Background: Women account for two thirds of the prevalence and incidence of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Evidence suggest that sex may differently influence the expression of proteins amyloid-beta (Aβ1-42) and tau, for which early detection is crucial in prevention of the disease. Objective: We investigated the effect of aging and cerebrospinal fluid (CSF) levels of Aβ1-42 and tau on frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) in a cohort of cognitively normal older women and women with MCI. Methods: 3T single-voxel MRS was performed on the medial frontal cortex, using Point Resolved Spectroscopy (PRESS) and Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) in 120 women (age range 50-85). CSF samples of Aβ1-42 and tau and scores of general cognition were also obtained. Results: Levels of frontal gamma aminobutyric acid (GABA+) were predicted by age, independently of disease and CSF biomarkers. Importantly, levels of GABA+ were reduced in MCI patients. Additionally, we found that levels of N-acetylaspartate relative to myo-inositol (tNAA/mI) predicted cognition in MCI patients only and were not related to CSF biomarkers. Conclusion: This study is the first to demonstrate a strong association between frontal GABA+ levels and neurological aging in a sample consisting exclusively of healthy older women with various levels of CSF tau and Aβ1-42 and women with MCI. Importantly, our results show no correlation between CSF biomarkers and MRS metabolites in this sample.

Elevated expression of β-amyloid (Aβ1-42) and tau are considered risk-factors for Alzheimer's disease in healthy older adults. We investigated the effect of aging and cerebrospinal fluid levels of Aβ1-42 and tau on 1) frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) and 2) cognition in cognitively normal older adults (n = 144; age range 50-85). Levels of frontal gamma aminobutyric acid (GABA+) and myo-inositol relative to creatine (mI/tCr) were predicted by age. Levels of GABA+ predicted cognitive performance better than mI/tCr. Additionally, we found that frontal levels of n-acetylaspartate relative to creatine (tNAA/tCr) were predicted by levels of t-tau. In cognitively normal older adults, levels of frontal GABA+ and mI/tCr are predicted by aging, with levels of GABA+ decreasing with age and the opposite for mI/tCr. These results suggest that age- and biomarker-related changes in brain metabolites are not only located in the posterior cortex as suggested by previous studies and further demonstrate that MRS is a viable tool in the study of aging and biomarkers associated with pathological aging and Alzheimer's disease.

The timing, amount, and quality of sleep are critical for an individual’s health and quality of life. This paper provides a focused narrative review of the existing literature around multidimensional environments and sleep health for aging adults. Five electronic databases, Scopus, Web of Science, PubMed/Medline; EBSCOhost, PsycINFO (ProQuest), and Google Scholar yielded 54,502 total records. After removing duplicates, non-peer reviewed academic articles, and nonrelevant articles, 70 were included for review. We were able to categorize environmental factors into housing security, home environment, and neighborhood environment, and, within each environmental category, specific elements/aspects are discussed. This paper provides a comprehensive map connecting identified levels of influence (individual, home/house, and neighborhood-level) in which subfactors are listed under each level of influence/category with the related literature list. Our review highlights that multidimensional environmental factors can affect aging adults’ sleep health and eventually their physical, mental, and cognitive health and that sleep disparities exist in racial minorities in socioeconomically disadvantaged communities in which cumulative environmental stressors coexist. Based on this focused narrative review on the multidimensional sleep environments for aging adults, knowledge gaps are identified, and future research directions are suggested.

The impact of prenatal alcohol exposure on memory and brain development was investigated in 92 African-American, young adults who were first identified in the prenatal period. Three groups (Control, n=26; Alcohol-related Neurodevelopmental Disorder, n=36; and Dysmorphic, n=30) were imaged using structural MRI with brain volume calculated for multiple regions of interest. Memory was measured using the Verbal Selective Reminding Memory Test and its nonverbal counterpart, the Nonverbal Selective Reminding Memory Test, which each yielding measures of learning and recall. For both Verbal and Nonverbal Recall and Slope, linear trends were observed demonstrating a spectrum of deficits associated with prenatal alcohol exposure. Dysmorphic individuals performed significantly poorer than unexposed controls on 5 of 6 memory outcomes. Alcohol-exposed individuals demonstrated significantly lower total brain volume than controls, as well as lower volume in a number of specific regions including hippocampus. Mediation analyses indicated that memory performance associated with effects of prenatal alcohol exposure was mediated from dysmorphic severity through hippocampal volume, particularly right hippocampus. These results indicate that the association between the physical effects of prenatal alcohol exposure and deficits in memory are mediated by volumetric reduction in specific brain regions.

