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INTRODUCTION: The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans. METHODS: U.S. POINTER was planned as a 2‐year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well‐established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER. RESULTS: U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and every 6 months. Both interventions focus on exercise, diet, cognitive/social stimulation, and cardiovascular health, but differ in intensity and accountability. The study partners with a worldwide network of similar trials for harmonization of methods and data sharing. DISCUSSION: U.S. POINTER is testing a potentially sustainable intervention to support brain health and Alzheimer's prevention for Americans. Impact is strengthened by the targeted participant diversity and expanded scientific scope through ancillary studies. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We assessed the effects of multivitamin‐mineral and cocoa extract supplementation on incident mild cognitive impairment (MCI) and all‐cause probable dementia. METHODS: COSMOS‐Mind (N = 2262), a 2 × 2 factorial, randomized‐controlled clinical trial administered a telephone‐based cognitive battery at baseline and annually for 3 years. Incidence rates of MCI, and separately dementia, were compared among treatment arms with proportional hazards regression. RESULTS: Over 3 years, 110 incident MCI and 14 incident dementia cases were adjudicated. Incidence rates did not vary by assignment to multivitamin‐mineral or cocoa extract (all p's ≥ 0.05); however, statistical power was low. When participants assigned to multivitamin‐mineral versus placebo converted to MCI, their scores for global cognition (p = 0.03) and executive function (p < 0.001) were higher and had declined less relative to the previous year (p = 0.03 for global cognition; p = 0.004 for executive function). DISCUSSION: Multivitamin‐mineral therapy may provide cognitive resilience, countering conversion to MCI, but not significantly reduce its incidence over 3 years. Highlights: Multivitamin‐mineral supplementation did not reduce risks for cognitive impairment.Cocoa extract supplementation did not reduce risks for cognitive impairment.Multivitamin‐mineral supplementation slowed cognitive declines for incident mild cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Elevated blood pressure levels during mid‐life have been found to be associated with an increased susceptibility to developing dementia later in life, particularly vascular dementia. Quantitative imaging biomarkers, such as Oxygen Extraction Fraction (OEF) and Cerebral Metabolism Rate of Oxygen (CMRO2), can be indicators of impaired cerebral metabolism. Calibrated Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) is a multi‐parametric approach utilizing hyperoxic and hypercapnic gas challenges (Figure 1). The impact of hypertension on OEF and CMRO2 has been investigated. Method: A cohort of 84 participants was recruited from the Wake Forest Alzheimer's Disease Research Center (ADRC) Clinical Core (Table 1). Among all the covariates, participants with prediabetes and diabetes were considered diabetic, and those who exhibited high blood pressure or were using medication to manage hypertension were classified as hypertensive. The MRI was conducted using a 3T Siemens Skyra MRI scanner with a 32‐channel head coil. Dynamic Pseudocontinuous Arterial Spin Labeling (PCASL) was used to acquire cerebral blood flow (CBF) and BOLD images during respiratory challenges with an end‐tidal forcing system. The ROI values in the frontal lobe, temporal lobe, parietal lobe, and occipital lobe regions were chosen. The correlation between hypertensive status and OEF and CMRO2 in the ROI was analyzed with a linear mixed model, with covariates of age, sex, cognitive status, APOE genotype, diabetic status, and hypertensive status. Result: A negative correlation was found between CBF, OEF, and CMRO2 with hypertensive status in frontal lobe region (Figure 2). Statistical significance was observed for OEF and CMRO2 (p = 0.049 and p = 0.028, respectively), indicating the potential influence of hypertensive status on these biomarkers. Conclusion: The study concludes that there is a significant negative association between hypertensive status and both OEF and CMRO2, particularly in the frontal lobe region. The observed reduction in OEF and CMRO2 is not solely due to decreased CBF, but rather complex and multifactorial processes involving vascular remodeling and altered oxygen metabolism. Additional research is necessary to fully understand the underlying pathophysiological mechanisms that link hypertension to decreased OEF and CMRO2, particularly in the context of regional specificity. [ABSTRACT FROM AUTHOR]

