Vascular Risk Burden Research Articles

Blood-Brain Barrier Permeability Is Associated With Cognitive Functioning in Normal Aging and Neurodegenerative Diseases.

The purpose of this study was to investigate the relationship between blood-brain barrier (BBB) permeability and cognitive functioning in healthy older adults and individuals with neurodegenerative diseases. A total of 124 participants with Alzheimer disease, cerebrovascular disease, or a mix Alzheimer's and cerebrovascular diseases and 55 controlparticipants underwent magnetic resonance imaging and neuropsychological testing. BBB permeability was measured with dynamic contrast-enhanced magnetic resonance imaging and white matter injury was measured using a quantitative diffusion-tensor imaging marker of white matter injury. Structural equation modeling was used to examine the relationships between BBB permeability, vascular risk burden, white matter injury, and cognitive functioning. Vascular risk burden predicted BBB permeability (r=0.24, P<0.05) and white matter injury (r=0.38, P<0.001). BBB permeability predicted increased white matter injury (r=0.34, P<0.001) and increased white matter injury predicted lower cognitive functioning (r=-0.51, P<0.001). The study provides empirical support for a vascular contribution to white matter injury and cognitive impairment, directly or indirectly via BBB permeability. This highlights the importance of targeting modifiable vascular risk factors to help mitigate future cognitive decline.

Vascular risk burden is a key player in the early progression of Alzheimer’s disease

Understanding whether vascular risk factors (VRFs) synergistically potentiate Alzheimer's disease (AD) progression is important in the context of emerging treatments for preclinical AD. In a group of 503 cognitively unimpaired individuals, we tested whether VRF burden interacts with AD pathophysiology to accelerate neurodegeneration and cognitive decline. Baseline VRF burden was calculated considering medical data and AD pathophysiology was assessed based on cerebrospinal fluid (CSF) amyloid-β1–42 (Aβ1–42) and tau phosphorylated at threonine 181 (p-tau181). Neurodegeneration was assessed with plasma neurofilament light (NfL) and global cognition with the modified version of the Preclinical Alzheimer’s Cognitive Composite. The mean (SD) age of participants was 72.9 (6.1) years, and 220 (43.7%) were men. Linear mixed-effects models revealed that an elevated VRF burden synergistically interacted with AD pathophysiology to drive longitudinal plasma NfL increase and cognitive decline. Additionally, VRF burden was not associated with CSF Aβ1–42 or p-tau181 changes over time. Our results suggest that VRF burden and AD pathophysiology are independent processes; however, they synergistically lead to neurodegeneration and cognitive deterioration. In preclinical stages, the combination of therapies targeting VRFs and AD pathophysiology might potentiate treatment outcomes.

Role of nutrition and metabolic regulation in multidomain trials for dementia risk reduction: findings from FINGER and FINGER 2.0 studies

AbstractBackgroundThe successful FINGER multidomain intervention model combined dietary intervention (healthy Nordic diet) with exercise, cognitive training, social activities, and cardiovascular risk monitoring. The FINGER model is being tested and optimized in the World‐Wide FINGERS network of multidomain dementia prevention trials (45+ countries). Advanced FINGER 2.0 models combine lifestyle interventions with multi‐nutrients and/or putative disease‐modifying drugs.MethodThe 11‐year extended follow‐up of FINGER trial participants (N:1260, at‐risk general population) was completed in Q1‐2023. The MIND‐AD pilot‐trial (N:93, prodromal Alzheimer’s disease (AD)) included medical food (Fortasyn Connect), tested alone or in combination with multidomain lifestyle intervention for 6 months. The MET‐FINGER trial (N:600, at‐risk general population enriched with APOE4‐carriers, 2‐year intervention) includes different dosages of metformin (in combination with upgraded FINGER lifestyle intervention).ResultNew nutrition/metabolic related data will be presented from FINGER where eg. adherence to healthier diet was still relatively high in the multidomain arm after the extended follow‐up. Higher adherence was also related to better cognition. Several dietary and metabolic biomarkers have been analyzed revealing underlying mechanisms and responders (eg persons with insulin resistance, higher HOMA, responded less). In the MIND‐AD trial, participants from 4 European countries were randomized to the multidomain lifestyle intervention alone (N:32), or in combination with medical food (N:31), and 30 to the control group. Adherence was high for all intervention domains (78‐87%). Compared with the control group, the group with lifestyle+medical food showed a decrease in vascular risk burden (P = 0.027) and an increase in healthy diet patterns (P = 0.045), and better cognition after the intervention (CDR‐SOB). There were no significant differences between the lifestyle only and control group. MET‐FINGER trial recruitment started in January 2023 (preliminary data presented).ConclusionLonger‐term dietary and lifestyle changes are feasible and effective in older adults in the at‐risk spectrum of AD/dementia. Beneficial effects (adherence to and effects of interventions) seemed to improve with the inclusion of medical food in prodromal AD. The unique long follow‐up of FINGER provides important information about long‐term effects and methodological aspects. The MET‐FINGER trial will provide data on synergistic effects between FINGER intervention and a drug targeting both glucose metabolism and AD pathology.