Objective: To explore the heterogeneity of neuropsychiatric symptom (NPS) complexes in individuals with mild cognitive impairment (MCI) and assess the relative risks of converting to dementia or dying. Design: Latent class analysis using 7,971 participants with MCI. Setting: Participants in the Uniform Data Set (UDS) from 39 NIH Alzheimer's Disease Centers. Participants: Persons with a diagnosis of MCI at initial visit from each center and with either a Mini-Mental State Examination (MMSE) score of 22 or greater or an equivalent education-adjusted Montreal Cognitive Assessment (MoCA) score of 16 or greater. Measurements: Neuropsychiatric Inventory Questionnaire (NPI-Q) administered at initial visit. Results: In addition to a subgroup with mild or no NPS (relative frequency, 50%), three empirically-based subgroups of NPS were identified: 1) an “affect” or “negative mood” subgroup (27%) with depression, anxiety, apathy, nighttime disturbance, and change in appetite; 2) a “hyperactive” subgroup (14%) with agitation, irritability, and disinhibition; and 3) a “psychotic with additional severe NPS” subgroup (9%) with the highest risk of delusions and hallucinations, as well as highest risk of all other NPS. Each of these three subgroups had significantly higher risk of converting to dementia than the “mild NPS” class, with the “psychotic with additional severe NPS” subgroup possessing a 64% greater risk. The subgroups did not differ in their risks of death without dementia. Conclusion: Our findings of three NPS subgroups in MCI characterized by affect, hyperactive, or psychotic features are largely consistent with a previous 3-factor model of NPS found in a demented population. The consistency of these findings across studies and samples, coupled with our results on the associated risks of converting to dementia, suggests that the NPS structure is robust, and warrants further consideration in classification models of MCI.

Introduction: Early detection of cognitive decline in older adults is a public health priority. Advancing Reliable Measurement in Alzheimer's Disease and Cognitive Aging (ARMADA), a multisite study, is validating cognition, emotion, motor, and sensory modules of the National Institutes of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) in the aging spectrum from cognitively normal to dementia of the Alzheimer's type (DAT). Methods: Participants 65 to 85 years old, in demographic groups racially proportional to the general US population, are recruited in one of three groups to validate the NIHTB: cognitively normal, amnestic mild cognitive impairment (aMCI), or mild DAT. Additional special emphasis cohorts include (1) Blacks in the three clinical groups; (2) Spanish-speakers in the three clinical groups; (3) cognitively normal, population-proportional, over age 85. Discussion: Longitudinal study will determine whether NIHTB can predict cognitive decline and is associated with Alzheimer's disease biomarkers. Here, we detail the methods for the ARMADA study.

Importance: Differences in cerebrospinal fluid (CSF) tau Alzheimer dementia (AD) biomarkers by self-identified race have been observed in prior studies. More recently, plasma biomarkers have been gaining recognition, but whether they exhibit similar differences is unclear. Furthermore, the underlying explanation for these differences in AD biomarkers is still unexplored. Objectives: To investigate differences in plasma biomarkers by race and genetic ancestry and explore potential underlying explanations for these differences. Design, Setting, and Participants: This cross-sectional study used participant data from the Brain, Stress, Hypertension, and Aging Research Program (B-SHARP), an observational study conducted in the greater Atlanta metropolitan area. Participants were enrolled from March 1, 2016, to January 1, 2020. Main Outcomes and Measures: Main outcomes were plasma and CSF amyloid-β (Aβ) 42, Aβ40, phosphorylated tau181(p-tau181), and neurofilament light. General linear models were used for key comparisons. Exposures: Main independent variables were self-identified race and genetic ancestry. Additional variables were cardiovascular factors, APOE4, educational attainment, Area Deprivation Index, and C-reactive protein (reflecting systemic inflammation state). Results: This analysis included 617 participants (mean [SD] age, 66 [7.9] years; 300 [49%] African American and 317 [51%] White; 429 [70%] with mild cognitive impairment). On the basis of self-reported race, plasma levels of Aβ42 (adjusted mean difference, -1.20 pg/mL; 95% CI, -2.33 to -0.07 pg/mL), Aβ40 (adjusted mean difference, -37.78 pg/mL; 95% CI, -60.16 to -15.39 pg/mL), p-tau181(adjusted mean difference, -4.66 pg/mL; 95% CI, -7.05 to -1.90 pg/mL), and neurofilament light (adjusted mean difference, -1.58; 95% CI, -2.83 to -0.19 pg/mL) were consistently lower in African American individuals after adjusting for demographic characteristics, educational attainment, cognition, APOE4, and cardiovascular factors. A similar pattern was observed in the CSF biomarkers except for Aβ42 and Aβ40. Although unadjusted analyses revealed an association between these biomarkers and African ancestry, these associations were not significant after adjusting for the same covariates. Differences by self-reported race were not explained by varied cardiovascular risk factors, C-reactive protein, educational attainment, or Area Deprivation Index. Conclusions and Relevance: In this cross-sectional study of plasma biomarkers by race and genetic ancestry, the results indicated that plasma p-tau181, Aβ40, and NFL were lower in African American individuals based on self-reported race but not genetic ancestry. These differences were not explained by cardiovascular risks or clinical stage differences. These racial differences should be considered in clinical interpretations and clinical trial screenings to avoid an additional increase in underrepresentation of African American individuals in AD trials..

