Post-traumatic stress disorder (PTSD) and hypertension are highly prevalent among Veterans. Cognitive dispersion, indicating within-person variability across neuropsychological measures at one time point, is associated with increased risk of dementia. We examined interactive effects of PTSD symptom severity and hypertension on cognitive dispersion among older Veterans.

We included 128 Vietnam-era Veterans from the Department of Defense-Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI) with a history of PTSD. Regression models examined interactions between PTSD symptom severity and hypertension on cognitive dispersion (defined as the intraindividual standard deviation across eight cognitive measures) adjusting for demographics and comorbid vascular risk factors.

There was an interaction between PTSD symptom severity and hypertension on cognitive dispersion (p = .026) but not on mean cognitive performance (p = .543). Greater PTSD symptom severity was associated with higher cognitive dispersion among those with hypertension (p = .002), but not among those without hypertension (p = .531). Results remained similar after adjusting for mean cognitive performance.

Findings suggest, among older Veterans with PTSD, those with both hypertension and more severe PTSD symptoms may be at greater risk for cognitive difficulties. Further, cognitive dispersion may be a useful marker of subtle cognitive difficulties. Future research should examine these associations longitudinally and in a diverse sample.

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. We identified cluster-derived subgroups of CU participants based on comprehensive neuropsychological data and compared baseline characteristics and rates of progression to MCI/dementia or a Dementia Rating Scale (DRS) of <129 across subgroups.

A hierarchical cluster analysis was conducted using 11 baseline neuropsychological test scores from 365 CU participants in the UCSD Shiley-Marcos Alzheimer’s Disease Research Center (age M=71.93 years, SD=7.51; 55.9% women; 15.6% Hispanic/Latino/a/x/e). A discriminate function analysis was then conducted to test whether the individual neuropsychological scores predicted cluster-group membership. Cox regressions examined the risk of progression to consensus diagnosis of MCI or dementia, or to DRS score <129, by cluster group.

Cluster analysis identified 5 groups: All-Average (n=139), Low-Visuospatial (n=46), Low-Executive (n=51), Low-Memory/Language (n=83), and Low-All Domains (n=46). The discriminant function analysis using the neuropsychological measures to predict group membership into these 5 clusters correctly classified 85.2% of the participants. Subgroups had unique demographic and clinical characteristics. Relative to the All-Average group, the Low-Visuospatial (hazard ratio [HR] 2.39, 95% CI [1.03, 5.56], p=.044), Low-Memory/Language (HR 4.37, 95% CI [2.24, 8.51], p<.001), and Low-All Domains (HR 7.21, 95% CI [3.59, 14.48], p<.001) groups had greater risk of progression to MCI/dementia. The Low-Executive group was also twice as likely to progress to MCI/dementia compared to the AllAverage group, but did not statistically differ (HR 2.03, 95% CI [0.88,4.70], p=.096). A similar pattern of results was found for progression to DRS score <129, with the Low-Executive (HR 2.82, 95% CI [1.26, 6.29], p=.012), Low-Memory/Language (HR 3.70, 95% CI [1.80, 7.56], p<.001) and Low-All Domains (HR 5.79, 95% CI [2.74, 12.27], p<.001) groups at greater risk of progression to a DRS score <129 than the All-Average group. The Low-Visuospatial group was also twice as likely to progress to DRS <129 compared to the All-Average group, but did not statistically differ (HR 2.02, 95% CI [0.80, 5.06], p=.135).

Our results add to a growing literature documenting heterogeneity in the earliest cognitive and pathological presentations associated with Alzheimer’s disease and related disorders. Participants with subtle memory/language, executive, and visuospatial weaknesses all declined at faster rates than the All-Average group, suggesting that there are multiple pathways and/or unique subtle cognitive decline profiles that ultimately lead to a diagnosis of MCI/dementia. These results have important implications for early identification of individuals at risk for MCI/dementia. Given that the same classification approach may not be optimal for everyone, determining profiles of subtle cognitive difficulties in CU individuals and implementing neuropsychological test batteries that assess multiple cognitive domains may be a key step towards an individualized approach to early detection and fewer missed opportunities for early intervention.

