Brain erythropoietin fine-tunes a counterbalance between neurodifferentiation and microglia in the adult hippocampus.

In adult cornu ammonis hippocampi, erythropoietin (EPO) expression drives the differentiation of new neurons, independent of DNA synthesis, and increases dendritic spine density. This substantial brain hardware upgrade is part of a regulatory circle: during motor-cognitive challenge, neurons experience "functional" hypoxia, triggering neuronal EPO production, which in turn promotes improved performance. Here, we show an unexpected involvement of resident microglia.

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave.

Microglia, the brain's resident myeloid cells, play central roles in brain defense, homeostasis, and disease. Using a prolonged colony-stimulating factor 1 receptor inhibitor (CSF1Ri) approach, we report an unprecedented level of microglial depletion and establish a model system that achieves an empty microglial niche in the adult brain. We identify a myeloid cell that migrates from the subventricular zone and associated white matter areas.

Emerging roles of oxidative stress in brain aging and Alzheimer's disease.

Reactive oxygen species (ROS) are metabolic byproducts that are necessary for physiological function but can be toxic at high levels. Levels of these oxidative stressors increase gradually throughout the lifespan, impairing mitochondrial function and damaging all parts of the body, particularly the central nervous system. Emerging evidence suggests that accumulated oxidative stress may be one of the key mechanisms causing cognitive aging and neurodegenerative diseases such as Alzheimer's disease (AD).

Insights Into the Mechanisms of Brain Endothelial Erythrophagocytosis.

The endothelial cells which form the inner cellular lining of the vasculature can act as non-professional phagocytes to ingest and remove emboli and aged/injured red blood cells (RBCs) from circulation. We previously demonstrated an erythrophagocytic phenotype of the brain endothelium for oxidatively stressed RBCs with subsequent migration of iron-rich RBCs and RBC degradation products across the brain endothelium , in the absence of brain endothelium disruption. However, the mechanisms contributing to brain endothelial erythrophagocytosis are not well defined, and herein we elucidate the cellular mechanisms underlying brain endothelial erythrophagocytosis.

Age affects white matter microstructure and episodic memory across the older adult lifespan.

Diffusion imaging studies have observed age-related degradation of white matter that contributes to cognitive deficits separately in younger-old (ages 65-89) and oldest-old (ages 90+) adults. But it remains unclear whether these age effects are magnified in advanced age groups, which may reflect disease-related pathology. Here, we tested whether age-related differences in white matter microstructure followed linear or nonlinear patterns across the entire older adult lifespan (65-98 years), these patterns were influenced by oldest-old adults at increased risk of dementia (cognitive impairment no dementia, CIND), and they explained age effects on episodic memory.

On the design of early-phase Alzheimer's disease clinical trials with cerebrospinal fluid tau outcomes.

Background/aims: The focus of Alzheimer's disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with "prodromal Alzheimer's disease" to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer's disease dementia. The use of these eligibility criteria may affect study power.

Apathy as a Treatment Target in Alzheimer's Disease: Implications for Clinical Trials.

Apathy is one of the most prevalent, stable and persistent neuropsychiatric symptom across the neurocognitive disorders spectrum. Recent advances in understanding of phenomenology, neurobiology and intervention trials highlight apathy as an important target for clinical intervention. We conducted a comprehensive review and critical evaluation of recent advances to determine the evidence-based suggestions for future trial designs.

Recruitment of a multi-site randomized controlled trial of aerobic exercise for older adults with amnestic mild cognitive impairment: The EXERT trial.

Introduction: Effective strategies to recruit older adults with mild cognitive impairment (MCI) into nonpharmacological intervention trials are lacking.

Methods: Recruitment for EXERT, a multisite randomized controlled 18-month trial examining the effects of aerobic exercise on cognitive trajectory in adults with amnestic MCI, involved a diverse portfolio of strategies to enroll 296 participants.

Results: Recruitment occurred September 2016 through March 2020 and was initially slow.

Asian Americans and Pacific Islanders' perspectives on participating in the CARE recruitment research registry for Alzheimer's disease and related dementias, aging, and caregiving research.

Introduction: This study elicited Asian Americans and Pacific Islanders' (AAPI) perspectives about recruitment strategies/messaging for participation in an aging, Alzheimer's disease and related dementias (ADRD), and caregiving research recruitment registry.

Methods: Using a mixed methods design, CARE (Collaborative Approach for AAPI Research and Education) conducted 14 focus groups (N = 123) with AAPI cultural groups (Asian Indian, Chinese, Filipino, Japanese, Korean, Samoan, Vietnamese) in different languages. Descriptive statistics and thematic qualitative analyses were conducted.

Trial of Pimavanserin in Dementia-Related Psychosis.

Background: Patients with dementia due to neurodegenerative disease can have dementia-related psychosis. The effects of the oral 5-HT inverse agonist and antagonist pimavanserin on psychosis related to various causes of dementia are not clear.

Methods: We conducted a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia.

Antemortem Visit-To-Visit Blood Pressure Variability Predicts Cerebrovascular Lesion Burden in Autopsy-Confirmed Alzheimer's Disease.