Background: The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) will determine whether interventions that simultaneously include multiple risk reduction strategies can protect cognitive health in older adults. The primary outcome, a global cognitive composite score derived from the POINTER‐Modified Neuropsychological Test Battery (PmNTB), was developed to allow for outcome harmonization with its forerunner, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) and other large trials (e.g., A4, EXERT). Here we describe the PmNTB and its initial validation in the baseline U.S. POINTER sample. Method: U.S. POINTER is a Phase 3, multicenter, randomized 2‐year clinical trial of two interventions varying in intensity and format, in older adults at increased risk for cognitive decline and dementia. The PmNTB includes performance from 7 cognitive tests and is computed as the mean of three domain‐specific composites: Episodic Memory, Processing Speed, and Executive Function. The Episodic Memory Composite includes Free and Cued Selective Reminding Test, Story Recall, and Visual Paired Associates. The Processing Speed Composite includes Trail Making Test (TMTA) and Digit Symbol Substitution Test. The Executive Function Composite includes Number Span, Word Fluency, and TMTB. PmNTB was assessed in relation to age, clinical status (Clinical Dementia Rating‐CDR), and other cognitive composites able to be computed in the current sample using overlapping measures (i.e., FINGER NTB, Preclinical Alzheimer's Cognitive Composite‐PACC‐5). Result: 2094 participants completed the baseline assessment (mean age = 68.2±5.2 years; 68.8% female, 69.1% non‐hispanic white, mean MMSE = 28.9± 1.3). Global CDR was 0 for 79.5% of participants, and 0.5 for 20.5% of participants. After adjusting for education, race, ethnicity, and sex, each additional year in age was associated with a drop in PmNTB z‐score by ‐0.064 (95%CI = ‐0.071,‐0.056, p<0.001). Likewise, global CDR = 0.5 (questionable dementia) was associated with a lower PmNTB score (z = ‐0.549) compared with global CDR = 0 (‐0.134 z‐scores). PmNTB correlated with the FINGER NTB (r = 0.858, p<0.001) and the PACC‐5 (r = 0.876, p<0.001). Conclusion: The PmNTB is a valid measure of cognitive functioning, capturing age‐related cognitive decrements and is associated with clinically relevant, functional outcomes. It also exhibits convergent validity with established cognitive outcomes. [ABSTRACT FROM AUTHOR]

Background: Brain vascular health is closely related to cognitive performance, and cerebrovascular reactivity (CVR), an indicator of cerebral blood flow (CBF) compensatory capacity in response to vasoactive stimuli, may help elucidate this relationship. Arterial spin labeling (ASL) and blood‐oxygen‐level‐dependent (BOLD) are two representative methods for measuring CVR, although BOLD is a complex combination of CBF, cerebral volume, and cerebral metabolic rate of oxygen. This study aimed to investigate the relationship between cognition and two different CVR methods. Method: Seventy‐nine subjects (age: 68.7±7.2 years) enrolled in the Wake Forest Alzheimer's Disease Research Center (ADRC) Clinical Core underwent MRI, including both dynamic pseudo‐continuous ASL (PCASL) under a hypercapnic respiratory challenge and multi‐TI PCASL for resting CBF and ATT mapping. The dynamic PCASL with a longer TE (20ms) provided simultaneous acquisition of ASL and BOLD. CVR was obtained by calculating CBF or BOLD signal changes during a hypercapnic period. Voxel‐wise multiple linear regression analyses were performed to examine the relationship between CVR and mild cognitive impairment (MCI), adjusting for age, sex, glycemic status, APOE e4 allele, hypertensive status, and years of education. False positive cluster thresholding was applied for each modality. Additional statistical analyses were conducted to investigate differences in baseline CBF and ATT between cognitively healthy and MCI groups within the voxel clusters that showed significantly different CVR values. Result: In the BOLD‐based CVR analysis, two voxel clusters in the white matter (WM) of superior temporal and parietal lobes showed lower CVR in the MCI group compared to the cognitively healthy group (Figure 1). Additionally, reduced CBF and prolonged ATT were observed within the clusters (Figure 2 and 3). Conclusion: Subjects with MCI exhibited lower BOLD‐based CVR in WM, while no association was found between ASL‐based CVR and MCI. BOLD‐based CVR may be a more sensitive measure than ASL‐based CVR in association with cognition, particularly in WM where optimization of ASL acquisition is challenging. The impaired CVR in the MCI group may be due to cerebrovascular impairments, such as reduced CBF and prolonged ATT. [ABSTRACT FROM AUTHOR]

Background: Cognitive assessments sensitive to the integrity of the medial temporal lobe, an area vulnerable to early tau deposition, may serve as a low‐cost, effective marker of underlying tau burden in older adults at risk of Alzheimer's dementia. The current post hoc analyses from the EXERT study examined the relationship between CSF phosphorylated tau181 (p‐tau181), total tau (t‐tau), hippocampal volume, and cognitive performance on three distinct memory assessments in older adults with amnestic mild cognitive impairment (aMCI). Method: The study used baseline data from 41 older adults with aMCI in the EXERT trial who consented to lumbar puncture and had CSF data available (mean age = 74.10±11.98 years, mean education = 16.24±2.39 years, 61% female). P‐tau181 and t‐tau levels were quantified using Lumipulse from CSF samples. Structural brain images were processed using NeuroQuant. Hippocampal volume measures were averaged across hemispheres and adjusted for intracranial volume. Memory measures included the computerized Cogstate Behavioral Pattern Separation of Objects task (BPSO; fine memory discrimination), the Auditory Verbal Learning Test (AVLT; long delay free recall), and the Logical Memory test (delayed recall). Linear regression models were adjusted for age, sex, and education. Result: Lower CSF p‐tau181 was significantly associated with better fine memory discrimination (β = ‐0.11, SE = 0.03, p<0.01). Lower CSF t‐tau was significantly associated with better fine memory discrimination (β = ‐0.09, SE = 0.03, p = 0.01). Larger hippocampal volume was significantly associated with better fine memory discrimination (β = 0.08, SE = 0.02, p<0.01), better AVLT delayed recall (β = 1.69, SE = 0.32, p<0.01), and better Logical Memory delayed recall (β = 1.69, SE = 0.40, p<0.01). Neither p‐tau181 or t‐tau were significantly associated with AVLT delayed recall or Logical Memory delayed recall. Conclusion: Fine memory discrimination measured via the computerized BPSO test was associated with CSF p‐tau181, CSF t‐tau, and hippocampal volume, while more traditional verbal memory tests of list learning and story recall were associated only with hippocampal volume. The BPSO test may be a sensitive indicator of early pathology in individuals with aMCI with underlying tau burden. EXERT was supported by the Alzheimer's Disease Cooperative Study (ADCS) and funded by the National Institutes of Health Grant U19 AG010483. [ABSTRACT FROM AUTHOR]