Alterations in cerebral blood flow (CBF) are associated with risk of cognitive decline and Alzheimer’s disease (AD). Although apolipoprotein E (APOE) ε4 and greater vascular risk burden have both been linked to reduced CBF in older adults, less is known about how APOE ε4 status and vascular risk may interact to influence CBF. We aimed to determine whether the effect of vascular risk on CBF varies by gene dose of APOE ε4 alleles (i.e., number of e4 alleles) in older adults without dementia.

144 older adults without dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) underwent arterial spin labeling (ASL) and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure assessment. Vascular risk was assessed using pulse pressure (systolic blood pressure -diastolic blood pressure), which is thought to be a proxy for arterial stiffening. Participants were classified by number of APOE ε4 alleles (n0 alleles = 87, m allele = 46, n2 alleles = 11). CBF in six FreeSurfer-derived a priori regions of interest (ROIs) vulnerable to AD were examined: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regression models tested the interaction between categorical APOE ε4 dose (0, 1, or 2 alleles) and continuous pulse pressure on CBF in each ROI, adjusting for age, sex, cognitive diagnosis (cognitively unimpaired vs. mild cognitive impairment), antihypertensive medication use, cerebral metabolism (FDG-PET composite), reference CBF region (precentral gyrus), and AD biomarker positivity defined using the ADNI-optimized phosphorylated tau/ß-amyloid ratio cut-off of > 0.0251 pg/ml.

A significant pulse pressure X APOE ε4 dose interaction was found on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex (ps < .005). Among participants with two e4 alleles, higher pulse pressure was significantly associated with lower CBF (ps < .001). However, among participants with zero or one ε4 allele, there was no significant association between pulse pressure and CBF (ps > .234). No significant pulse pressure X APOE ε4 dose interaction was found in the inferior temporal cortex, rostral middle frontal gyrus, or medial orbitofrontal cortex (ps > .109). Results remained unchanged when additionally controlling for general vascular risk assessed via the modified Hachinski Ischemic Scale.

These findings demonstrate that the cross-sectional association between pulse pressure and region-specific CBF differs by APOE ε4 dose. In particular, a detrimental effect of elevated pulse pressure on CBF in AD-vulnerable regions was found only among participants with the e4/e4 genotype. Our findings suggest that pulse pressure may play a mechanistic role in neurovascular unit dysregulation for those genetically at greater risk for AD. Given that pulse pressure is just one of many potentially modifiable vascular risk factors for AD, future studies should seek to examine how these other factors (e.g., diabetes, high cholesterol) may interact with APOE genotype to affect cerebrovascular dysfunction.

Higher educational attainment is associated with reduced risk for Alzheimer's disease (AD) dementia, and its protective effect may act through alterations in cerebral blood flow (CBF) that allow for better coping with accumulating neuropathology. Additionally, there are sex differences in both the risk of developing AD as well as the potential protective effects of education. We therefore sought to investigate whether education moderates the association of hippocampal CBF and memory in cognitively unimpaired older adults, and to examine if these interactions were moderated by sex.

Cognitively unimpaired older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 51 men, 50 women) underwent neuropsychological evaluation and arterial spin labeling MRI, which was used to quantify bilateral hippocampal CBF. Sex was defined as sex at birth. Multiple linear regressions assessed (1) the independent associations among education, CBF, and memory performance separately in men and women and (2) the three-way interactions among CBF, sex, and education, followed by sex-stratified analyses. Three outcome measures were examined: Logical Memory Story A immediate and delayed recall, and Rey Auditory Verbal Learning Test (RAVLT) intrusions. All models adjusted for age and APOE epsilon-4 allele frequency, and all models with CBF additionally adjusted for cerebral metabolism (baseline FDG-PET composite) and pulse pressure.

CBF was not associated with education or memory in either women or men. There was a positive association between education and delayed memory in women (ß=0.14, t=2.64, p=0.008) as well as trending, positive associations between education and immediate memory in women (ß=0.09, t=1.79, p=0.074) and education and delayed memory in men (ß=0.09, t=1.94, p=0.054). Three-way interactions among sex, CBF, and education were significant on immediate recall (ß=2.55, t=2.53, p=0.013), delayed recall (ß=2.56, t=2.44, p=0.017), and RAVLT intrusions (ß=-2.28, t=-2.27, p=0.026). In women, there were interactions between education and hippocampal CBF on both immediate (ß=2.49, t=2.90, p=0.006) and delayed recall (ß=2.30, t=2.78, p=0.009), such that as education increased, the strength of the association between CBF and immediate memory increased. There was also an interaction between education and hippocampal CBF on RAVLT intrusions in women (ß=-2.42, t=-3.05, p=0.004), such that as education increased, the strength of the association between CBF and number of intrusions decreased; there was a main effect where in women with lower education, as CBF increased, the number of intrusions increased (ß=0.76, t=2.59, p=0.032); in women with higher education, there was no association between CBF and intrusions. In men, none of these two-way interactions were significant.

