Phase III Randomized, Placebo-Controlled Clinical Trial of Donepezil for Treatment of Cognitive Impairment in Breast Cancer Survivors After Adjuvant Chemotherapy (WF-97116).

PURPOSE: To test efficacy of donepezil, a cognitive enhancer, to improve memory in breast cancer survivors who report cancer-related cognitive impairment 1-5 years postchemotherapy. PATIENTS AND METHODS: Adult female BCS exposed to ≥4 cycles of adjuvant chemotherapy 1-5 years before enrollment who reported cancer-related cognitive impairment were eligible. Participants, enrolled at sites affiliated with the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base, were randomly assigned to receive 5 mg of donepezil once daily for 6 weeks titrated to 10 mg once daily for 18 weeks or placebo. Cognition and self-report cognitive functioning was assessed at baseline, 12, 24 (end of intervention), and 36 (washout) weeks postrandomization. Mixed-effects repeated measures analysis of covariance models were used to assess treatment differences in immediate recall (primary outcome) on the Hopkins Verbal Learning Test-Revised (HVLT-R) and other cognitive domains (secondary outcomes) with covariates of treatment, time, time by treatment interaction, baseline outcome level, age stratification, and an unstructured covariance matrix to account for within participant correlation over time. RESULTS: Two hundred seventy-six BCS from 87 NCORP practices (mean age, 57.1, standard deviation [SD], 10.5) who were at a mean of 29.6 months (SD, 14.2) postchemotherapy were randomly assigned to donepezil (n = 140) or placebo (n = 136). At 24 weeks, treatment groups did not differ on HVLT-R scores (donepezil mean = 25.98, placebo = 26.50, P = .32). There were no statistically significant differences between treatments at 12, 24, or 36 weeks for attention, executive function, verbal fluency, processing speed, or self-reported cognitive functioning. Endocrine therapy and menopausal status did not affect results. CONCLUSION: BCS 1-5 years after completing chemotherapy with documented memory problems, randomly assigned to 24 weeks of 5-10 mg of donepezil once daily, did not perform differently at the end of treatment on tests of memory, other cognitive functions, or subjective functioning than those randomly assigned to placebo.

Study protocol for measuring stigmatization in persistent tic disorders: development and validation of the Tourette discrimination-stigmatization scale.

Introduction: Persistent Tic Disorders such as Tourette Syndrome are common neurodevelopmental disorders that are highly stigmatized. Many individuals with Persistent Tic Disorders experience peer rejection, loneliness, and self-stigma. Experiencing stigmatization during childhood can influence the persistence of moderate-to-severe tics later in life. Additionally, these factors have been associated with increased suicidal ideation, suicide attempts, and psychiatric symptom severity. There is a need for interventions to reduce stigma and stigmatization in Persistent Tic Disorders. Before developing cost-effective interventions to mitigate stigma's profound downstream health impacts, a reliable measure of stigmatization must be created. The overarching goal of this research is to develop and validate the Tourette Discrimination-Stigmatization (TD-STIGMA) Scale. Methods: This paper presents the study protocol for developing and validating the TD-STIGMA Scale. The study is designed as a mixed methods study to develop the TD-STIGMA scale and evaluate its psychometric properties. The study uses a phased approach: (1) collection of narrative and thematic content data through in-depth qualitative interviews of stakeholders, (2) development of a novel TD-STIGMA self-report scale using the Delphi Method based on these results, and (3) completion of analyses to determine the scale's psychometric properties (confirmatory factor analysis, convergent, known-group, criterion validity, and test-retest reliability). Discussion: This project will result in a personalized approach to stigma measurement about youth and young adults with Persistent Tic Disorders, which to date does not exist. There are several limitations. Comorbidities or spiritual or cultural beliefs may affect perceptions of stigma and are not directly assessed in this study. We will utilize institutional resources for community outreach to purposefully sample underrepresented minorities who may be at disproportionate risk of adverse outcomes. However, this may not be fully representative of the generalized tic population. The study team will be purposeful in maintaining participant engagement for study retention. Lastly, participants from a tertiary referral center may not fully represent the generalized tic community. However, we hope our broad recruitment strategy and virtual study visits will facilitate a diverse and inclusive sampling of the patient population.