Background: Mid‐ and late‐life exercise has been associated with lower dementia risk. The EXERT trial tested whether aerobic training (AX), compared to stretching/balance/range‐of‐motion training (SBR), could slow cognitive decline in MCI. While no difference was detected between exercise arms, EXERT participants overall showed little cognitive change over 12 months. It is possible that the amount of exercise, rather than the type, may be protective against decline. In this exploratory, post‐hoc analysis of EXERT data, we assessed whether intervention adherence, operationalized as the number of supervised exercise sessions completed, was associated with slower brain atrophy over 12 months. Method: 194 EXERT participants with baseline and follow‐up MRI were included in this analysis. For each participant, the number of supervised exercise sessions of at least 40 minutes in duration completed during the first 12 months was determined. MRI data were processed using FreeSurfer. Repeated measures ANOVAs were conducted using regional volume or thickness as the dependent variable, and the interaction between number of sessions (continuous scale) and study visit as the independent variable. Baseline age and sex, as well as their interactions with time were included in the model. FDR‐adjusted p‐values <0.05 were considered significant. Result: Greater number of sessions completed was associated with less brain atrophy over 12 months in the hippocampus and parahippocampus, and less ventricular expansion in the lateral and inferior lateral ventricles (Table 1, Figure 1; FDR‐corrected p<0.05 for interaction term). Results remained unchanged when including exercise type (AX vs. SBR), baseline CDR‐SB, or baseline plasma Aβ42/40 in the model. Findings were similar when analyses were restricted to participants who completed the study prior to the onset of the COVID‐19 pandemic. Conclusion: Our results show that higher adherence to a supervised exercise intervention over 12 months was associated with reduced brain atrophy in adults with amnestic MCI. These findings were obtained in post‐hoc, exploratory analyses, so causality should be interpreted with caution. EXERT was supported by the Alzheimer's Disease Cooperative Study and funded by the National Institutes of Health grant U19‐AG010483. [ABSTRACT FROM AUTHOR]

Background: Hypertension is one of the key vascular risk factors of AD and related dementia. Cerebral blood flow (CBF) and white matter (WM) integrity may play an essential role in understanding the vascular contributions to dementia (VCID). We investigated if hypertension is related to WM microstructural and vascular imaging metrics in WM. Method: Four‐hundred‐seven subjects (age: 69.7±8.1 years) enrolled in the Wake Forest Alzheimer's Disease Research Center (ADRC) Clinical Core underwent MRI, including neurite orientation dispersion and density imaging (NODDI) and eight‐phase pseudo‐continuous ASL (PCASL). The subjects included 158 MCI, 111 APOE e4 allele carriers, 224 with hypertension, and 249 with impaired glycemic status which includes type 2 diabetes and prediabetics. Hypertension status was defined as SBP≥130mmHG and DBP≥80mmHG. The microstructural imaging metrics including intracellular volume fraction (ICVF), isotropic volume fraction (ISOVF), and orientation dispersion index (ODI) were obtained from NODDI. The vascular imaging metric included CBF. CBF was obtained from PCASL sequence. Voxel‐wise linear regression analyses were performed to examine if CBF, ICVF, ISOVF, or ODI were related to hypertension adjusting for cognitive status, glycemic status, APOE e4 allele, age, sex, and years of education. All images were normalized into standard space. Tract‐based spatial statistics (TBSS) were used to normalize NODDI images. The false positive cluster thresholding was applied. Result: Hypertensive subjects showed impairments in both microstructural and vascular imaging metrics. Based on Figures 1‐(A), 2‐(A) and 3‐(A), there are overlapping brain image voxels between the microstructural and vascular imaging metrics. Additionally, the hypertensive subjects showed significantly lower CBF, higher ISOVF, and higher ODI than normal subjects within the voxel clusters (Figures 1‐(B), 2‐(B), and 3‐(B)). Note that APOE e4 allele, glycemic status, and cognitive status also showed statistical significance in the NODDI parameters, but there was no association in CBF. Conclusion: Hypertension showed the potential association between the microstructural and vascular impairments in the WM. Each risk factor and cognitive status differently affected WM microstructural and vascular dynamic imaging parameters. These findings warrant further investigations of contributions of hypertension to the microstructural and vascular abnormalities in dementia. [ABSTRACT FROM AUTHOR]