These results suggest that, in cognitively unimpaired older women, the relationship between hippocampal CBF and memory is moderated by education level, even when adjusting for several other factors. Specifically, higher education may serve as a protective factor in the hippocampal CBF-memory relationship, and this relationship was sex-dependent, occurring in women only. Further research is needed to examine these relationships longitudinally across the clinical continuum of AD. Additionally, this work needs to be conducted in more diverse samples to allow for analyses investigating the impact of education on the intersection of race/ethnicity and sex/gender.

Type 2 diabetes (T2D) is a risk factor for cognitive impairment/dementia and has been shown to modify the impact of Alzheimer’s disease (AD) biomarkers on cognition and everyday functioning. Studies examining amyloid-ß (Aß), one of the hallmark AD pathologies, have shown mixed results regarding associations of Aß biomarkers with cross-sectional cognition as well as T2D, though Aß is generally associated with future cognitive declines. The purpose of the present study is to examine whether T2D impacts the associations between amyloid positron emission tomography (PET) and cognition in older Veterans.

The current study included 202 mostly male Vietnam-Era Veterans from the Department of Defense-Alzheimer’s Disease Neuroimaging Initiative (DOD ADNI) study (age M=69.38 years, SD=4.37; 40% with self-reported T2D) who completed neuropsychological testing and florbetapir PET imaging. The Aß PET standardized uptake variable ratio (SUVR) was measured using a previously-validated summary SUVR calculated by dividing the mean uptake across 4 AD-vulnerable cortical regions by whole cerebellar uptake. General linear models examined whether T2D moderated the relationship of Aß PET with memory, attention/executive functioning, and language composite scores. Models adjusted for age, education, apolipoprotein E e4 carrier status, vascular risk burden, depressive symptoms, post-traumatic stress disorder (PTSD) symptom severity, and history of traumatic brain injury (TBI).

There was no main effect of diabetes on memory, attention/executive functioning, or language performance, and higher Aß PET SUVR was only associated with worse attention/executive functioning performance (ß=-.146, 95% CI [-.261, -.031], p=.013). The Aß PET x T2D interaction was significant for attention/executive functioning such that higher Aß PET SUVR was associated with lower attention/executive functioning scores, but only in those with T2D (ß=-.116, [-.225, -.006], p=.038). This interaction was not significant for language or memory.

The results show that Aß may negatively impact attention/executive functioning, but this effect was only found in Veterans with T2D. Prior work has suggested that T2D may be more associated with tau biomarkers than markers of Aß, so it is possible that the current results are due to a compounding effect of Aß pathology plus microvascular and/or tau pathology. Notably, the sample was relatively young, a relatively large proportion had elevated PTSD symptoms and/or a TBI history (which have both been shown to relate to attention/executive function), and the measures that made up the attention/executive composite (Trail Making Test A and B) have been shown to be particularly sensitive - all of which may have contributed to the domain-specific effects. Future research is needed to investigate the role that tau and vascular pathology may play in cognition among individuals with T2D. Longitudinal studies are also needed to better understand the timing and progression of these relationships.

Prior work on associations between self-reported cognition and objective cognitive performance in Veterans has yielded mixed findings, with some evidence indicating that mild traumatic brain injury (TBI) may not impact the associations between subjective and objective cognition. However, few studies have examined these relationships in both mild and moderate-to-severe TBI, in older Veterans, and within specific cognitive domains. Therefore, we assessed the moderating effect of TBI severity on subjective and objective cognition across multiple cognitive domains.

This study included 246 predominately male Vietnam-Era Veterans (age M=69.61, SD=4.18, Range = 60.87 – 85.16) who completed neuropsychological testing and symptom questionnaires as part of the Department of Defense-Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI). Participants were classified as having history of no TBI (n=81), mild TBI (n=80), or moderate-tosevere TBI (n=85). Neuropsychological composite scores in the domains of memory, attention/executive functioning, and language were included as the outcome variables. The Everyday Cognition (ECog) measure was used to capture subjective cognition and, specifically, the ECog domain scores of memory, divided attention, and language were chosen as independent variables to mirror the objective cognitive domains. General linear models, adjusting for age, education, apolipoprotein E ε4 carrier status, pulse pressure, depressive symptom severity, and PTSD symptom severity, tested whether TBI severity moderated the associations of domain-specific subjective and objective cognition.

