Sex-specific effects of microglial activation on Alzheimer's disease proteinopathy in older adults.

Females show a disproportionate burden of Alzheimer's disease pathology and higher Alzheimer's disease dementia prevalences compared to males, yet the mechanisms driving these vulnerabilities are unknown. There is sexual dimorphism in immunological functioning, and neuroimmune processes are implicated in Alzheimer's disease genesis. Using neuropathology indicators from human brain tissue, we examined the mediational role of microglial activation on the relationship between amyloid and tau and how it differs by sex. 187 decedents (64% female; 89 mean age at death; 62% non-demented) from the Rush Memory and Aging Project completed neuropathological evaluations with brain tissue quantified for microglial activation, amyloid-ß and tau. Proportion of morphologically activated microglia was determined via immunohistochemistry (HLA-DP-DQ-DR) and morphological staging (stage I, II or III). Amyloid-ß and tau burden were quantified via immunohistochemistry (M00872 or AT8, respectively). Using causal counterfactual modelling, we estimated the mediational effect of microglial activation on the amyloid-ß to tau relationship in the whole sample and stratified by sex (amyloid-ß â†’ microglial activation → tau). Alternative models tested the role of microglia activation as the precipitating event (microglial activation → amyloid-ß â†’ tau). Microglial activation significantly mediated 33% [95% confidence interval (CI) 10-67] of the relationship between amyloid-ß and tau in the whole sample; stratified analyses suggested this effect was stronger and only statistically significant in females. 57% (95% CI 22-100) of the effect of amyloid-ß on tau was mediated through microglial activation in females, compared to 19% (95% CI 0-64) in males. Regional analyses suggested that mediational effects were driven by greater cortical versus subcortical microglial activation. Relationships were independent of cerebrovascular disease indices. Alternative models suggested that in females, microglial activation was a significant exposure both preceding the amyloid-ß to tau relationship (mediational effect: 50%, 95% CI 23-90) and directly related to tau burden (microglia direct effect: 50%, 95% CI 10-77). By contrast, in males, only the direct effect of microglial activation to tau reached significance (74%, 95% CI 32-100) (mediational effect: 26%, 95% CI 0-68). Our models suggest a reciprocal, bidirectional relationship between amyloid-ß and microglial activation that significantly accounts for tau burden in females. By contrast, in males, direct independent (non-mediational) relationships between microglial activation or amyloid-ß with tau were observed. Microglial activation may be disproportionately important for Alzheimer's disease pathogenesis in females. Determining sex-specific vulnerabilities to Alzheimer's disease development both inform fundamental pathophysiology and support precision health approaches for this heterogeneous disease.

Cerebral Hypoxia: Its Role in Age-Related Chronic and Acute Cognitive Dysfunction.

Postoperative cognitive dysfunction (POCD) has been reported with widely varying frequency but appears to be strongly associated with aging. Outside of the surgical arena, chronic and acute cerebral hypoxia may exist as a result of respiratory, cardiovascular, or anemic conditions. Hypoxia has been extensively implicated in cognitive impairment. Furthermore, disease states associated with hypoxia both accompany and progress with aging. Perioperative cerebral hypoxia is likely underdiagnosed, and its contribution to POCD is underappreciated. Herein, we discuss the various disease processes and forms in which hypoxia may contribute to POCD. Furthermore, we outline hypoxia-related mechanisms, such as hypoxia-inducible factor activation, cerebral ischemia, cerebrovascular reserve, excitotoxicity, and neuroinflammation, which may contribute to cognitive impairment and how these mechanisms interact with aging. Finally, we discuss opportunities to prevent and manage POCD related to hypoxia.

Preliminary validation of the Virtual Kitchen Challenge as an objective and sensitive measure of everyday function associated with cerebrovascular disease.

Preliminary validity of a computer-based test of everyday function (Virtual Kitchen Challenge [VKC]) was examined against brain-imaging markers of cerebrovascular disease and in contrast to conventional neuropsychological and self-report measures. Twenty community-dwelling older adults (n = 6 mild cognitive impairment) performed simulated breakfast and lunch tasks using a computer touchscreen (VKC). Automated measures (completion time, proportion time off screen, etc.) were computed during training and test conditions. White matter hyperintensity (WMH) volumes from brain magnetic resonance imaging and conventional measures of cognition and function also were obtained. VKC completion time and proportion time off screen improved significantly from training to test and were significantly associated with WMH volume (r > 0.573). VKC measures and WMH were not significantly correlated with conventional cognitive or self-report measures. The VKC holds promise as a valid measure of subtle functional difficulties in older adults that is sensitive to change and cerebrovascular pathology, highlighting its potential for clinical trials. Highlights: Virtual Kitchen Challenge (VKC) scores showed significant improvement from training to test conditions.VKC scores (completion time and proportion of time off screen) were associated with a neuroimaging biomarker of brain health (white matter hyperintensities).

