Whitney Wharton

Neuroprotective properties of estrogen have poorly translated to reduced neurodegeneration in clinical trials of systemic estrogen replacement therapy. To

Objective: Examine the association between types of childhood maltreatment and surrogate markers of vascular function, and to test whether sex modifies these relationships. Methods: Childhood maltreatment and indices of vascular function were assessed in a cohort of healthy Black adults without known CVD (n=404). Maltreatment (physical, sexual, emotional, and general trauma) domains were assessed using the Early Trauma Inventory Short Form. A trauma severity index score was calculated by summing the indexes for each domain. Outcomes of central augmentation index (cAIx) corrected for a heart rate of 75 bpm, and carotid femoral pulse wave velocity were measured as indices of wave reflections and arterial stiffness, respectively, and central pulse pressure (CPP). Associations between each domain and outcomes were assessed using multivariate-adjusted (demographics, clinical, health behaviors, and depressive symptoms) and sex-stratified linear regression models. Results: The cohort had a mean age of 53±10.3 years, and 61% were women. After adjustments, emotional abuse (2.68 [95% CI: −4.78, −0.58, P =.013]) and physical abuse (−2.38 [−4.26, −0.50, P =<.001]) were associated with cAIx in the overall cohort. Significant sex interactions were identified for emotional ( P= .009) and physical abuse ( P= .001) with cAIx and for emotional abuse with CPP ( P =.021). Among women, physical abuse was associated with a higher cAIx (2.22 [95% CI: 0.70, 3.73, P =.004]), and among men, a lower cAIx (−2.59 [95% CI: −4.98, −0.19, P =.035]). Emotional abuse was also associated with higher CPP measures among women (1.31 [95% CI: 0.15, 2.46, P =.027]) with no associations identified in men. Conclusions: Physical and emotional abuse was associated with higher cAIx and CPP in women, but not men, suggesting sex-specific effects of early trauma on vascular function.

Summary: Neuroprotective properties of estrogen have poorly translated to reduced neurodegeneration in clinical trials of systemic estrogen replacement therapy. To more directly assess biological processes associated with brain estrogen (estrone, estradiol) levels, we recruited 81 women (42 non-white) and 28 men (13 non-white) for cerebrospinal fluid (CSF) proteomic and volumetric brain analysis. In these mostly post-menopausal women, we found low CSF estrogen levels to only modest correlate with their corresponding plasma levels. Aptamer-based proteomic analysis of CSF markers for inflammation, proteolysis, and DNA/RNA regulation revealed higher CSF estrogen to associate with changes involved in recruitment or activation of neutrophils, monocytes, and complement-related proteins in a race-dependent fashion. Parallel MRI analysis correlated higher CSF estrogen with smaller volumes of the brain somatosensory and posterior-medial networks without influence from cognition or neurodegeneration. These outcomes were only partially associated with plasma estrogens, reinforcing the need for improved CSF estrogen analysis to elucidate brain-specific effects.

Background: More than 6 million people in the U.S. are currently living with Alzheimer’s disease and related dementias (ADRD), and informal caregivers provide them with more than $270 billion annually in unpaid care. Few studies on ADRD caregiving have engaged caregivers from diverse sexual and gender minorities (SGM), or lesbian, gay, bisexual, transgender, queer, intersex, asexual, and/or another identity.Methods: This study explores ways to engage and recruit diverse SGM ADRD caregivers into ADRD and aging‐related clinical research. We conducted focus groups and individual interviews with 25 SGM adults who were current, past, or prospective ADRD caregivers. Interviews explored barriers and facilitators to research participation, innovative recruitment strategies, SGM‐specific caregiver needs, and awareness of diverse types of aging and ADRD‐related research. We used thematic analysis to identify key themes.Results: Caregivers’ ages ranged from 18‐78 years. In terms of race/ethnicity, 48% identified as White, 48% African American, 4% American Indian or Alaska Native, and 10% Hispanic/Latino. For relationships to their care recipients, most reported caring for a parent (47%), followed by a friend (18%), partner/spouse (12%), other relative (12%), or another relationship (11%). The majority provided care for more than a year (52%), followed by 17% providing care for less than a year and 30% expecting to provide care within the next year. We identified five initial themes around recruitment and engagement of SGM ADRD caregivers into research: (1) ensuring inclusion of those from diverse racial/ethnic backgrounds, (2) developing trust through relationship building, (3) safety and privacy measures necessary for SGM identity disclosure, (4) novel recruitment and engagement efforts (media, arts, entertainment), and (5) emphasizing how participating in research supports SGM progress toward equity.Conclusions: We identified novel ways to recruit and engage diverse SGM ADRD caregivers into research. Future research should explore and test strategies to engage and enhance inclusion of racially/ethnically diverse SGM ADRD caregivers in ADRD research. There is also a need for additional novel strategies to effectively recruit and engage diverse SGM ADRD into research and identify solutions for addressing their health challenges and caregiving needs.