Background: A key focus of the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is recruitment of unimpaired older individuals at risk for cognitive decline with heterogeneous characteristics (under‐represented racial and ethnicity groups (URG), family history of cognitive decline, hypertension, geographic diversity), and a subset of individuals undergo PET and MRI. Method: To examine effects of heterogeneity on relationships between risk factors, AD biomarkers (Aß and entorhinal tau PET, hippocampal volume (HV)) and cognition (global, executive function, and memory) were examined from U.S. POINTER neuroimaging participants (N = 602, about 65% of the anticipated total sample) and a subset of Alzheimer's Disease Neuroimaging Initiative participants (N = 503). Neuroimaging data were processed and analyzed using harmonized methods across studies. Some cohort‐specific measurements were standardized using a within‐cohort reference group (Aß‐negative individuals <70yrs and with global CDR = 0). Result: U.S. POINTER imaging participants are younger than those in ADNI (68.6+/‐5.0yrs vs 70.7+/‐4.4yrs), more likely to be female (65% vs 58%) and from URG (27% vs 15%), and had lower education (14.7+/‐3.3yrs vs 16.7+/‐2.3yrs) and higher Framingham Cardiovascular Risk scores (9.9+/‐8.3 vs 7.7+/‐5.3). The groups differed on several AD biomarkers and cognitive measures (Table). In regression models, AD biomarkers were stronger predictors of cognitive performance in ADNI compared to POINTER. Specifically, Aß+ individuals with elevated tau had disproportionately poorer cognitive performance in ADNI, and this relationship remained consistent across cognitive measures (Figure). Conversely, demographic/risk variables were stronger predictors in POINTER. Demographic/risk predictors (age, sex, education, race, and FRS) together explained twice as much variance in global cognition in POINTER compared to ADNI (Adjusted R2 = 29% vs 14%). The addition of AD biomarkers to the model further increased the amount of variance in global cognition explained from 14% to 34% in ADNI, but addition of AD biomarkers did not increase variance explained in the POINTER model. Conclusion: Heterogeneity among study participants appears to influence baseline biomarker‐cognition relationships such that AD biomarkers explain more variability in cognitive performance in ADNI than POINTER. These findings further suggest that cohort characteristics may affect the potential influence of amyloid‐ and tau‐modifying treatments on cognition. [ABSTRACT FROM AUTHOR]

Background To evaluate whether contrast sensitivity is associated with lower extremity physical function in cognitively intact older adults. Methods Cross-sectional analysis of the relationship of binocular and worse eye log contrast sensitivity (LCS) to expanded Short Physical Performance Battery (eSPPB) and its components (gait speed, narrow walking speed, chair stand pace, and balance) in 192 cognitively healthy older adults. The association of LCS with postural sway and gait was also tested with tasks that further challenged functional reserve. Results Mean age was 76.4 years with 56% identifying as female and over 98.5% having good corrected visual acuity. Lower LCS was significantly associated with worse performance on the eSPPB, 4-M gait speed, narrow walking speed, and balance time in unadjusted and adjusted models. The relationship between worse eye LCS and larger postural sway was 3 times greater on a foam surface (beta 1.07, 95% CI [0.35, 1.80]) than a firm surface (beta 0.35, 95% CI [0.05, 0.65]), and both were robust to adjustment for confounders; similar findings were observed with binocular LCS. Lower binocular LCS had a greater decremental effect on gait velocity during the fast pace (beta −0.58, 95% CI [−0.90, −0.27]) than the usual pace (Beta −0.39 [−0.63, −0.15]) gait task. Conclusions These findings suggest that cognitively unimpaired older adults without significant visual acuity impairment can have subtle preclinical deficits in contrast sensitivity and physical function that could place them at risk of mobility and balance issues. Future studies should determine whether this subset of older adults may benefit from targeted intervention to prevent disability. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Post‐mortem analysis provides definitive diagnoses of neurodegenerative diseases; however, only a few can be diagnosed during life. METHODS: This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the model's robustness by splitting train/test sets by clinical sites. A similar study was performed for predicting Alzheimer's disease (AD) neuropathologic change without specific comorbidities. RESULTS: Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased. DISCUSSION: Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion‐specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions. [ABSTRACT FROM AUTHOR]