20-year depressive symptoms, dementia, and structural neuropathology in older women.

INTRODUCTION: The course of depressive symptoms and dementia risk is unclear, as are potential structural neuropathological common causes. METHODS: Utilizing joint latent class mixture models, we identified longitudinal trajectories of annually assessed depressive symptoms and dementia risk over 21 years in 957 older women (baseline age 72.7 years old) from the Women's Health Initiative Memory Study. In a subsample of 569 women who underwent structural magnetic resonance imaging, we examined whether estimates of cerebrovascular disease and Alzheimer's disease (AD)-related neurodegeneration were associated with identified trajectories. RESULTS: Five trajectories of depressive symptoms and dementia risk were identified. Compared to women with minimal symptoms, women who reported mild and stable and emerging depressive symptoms were at the highest risk of developing dementia and had more cerebrovascular disease and AD-related neurodegeneration. DISCUSSION: There are heterogeneous profiles of depressive symptoms and dementia risk. Common neuropathological factors may contribute to both depression and dementia. Highlights The progression of depressive symptoms and concurrent dementia risk is heterogeneous. Emerging depressive symptoms may be a prodromal symptom of dementia. Cerebrovascular disease and AD are potentially shared neuropathological factors.

Plasma oxysterols are associated with serum lipids and dementia risk in older women.

INTRODUCTION: Apolipoprotein E4 (APOE4) carriers' tendency toward hypercholesterolemia may contribute to Alzheimer's disease (AD) risk through oxysterols, which traverse the blood-brain barrier. METHODS: Relationships between baseline plasma oxysterols, APOE status, serum lipids, and cognitive impairment risk were examined in 328 postmenopausal women from the Women's Health Initiative Memory Study. Women were followed for 25 years or until incident dementia or cognitive impairment. RESULTS: Levels of 24(S)-hydroxycholesterol (24-OHC), 27-hydroxycholesterol (27-OHC), and 24-OHC/27-OHC ratio did not differ by APOE status (p's > 0.05). Higher 24-OHC and 27-OHC were associated with higher total, low density lipoprotein (LDL), non-high density lipoprotein (HDL), remnant, LDL/HDL, and total/HDL cholesterol and triglycerides (p's < 0.05). Higher 24-OHC/27-OHC was associated with greater dementia risk (hazard ratio = 1.51, 95% confidence interval:1.02-2.22), which interaction analyses revealed as significant for APOE3 and APOE4+, but not APOE2+ carriers. DISCUSSION: Less favorable lipid profiles were associated with higher oxysterol levels. A higher ratio of 24-OHC/27-OHC may contribute to dementia risk in APOE3 and APOE4+ carriers.

Subclinical vascular composites predict clinical cardiovascular disease, stroke, and dementia: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Subclinical cardiovascular disease (CVD) measures may reflect biological pathways that contribute to increased risk for coronary heart disease (CHD) events, stroke, and dementia beyond conventional risk scores. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) followed 6814 participants (45-84 years of age) from baseline in 2000-2002 to 2018 over 6 clinical examinations and annual follow-up interviews. MESA baseline subclinical CVD procedures included: seated and supineblood pressure, coronary calcium scan, radial artery tonometry, and carotid ultrasound. Baseline subclinical CVD measures were transformed into z-scores before factor analysis to derive composite factor scores. Time to clinical event for all-cause CVD, CHD, stroke and ICD code-based dementia events were modeled using Cox proportional hazards models reported as area under the curve (AUC) with 95% Confidence Intervals (95%CI) at 10 and 15 years of follow-up. All models included all factor scores together, and adjustment for conventional risk scores for global CVD, stroke, and dementia. RESULTS: After factor selection, 24 subclinical measures aggregated into four distinct factors representing: blood pressure, atherosclerosis, arteriosclerosis, and cardiac factors. Each factor significantly predicted time to CVD events and dementia at 10 and 15 years independent of each other and conventional risk scores. Subclinical vascular composites of atherosclerosis and arteriosclerosis best predicted time to clinical events of CVD, CHD, stroke, and dementia. These results were consistent across sex and racial and ethnic groups. CONCLUSIONS: Subclinical vascular composites of atherosclerosis and arteriosclerosis may be useful biomarkers to inform the vascular pathways contributing to events of CVD, CHD, stroke, and dementia.