Detecting Alzheimer’s risk with cognitive dispersion on neuropsychological testing

AbstractBackgroundCognitive dispersion refers to the within‐person variability across tasks. Relative to the normative approach, cognitive dispersion may be more sensitive to subtle changes in preclinical Alzheimer’s disease. Greater dispersion has been associated with increased risk for conversion to mild cognitive impairment and faster rates of medial temporal lobe atrophy. This metric can be derived from a regular neuropsychological assessment and complement traditional outcome approaches, particularly in those underrepresented in normative data. This study evaluated cognitive dispersion as an independent predictor of clinical status across racial and ethnic groups.MethodBaseline data on 1811 cognitively unimpaired older adults with high vascular risk from the U.S. POINTER multisite lifestyle intervention study were examined. Sample characteristics included mean age of 68 (SD = 5.2), 70% female, 30% less‐than‐college education, and 29% underrepresented groups (301 Black, 231 Other). Correlations between cognitive dispersion and other brain health risks (vascular, subjective cognitive decline (SCD), physical activity) were tested. Cognitive dispersion was defined as the standard deviation of individuals’ z‐transformed scores of 8 cognitive tests. Vascular risk burden was the sum of 5 conditions (hypertension, diabetes, hypercholesterolemia, heart disease, obesity). Self‐report SCD was measured by the Cognitive Function Instrument (CFI) and Measurement of Everyday Cognition (ECOG12). Logistic Regression Models were fitted to predict Clinical Dementia Global Ratings (CDR 0.5 vs. 0) to evaluate cognitive dispersion as an independent predictor in the whole sample, White participants and Black participants, controlled for demographics, vascular risk, and physical activity. Logistic Regression Models were also evaluated with CFI or ECOG12 as additional covariate.ResultGreater cognitive dispersion was correlated with older age, greater vascular burden and less physical activity, but not SCD. Cognitive dispersion was significantly higher in men, Black participants, and participants with less education. Cognitive dispersion predicted CDR in Black participants (OR = 4.7, p&lt;0.01), and trended in the whole sample (OR = 1.6, p = 0.05), but was not significant in White participants (OR = 1.2, p = 0.63). Results hold when controlled for SCD (Table 1).ConclusionResults supported cognitive dispersion as a sensitive objective metric, in addition to self‐report SCD, to identify individuals showing the earliest clinical signs of decline, particularly among those underrepresented in traditional norms.

Prevalence and type of subjective cognitive concerns among participants at baseline and their relationship to cognition and other factors

AbstractBackgroundThe U.S. POINTER study is a phase 3, multicenter, 2‐year randomized controlled trial (RCT) of two lifestyle interventions varying in intensity and format, conducted in older adults living in the U.S. who do not have objective cognitive impairment at study entry, but have increased risk of cognitive decline and dementia. Inclusion criteria included specific risk factors (e.g., family history of dementia, vascular risk factors) but not subjective cognitive concerns (SCCs). However, SCCs are likely to be common in this group of at‐risk individuals. U.S. POINTER provides a unique opportunity to evaluate the prevalence of SCCs and their demographic and clinical correlates in an at‐risk group.MethodsRecruitment for the U.S. POINTER study is still ongoing, and the following is based on a partial sample. The sample includes 1811 U.S. POINTER participants with complete baseline data (collected by December 2022), mean age = 68.2y (SD = 5.2), 73.5% are female, 70.2% have18+ years education, and 29.3% are from underrepresented groups. SCCs were measured by the brief 12‐item Everyday Cognition (ECog) questionnaire which includes two items in each of 6 domains: everyday memory, language, visuospatial abilities, planning, organization and divided attention. Responses on the ECog range from 0 = no change/better compared to baseline, 1 = questionably/inconsistently worse, 2 = consistently a little worse, 3 = much worse. Neuropsychological performance was measured using a global composite and episodic memory, executive functioning, and processing speed composites. Other variables included demographics, depression (Geriatric Depression Scale total score; GDS) and sleep (Insomnia severity index (ISI)) and vascular disease burden index.ResultsThirty‐five percent of the cohort endorsed having a subjective complaint on the ECog (score ≥2 on any item). The most frequent complaint was “Remembering where I have placed objects” (23%). SCCs did not differ by age, sex or education. ECog‐12 Total were related to insomnia and depression (p&lt;.0001). After adjusting for age, sex, education, vascular risk burden, GDS and ISI, greater SCC (ECog‐12 Total) was still associated with the global composite and all three domains (ps &lt; 0.003).ConclusionsSCCs, particularly everyday memory complaints, were relatively common in this at‐risk cohort. While SCCs were related to depression and sleep, they were also independently associated with slightly worse cognitive function.

