Improved Patient-Reported Outcomes With Post-Transplant Cyclophosphamide: A Quality-of-Life Evaluation and 2-Year Outcomes of BMT CTN 1703.

The BMT CTN 1703 phase III trial confirmed that graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) results in superior GVHD-free, relapse-free survival (GRFS) compared with Tac/methotrexate (MTX) prophylaxis. This companion study assesses the effect of these regimens on patient-reported outcomes (PROs). Using the Lee Chronic GVHD Symptom Score and PROMIS subscales (physical function, GI symptoms, social role satisfaction) as primary end points and hemorrhagic cystitis symptoms and Lee subscales as secondary end points, responses from English and Spanish speakers were analyzed at baseline and days 100, 180, and 365 after transplant.

The American Clinical Neurophysiology Society Guideline on Indications for Continuous Electroencephalography Monitoring in Neonates.

Purpose: Continuous EEG (cEEG) monitoring is increasingly used in the management of neonates with seizures. There remains debate on what clinically relevant information can be gained from cEEG in neonates with suspected seizures, at high risk for seizures, or with definite seizures, as well as the use of cEEG for prognosis in a variety of conditions. In this guideline, we address these questions using American Clinical Neurophysiology Society structured methodology for clinical guideline development.

Antibiotic prescribing patterns at outpatient clinics in Western and Coastal Kenya.

Antimicrobial resistant pathogens are a leading cause of morbidity and mortality worldwide, with overuse and misuse of antimicrobials being key contributors. We aimed to identify factors associated with antibiotic prescriptions among patients presenting to clinics in Kenya. We performed a retrospective, descriptive cohort study of persons presenting to outpatient clinics in Western and Coastal Kenya, including symptoms, physical exams, clinician assessments, laboratory results and prescriptions.

The Interaction of Racial-Ethnic and Economic Concentration and its Association with Premature Mortality in U.S. Neighborhoods.

Recent research shows a significant link between race-ethnicity and income concentration and premature death rates in the U.S. However, most studies focus on Black-White residential concentration, overlooking racial-ethnic diversity.

BayesAge 2.0: a maximum likelihood algorithm to predict transcriptomic age.

Aging is a complex biological process influenced by various factors, including genetic and environmental influences. In this study, we present BayesAge 2.0, an upgraded version of our maximum likelihood algorithm designed for predicting transcriptomic age (tAge) from RNA-seq data.

Basic Science and Pathogenesis.

Background: Genome-wide association studies (GWAS) in Alzheimer's disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.

Method: We conducted a meta-analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.

Basic Science and Pathogenesis.

Background: Vascular dysfunction, blood-brain barrier (BBB) dysregulation, and neuroinflammation are thought to participate in Alzheimer`s disease (AD) pathogenesis, though the mechanism is poorly understood. Among pathways of interest, AD pathology appears to affect vascular endothelial growth factor-A (VEGFA) signaling in a bidirectional manner. Higher VEGF levels are thought to have a protective role and slow cognitive decline.

Basic Science and Pathogenesis.

Background: Subjective Memory Complaints (SMC) are defined as the perception of one's own memory. In several studies SMC are associated with Alzheimer's disease (AD) neuropathologic changes, and only one study has analyzed and found an association of SMC with other neurodegenerative, but not vascular, neuropathologic changes. Yet, the evidence on the association of SMC with non-AD neuropathologic changes is insufficient.

Basic Science and Pathogenesis.

Background: APOE*4 is the strongest genetic risk for late-onset Alzheimer's disease (AD), but other genetic loci may counter its detrimental effect, providing therapeutic avenues. Expanding beyond non-Hispanic White subjects, we sought to additionally leverage genetic data from non-Hispanic and Hispanic subjects of admixed African ancestry to perform trans-ancestry APOE*4-stratified GWAS, anticipating that allele frequency differences across populations would boost power for gene discovery.

Method: Participants were ages 60+, of European (EU; ≥75%) or admixed African (AFR; ≥25%) ancestry, and diagnosed as cases or controls.

Basic Science and Pathogenesis.

Background: Mediterranean diets may reduce Alzheimer's disease (AD) risk and preserve cognitive function relative to Western diets by protecting against inflammation. In a long term controlled randomized trial of Mediterranean vs. Western diet consumption in cynomolgus macaques (Macaca fascicularis), difficult to conduct in humans, we found significant anti-inflammatory effects of Mediterranean diet on circulating monocyte and brain temporal cortex transcriptional profiles.

Basic Science and Pathogenesis.

Background: Cerebrovascular disease (CVD) is a major cause of mortality in females, while two-thirds of Alzheimer's disease (AD) patients are female. AD and CVD share many genetic risk factors, one of them being apolipoprotein E (APOE) genotype. Sex differences in APOE and AD are well-established; it is unclear if associations between APOE and CVD are sex-specific.

Basic Science and Pathogenesis.

Background: Western and Mediterranean diets differentially affect cerebral cortical gene expression, brain structure, and socioemotional behavior in middle-aged female nonhuman primates (NHP) (Macaca fascicularis). In this study, we investigate the effect of diet on brain molecular composition.

Method: Using a machine learning approach, we quantified the impact of these diets on the presynaptic proteome in the lateral temporal cortex determined by synaptometry by time of flight (SynTOF) mass spectrometry and examined associations between the proteome, transcriptome, and an array of multisystem phenotypes.