INTRODUCTION: There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high‐risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle‐aged Black/African American (B/AA) and non‐Hispanic White (NHW) participants.METHODS: Adults (45–65 years) with a parental history of AD were enrolled (n = 82). CSF and blood biomarkers were collected at baseline and year 2.RESULTS: CSF total tau (t‐tau), phosphorylated tau (p‐tau), and amyloid beta (Aβ)40 were elevated at year 2 compared to baseline. CSF soluble platelet‐derived growth factor receptor β (sPDGFRβ) levels, a marker of pericyte injury, correlated positively with t‐tau, p‐tau, Aβ40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRβ and tau were significantly lower in B/AA than NHW.DISCUSSION: Vascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race‐related differences in these relationships.Highlights: Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high‐risk middle‐aged adults. Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau. AD biomarkers were lower in Black compared to non‐Hispanic White individuals. Markers of vascular dysfunction were lower among Black individuals.

Nearly 350,000 lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ+) adults in the U.S. are currently living with Alzheimer’s disease and related dementias (ADRD). Informal caregivers face challenges impacting their ability to access and receive adequate and inclusive care for LGBTQ+ persons living with ADRD. The purpose of this study was to determine the feasibility and acceptability of the Savvy Caregiver Program for caregivers of LGBTQ+ individuals living with ADRD. Data for this secondary analysis come from caregivers (n = 17) who completed 6 sessions of the Savvy program. Caregivers were very satisfied with tailored program activities. Analyses of trends suggest non-significant increases in positive aspects of caregiving and decreases in caregiver burden and depressive symptoms. This is the first known study assessing the feasibility of the Savvy Caregiver Program for caregivers of LGBTQ+ individuals living with ADRD. Future research on the Savvy Caregiver Program for caregivers of LGBTQ+ people living with ADRD is needed.

S-equol, a metabolite of soy isoflavone daidzein transformed by the gut microbiome, is the most biologically potent among all soy isoflavones and their metabolites. Soy isoflavones are phytoestrogens and exert their actions through estrogen receptor-β. Epidemiological studies in East Asia, where soy isoflavones are regularly consumed, show that dietary isoflavone intake is inversely associated with cognitive decline and dementia; however, randomized controlled trials of soy isoflavones in Western countries did not generally show their cognitive benefit. The discrepant results may be attributed to S-equol production capability; after consuming soy isoflavones, 40–70% of East Asians produce S-equol, whereas 20–30% of Westerners do. Recent observational and clinical studies in Japan show that S-equol but not soy isoflavones is inversely associated with multiple vascular pathologies, contributing to cognitive impairment and dementia, including arterial stiffness and white matter lesion volume. S-equol has better permeability to the blood–brain barrier than soy isoflavones, although their affinity to estrogen receptor-β is similar. S-equol is also the most potent antioxidant among all known soy isoflavones. Although S-equol is available as a dietary supplement, no long-term trials in humans have examined the effect of S-equol supplementation on arterial stiffness, cerebrovascular disease, cognitive decline, or dementia.

Introduction: African Americans (AA)s have worse inflammation, worse sleep, and a greater incidence of Alzheimer's disease (AD) compared to whites; however, no studies have examined associations between biomarkers, sleep, and cognition, and differences by race. Methods: Seventy‐six cognitively normal, middle aged (45–65 years) adults with a parental history of AD were included in this study. Associations between biomarkers (tumor necrosis factor‐α [TNF‐α], interleukin‐10 [IL‐10], intercellular adhesion molecule‐1 [ICAM‐1],, and C‐reactive protein [CRP]) and self‐reported sleep or cognition measures, were assessed. Results: Average sleep duration was significantly lower for AA versus whites (average[SD]) in hours: 6.02(1.18) versus 7.23(0.91), P = .000004). We found a statistically significant association between plasma IL‐10 and sleep duration (Spearman's ρ = 0.26, P = .04) and CSF ICAM‐1 and sleep quality (Spearman's ρ = 0.30, P = .03). Discussion: Longer sleep duration is positively associated with plasma IL‐10 levels irrespective of race. Sleep quality was positively associated with CSF ICAM‐1 only in African Americans.

Individuals with Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) have increased gait disturbances throughout disease progression. However, an understanding of gait impairment and progression in early versus late AD is lacking. Further, the longitudinal progression of gait impairment in AD as well as in those with MCI that transition to AD is lacking. Understanding gait pathology and progression of gait impairment is critical for implementation of strategies that could limit the high prevalence of gait related falls, mobility disability and decreased overall function. Further, better understanding of the gait impairment progression may provide insight into disease processes. As such, this retrospective study aimed to evaluate, via cross sectional and longitudinal analyses, the relationship between MCI and AD diagnosis and gait parameters. Cross-sectional findings demonstrate significantly slower gait velocity and decreased step length as well as increased double limb support time and step length variability of both early and late AD when compared to MCI. For the longitudinal data the average time between gait assessment visits was 561 ± 267 days. The results demonstrate increasing gait impairment from intial gait assesement (visit 1) to a follow up gait assessment (visit 2) in both the early AD and late AD groups as well as significant decline in the gait profile from visit 1 to visit 2 in those with MCI that transitioned to having AD. These findings are important as they indicate an increasingly pathological gait profile among these populations suggesting need for early intervention.