Retinal vessel caliber and cognitive performance: the multi-ethnic study of atherosclerosis (MESA).

Retinal vessel calibers share anatomic and physiologic characteristics with the cerebral vasculature and can be visualized noninvasively. In light of the known microvascular contributions to brain health and cognitive function, we aimed to determine if, in a community based-study, retinal vessel calibers and change in caliber over 8 years are associated with cognitive function or trajectory. Participants in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort who completed cognitive testing at Exam 5 (2010-2012) and had retinal vascular caliber measurements (Central Retinal Artery and Vein Equivalents; CRAE and CRVE) at Exam 2 (2002-2004) and Exam 5 were included. Using multivariable linear regression, we evaluated the association of CRAE and CRVE from Exam 2 and Exam 5 and their change between the two exams with scores on tests of global cognitive function (Cognitive Abilities Screening Instrument; CASI), processing speed (Digit Symbol Coding; DSC) and working memory (Digit Span; DS) at Exam 5 and with subsequent change in cognitive scores between Exam 5 and Exam 6 (2016-2018).The main effects are reported as the difference in cognitive test score per SD increment in retinal vascular caliber with 95% confidence intervals (CI). A total of 4334 participants (aged 61.6 ± 9.2 years; 53% female; 41% White) completed cognitive testing and at least one retinal assessment. On multivariable analysis, a 1 SD larger CRAE at exam 5 was associated with a lower concomitant CASI score (- 0.24, 95% CI - 0.46, - 0.02). A 1 SD larger CRVE at exam 2 was associated with a lower subsequent CASI score (- 0.23, 95%CI - 0.45, - 0.01). A 1 SD larger CRVE at exam 2 or 5 was associated with a lower DSC score [(- 0.56, 95% CI - 1.02, - 0.09) and - 0.55 (95% CI - 1.03, - 0.07) respectively]. The magnitude of the associations was relatively small (2.8-3.1% of SD). No significant associations were found between retinal vessel calibers at Exam 2 and 5 with the subsequent score trajectory of cognitive tests performance over an average of 6 years. Wider retinal venular caliber was associated with concomitant and future measures of slower processing speed but not with later cognitive trajectory. Future studies should evaluate the utility of these measures in risk stratification models from a clinical perspective as well as for screening on a population level.

Feasibility of Remote Administration of the Uniform Data Set-Version 3 for Assessment of Older Adults With Mild Cognitive Impairment and Alzheimer's Disease.

OBJECTIVE: Assess the feasibility and concurrent validity of a modified Uniform Data Set version 3 (UDSv3) for remote administration for individuals with normal cognition (NC), mild cognitive impairment (MCI), and early dementia. METHOD: Participants (N = 93) (age: 72.8 [8.9] years; education: 15.6 [2.5] years; 72% female; 84% White) were enrolled from the Wake Forest ADRC. Portions of the UDSv3 cognitive battery, plus the Rey Auditory Verbal Learning Test, were completed by telephone or video within ~6 months of participant's in-person visit. Adaptations for phone administration (e.g., Oral Trails for Trail Making Test [TMT] and Blind Montreal Cognitive Assessment [MoCA] for MoCA) were made. Participants reported on the pleasantness, difficulty, and preference for each modality. Staff provided validity ratings for assessments. Participants' remote data were adjudicated by cognitive experts blinded to the in person-diagnosis (NC [N = 44], MCI [N = 35], Dementia [N = 11], or other [N = 3]). RESULTS: Remote assessments were rated as pleasant as in-person assessments by 74% of participants and equally difficult by 75%. Staff validity rating (video = 92%; phone = 87.5%) was good. Concordance between remote/in-person scores was generally moderate to good (r = .3 -.8; p < .05) except for TMT-A/OTMT-A (r = .3; p > .05). Agreement between remote/in-person adjudicated cognitive status was good (k = .61-.64). CONCLUSIONS: We found preliminary evidence that older adults, including those with cognitive impairment, can be assessed remotely using a modified UDSv3 research battery. Adjudication of cognitive status that relies on remotely collected data is comparable to classifications using in-person assessments.