Across the sample, subjective memory was associated with objective memory (β=-.205, 95% CI [-.332, -.078], p=.002) and subjective language was associated with objective language (β=-.267, 95% CI [-.399, -.134], p<.001). However, the main effect of subjective divided attention was not associated with objective attention/executive functioning (p=.124). The main effect of TBI severity was not associated with any of the objective cognitive domain scores after adjusting for the other variables in the model. The TBI severity x subjective cognition interaction was significant for attention/executive functioning [F(2,234)=5.18, p=.006]. Specifically, relative to Veterans without a TBI, participants with mild TBI (β=-.311, 95% CI [-.620, -.002], p=.048) and moderate-to-severe TBI (β=-.499, 95% CI [-.806, -.193], p=.002) showed stronger negative associations between subjective divided attention and objective attention/executive functioning. TBI severity did not moderate the associations between subjective and objective cognition for memory or language domains. The pattern of results did not change when the total number of TBIs was included in the models.

In this DoD-ADNI sample, stronger associations between subjective and objective attention were evident among individuals with mild and moderate-to-severe TBI compared to Veterans without a TBI history. Attention/executive functioning measures (Trails A and B) may be particularly sensitive to detecting subtle cognitive difficulties related to TBI and/or comorbid psychiatric symptoms, which may contribute to these attention-specific findings. The strongest associations were among those with moderate-to-severe TBI, potentially because the extent to which their attention difficulties are affecting their daily lives are more apparent despite no significant differences in objective attention performance by TBI group. This study highlights the importance of assessing both subjective and objective cognition in older Veterans and the particular relevance of the attention domain within the context of TBI.

Veterans with a history of mild traumatic brain injury (mTBI) often endorse enduring postconcussive symptoms (PCS) including cognitive and neuropsychiatric complaints. However, although several studies have shown associations between these complaints and brain structure and cerebrovascular function, few studies have examined relationships between structural and functional brain alterations and PCS in the context of remote mTBI. We therefore examined whether PCS were associated with cortical thickness and cerebral blood flow (CBF) in a well-characterized sample of Veterans with a history of mTBI.

116 Veterans underwent structural neuroimaging and a clinical interview to obtain detailed TBI history and injury-related information. Participants also completed the following self-report measures: the Neurobehavioral Symptom Inventory (NSI) for ratings of cognitive, emotional, somatic-sensory, and vestibular symptoms, and the Posttraumatic Stress Disorder (PTSD) Checklist for PTSD symptom severity. Regional brain thickness was indexed using FreeSurfer-derived cortical parcellations of frontal and temporal regions of interest (ROIs) including the superior frontal gyrus (SFG), middle frontal gyrus (MFG), inferior frontal gyrus (IFG), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), medial temporal lobe (MTL), and lateral temporal lobe (LTL). A subset of Veterans (n=50) also underwent multi-phase pseudo-continuous arterial spin labeling (MPPCASL) to obtain resting CBF. T1-weighted structural and MPPCASL scans were co-registered and CBF estimates were extracted from the 7 bilateral parcellations of ROIs. To assess the relationship between NSI total and subscale scores and ROI thickness and CBF, multiple regression analyses were conducted adjusting for age, sex, and PTSD symptom severity. False Discovery Rate was used to correct for multiple comparisons.

NSI total and subscale scores were not associated with cortical thickness of any ROI. However, higher NSI scores were associated with increased ROI CBF of the SFG (q=.014) and MFG CBF (q=.014). With respect to symptom subscales, higher affective subscale scores were associated with increased SFG (q=.001), MFG (q=.001), IFG (q=.039), ACC (q=.026), and LTL CBF (q=.026); higher cognitive subscale scores were associated with increased SFG (q=.014) and MFG CBF (q=.032); and higher vestibular subscale scores were associated with increased ACC CBF (q=.021). NSI somatic-sensory subscale scores were not associated with ROI CBF.