Systemic vascular risk, white matter injury, and relative cerebral blood flow independently contribute to cognitive decline beyond amyloid and tau burden

AbstractBackgroundAge, systemic vascular risk factors, white matter injury, cerebral blood flow, amyloid, and tau burden are well‐established contributors to late‐life cognitive decline. Given the strong relationship among these measures, we proposed a model to extract latent factors and isolate domain‐specific measures that underlie cognitive decline in preclinical AD.MethodData were available for 166 cognitively unimpaired older adults from Harvard Aging Brain Study (Table1). We used the following measures: 1) cortical amyloid burden from PiB‐PET; 2) inferior temporal cortex FTP‐PET; 3) relative cerebral blood flow (R1) from dynamically‐acquired PiB‐PET; 4) white matter hyperintensities (WMH) from FLAIR‐MRI; 5) Peak width of skeletonized mean diffusivity (PSMD) from DTI‐MRI; 6) gray matter volume (GMV) from MPRAGE‐MRI; 7) Framingham Heart Study cardiovascular disease risk (CVD); 8) Preclinical Alzheimer Cognitive Composite‐5 (PACC). We extracted slopes using linear mixed effect models for longitudinal PACC decline and GMV atrophy (follow‐up = 7.4±2.8 years). The remaining data were obtained from baseline. We used exploratory factor analysis (varimax rotations) to extract orthogonal factors. These factors were used in a regression model to explain PACC decline. We next examined whether GMV atrophy acts as a mediator of factors and PACC decline. Subsequently, we investigated whether factors interact to further explain PACC decline.ResultsOriginal variables were highly interrelated (Figure1A) and correlated with PACC decline (Figure1B). Scree test showed 6 factors were sufficient (cumulative variance:96%, Figure2A). All factors except Factor5 (age) independently explained PACC decline (Figure2B, r2 = 0.44). Including GMV atrophy removed effect of Factor1 (white matter injury, Figure2B, r2 = 0.51). Factor3 (amyloid) interacted with Factor1 and Factor4 (tau) in explaining PACC decline (Figure2C, r2 = 0.58).ConclusionLatent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow (but not age) independently explain cognitive decline beyond amyloid and tau burden in this preclinical AD cohort. GMV atrophy mediates these associations with the strongest effect on white matter injury suggesting a strong link between white matter injury and neurodegeneration. These results suggest that current markers of cerebrovascular injury contribute to cognitive decline beyond systemic vascular risk (CVD), amyloid, and tau burden. The mechanism by which systemic vascular risk impacts cognition requires further explication.

Impairment of Endothelial Function by Aerosol From Marijuana Leaf Vaporizers.

Marijuana leaf vaporizers, which heat plant material and sublimate Δ-9-tetrahydrocannabinol without combustion, are popular alternatives to smoking cannabis that are generally perceived to be less harmful. We have shown that smoke from tobacco and marijuana, as well as aerosol from e-cigarettes and heated tobacco products, impair vascular endothelial function in rats measured as arterial flow-mediated dilation (FMD). We exposed 8 rats per group to aerosol generated by 2 vaporizer systems (Volcano and handheld Yocan) using marijuana with varying Δ-9-tetrahydrocannabinol levels, in a single pulsatile exposure session of 2 s/min over 5 minutes, and measured changes in FMD. To model secondhand exposure, we exposed rats for 1 minute to diluted aerosol approximating release of uninhaled Volcano aerosol into typical residential rooms. Exposure to aerosol from marijuana with and without cannabinoids impaired FMD by ≈50%. FMD was similarly impaired by aerosols from Yocan (237 °C), and from Volcano at both its standard temperature (185 °C) and the minimum sublimation temperature of Δ-9-tetrahydrocannabinol (157 °C), although the low-temperature aerosol condition did not effectively deliver Δ-9-tetrahydrocannabinol to the circulation. Modeled secondhand exposure based on diluted Volcano aerosol also impaired FMD. FMD was not affected in rats exposed to clean air or water vapor passed through the Volcano system. Acute direct exposure and modeled secondhand exposure to marijuana leaf vaporizer aerosol, regardless of cannabinoid concentration or aerosol generation temperature, impair endothelial function in rats comparably to marijuana smoke. Our findings indicate that use of leaf vaporizers is unlikely to reduce the vascular risk burden of smoking marijuana.

3 Type 2 Diabetes Moderates the Association between Amyloid PET and Attention/Executive Functioning in Older Veterans

Objective: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.Participants and Methods: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).Results: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.Conclusions: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.