Association of fractal dimension and other retinal vascular network parameters with cognitive performance and neuroimaging biomarkers: The Multi-Ethnic Study of Atherosclerosis (MESA).

INTRODUCTION: Retinal vascular network changes may reflect the integrity of the cerebral microcirculation, and may be associated with cognitive impairment. METHODS: Associations of retinal vascular measures with cognitive function and MRI biomarkers were examined amongst Multi-Ethnic Study of Atherosclerosis (MESA) participants in North Carolina who had gradable retinal photographs at Exams 2 (2002 to 2004, n = 313) and 5 (2010 to 2012, n = 306), and detailed cognitive testing and MRI at Exam 6 (2016 to 2018). RESULTS: After adjustment for covariates and multiple comparisons, greater arteriolar fractal dimension (FD) at Exam 2 was associated with less isotropic free water of gray matter regions (ß = -0.0005, SE = 0.0024, p = 0.01) at Exam 6, while greater arteriolar FD at Exam 5 was associated with greater gray matter cortical volume (in mm3 , ß = 5458, SE = 20.17, p = 0.04) at Exam 6. CONCLUSION: Greater arteriolar FD, reflecting greater complexity of the branching pattern of the retinal arteries, is associated with MRI biomarkers indicative of less neuroinflammation and neurodegeneration.

Alzheimer's Related Neurodegeneration Mediates Air Pollution Effects on Medial Temporal Lobe Atrophy.

Exposure to ambient air pollution, especially particulate matter with aerodynamic diameter <2.5 µm (PM2.5) and nitrogen dioxide (NO2), are environmental risk factors for Alzheimer's disease and related dementia. The medial temporal lobe (MTL) is an important brain region subserving episodic memory that atrophies with age, during the Alzheimer's disease continuum, and is vulnerable to the effects of cerebrovascular disease. Despite the importance of air pollution it is unclear whether exposure leads to atrophy of the MTL and by what pathways. Here we conducted a longitudinal study examining associations between ambient air pollution exposure and MTL atrophy and whether putative air pollution exposure effects resembled Alzheimer's disease-related neurodegeneration or cerebrovascular disease-related neurodegeneration. Participants included older women (n = 627; aged 71-87) who underwent two structural brain MRI scans (MRI-1: 2005-6; MRI-2: 2009-10) as part of the Women's Health Initiative Memory Study of Magnetic Resonance Imaging. Regionalized universal kriging was used to estimate annual concentrations of PM2.5 and NO2 at residential locations aggregated to 3-year averages prior to MRI-1. The outcome was 5-year standardized change in MTL volumes. Mediators included voxel-based MRI measures of the spatial pattern of neurodegeneration of Alzheimer's disease (Alzheimer's disease pattern similarity scores [AD-PS]) and whole-brain white matter small-vessel ischemic disease (WM-SVID) volume as a proxy of global cerebrovascular damage. Structural equation models were constructed to examine whether the associations between exposures with MTL atrophy were mediated by the initial level or concurrent change in AD-PS score or WM-SVID while adjusting for sociodemographic, lifestyle, clinical characteristics, and intracranial volume. Living in locations with higher PM2.5 (per interquartile range [IQR]=3.17µg/m3) or NO2 (per IQR=6.63ppb) was associated with greater MTL atrophy (ßPM2.5 = -0.29, 95% confidence interval [CI]=[-0.41,-0.18]; ßNO2 =-0.12, 95%CI=[-0.23,-0.02]). Greater PM2.5 was associated with larger increases in AD-PS (ßPM2.5 = 0.23, 95%CI=[0.12,0.33]) over time, which partially mediated associations with MTL atrophy (indirect effect= -0.10; 95%CI=[-0.15, -0.05]), explaining approximately 32% of the total effect. NO2 was positively associated with AD-PS at MRI-1 (ßNO2=0.13, 95%CI=[0.03,0.24]), which partially mediated the association with MTL atrophy (indirect effect= -0.01, 95% CI=[-0.03,-0.001]). Global WM-SVID at MRI-1 or concurrent change were not significant mediators between exposures and MTL atrophy. Findings support the mediating role of Alzheimer's disease-related neurodegeneration contributing to MTL atrophy associated with late-life exposures to air pollutants. Alzheimer's disease-related neurodegeneration only partially explained associations between exposure and MTL atrophy suggesting the role of multiple neuropathological processes underlying air pollution neurotoxicity on brain aging.

