executive function, fluency, processing speed, visual memory, and visuospatial). At each wave we compared MCI prevalence based on unadjusted versus PE-adjusted scores. RESULT: Among returnees completing all 4 assessments, we found significant PEs for 11 tests at wave 2, 8 tests at wave 3, and 5 tests at wave 4. PEs were most apparent among episodic and visual memory tests. PE-adjusted cognitive factor scores were significantly lower than unadjusted factor scores at all follow-ups for all domains except fluency. MCI prevalence increased up to 20% after PE adjustment (from 14% to 18% at wave 4), indicating earlier detection. CONCLUSION: PEs persist across multiple assessments and decades, even with long testing intervals. Importantly, even very small PEs can shift scores below the impairment threshold, resulting in earlier detection and diagnosis of MCI. Additionally, we previously showed that PE-adjusted MCI diagnosis increases accuracy based on biomarker concordance and would dramatically reduce costs and length of clinical trials by reducing necessary sample size and increasing power. These results underscore the importance of accounting for PEs in longitudinal studies.
Journal of the International Neuropsychological Society · 2025-05-01 · 4 citations
articleOpen access
Abstract Background: The impact of chronic pain and opioid use on cognitive decline and mild cognitive impairment (MCI) is unclear. We investigated these associations in early older adulthood, considering different definitions of chronic pain. Methods: Men in the Vietnam Era Twin Study of Aging (VETSA; n = 1,042) underwent cognitive testing and medical history interviews at average ages 56, 62, and 68. Chronic pain was defined using pain intensity and interference ratings from the SF-36 over 2 or 3 waves (categorized as mild versus moderate-to-severe). Opioid use was determined by self-reported medication use. Amnestic and non-amnestic MCI were assessed using the Jak-Bondi approach. Mixed models and Cox proportional hazards models were used to assess associations of pain and opioid use with cognitive decline and risk for MCI. Results: Moderate-to-severe, but not mild, chronic pain intensity ( β = −.10) and interference ( β = −.23) were associated with greater declines in executive function. Moderate-to-severe chronic pain intensity ( HR = 1.75) and interference ( HR = 3.31) were associated with a higher risk of non-amnestic MCI. Opioid use was associated with a faster decline in verbal fluency ( β = −.18) and a higher risk of amnestic MCI ( HR = 1.99). There were no significant interactions between chronic pain and opioid use on cognitive decline or MCI risk (all p -values > .05). Discussion: Moderate-to-severe chronic pain intensity and interference related to executive function decline and greater risk of non-amnestic MCI; while opioid use related to verbal fluency decline and greater risk of amnestic MCI. Lowering chronic pain severity while reducing opioid exposure may help clinicians mitigate later cognitive decline and dementia risk.
The Clinical Neuropsychologist · 2024-05-01 · 3 citations
articleOpen access
: Although subtle and limited findings were present in this group of women veterans, it suggests that continued follow-up of GW women veterans is warranted. Future research should continue to evaluate differences between men and women in GW veteran samples. The BBRAIN women sub-repository is recruiting and these data are available to the research community for studies of women veterans.