93 Impact of Cardiovascular Risk on Cognitive and Brain Aging in Autosomal Dominant Frontotemporal Dementia

Objective:Poor cardiovascular health occurs with age and is associated with increased dementia risk, yet its impact on frontotemporal lobar degeneration (FTLD) and autosomal dominant neurodegenerative disease has not been well established. Examining cardiovascular risk in a population with high genetic vulnerability provides an opportunity to assess the impact of lifestyle factors on brain health outcomes. In the current study, we examined whether systemic vascular burden associates with accelerated cognitive and brain aging outcomes in genetic FTLD.Participants and Methods:166 adults with autosomal dominant FTLD (C9orf72 n= 97; GRN n= 34; MAPT n= 35; 54% female; Mage = 47.9; Meducation = 15.6 years) enrolled in the Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Longitudinal FTD study (ALLFTD) were included. Participants completed neuroimaging and were screened for cardiovascular risk and functional impairment during a comprehensive neurobehavioral and medical interview. A vascular burden score (VBS) was created by summing vascular risk factors (VRS) [diabetes, hypertension, hyperlipidemia, and sleep apnea] and vascular diseases (VDS) [cerebrovascular disease (e.g., TIA, CVA), cardiac arrhythmia (e.g., atrial fibrillation, pacemaker, defibrillator), coronary artery disease (e.g., myocardial infarction, cardiac bypass, stent), and congestive heart failure] following a previously developed composite (range 0 to 8). We examined the interaction between each vascular health metric (VBS, VDS, VRS) and age (vascular health*age) on clinical severity (CDR plus NACC FTLD-SB), and white matter hyperintensity (WMH) volume outcomes, adjusting for age and sex. Vascular risk, disease, and overall burden scores were examined in separate models.Results:There was a statistically significant interaction between total VBS and age on both clinical severity (ß=0.20, p=0.044) and WMH burden (ß=0.20, p=0.032). Mutation carriers with higher vascular burden evidenced worse clinical and WMH outcomes for their age. When breaking down the vascular burden score into (separate) vascular risk (VRS) and vascular disease (VDS) scores, the interaction between age and VRS remained significant only for WMH (ß=0.26, p=0.009), but not clinical severity (ß=0.04, p=0.685). On the other hand, the interaction between VDS and age remained significant only for clinical severity (ß=0.20, p=0.041) but not WMH (ß=0.17, p=0.066).Conclusions:Our results demonstrate that systemic vascular burden is associated with an “accelerated aging” pattern on clinical and white matter outcomes in autosomal dominant FTLD. Specifically, mutation carriers with greater vascular burden show poorer neurobehavioral outcomes for their chronological age. When separating vascular risk from disease, risk was associated with higher age-related WMH burden, whereas disease was associated with poorer age-related clinical severity of mutation carriers. This pattern suggests preferential brain-related effects of vascular risk factors, while the functional impact of such factors may be more closely aligned with fulminant vascular disease. Our results suggest cardiovascular health may be an important, potentially modifiable risk factor to help mitigate the cognitive and behavioral disturbances associated with having a pathogenic variant of autosomal dominant FTLD. Future studies should continue to examine the neuropathological processes underlying the impact of cardiovascular risk in FTLD to inform more precise recommendations, particularly as it relates to lifestyle interventions.

69 Influence of Cardiovascular Risk Factors on Neuropsychological Trajectories in Black/African American Adults Living with HIV