Association between late-life air pollution exposure and medial temporal lobe atrophy in older women.

Background: Ambient air pollution exposures increase risk for Alzheimer's disease (AD) and related dementias, possibly due to structural changes in the medial temporal lobe (MTL). However, existing MRI studies examining exposure effects on the MTL were cross-sectional and focused on the hippocampus, yielding mixed results. Method: To determine whether air pollution exposures were associated with MTL atrophy over time, we conducted a longitudinal study including 653 cognitively unimpaired community-dwelling older women from the Women's Health Initiative Memory Study with two MRI brain scans (MRI-1: 2005-6; MRI-2: 2009-10; Mage at MRI-1=77.3±3.5years). Using regionalized universal kriging models, exposures at residential locations were estimated as 3-year annual averages of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) prior to MRI-1. Bilateral gray matter volumes of the hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex (ERC) were summed to operationalize the MTL. We used linear regressions to estimate exposure effects on 5-year volume changes in the MTL and its subregions, adjusting for intracranial volume, sociodemographic, lifestyle, and clinical characteristics. Results: On average, MTL volume decreased by 0.53±1.00cm3 over 5 years. For each interquartile increase of PM2.5 (3.26µg/m3) and NO2 (6.77ppb), adjusted MTL volume had greater shrinkage by 0.32cm3 (95%CI=[-0.43, -0.21]) and 0.12cm3 (95%CI=[-0.22, -0.01]), respectively. The exposure effects did not differ by APOE ε4 genotype, sociodemographic, and cardiovascular risk factors, and remained among women with low-level PM2.5 exposure. Greater PHG atrophy was associated with higher PM2.5 (b=-0.24, 95%CI=[-0.29, -0.19]) and NO2 exposures (b=-0.09, 95%CI=[-0.14, -0.04]). Higher exposure to PM2.5 but not NO2 was also associated with greater ERC atrophy. Exposures were not associated with amygdala or hippocampal atrophy. Conclusion: In summary, higher late-life PM2.5 and NO2 exposures were associated with greater MTL atrophy over time in cognitively unimpaired older women. The PHG and ERC - the MTL cortical subregions where AD neuropathologies likely begin, may be preferentially vulnerable to air pollution neurotoxicity.

Reframing stigma in Tourette syndrome: an updated scoping review.

Persistent tic disorders (PTD) such as Tourette's syndrome (TS) are common childhood-onset neurodevelopmental disorders. Stigmatization of individuals with these disorders remains an ongoing problem. The purpose of this scoping review is to serve as an updated review of the research regarding stigmatization in youth with PTD since the publication of the original systematic review about this topic in 2016. The electronic databases Embase, Web of Science, PubMed, PsycINFO, and CINAHL were searched. Of the 4751 initial articles screened after removing duplications, 47 studies met the inclusion criteria. The studies were examined under the social-ecological stigmatization model, which helps categorize stigmatization into individual, interpersonal, community, and structural levels and serves as a broader definition of stigmatization than the previous systematic review. On the individual level, youth with PTD had lower self-esteem than peers, often leading to fear of future stigmatization, avoidant behaviors, and self-stigmatization. They also experienced higher rates of bullying and other forms of abuse than peers at the interpersonal level. At the community level, youth with PTD faced discriminatory environments in school and work and limited availability of community services and healthcare access. At the structural level, knowledge about PTD was limited in the general population, often about the limited portrayals of PTD in the media. We hope that the broader scope of this review serves to help inform future efforts to decrease the stigmatization faced by this group.