Introduction: Dietary supplements are touted for cognitive protection, but supporting evidence is mixed. COSMOS‐Mind tested whether daily administration of cocoa extract (containing 500 mg/day flavanols) versus placebo and a commercial multivitamin‐mineral (MVM) versus placebo improved cognition in older women and men. Methods: COSMOS‐Mind, a large randomized two‐by‐two factorial 3‐year trial, assessed cognition by telephone at baseline and annually. The primary outcome was a global cognition composite formed from mean standardized (z) scores (relative to baseline) from individual tests, including the Telephone Interview of Cognitive Status, Word List and Story Recall, Oral Trail‐Making, Verbal Fluency, Number Span, and Digit Ordering. Using intention‐to‐treat, the primary endpoint was change in this composite with 3 years of cocoa extract use. The pre‐specified secondary endpoint was change in the composite with 3 years of MVM supplementation. Treatment effects were also examined for executive function and memory composite scores, and in pre‐specified subgroups at higher risk for cognitive decline. Results: A total of 2262 participants were enrolled (mean age = 73y; 60% women; 89% non‐Hispanic White), and 92% completed the baseline and at least one annual assessment. Cocoa extract had no effect on global cognition (mean z‐score = 0.03, 95% CI: ‐0.02 to 0.08; P =.28). Daily MVM supplementation, relative to placebo, resulted in a statistically significant benefit on global cognition (mean z = 0.07, 95% CI 0.02 to 0.12; P =.007), and this effect was most pronounced in participants with a history of cardiovascular disease (no history: 0.06, 95% CI 0.01 to 0.11; history: 0.14, 95% CI ‐0.02 to 0.31; interaction, nominal P =.01). Multivitamin‐mineral benefits were also observed for memory and executive function. The cocoa extract by MVM group interaction was not significant for any of the cognitive composites. Discussion: Cocoa extract did not benefit cognition. However, COSMOS‐Mind provides the first evidence from a large, long‐term, pragmatic trial to support the potential efficacy of a MVM to improve cognition in older adults. Additional work is needed to confirm these findings in a more diverse cohort and to identify mechanisms to account for MVM effects. Highlights: COSMOS‐Mind was a large simple pragmatic randomized clinical trial in older adults conducted by mail and telephone.The trial used a two‐by‐two factorial design to assess treatment effects of two different interventions within a single large study.We found no cognitive benefit of daily cocoa extract administration (containing 500 mg flavanols) for 3 years.Daily multivitamin‐mineral (MVM) supplementation for 3 years improved global cognition, episodic memory, and executive function in older adults.The MVM benefit appeared to be greater for adults with cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Cardiometabolic disorders (hypertension, diabetes) are key modifiable risk factors for Alzheimer's disease and related disorders. They often co-occur; yet, the extent to which they independently affect brain structure and function is unclear.Objective: We hypothesized their combined effect is greater in associations with cognitive function and neuroimaging biomarkers of white matter (WM) health and cerebral perfusion in a diverse older adult cohort.Methods: Participants aged 50-85 years received: clinical evaluation, oral glucose tolerance testing, neuroimaging, cognitive testing, and adjudication. Neuroimaging included: T1 (gray [GM]/WM segmentation, regional volumes/thicknesses); FLAIR (WM hyperintensity volume [WMHv]; arterial spin labeling (cerebral blood flow); diffusion tensor imaging (fractional anisotropy [FA]); and neurite orientation dispersion and density imaging (Free Water). Hypertension (HTN) and impaired glucose tolerance (IGT) were staged and cardiometabolic status was categorized (HTN only, IGT only, IGT+HTN, neither). Multivariable linear regression modeled associations with cognitive and neuroimaging measures (covariates: age, gender, race).Results: MRI was available for 478 participants (35% mild cognitive impairment, 10% dementia) with mean age 70±8 years, 74% with HTN, 61% with IGT, and 15% self-identified as Black/African-American. IGT+HTN was significantly associated with cognitive impairment, higher WM Free Water and WMHv, lower FA, and lower GM perfusion compared to neither factor. HTN alone was associated with poorer cognition and lower GM perfusion. Cardiometabolic factors were not associated with GM macrostructure (volumes, temporal lobe cortical thickness) or cognitive status.Conclusion: HTN and its co-occurrence with IGT (HTN+IGT) were associated with lower global cognitive performance and reduced GM perfusion and impaired WM microstructure. [ABSTRACT FROM AUTHOR]

Background: The association of cognitive function with symptoms of psychological distress during the coronavirus disease 2019 (COVID-19) pandemic or adherence to COVID-19 protective health behaviors is not well-understood.Methods: We examined 2 890 older women from the Women's Health Initiative cohort. Prepandemic (ie, within 12 months prior to pandemic onset) and peripandemic global cognitive function scores were assessed with the modified Telephone Interview for Cognitive Status (TICS-m). Anxiety, stress, and depressive symptom severity during the pandemic were assessed using validated questionnaires. We examined adherence to protective behaviors that included safe hygiene, social distancing, mask wearing, and staying home. Multivariable models were adjusted for age, race, ethnicity, education, region of residence, alcohol intake, and comorbidities.Results: Every 5-point lower prepandemic TICS-m score was associated with 0.33-point mean higher (95% confidence interval [CI], 0.20, 0.45) perceived stress and 0.20-point mean higher (95% CI, 0.07, 0.32) depressive symptom severity during the pandemic. Higher depressive symptom severity, but not anxiety or perceived stress, was associated with a 0.69-point (95% CI, -1.13, -0.25) mean decline in TICS-m from the prepandemic to peripandemic period. Every 5-point lower peripandemic TICS-m score was associated with 12% lower odds ratio (OR, 0.88; 95% CI, 0.80, 0.97) of practicing safe hygiene.Conclusions: Among older women, we observed that: (a) lower prepandemic global cognitive function was associated with higher stress and depressive symptom severity during the pandemic; (b) higher depressive symptom severity during the pandemic was associated with cognitive decline; and (c) lower global cognitive function during the pandemic was associated with lower odds of practicing safe hygiene. [ABSTRACT FROM AUTHOR]