Objective:Human immunodeficiency virus (HIV) type 1 (HIV-1), cardiovascular disease, and HIV-associated neurocognitive disorders (HAND) disproportionately affect Black/African American individuals compared to other racial and ethnic groups. Understanding the mechanisms of cognitive health disparities is essential for developing policy and health interventions to combat such disparities. Cardiovascular risk factors/diseases are common comorbidities that likely contribute to cognitive health disparities among Black/African American people living with HIV (PWH), but their impacts on cognition longitudinally in this population are unclear. The current study examines the relationship between cardiovascular risk and cognitive functioning over time in Black/African American adults living with HIV.Participants and Methods:A sample of 122 Black/African American adults with HIV (ages 25-68, M=51.8, SD=7.7; 98% on antiretroviral therapy; 91% with undetectable viral load) were selected from the Drexel/Temple Comprehensive NeuroHIV Center, Clinical and Translational Research Support Core (CTRSC; based at Drexel University College of Medicine) Cohort. They completed longitudinal visits (300 total visits, average follow-up time=4.9 years) that included clinical interviews, medical record review, biometric measurements, and comprehensive neuropsychological assessments. Cardiovascular risk factors of interest were body mass index (BMI), waist-to-height ratio (WHtR), and a total vascular risk burden score (VBS) representing five risk factors: obesity, central obesity, diabetes, hyperlipidemia, and hypertension. Based on a prior principal component analysis, three cognitive domains were examined: (1) verbal fluency, (2) visual memory/visuoconstruction, and (3) motor speed/executive functions. Mixed models were used to examine domain-specific cognitive trajectories in relation to baseline cardiovascular risk factors and changes in cardiovascular risk factors.Results:Overall, cognitive test performance improved over time (p&lt;.003). Baseline VBS was marginally associated with longitudinal change in verbal fluency (p=.06). Participants with low baseline VBS (0-1 risk factors) demonstrated improvement in verbal fluency (p=.002), while those with higher VBS (2-5 risk factors) demonstrated stability in verbal fluency. In contrast, greater increases in BMI and in WHtR predicted more favorable trajectories in motor speed/executive function (both p&lt;.001). Patients with increasing BMI over time improved in this domain (p=.02), while patients with stable or decreasing BMI did not. A similar pattern was observed for WHtR change. No vascular risk factors were associated with trajectories of visual memory/visuoconstruction.Conclusions:Higher total vascular risk burden was associated with less favorable verbal fluency trajectories, reflecting the negative cognitive consequences of disorders such as diabetes, hyperlipidemia, and hypertension. Unexpectedly, greater increases in BMI and WHtR were associated with more favorable trajectories in motor speed and executive functioning. In this population, weight gain may be a proxy for other positive health factors, such as immune reconstitution, which will be examined in future analyses. Taken together, cardiovascular risk factors have heterogeneous associations with cognitive trajectories, emphasizing the importance of examining the mechanisms of these varying relationships. Future research will examine how social determinants of health, such as racial/ethnic discrimination, contribute to disparities in cardiovascular risk factors and cognitive outcomes.

6 Pulse Pressure and APOE ε4 Dose Interact to Affect Cerebral Blood Flow in Older Adults Without Dementia

Objective: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.Participants and Methods: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 &gt; 0.0251 pg/ml.Results:A significant pulse pressure X APOE ε4 dose interaction was found on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex (ps &lt; .005). Among participants with two e4 alleles, higher pulse pressure was significantly associated with lower CBF (ps &lt; .001). However, among participants with zero or one ε4 allele, there was no significant association between pulse pressure and CBF (ps &gt; .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 &gt; .109). Results remained unchanged when additionally controlling for general vascular risk assessed via the modified Hachinski Ischemic Scale.Conclusions: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.

Abstract 47: Mid-Life Vascular Risk and Rate of Physical Function Decline Among Older Adults: The Atherosclerosis Risk in Communities Study

Introduction: Physical function decline is associated with poor outcomes, including disability and death. Late-life vascular risk burden is associated with faster physical decline, but earlier life course influence is still unknown. We hypothesized that higher mid-life vascular risk is associated with faster late-life physical function decline. Methods: We studied 5,481 adults at visit 5 (mean [SD] age=75.8 [5.0], range=67-91 years, 58% women, 21% Black) without stroke or Parkinson disease. Mid-life hypertension (≥140/90 mm Hg or treatment), diabetes (≥126 mg/dL or treatment), high cholesterol (≥240 mg/dL or treatment), and current smoking were assessed at visit 1 (age=45-64 years) and across visits 1-4. Late-life physical function in the Short Physical Performance Battery (SPPB) was assessed at visits 5-7 (median follow-up: 4.8 years). Random-slope, random-intercept linear mixed models tested interactions between rate of SPPB decline and mid-life risk factors, adjusted for visit 5 age, sex, race-site, education, BMI, coronary heart disease, and heart failure. Results: Mid-life hypertension (+57% decline: 0.47 per 5 years, 95% CI: 0.30-0.64, p&lt;0.001) and diabetes (+73% decline: 0.67 per 5 years, 95% CI: 0.24-1.09, p=0.002) were associated with faster SPPB decline compared to midlife low risk (Figure 1), as were higher systolic blood pressure (+17% per SD: 0.16 per 5 years, 95% CI: 0.10-0.23, p&lt;0.001) and fasting blood glucose (+16% per SD: 0.015 per 5 years, 95% CI: 0.06-0.24, p=0.002). Greater cumulative years of exposure to hypertension and diabetes were associated with faster rates of SPPB decline (+32% decline: 0.93 per 5 years, 95% CI: 0.61-1.25, p&lt;0.001) and diabetes (+35% decline: 1.03 per 5 years, 95% CI: 0.38-1.68, p=0.002). Conclusions: Older adults with mid-life hypertension and diabetes had faster rates of late-life physical function decline. Midlife control of blood pressure and diabetes may ameliorate late-life functional decline.