Changes in physical function in older women with endometrial cancer with or without adjuvant therapy.

OBJECTIVE: To evaluate changes in physical function (PF) for older women with endometrial cancer (EC) + / - adjuvant therapy in the Women's Health Initiative Life and Longevity after Cancer cohort. MATERIALS AND METHODS: This study examined women ≥ 70 years of age with EC with available treatment records. Change in PF was measured using the RAND-36 and compared between groups using Wilcoxon rank-sum tests. Multivariable median regression was used to compare the changes in scores while adjusting for confounding variables. RESULTS: Included in the study were 287 women, 150 (52.3%) women who did not receive adjuvant therapy and 137 (47.7%) who received adjuvant therapy. When comparing PF scores, there was a statistically significant difference in the median percent change in functional decline, with a greater decline in those who received adjuvant therapy (- 5.9% [- 23.5 to 0%]) compared to those who did not (0 [- 18.8 to + 6.7%]), p = 0.02). Results were not statistically significant after multivariable adjustment, but women who underwent chemotherapy had a greater percent change (median ∆ - 13.8% [- 35.5 to 0%]) compared to those who received radiation alone (median ∆ - 5.9% [- 31.3 to 0%]) or chemotherapy and radiation (median ∆ - 6.5% [- 25.8 to + 5.7%]. CONCLUSIONS: Older women with EC who received adjuvant therapy experienced greater change in PF than those who did not receive adjuvant therapy, particularly women who received chemotherapy. These results were not statistically significant on multivariate analysis. IMPLICATIONS FOR CANCER SURVIVORS: EC survivors may experience changes in PF because of chemotherapy and/or radiation therapy. Additional supportive care may need to be provided to older women to mitigate functional decline.

Visit-to-Visit Glucose Variability, Cognition, and Global Cognitive Decline: The Multi-Ethnic Study of Atherosclerosis.

CONTEXT: Higher visit-to-visit glucose variability (GV) is associated with dysglycemia and type 2 diabetes (T2D), key risk factors for cognitive decline. OBJECTIVE: Evaluate the association of GV with cognitive performance and decline in racially/ethnically diverse older populations with and without T2D. METHODS: We calculated the standard deviation of glucose (SDG), average real variability (ARV), and variability independent of the mean (VIM) among 4367 Multi-Ethnic Study of Atherosclerosis participants over 6 clinical examinations. Participants completed a cognitive assessment at the fifth examination, and a subset completed a second assessment 6 years later. We used multivariable linear regression to estimate the association of intraindividual GV with cognitive test scores after adjustments for cardiovascular risk factors and mean glucose level over the study period. RESULTS: Two-fold increments in the VIM and SDG were associated with worse Cognitive Abilities Screening Instrument (CASI) performance, while two-fold increments in VIM and ARV were associated with worse Digit Symbol Coding test score. GV measures were not associated with change in CASI performance among 1834 participants with repeat CASI data 6 years later. However, among 229 participants with incident T2D, the SDG and VIM were associated with decline in CASI (-1.7 [95% CI: -3.1, -0.3] and -2.1 [-3.7, -0.5] points, respectively). In contrast, single-timepoint glucose and HbA1c were not associated with CASI decline among participants with or without incident T2D. CONCLUSION: Higher visit-to-visit GV over 16 to 18 years is associated with worse cognitive performance in the general population, and with modest global cognitive decline in participants with T2D.

Associations of dietary cholesterol and fat, blood lipids, and risk for dementia in older women vary by APOE genotype.