Results demonstrate that in TBI-susceptible anterior ROIs, alterations in CBF but not cortical thickness are associated with postconcussive symptomatology in Veterans with a history of mTBI. Specifically, postconcussive total symptoms as well as affective, cognitive, and vestibular subscale symptoms were strongly linked primarily to CBF of frontal regions. Remarkably, these results indicate that enduring symptoms in generally younger samples of Veterans with head injury histories may be closely tied to cerebrovascular function rather than brain structure changes. These findings may provide a neurological basis for negative clinical outcomes (e.g., enduring PCS and poor quality of life) that is frequently reported by many individuals following mTBI. Future work is needed to examine unique effects of blast exposure as well as associations with repeated injury on brain-behavior relationships.

Physical activity (PA) may help maintain brain structure and function in aging. Since the intensity of PA needed to effect cognition and cerebrovascular health remains unknown, we examined associations between PA and cognition, regional white matter hyperintensities (WMH), and regional cerebral blood flow (CBF) in older adults.

Forty-three older adults without cognitive impairment underwent magnetic resonance imaging (MRI) and comprehensive neuropsychological assessment. Waist-worn accelerometers objectively measured PA for approximately one week.

Higher time spent in moderate to vigorous PA (MVPA) was uniquely associated with better memory and executive functioning after adjusting for all light PA. Higher MVPA was also uniquely associated with lower frontal WMH volume although the finding was no longer significant after additionally adjusting for age and accelerometer wear time. MVPA was not associated with CBF. Higher time spent in all light PA was uniquely associated with higher CBF but not with cognitive performance or WMH volume.

Engaging in PA may be beneficial for cerebrovascular health, and MVPA in particular may help preserve memory and executive function in otherwise cognitively healthy older adults. There may be differential effects of engaging in lighter PA and MVPA on MRI markers of cerebrovascular health although this needs to be confirmed in future studies with larger samples. Future randomized controlled trials that increase PA are needed to elucidate cause-effect associations between PA and cerebrovascular health.

Subjective cognitive decline (SCD) is a potential early risk marker for Alzheimer’s disease (AD), but its utility may vary across individuals. We investigated the relationship of SCD severity with memory function and cerebral blood flow (CBF) in areas of the middle temporal lobe (MTL) in a cognitively normal and overall healthy sample of older adults. Exploratory analyses examined if the association of SCD severity with memory and MTL CBF was different in those with lower and higher cardiovascular disease (CVD) risk status.

Fifty-two community-dwelling older adults underwent magnetic resonance imaging, neuropsychological testing, and were administered the Everyday Cognition Scale (ECog) to measure SCD. Regression models investigated whether ECog scores were associated with memory performance and MTL CBF, followed by similar exploratory regressions stratified by CVD risk status (i.e., lower vs higher stroke risk).

Higher ECog scores were associated with lower objective memory performance and lower entorhinal cortex CBF after adjusting for demographics and mood. In exploratory stratified analyses, these associations remained significant in the higher stroke risk group only.

Our preliminary findings suggest that SCD severity is associated with cognition and brain markers of preclinical AD in otherwise healthy older adults with overall low CVD burden and that this relationship may be stronger for individuals with higher stroke risk, although larger studies with more diverse samples are needed to confirm these findings. Our results shed light on individual characteristics that may increase the utility of SCD as an early risk marker of cognitive decline.

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.

One hundred and forty-eight Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants underwent neuropsychological testing and neuroimaging. Pulsed arterial spin labeling (ASL) magnetic resonance imaging (MRI) was acquired to quantify CBF. Florbetapir positron emission tomography (PET) imaging determined Aβ positivity.

Adjusting for age, gender, education, and mean cognitive performance, older adults who were Aβ+ showed higher cognitive dispersion relative to those who were Aβ-. Across the entire sample, higher cognitive dispersion was associated with reduced CBF in inferior parietal and temporal regions. Secondary analyses stratified by Aβ status demonstrated that higher cognitive dispersion was associated with reduced CBF among Aβ+ individuals but not among those who were Aβ-.

Cognitive dispersion may be sensitive to early Aβ accumulation and cerebrovascular changes adjusting for demographics and mean neuropsychological performance. Associations between cognitive dispersion and CBF were observed among Aβ+ individuals, suggesting that cognitive dispersion may be a marker of brain changes among individuals on the AD continuum. Future studies should examine whether cognitive dispersion predicts brain changes in diverse samples and among those with greater vascular risk burden.