Cardiovascular health trajectories and subsequent cardiovascular disease and mortality: The multi-ethnic study of atherosclerosis (MESA)

ObjectiveLongitudinal trajectories of cardiovascular health (CVH) may reflect vascular risk burden due to prolonged cumulative exposure to non-ideal CVH levels. Identifying individuals who have a higher risk CVH trajectory may facilitate treatment, screening, and prevention. We aimed to characterize 10-year trajectories of CVH and examine the associations between CVH trajectories and subsequent cardiovascular disease (CVD) and mortality. MethodsWe analyzed 3674 MESA participants who completed four exams and remained CVD-free from 2000 to 2011. A 12-point CVH score was calculated based on physical activity, smoking status, body mass index, cholesterol, blood pressure, and glucose. Ideal CVH was defined as a score ≥ 9. Group-based trajectory modeling was used to identify trajectories of ideal CVH. Cox models were used to examine the association of CVH trajectories with incident CVD and death from 2011 to 2018, adjusting for age, sex, race/ethnicity, income, education, and marital status. ResultsThree trajectories were identified based on the probability of achieving ideal CVH: high (n = 1251), medium (n = 760), and persistently low (n = 1663). Almost half (45.3%) of the participants had a persistently low trajectory. During a median of 7.7 years follow-up, 392 incident CVD events and 459 deaths occurred. Compared with the high CVH group, participants in the persistently low CVH trajectory group had elevated risks for CVD (adjusted hazard ratios 1.49, 95% confidence interval 1.15–1.93) and mortality (1.34, 1.06–1.70), and participants in the medium group had moderate risks for CVD (1.17, 0.86–1.59) and mortality (1.15, 0.87–1.53) (p-value for trend 0.002 for CVD, 0.014 for mortality). ConclusionPersistently nonideal CVH is a common trajectory. Targeted prevention programs might benefit individuals with persistently nonideal CVH given their elevated risk of subsequent CVD and mortality.

Cognitive dispersion is elevated in amyloid-positive older adults and associated with regional hypoperfusion.

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.

Tau Mediates Synergistic Influence of Vascular Risk and Aβ on Cognitive Decline.

Elevated vascular risk and beta-amyloid (Aβ) burden have been synergistically associated with cognitive decline in preclinical Alzheimer's disease (AD), although the underlying mechanisms remain unclear. We examined whether accelerated longitudinal tau accumulation mediates the vascular risk-Aβ interaction on cognitive decline. We included 175 cognitively unimpaired older adults (age 70.5 ± 8.0 years). Baseline vascular risk was quantified using the office-based Framingham Heart Study general cardiovascular disease risk score (FHS-CVD). Baseline Aβ burden was measured with Pittsburgh Compound-B positron emission tomography (PET). Tau burden was measured longitudinally (3.6 ± 1.5 years) with Flortaucipir PET, focusing on inferior temporal cortex (ITC). Cognition was assessed longitudinally (7.0 ± 2.0 years) using the Preclinical Alzheimer's Cognitive Composite. Linear mixed effects models examined the interactive effects of baseline vascular risk and Aβ on longitudinal ITC tau. Additionally, moderated mediation was used to determine whether tau accumulation mediated the FHS-CVD*Aβ effect on cognitive decline. We observed a significant interaction between elevated baseline FHS-CVD and Aβ on greater ITC tau accumulation (p=0.004), even in individuals with Aβ burden below the conventional threshold for amyloid positivity. Examining individual vascular risk factors, we found elevated systolic blood pressure and body mass index showed independent interactions with Aβ on longitudinal tau (both p < 0.0001). ITC tau accumulation mediated 33% of the interactive association of FHS-CVD and Aβ on cognitive decline. Vascular risks interact with subthreshold levels of Aβ to promote cognitive decline, partially by accelerating early neocortical tau accumulation. Our findings support vascular risk reduction, especially treating hypertension and obesity, to attenuate Aβ-related tau pathology and reduce late-life cognitive decline. ANN NEUROL 2022;92:745-755.

Associations of Vascular Risk and Amyloid Burden with Subsequent Dementia.