INTRODUCTION: Whether apolipoprotein E's (APOE's) involvement in lipid metabolism contributes to Alzheimer's disease (AD) risk remains unknown. METHODS: Incident probable dementia and cognitive impairment (probable dementia+mild cognitive impairment) were analyzed in relation to baseline serum lipids (total, low-density lipoprotein [LDL], high-density lipoprotein [HDL], non-HDL cholesterol, total-to-HDL, LDL-to-HDL, remnant cholesterol, and triglycerides) using Mendelian randomization in 5358 postmenopausal women from the Women's Health Initiative Memory Study. We also examined associations of baseline dietary cholesterol and fat with lipids based on APOE status. RESULTS: After an average of 11.13 years, less favorable lipid levels related to greater dementia and cognitive impairment risk. Dementia (odds ratio [OR] = 3.13; 95% confidence interval [CI]: 2.31 to 4.24) and cognitive impairment (OR = 2.38; 95% CI: 1.85 to 3.06) risk were greatest in relation to higher remnant cholesterol levels. Greater cholesterol consumption related to poorer lipids in APOE4+ compared to APOE3 carriers. DISCUSSION: APOE4+ carriers consuming more cholesterol had less favorable lipids, which were associated with greater dementia and cognitive impairment risk. HIGHLIGHTS: Less favorable serum lipids were associated with higher dementia incidence. Mendelian randomization findings suggest causality between lipids and dementia. Lipid levels in older women may be clinical indicators of dementia risk. APOE4 carriers had poorest lipid profiles in relation to cholesterol consumption. APOE risk for dementia may be modifiable through lipid management.

Subclinical Vascular Composites Predict Clinical Cardiovascular Disease, Stroke, and Dementia: The Multi-Ethnic Study of Atherosclerosis (MESA).

Background: Subclinical cardiovascular disease (CVD) measures may reflect biological pathways that contribute to increased risk for coronary heart disease (CHD) events, stroke, and dementia beyond conventional risk scores. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) followed 6,814 participants (45-84 years of age) from baseline in 2000-2002 to 2018 over 6 clinical examinations and annual follow-up interviews. MESA baseline subclinical CVD procedures included: seated and supine blood pressure, coronary calcium scan, radial artery tonometry, and carotid ultrasound. Baseline subclinical CVD measures were transformed into z-scores before factor analysis to derive composite factor scores. Time to clinical event for all CVD, CHD, stroke and ICD code-based dementia events were modeled using Cox proportional hazards models reported as area under the curve (AUC) with 95% Confidence Intervals (95%CI) at 10 and 15 years of follow-up. All models included all factor scores together and adjustment for conventional risk scores for global CVD, stroke, and dementia. Results: After factor selection, 24 subclinical measures aggregated into four distinct factors representing: blood pressure, arteriosclerosis, atherosclerosis, and cardiac factors. Each factor significantly predicted time to CVD events and dementia at 10 and 15 years independent of each other and conventional risk scores. Subclinical vascular composites of arteriosclerosis and atherosclerosis best predicted time to clinical events of CVD, CHD, stroke, and dementia. These results were consistent across sex and racial and ethnic groups. Conclusions: Subclinical vascular composites of arteriosclerosis and atherosclerosis may be useful biomarkers to inform the vascular pathways contributing to events of CVD, CHD, stroke, and dementia.

Impact of multivitamin-mineral and cocoa extract on incidence of mild cognitive impairment and dementia: Results from the COcoa Supplement and Multivitamin Outcomes Study for the Mind (COSMOS-Mind).

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.

Self-reported experiences of discrimination and incident dementia.