Background: White matter (WM) degeneration in older adults is often characterized unimodally by diffusion tensor imaging (DTI), T1w and T2‐FLAIR MRI. However, approaches integrating multimodal MRI information will be necessary for better understanding WM degeneration in early stages of AD. Method: This study characterizes the longitudinal changes of WM structure among 66 participants with marked baseline white matter hyperintensity volume (WMHv > 2000 mm3). 42 cognitively normal [CN, 72±7.2y, F = 25] and 24 mild cognitive impairment [MCI, 74±5.7y, F = 14]) adults underwent longitudinal MRI (scan interval: 2.8±0.85 years) within the Wake Forest AD Research Center. DTI metrics were estimated using FMRIB's Diffusion Toolbox, voxel‐wise volumetric changes of WM (Jacobian Determinant [JD]) were estimated from fractional anisotropy (FA) maps using SPM CAT12, and WMHv were quantified using SPM's Lesion Segmentation Toolbox. We segmented WM into WMH and normal‐appearing WM (NAWM) to characterize different degeneration patterns by integrating multimodal MRI information. We performed a linear regression analysis of %WMHv change with cognitive status, scan interval, and baseline WMH volume as covariates. Result: Decreased FA and increased mean diffusivity (MD) were observed in WMH regions compared with NAWM. Within WMH, interestingly, volume and FA increased, while MD decreased (p <0.001) during the longitudinal follow‐up (Figs. 1 and 2). Baseline WMHv was not significantly associated with cognitive status, but trended toward higher WMHv in MCI compared to CN (p = 0.07). Adjusted for baseline WMHv, cognitive status was associated with WMHv change (p = 0.036, MCI faster than CN, Fig. 3). While FA (p = 0.99) and MD (p = 0.16) did not change in the NAWM, volumetric change rate (JD) indicated volumetric contraction (p<0.001, Figs. 4 and 5). WMH progresses with time in older adults at risk of AD dementia by occupying neighboring NAWM regions, resulting in relative increases in FA and decreases in MD. Conclusion: In NAWM, WM degeneration can be better characterized by volumetric contraction than white matter microstructural integrity. This observation could implicate that secondary or peripheral WM fibers may reveal more vulnerable tracts in early stages of AD. Further investigation incorporating imaging makers of blood perfusion and metabolism could better explain structural mechanisms of WM degeneration. [ABSTRACT FROM AUTHOR]

Background: Arterial stiffness may play a role in the development of dementia, presumably through its effects on white matter integrity and hyperintensities (WMH). However, relationships among arterial stiffness, white matter microstructure, and WMH volumes remain poorly understood. Arterial stiffness increases monotonically with age and its increase is accelerated by cardiometabolic disorders (e.g., hypertension, metabolic syndrome, diabetes). Further exploration of these relationships is key to the development of targeted therapies, early management, and detection. Method: Arterial stiffness was measured using carotid‐femoral pulse wave velocity (cfPWV) in ADRC participants with baseline systolic blood pressure (SBP) measurements, detailed cognitive testing, cognitive adjudication, and brain MRI. We examined associations of cfPWV and SBP with cognitive function (Montreal Cognitive Assessment [MoCA], Preclinical Alzheimer's Cognitive Composite [PACC5], and domain measures of memory and executive function) and brain MRI measures of: macrostructure (volume of gray matter [GM] and WMH from T1‐weighted and FLAIR imaging), white matter microstructure (neurite orientation dispersion and density imaging [NODDI] free water [FW] and diffusion tensor imaging [DTI] fractional anisotropy [FA]), and cerebral blood flow (CBF) in white matter (WM) and GM. Age, race, gender, education, and APOE‐4 status were included as covariates and in interaction terms in linear regression analyses. Result: Among 458 participants with a mean age 70±8 years and cognitive adjudication (44 dementia, 157 MCI, 257 normal cognition; Table 1), higher cfPWV was associated with worse cognitive performance (MoCA, PACC5), as was SBP (MoCA, PACC5, executive domain, language domain; Table 2). Higher cfPWV was associated with differences in WM microstructure (higher FW, lower FA) and higher WMH volume. While no overall associations between cfPWV and CBF were detected, cfPWV had stronger associations with FW, FA, and WMH in men. Higher SBP was associated with higher FW, higher WMH volume, and lower WM and GM CBF (Table 3). SBP had stronger associations with WMH in younger participants (<70y) and GM CBF in Black/AA participants and participants with impaired fasting glucose. No other interactions were detected. Conclusions: Arterial stiffness is associated with microstructural and macrostructural differences and poorer global and executive cognitive function. [ABSTRACT FROM AUTHOR]