Midlife vascular risk factors (MVRFs) are associated with incident dementia, as are amyloid β (Aβ) deposition and neurodegeneration. Whether vascular and Alzheimer disease-associated factors contribute to dementia independently or interact synergistically to reduce cognition is poorly understood. Participants in the Atherosclerosis Risk in Communities-Positron Emission Tomography study were followed from 1987-1989 (45-64 years old) through 2016-2017 (74-94 years old), with repeat cognitive assessment and dementia adjudication. In 2011-2013, dementia-free participants underwent brain magnetic resonance imaging (with white matter hyperintensity [WMH] and brain volume measurement) and florbetapir (Aβ) positron emission tomography. The relative contributions of vascular risk and injury (MVRFs, WMH volume), elevated Aβ standardized uptake value ratio (SUVR), and neurodegeneration (smaller temporoparietal brain regions) to incident dementia were evaluated with adjusted Cox models. In 298 individuals, 36 developed dementia (median follow-up=4.9 years). Midlife hypertension and Aβ each independently predicted dementia risk (hypertension: hazard ratio [HR] = 2.57, 95% confidence interval [CI] = 1.16-5.67; Aβ SUVR [per standard deviation (SD)]: HR=2.57, 95% CI=1.72-3.84), but did not interact significantly, whereas late life diabetes (HR=2.50, 95% CI=1.18-5.28) and Aβ independently predicted dementia risk. WMHs (per SD: HR=1.51, 95% CI=1.03-2.20) and Aβ SUVR (HR=2.52, 95% CI=1.83-3.47) independently contributed to incident dementia, but WMHs lost significance when MVRFs were included. Smaller temporoparietal brain regions were associated with incident dementia, independent of Aβ and MVRFs (HR=2.18, 95% CI=1.18-4.01). Midlife hypertension and late life Aβ are independently associated with dementia risk, without evidence for synergy on a multiplicative scale. Given the independent contributions of vascular and amyloid mechanisms, multiple pathways should be considered when evaluating interventions to reduce the burden of dementia. ANN NEUROL 2022;92:607-619.

Association of β-Amyloid and Vascular Risk on Longitudinal Patterns of Brain Atrophy.

Vascular risk factors and elevated β-amyloid (Aβ) are commonly observed together among older adults. Here, we examined the interactive vs independent effects of systemic vascular risk and Aβ burden on longitudinal gray matter atrophy and how their co-occurrence may be related to cognitive decline in a cohort of clinically normal adults. A secondary goal was to examine whether vascular risk influences gray matter atrophy independently from markers of white matter injury. Participants were 196 adults (age 73.8 ± 6.1 years) from the Harvard Aging Brain Study. Baseline Aβ burden was quantified with Pittsburgh compound B PET. Baseline vascular risk was measured with the Framingham Heart Study cardiovascular disease risk score. Brain atrophy was quantified longitudinally with structural MRI over a median of 4.50 (±1.26) years. Cognition was assessed yearly with the Preclinical Alzheimer Cognitive Composite over a median of 6.25 (±1.40) years. Linear mixed-effects models examined vascular risk and Aβ burden as interactive vs independent predictors of gray matter atrophy, with adjustment for age, sex, years of education, APOE ε4 status, intracranial volume (when appropriate), and their interactions with time. In subsequent models, we adjusted for markers of white matter injury to determine whether vascular risk accelerated brain atrophy independently from diffusion- and fluid-attenuated inversion recovery (FLAIR)-based markers. Mediation analyses examined whether brain atrophy mediated the interactive association of vascular risk and Aβ burden on cognitive decline. Higher vascular risk and elevated Aβ burden interacted to predict more severe atrophy in frontal and temporal lobes, thalamus, and striatum. Higher Aβ burden, but not vascular risk, was associated with more severe atrophy in parietal and occipital lobes, as well as the hippocampus. Adjusting for diffusion- and FLAIR-based markers of white matter injury had little impact on the above associations. Gray matter atrophy mediated the association between vascular risk and cognitive decline at higher levels of Aβ burden. We observed an interaction between elevated vascular risk and higher Aβ burden with longitudinal brain atrophy, which in turn influenced cognitive decline. These results support vascular risk factor management as a potential intervention to slow neurodegeneration and cognitive decline in preclinical Alzheimer disease.

Effect of Vascular Comorbidity on Visual and Disability Outcomes in a Secondary Progressive Multiple Sclerosis Clinical Trial Cohort.

Vascular comorbidity (VC) is associated with multiple sclerosis (MS) disease progression and visual dysfunction. The longitudinal effect of VC in people with secondary progressive MS (SPMS) is unclear. This study explored the impact of VC on standard clinical, MRI, and visual outcomes in people with SPMS enrolled in a clinical trial. Data were extracted from a 2-year randomized controlled trial (N = 51) testing the supplement lipoic acid in people with SPMS who underwent annual Expanded Disability Status Scales, Timed 25-Foot Walk tests, MRIs, visual acuity testing, and retinal nerve fiber layer (RNFL) and ganglion cell/inner plexiform layer (GCIPL) thicknesses per optical coherence tomography (OCT). Post hoc linear mixed-effects regression analysis compared baseline and annualized outcomes between participants without VC (VC-) and with 1 or more VCs (VC+) (hypertension, dyslipidemia, obesity, diabetes, peripheral or cardiovascular disease, tobacco use). The VC- (n = 19) and VC+ (n = 28) participants were similar in age, sex, and MS disease duration and had comparable MS disability, mobility, and brain atrophy at baseline and throughout the 2-year parent study. The VC+ participants had worse baseline visual acuity than those in the VC- group by 0.13 logMAR (P = .041). No significant differences were detected in RNFL or GCIPL baseline thickness or atrophy between groups. In an SPMS cohort, VC had an inconsistent effect on standard clinical, MRI, and exploratory OCT outcomes, suggesting that the effect of VC may not be evident in smaller cohort studies. Using a more refined definition of VC in future, adequately powered investigations may help effectively elucidate and account for the interaction between vascular risk burden and MS disability.