INTRODUCTION: Discrimination negatively impacts health and may contribute to racial/ethnic disparities in dementia risk. METHODS: Experiences of lifetime and everyday discrimination were assessed among 6509 Multi-Ethnic Study of Atherosclerosis (MESA) participants. We assessed the association of discrimination with incidence of dementia including adjustment for important risk factors, cohort attrition, and we assessed for effect modification by race/ethnicity. RESULTS: Prevalence of any lifetime discrimination in MESA was 42%, highest among Black adults (72%). Over a median 15.7 years of follow-up, there were 466 incident cases of dementia. Lifetime discrimination, but not everyday discrimination, was associated with incident dementia (Wald p = 0.03). Individuals reporting lifetime discrimination in ≥2 domains (compared to none) had greater risk for dementia (hazard ratio: 1.40; 95%: 1.08, 1.82) after adjustment for sociodemographic, clinical, and behavioral risk factors. Associations did not differ by race/ethnicity. CONCLUSIONS: These findings demonstrate an association of greater experiences of lifetime discrimination with incident dementia.

Plasma proteins related to inflammatory diet predict future cognitive impairment.

Dysregulation of the immune system and dietary patterns that increase inflammation can increase the risk for cognitive decline, but the mechanisms by which inflammatory nutritional habits may affect the development of cognitive impairment in aging are not well understood. To determine whether plasma proteins linked to inflammatory diet predict future cognitive impairment, we applied high-throughput proteomic assays to plasma samples from a subset (n = 1528) of Women's Health Initiative Memory Study (WHIMS) participants (mean [SD] baseline age, 71.3 [SD 3.8] years). Results provide insights into how inflammatory nutritional patterns are associated with an immune-related proteome and identify a group of proteins (CXCL10, CCL3, HGF, OPG, CDCP1, NFATC3, ITGA11) related to future cognitive impairment over a 14-year follow-up period. Several of these inflammatory diet proteins were also associated with dementia risk across two external cohorts (ARIC, ESTHER), correlated with plasma biomarkers of Alzheimer's disease (AD) pathology (Aß42/40) and/or neurodegeneration (NfL), and related to an MRI-defined index of neurodegenerative brain atrophy in a separate cohort (BLSA). In addition to evaluating their biological relevance, assessing their potential role in AD, and characterizing their immune-tissue/cell-specific expression, we leveraged published RNA-seq results to examine how the in vitro regulation of genes encoding these candidate proteins might be altered in response to an immune challenge. Our findings indicate how dietary patterns with higher inflammatory potential relate to plasma levels of immunologically relevant proteins and highlight the molecular mediators which predict subsequent risk for age-related cognitive impairment.

An Association Between Large Optic Cupping and Total and Regional Brain Volume: The Women's Health Initiative.

PURPOSE: To investigate the relationships between optic nerve cupping and total and regional brain volumes. DESIGN: Secondary analysis of randomized clinical trial data. METHODS: Women 65 to 79 years of age without glaucoma with cup-to-disc ratio (CDR) measurements from the Women's Health Initiative (WHI) Sight Examination study and magnetic resonance imaging (MRI)-based total and regional brain volumes from the WHI Memory Study MRI-1 were included. Large CDR was defined as 0.6 or greater in either eye. Generalized estimating equation models were used to account for intra-brain correlations between the right and left sides. The final analysis was adjusted for demographic and clinical characteristics and for total brain volume (for regional analyses). RESULTS: Final analyses included 471 women, with the mean age ± SD was 69.2 ± 3.6 years; 92.8% of the subjects were white. Of 471 women, 34 (7.2%) had large CDR. Controlling for total brain volume and for demographic and clinical characteristics, lateral ventricle volume was 3.01 cc larger for subjects with large CDR compared to those without large CDR (95% CI = 0.02 to 5.99; P = .048). Furthermore, frontal lobe volume was 4.78 cc lower for subjects with large CDR compared to those without (95% CI = -8.71, -0.84; P = 0.02), and occipital lobe volume was 1.86 cc lower for those with large CDR compared to those without (95% CI = -3.39, -0.3; P =.02). CONCLUSIONS: Our analysis suggests that in women aged 65 years or more, large CDR is associated with lower relative total brain volume and absolute regional volume in the frontal and occipital lobes. Enlarged CDR in individuals without glaucoma may represent a sign of optic nerve and brain aging, although more longitudinal data are needed.