Basic Science and Pathogenesis.

Background: Several studies have indicated sex-specific genetic risk for Alzheimer's disease (AD), but these were centered on non-Hispanic White individuals of European ancestry. We sought to identify sex-specific genetic variants for AD in non-Hispanic and Hispanic subjects of admixed African ancestry.

Method: Participants were ages 60+, of African ancestry (≥25%), and diagnosed as cases or controls.

Basic Science and Pathogenesis.

Background: Single nucleus RNA sequencing (snRNA-seq) has revolutionized our ability to dissect transcriptional profiles in specific cell types. While nuclear sequencing enhances analysis robustness, it captures only 20-50% of the cellular transcriptional information, limiting our comprehensive understanding of the cellular transcriptional ensemble. Therefore, we propose a computational approach to extract the cellular signal from bulk transcriptomic data from brain tissue, allowing us to investigate cell type-specific transcriptomic programs underlying neurodegeneration.

Basic Science and Pathogenesis.

Background: Several lines of evidence now suggest that ABCA1 plays a role in Alzheimer's disease (AD). Rare variants on ABCA1 increased AD risk in a large genetic study, and mouse models suggest that increasing ABCA1 activity can reverse signs of AD pathology. While there is growing consensus that ABCA1 and ApoE directly interact, it is unclear how APOE genotype affects this interaction in the context of neurodegeneration.

Basic Science and Pathogenesis.

Background: Cerebrovascular pathology frequently co-occurs with Alzheimer's disease (AD) pathology and the combinations of these forms of pathology may underly AD dementia. Sex hormones influence many aspects of cerebrovascular systems and may contribute to cerebrovascular pathology, but many studies of aging and AD do not measure hormones. Therefore, in this study, we explored whether a polygenic score predicting sex hormone levels relates to cerebrovascular pathology in the AD brain.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is the most common form of dementia. Neuropathologically, AD stands out as a mixed proteinopathy. Beta-amyloid and tau biomarkers can now add in-vivo support to the AD diagnosis.

Basic Science and Pathogenesis.

Background: The X-chromosome remains largely unexplored in Alzheimer's disease (AD). We performed the first, stratified X-wide association study (XWAS) of AD to chart the role of X-chromosome genetic variation in AD sexual dimorphism and heterogeneity of APOE*4-related AD risk.

Method: The study overview is shown in Figure 1A.

Basic Science and Pathogenesis.

Background: Hallmark pathologies of Alzheimer's Disease (AD) include the accumulation of both extracellular amyloid and intracellular tau proteins. While a significant body of knowledge exists surrounding the role of the protein aggregates in the context of AD, research supporting these as targets for therapeutic development have yielded inconsistent findings. One significant barrier is the inability to restore cognitive function despite the successful clearance of these proteins.

Clinical Manifestations.

Background: Corticobasal syndrome (CBS) corresponds to a clinical phenotype with heterogeneous neuropathology, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Alzheimer's disease (AD), and synucleinopathies such as Lewy Body Disease (LBD), in rare cases. Previous reports of CBS-LBD describe patients with diffuse LBD, a younger age of onset and occasionally lacking core features like REM sleep Behavior Disorder (RBD).

Method: We present a young patient with CBS who had a rapid progression and was found to have a high burden of limbic LBD and high AD co-pathology at autopsy.

Clinical Manifestations.

Background: Olfactory deficiency can be present in preclinical Alzheimer's (AD) and Parkinson's disease (PD), predicting their subsequent manifestation, including mild cognitive impairment (MCI). Analyzing key regions within the olfactory circuit could reveal important insights into the neuropathological progression. Dysfunction in the olfactory circuit has been shown in the olfactory nerve in limited postmortem studies, including involvement of a key region, the piriform cortex.

Clinical Manifestations.

Background: More than 2/3 of Alzheimer's Disease (AD) patients are women, which has led to increased interest in the neurophysiological impact of estrogen decline during menopause. While early evidence suggested that hormone replacement therapy (HRT) may be protective against dementia, more recent studies have found inconclusive or even harmful effects.

Method: We tested the association between HRT use (estrogen or estrogen + progestin) and AD-related neuropathological outcomes measured on autopsy data in females from the National Alzheimer's Coordinating Center (NACC) (N = 3423).

Antihypertensive Deprescribing and Functional Status in VA Long-Term Care Residents With and Without Dementia.

Background: Deprescribing antihypertensives is of growing interest in geriatric medicine, yet the impact on functional status is unknown. We emulated a target trial of deprescribing antihypertensive medications compared with continued use on functional status measured by activities of daily living (ADL) in a long-term care population.

Methods: We included 12,238 Veteran Affairs long-term care residents age 65+ who had a stay ≥ 12 weeks between 2006 and 2019.

Optimal population screening strategies for liver fibrosis associated with metabolic dysfunction-associated steatotic liver disease.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important public health threat, potentially leading to chronic liver disease and liver cancer. Current guidelines recommend using the FIB-4 score for initial identification of subjects at risk of future complications. We formulate a novel population screening strategy based on the Steatosis-Associated Fibrosis Estimator (SAFE) score, recently developed for MASLD risk stratification in primary care.