Magnetic susceptibility in the deep gray matter may be modulated by apolipoprotein E4 and age with regional predilections: a quantitative susceptibility mapping study.

To examine the relationship between apolipoprotein E gene (APOE) mutation status and iron accumulation in the deep gray matter of subjects with cognitive symptoms using quantitative susceptibility mapping (QSM). A total of 105 patients with cognitive symptoms were enrolled. QSM data were generated from 3D gradient-echo data using an STI Suite algorithm. A region of interest-based analysis with QSM was performed in the deep gray matter. Differences between APOE4 carriers and non-carriers were assessed by analysis of covariance. Multiple regression analysis was performed to identify the factors associated with magnetic susceptibility. Clinical characters such as age, education, MMSE, vascular risk burden, and systolic blood pressure differ between APOE4 carrier and non-carrier groups. The APOE4 carrier group had higher magnetic susceptibility values than the non-carrier group, with significant differences in the caudate (p = 0.004), putamen (p < 0.0001), and globus pallidus (p < 0.0001) which imply higher iron accumulation. In a multiple regression analysis, APOE4 status was found to be a predictor of magnetic susceptibility value in the globus pallidus (p = 0.03); age for magnetic susceptibility value in the caudate nucleus (p = 0.0064); and age and hippocampal atrophy for magnetic susceptibility value in the putamen (p < 0.05). Our study demonstrates that magnetic susceptibility in globus pallidus is related to APOE4 status while those of caudate and putamen are related to other factors including age. It suggests that brain iron accumulation in the deep gray matter is modulated by APOE4 and age with differential regional predilection.

Determinants of enlarged perivascular spaces (ePVS) on MRI: The Florida Vascular Imaging Phenotypes (FL‐VIP) Study of AD risk

AbstractBackgroundPVS are fluid filled compartments surrounding small intracerebral vessels. They are conduits for fluid transport, exchange, and waste clearance. Their relationship to cardiovascular markers is unknown. We tested whether ePVS counts are affected by vascular risk factors and comorbidities.MethodWe analyzed nondemented subjects’ brains from the FL‐VIP (comprised of 1Florida ADRC participants with available high quality 3T MRI). ePVS were defined as parenchymal hypo/hyperintensities of &lt;3 mm seen on a single axial T1, T2 or FLAIR section through the basal ganglia (BG) and centrum semiovale (CSO). ePVS were defined as parenchymal hyperintensities &lt;3 mm and graded as 0 (none), 1 (&lt;10), 2 (11‐20), 3 (21‐40), and 4 (&gt;40). The side with highest ePVS count was graded. BG and CSO scores were summed to yield a 0‐8 total. Generalized linear models were used to estimate ePVS score associations with demographics, vascular risk factors, and vascular comorbidities (VASCom score).ResultOf 228 non‐demented participants (mean age 72±8 years; 61% women, 60% Hispanic, mean education 15±4 years, 33% ApoE4 carriers), 59% were hypertensive, 21% diabetic, 66% hypercholesteremic, and 30% obese. Mean VASCom score was 2.3±1.6. ePVS scores ranged from 0‐7 (mean 2.5±1.4), 0‐4 for BG (mean 1.3±0.7) and CSO (mean 1.2 ±0.9). Majority of subjects (73%) had a total ePVS score greater than 1. In unadjusted analysis, BG ePVS were correlated with age (r=0.27, P&lt;0.001), hypertension (r=0.19, p=0.008), MI/CHF/Angina (r=0.14, P=0.03), and coronary bypass (r=0.20, P=0.004). CSO ePVS were correlated with age (r=0.23, P=0.0005), obesity (r=‐0.15, p=0.03), and dyslipidemia (r=‐0.14, P=0.04). In multivariable stepwise regression analyses, BG ePVS were associated with age (β=0.024 per year, p=0.0001), being Hispanic (OR=0.21, P=0.035), coronary bypass (OR=0.70, p=0.025), and hypertension (OR =0.17, p=0.079). CSO PeVS were associated with age (β=0.028 per year, P&lt;0.001) and dyslipidemia (OR=‐0.31, P=0.02).ConclusionePVS were more prevalent with aging, greater vascular risk burden, and Hispanic origin. Hypertension, cardiovascular disease and prior coronary bypass surgery were associated with ePVS in BG, but not in CSO. BG ePVS may be an important marker of small vessel disease linking vascular burden and cognitive impairment.