Background Vascular risk scores are associated with incident dementia. Information regarding their association with cognitive performance and decline in racially/ethnically diverse cohorts is lacking. Method In 4 392 Multi-Ethnic Study of Atherosclerosis participants (aged 60.1 ± 9.4 years; 53% women; 41% White, 11% Chinese American, 26% African American, 21% Hispanic), we compared associations of Exam 1 (2000–2002) Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham Stroke Risk Profile (FSRP), and atherosclerotic cardiovascular disease pooled cohort equation (ASCVD-PCE) risk scores with Exam 5 (2010–2012) Cognitive Abilities Screening Instrument (CASI), Digit Symbol Coding (DSC), and Digit Span (DS) cognitive test performance using multivariable linear regression, and examined racial/ethnic interactions. In 1 838 participants with repeat CASI data at Exam 6 (2016–2018), we related risk scores to odds of a 1- SD decline in CASI performance using multivariable logistic regression. Results SD increments in each risk score were associated with worse cognitive performance. CAIDE had stronger associations with CASI performance than the FSRP and ASCVD-PCE, but associations of ASCVD-PCE with the DSC and DS were similar to CAIDE (difference in β [95% CI] = −0.57 [−1.48, 0.34] and −0.21 [−0.43, 0.01], respectively). Race/ethnicity modified associations. For example, associations between CAIDE and CASI were greater in African Americans and Hispanics than in Whites (difference in β = 0.69 [0.02, 1.36] and 1.67 [0.95, 2.39], respectively). Risk scores were comparably associated with decline in CASI performance. Conclusions Antecedent vascular risk scores are associated with cognitive performance and decline in the 4 most common U.S. racial/ethnic groups, but associations differ among risk scores and by race/ethnicity. [ABSTRACT FROM AUTHOR]

Introduction: Mid‐life dietary patterns are associated with Alzheimer's disease (AD) risk, although few controlled trials have been conducted. Methods: Eighty‐seven participants (age range: 45 to 65) with normal cognition (NC, n = 56) or mild cognitive impairment (MCI, n = 31) received isocaloric diets high or low in saturated fat, glycemic index, and sodium (Western‐like/West‐diet vs. Mediterranean‐like/Med‐diet) for 4 weeks. Diet effects on cerebrospinal fluid (CSF) biomarkers, cognition, and cerebral perfusion were assessed to determine whether responses differed by cognitive status. Results: CSF amyloid beta (Aβ)42/40 ratios increased following the Med‐diet, and decreased after West‐diet for NC adults, whereas the MCI group showed the reverse pattern. For the MCI group, the West‐diet reduced and the Med‐diet increased total tau (t‐tau), whereas CSF Aβ42/t‐tau ratios increased following the West‐diet and decreased following the Med‐diet. For NC participants, the Med‐diet increased and the West‐diet decreased cerebral perfusion. Discussion: Diet response during middle age may highlight early pathophysiological processes that increase AD risk. [ABSTRACT FROM AUTHOR]

Background: Vascular risk factors are associated with cerebral small vessel disease and dementia pathology and reduced WM integrity is correlated with the severity of cognitive impairment in dementia. We have investigated if vascular risk factors are related to white matter structural and vascular imaging metrics. Imaging metrics include intracellular volume fraction (ICVF), white matter hyperintensities (WMH), and cerebrovascular measures such as cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and arterial transit time (ATT). Method: Sixty‐four subjects (Table 1) enrolled in the Wake Forest Alzheimer's Disease Research Center (ADRC) Clinical Core cohort underwent MRI, including T2 FLAIR, neurite orientation dispersion and density imaging (NODDI), pseudo‐continuous ASL (PCASL). CVR was measured as a percent of increased CBF during a hypercapnic respiratory paradigm. ATT and resting CBF were obtained from a multi‐TI PCASL sequence. ICVF was obtained from NODDI. Head size adjusted WM total lesion volume (TLV) was calculated using SPM12‐LST2 toolbox with T2‐FLAIR image. Linear regression models were performed to examine if CBF, CVR, ATT, ICVF, or TLV are related to the risk factors or cognitive status adjusted covariates: age, sex, and years of education. A covariates adjusted logistic regression estimated weighting factors for each interrelated vascular imaging parameter to create novel cerebrovascular functional composites for each vascular risk group and mild cognitive impairment (MCI) group. The factor score p‐values were also calculated from two‐sample t‐tests with the cerebrovascular composite. The entire analyses were performed within the whole brain WM. Result: In the whole brain WM, hypertension subjects (p=0.031) showed higher CVR (Figure 1). T2DM subjects (p=0.007) showed higher WM TLV (Figure 2). T2DM and MCI subjects showed lower ICVF than normal subjects did (Figure 3). Based on the weights of each cerebrovascular parameter in the composite (Table 2), the effects of CBF and CVR are stronger in hypertension group while all three cerebrovascular measures had substantial contribution to cognition status. Conclusion: Each risk factor and cognitive status differently affected WM structural and vascular dynamic imaging parameters. The findings warrant further investigations of contributions of vascular risk factors to the structural and vascular abnormalities in dementia. [ABSTRACT FROM AUTHOR]