Background: Blood pressure variability is linked to Alzheimer's disease (AD) risk and MRI-based markers of cerebrovascular disease. Less is known about the role of blood pressure variability in postmortem evaluation of cerebrovascular disease and AD.

Objective: To determine whether antemortem blood pressure variability predicts cerebrovascular and AD pathology and follow-up cognitive change in autopsy-confirmed AD.

Resting-State Functional Connectivity Signatures of Apathy in Community-Living Older Adults.

Apathy predicts poor outcomes in older adults, and its underlying neural mechanism needs further investigation. We examined the association between symptoms of apathy and functional connectivity (FC) in older adults without stroke or dementia. Participants included 48 individuals (mean age = 70.

Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer's disease.

The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across distinct cell types. Here, we present a multi-omic single-nucleus study of 191,890 nuclei in late-stage Alzheimer's disease (AD), accessible through our web portal, profiling chromatin accessibility and gene expression in the same biological samples and uncovering vast cellular heterogeneity. We identified cell-type-specific, disease-associated candidate cis-regulatory elements and their candidate target genes, including an oligodendrocyte-associated regulatory module containing links to APOE and CLU.

Disparities by Race and Ethnicity Among Adults Recruited for a Preclinical Alzheimer Disease Trial.

Importance: Underrepresentation of many racial/ethnic groups in Alzheimer disease (AD) clinical trials limits generalizability of results and hinders opportunities to examine potential effect modification of candidate treatments.

Objective: To examine racial and ethnic differences in recruitment methods and trial eligibility in a multisite preclinical AD trial.

Design, Setting, And Participants: This cross-sectional study analyzed screening data from the Anti-Amyloid in Asymptomatic AD study, collected from April 2014 to December 2017.

Reasons for undergoing amyloid imaging among cognitively unimpaired older adults.

Objectives: Preclinical Alzheimer's disease (AD) clinical trials screen cognitively unimpaired older adults for biomarker criteria and disclose their results. We examined whether participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease Study with "elevated" and "not elevated" amyloid differed in scores on the "Views and Perceptions of Amyloid Imaging" questionnaire. We hypothesized that, prior to disclosure, those with elevated amyloid would score higher than those with not elevated amyloid.

Blood-Brain Barrier Crossing Renin-Angiotensin Drugs and Cognition in the Elderly: A Meta-Analysis.

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Childbearing vs. clinical trial participation: is it one or the other?

Recent advances have shed light on the importance of early therapeutic intervention for neurodegenerative diseases. Primary prevention trials present a potential disease-modifying strategy for pre-symptomatic patients of autosomal dominant neurodegenerative diseases (ADND), such as early onset familial Alzheimer's disease (AD) and Huntington's disease (HD). As trials target earlier disease stages, however, prospective participants face new ethical and logistical challenges, namely childbearing and reproductive health decisions.

Freshly Thawed Cryobanked Human Neural Stem Cells Engraft within Endogenous Neurogenic Niches and Restore Cognitive Function after Chronic Traumatic Brain Injury.

Human neural stem cells (hNSCs) have potential as a cell therapy after traumatic brain injury (TBI). While various studies have demonstrated the efficacy of NSCs from ongoing culture, there is a significant gap in our understanding of freshly thawed cells from cryobanked stocks-a more clinically relevant source. To address these shortfalls, the therapeutic potential of our previously validated Shef-6.

Implications of FDA Approval of a First Disease-Modifying Therapy for a Neurodegenerative Disease on the Design of Subsequent Clinical Trials.

The goal of clinical research is to improve clinical practice. In progressive neurodegenerative conditions without any disease-slowing therapies, this will result in eventual approval of a first disease-modifying treatment. Clinical trials will still be needed to discover treatments that are more effective, safer, or more convenient.

Exosome loaded immunomodulatory biomaterials alleviate local immune response in immunocompetent diabetic mice post islet xenotransplantation.

Foreign body response (FBR) to biomaterials compromises the function of implants and leads to medical complications. Here, we report a hybrid alginate microcapsule (AlgXO) that attenuated the immune response after implantation, through releasing exosomes derived from human Umbilical Cord Mesenchymal Stem Cells (XOs). Upon release, XOs suppress the local immune microenvironment, where xenotransplantation of rat islets encapsulated in AlgXO led to >170 days euglycemia in immunocompetent mouse model of Type 1 Diabetes.

Norms and equivalences for MoCA-30, MoCA-22, and MMSE in the oldest-old.

Background: Cognitive screening is important for the oldest-old (age 90 +). This age group is the fastest growing and has the highest risk of dementia. However, norms and score equivalence for screening tests are lacking for this group.

Visit-to-visit blood pressure variability and regional cerebral perfusion decline in older adults.

Blood pressure variability (BPV) is linked to dementia risk, possibly through cerebral hypoperfusion. We investigated BPV over 1 year and concurrent regional cerebral perfusion decline in older adults without dementia. Participants underwent 4 blood pressure measurements across 12 months, ASL-MRI at baseline and 12-months, and baseline FDG-PET.