Age, Loneliness, and Social Media Use in Adults during COVID-19: A Latent Profile Analysis.

Loneliness has been linked to morbidity and mortality across the lifespan. Social media could reduce loneliness, though research on the relation between social media and loneliness has been inconclusive. This study used person-centered analyses to elucidate the inconsistencies in the literature and examine the possible role technology barriers played in the relation between social media use and loneliness during the COVID-19 pandemic. Participants (n = 929; M age = 57.58 ± 17.33) responded to a series of online questions covering demographics, loneliness, technology barriers, and social media use (e.g., Facebook, Twitter, etc.) across a range of devices (e.g., computer, smartphone, etc.). A latent profile analysis was conducted to identify distinct profiles of social media use, loneliness patterns, and age. Results yielded five distinct profiles characterized that showed no systematic associations among age, social media use, and loneliness. Demographic characteristics and technology barriers also differed between profiles and were associated with loneliness. In conclusion, person-centered analyses demonstrated distinct groups of older and younger adults that differed on social media use and loneliness and may offer more fruitful insights over variable-centered approaches (e.g., regression/correlation). Technology barriers may be a viable target for reducing loneliness in adults.

Preoperative cognition predicts clinical stroke/TIA and mortality after surgical aortic valve replacement in older adults.

Stroke and death remain risks of surgical aortic valve replacement (SAVR). Preoperative cognitive screeners repeatedly show that reduced scores predict postoperative outcome, but less is known about comprehensive neuropsychological measures predicting risk. This study had two aims: 1) investigate whether preoperative cognitive measures predicted postoperative clinical stroke/transient ischemic attack (TIA) and mortality in older adults undergoing SAVR, and 2) identify the best predictors within a comprehensive cognitive protocol. A total of 165 participants aged 65 + with moderate-to-severe aortic stenosis completed a comprehensive cognitive test battery preoperatively. Postoperative stroke evaluations were conducted by trained stroke neurologists preoperatively and postoperatively, and mortality outcomes were obtained by report and records. Logistic regressions were conducted to evaluate preoperative cognitive predictors of clinical stroke/TIA within 1 week of surgery and mortality within 1 year of surgery. Multivariate models showed measures of delayed verbal memory recall (OR = 0.86; 95% CI 0.74-0.99) and visuospatial skills (OR = 0.95; 95% CI 0.90-1.01) predicted clinical stroke/TIA within 1 week of surgery, R2 = .41, p < .001, ƒ2 = .69. Measures of naming ability (OR = 0.88; 95% CI 0.80-0.96), verbal memory recall (OR = 1.23; 95% CI 0.99-1.51), visual memory recall (OR = 0.90; 95% CI 0.80-1.00), medical comorbidities (OR = 1.71; 95% CI 1.22-2.65), and sex (OR = 2.39; 95% CI 0.90-7.04) were significant predictors of death within 1 year of surgery, R2 = .68, p < .001, ƒ2 = 2.12. Preoperative cognitive measures reflecting temporal and parietal lobe functions predicted postoperative clinical stroke/TIA within 1 week of SAVR and mortality within 1 year of SAVR. As such, cognitive measures may offer objective and timely indicators of preoperative health, specifically vulnerabilities in cerebral hypoperfusion, which may inform intervention and/or intensive postoperative monitoring and follow-up after SAVR.

The goal-control model: An integrated neuropsychological framework to explain impaired performance of everyday activities.

OBJECTIVE: This review describes the relatively small body of neuropsychological and cognitive research conducted over the past 100 years focused on theoretical models explaining the neurocognitive processes that support everyday functioning and the breakdown of functional abilities in the face of neurological damage or disease. METHOD: The historical roots of the theories of everyday activities based on direct observation of behavior in neurology and diary reports of everyday errors in cognitive psychology are presented, followed by a review of the empirical findings and resulting theoretical conceptualizations from case studies and group studies of various clinical populations in neuropsychology. RESULTS: We conclude with a new framework (the goal-control model) that integrates the most recent empirical findings in neuropsychology with mechanisms proposed by cognitive models. CONCLUSIONS: The goal-control model offers empirically supported solutions to understanding and predicting functioning in the real world. This new model generates testable predictions for future research and provides guidance for clinical assessment and interventions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).