Background: Cerebrovascular functional parameters such as cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and arterial transit time (ATT) may play an essential role in understanding the vascular contributions to dementia (VCID). We investigated the relationships between cerebrovascular functional parameters and AD risk factors, including APOE genotype, hypertension, and diabetes. Method: Sixty‐five subjects (Table 1) enrolled in the Wake Forest Alzheimer's Disease Research Center (ADRC) Clinical Core cohort underwent MRI, including pseudo‐continuous ASL (PCASL). CVR maps were obtained under a hypercapnic challenge using a computer‐controlled gas blender. A multi‐TI PCASL sequence was also employed to obtain resting CBF and ATT. Separate linear regression models were tested with response variables of quantitative CBF, CVR and ATT in whole brain gray matter (GM) and AD‐prone GM regions including hippocampus, parahippocampal, entorhinal, inferior parietal lobule, precuneus, and cuneus, adjusted for covariates: age, sex, and years of education. To investigate the effects of a risk factor on the interrelated vascular dynamic parameters, a cerebrovascular composite was created with the implementation of the weighting factors, obtained from covariates adjusted logistic regression, for each AD risk group and mild cognitive impairment (MCI). The factor score p‐values were calculated from two‐sample t‐tests with the cerebrovascular composite. Result: In both whole brain GM and AD‐prone GM regions, subjects with the risk factors generally had lower resting CBF, but differential relationship with CVR. Subjects with hypertension had significantly higher CVR, while APOE e4 carriers showed significantly lower CVR (Figure 1 and 2). From the cerebrovascular composite analysis, CVR showed higher weights in hypertension and APOE e4 carrier groups in both whole brain GM and AD‐prone GM regions (Table 2) although there still were fractions of linear weights of CBF or ATT, which were not negligible. Conclusion: Hypertension and APOE e4 carrier showed group differences of CVR in both whole brain GM and AD‐prone GM regions and the directions were opposite, implying their pathophysiological mechanisms may differ. As resting CBF and ATT showed lower weights in the composite than CVR, CVR may be a more sensitive brain perfusion parameter relating VCID. [ABSTRACT FROM AUTHOR]

Background: Arterial stiffness may play a role in the development of dementia, presumably through its effects on white matter integrity and hyperintensities (WMH). However, relationships among arterial stiffness, white matter microstructure, and WMH volumes remain poorly understood. Arterial stiffness increases monotonically with age and its increase is accelerated by cardiometabolic disorders (e.g., hypertension , metabolic syndrome, diabetes). Further exploration of these relationships is key to the development of targeted therapies, early management, and detection. Method: Arterial stiffness was measured using carotid‐femoral pulse wave velocity (cfPWV) in ADRC participants with baseline systolic blood pressure (SBP) measurements, detailed cognitive testing, cognitive adjudication, and brain MRI. We examined associations of cfPWV and SBP with cognitive function (Montreal Cognitive Assessment [MoCA], Preclinical Alzheimer's Cognitive Composite [PACC5], and domain measures of memory and executive function) and brain MRI measures of: macrostructure (volume of gray matter [GM] and WMH from T1‐weighted and FLAIR imaging), white matter microstructure (neurite orientation dispersion and density imaging [NODDI] free water [FW] and diffusion tensor imaging [DTI] fractional anisotropy [FA]), and cerebral blood flow (CBF) in white matter (WM) and GM. Age, race, gender, education, and APOE‐4 status were included as covariates and in interaction terms in linear regression analyses. Result: Among 458 participants with a mean age 70±8 years and cognitive adjudication (44 dementia, 157 MCI, 257 normal cognition; Table 1), higher cfPWV was associated with worse cognitive performance (MoCA, PACC5), as was SBP (MoCA, PACC5, executive domain, language domain; Table 2). Higher cfPWV was associated with differences in WM microstructure (higher FW, lower FA) and higher WMH volume. While no overall associations between cfPWV and CBF were detected, cfPWV had stronger associations with FW, FA, and WMH in men. Higher SBP was associated with higher FW, higher WMH volume, and lower WM and GM CBF (Table 3). SBP had stronger associations with WMH in younger participants (<70y) and GM CBF in Black/AA participants and participants with impaired fasting glucose. No other interactions were detected. Conclusions: Arterial stiffness is associated with microstructural and macrostructural differences and poorer global and executive cognitive function. [ABSTRACT FROM AUTHOR]

Introduction: Sleep and diet are modifiable risk factors for Alzheimer's disease (AD) that may be salient areas for the development of preventive intervention strategies against dementia in people with mild cognitive impairment (MCI). Sleep disturbances account for up to 15% of the population attributable risk for AD. Diet influences sleep quality, such that diets high in sugars, fat, and processed food affect sleep quality and cognition in older adults. The combination of poor sleep and diet health may increase risk for dementia in people with MCI, yet it is unknown how intervening on diet may influence sleep health. Methods: TheMCI Sleep Study assesses longitudinal changes in objective and subjective measures of sleep between two investigational diet groups in the Brain Energy for Amyloid Transformation in Alzheimer's Disease study: the modified Mediterranean ketogenic diet (MMKD) and the American Heart Association diet. Objective sleep assessments include an in-home sleep study using theWatchPAT Central Plus (Itamar Medical, Ltd) at baseline and the end of the 4-month diet intervention. Subjective sleep questionnaires include the Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index. TheMCI Sleep Study outcome measures include longitudinal change in cognitive performance, mood, behavior, and quality of life. Results: Study recruitment is currently ongoing. We hypothesize the low-carbMMKD diet to have a beneficial impact on sleep health in individuals with MCI. Pre- and postdiet changes in sleep metrics across diet groups will be examined using mixed effects analysis of variance models. Discussion: Early assessment of chronic sleep and diet behaviorsmay be vital in understanding when interventions are necessary and the lifestyle modifications that should accompany future AD prevention and therapy recommendations. [ABSTRACT FROM AUTHOR]