Objective: Advanced age poses an increased risk for cognitive impairment, and therefore, poor knowledge regarding the risks associated with COVID-19 may confer vulnerability. We administered a COVID-19 Knowledge Questionnaire to older persons to evaluate the association between knowledge regarding public health recommendations, and cognitive status as measured by the Montreal Cognitive Assessment (MoCA). Method: Ninety-nine participants completed a 22-item questionnaire about COVID-19 symptoms, risks, and protective strategies, and they also completed the MoCA. Associations between knowledge and cognitive status were examined via Spearman correlations. Results: The mean (SD) age of participants was 72.6 (7.6) years, and MoCA scores averaged 23.4 (4.5) points. Higher MoCA total scores were significantly (p <.001) correlated with a greater number of correct questionnaire responses. Higher Orientation and Memory Index scores were moderately associated with an increased number of correct responses (p <.001), with the Executive Index exhibiting a significant albeit weaker association. MoCA Index scores assessing attention, language, and visuospatial functioning were not significantly associated with COVID-19 knowledge. Conclusions: Given the rapid transmission rate of the SARS CoV-2 infections, COVID knowledge lapses will likely have deleterious repercussions. Public health messages should ensure effective acquisition and retention of COVID specific information, especially in cognitively compromised older adults.

Background The impact of COVID-19 severity on development of long-term sequelae remains unclear, and symptom courses are not well defined. Methods This ambidirectional cohort study recruited adults with new or worsening symptoms lasting >3 weeks from confirmed SARS-CoV-2 infection between August 2020–December 2021. COVID-19 severity was defined as severe for those requiring hospitalization and mild for those not. Symptoms were collected using standardized questionnaires. Multivariable logistical regression estimated odds ratios (OR) and 95% confidence intervals (CI) for associations between clinical variables and symptoms. Results Of 332 participants enrolled, median age was 52 years (IQR 42–62), 233 (70%) were female, and 172 (52%) were African American. Antecedent COVID-19 was mild in 171 (52%) and severe in 161 (48%). In adjusted models relative to severe cases, mild COVID-19 was associated with greater odds of fatigue (OR:1.83, CI:1.01–3.31), subjective cognitive impairment (OR:2.76, CI:1.53–5.00), headaches (OR:2.15, CI:1.05–4.44), and dizziness (OR:2.41, CI:1.18–4.92). Remdesivir treatment was associated with less fatigue (OR:0.47, CI:0.26–0.86) and fewer participants scoring >1.5 SD on PROMIS Cognitive scales (OR:0.43, CI:0.20–0.92). Fatigue and subjective cognitive impairment prevalence was higher 3–6 months after COVID-19 and persisted (fatigue OR:3.29, CI:2.08–5.20; cognitive OR:2.62, CI:1.67–4.11). Headache was highest at 9–12 months (OR:5.80, CI:1.94–17.3). Conclusions Mild antecedent COVID-19 was associated with highly prevalent symptoms, and those treated with remdesivir developed less fatigue and cognitive impairment. Sequelae had a delayed peak, ranging 3–12 months post infection, and many did not improve over time, underscoring the importance of targeted preventative measures.

While hippocampal atrophy and its regional susceptibility to Alzheimer’s disease (AD) are well reported at late stages of AD, studies of the asymptomatic stage of AD are limited but could elucidate early stage pathophysiology as well as provide predictive biomarkers. In this study, we performed multi-modal magnetic resonance imaging (MRI) to estimate morphometry, functional connectivity, and tissue microstructure of hippocampal subfields in cognitively normal adults including those with asymptomatic AD. High-resolution resting-state functional, diffusion and structural MRI, cerebral spinal fluid (CSF), and neuropsychological evaluations were performed in healthy young adults (HY: n = 40) and healthy older adults with negative (HO−: n = 47) and positive (HO+ : n = 25) CSF biomarkers of AD. Morphometry, functional connectivity, and tissue microstructure were estimated from the structural, functional, and diffusion MRI images, respectively. Our results indicated that normal aging affected morphometry, connectivity, and microstructure in all hippocampal subfields, while the subiculum and CA1-3 demonstrated the greatest sensitivity to asymptomatic AD pathology. Tau, rather than amyloid-β, was closely associated with imaging-derived synaptic and microstructural measures. Microstructural metrics were significantly associated with neuropsychological assessments. These findings suggest that the subiculum and CA1-3 are the most vulnerable in asymptomatic AD and tau level is driving these early changes.