Biomarkers.

Background: In the era of disease-modifying treatments for Alzheimer's disease (AD), accurate detection of underlying AD pathology is critical. Blood-based biomarkers for AD are increasingly available, but their diagnostic performance is not well-understood across the spectrum of neurodegenerative disease, especially when AD presents as co-pathology in non-AD syndromes. We investigated the diagnostic performance of three plasma biomarkers (phosphorylated tau 217 [p-tau217], neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]) to detect AD, confirmed by autopsy, across 12 clinical neurodegenerative syndromes with various underlying etiologies.

Biomarkers.

Background: Tau-PET with [18F]Flortaucipir is FDA-approved for the identification of AD tau neuropathology in the differential diagnosis of patients with cognitive impairment. However, its performance in detecting early AD stages requires further assessment. We aimed to i) examine the relationships between Flortaucipir-PET and AD neuropathology, and ii) characterize the relationship between Flortaucipir-PET and emerging plasma ptau217 biomarker in autopsy cases.

Biomarkers.

Background: Neuropathological studies indicate that locus coeruleus(LC) volume decreases in Alzheimer's disease(AD) by 8% at each stage, (from Braak 0-1), whereas in normal aging, the LC remains unchanged. These changes make LC volumetry by neuroimaging a promising way to track AD progression even before symptoms appear. However, LC's small size and location make it prone to imaging artifacts.

Biomarkers.

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy specific to individuals with repetitive head trauma. Traumatic encephalopathy syndrome (TES) is the proposed clinical syndrome resulting from CTE with or without other contributing neuropathologies. Pathophysiological mechanisms driving CTE and underlying TES symptoms are not understood.

Public Health.

Background: Racial differences in dementia prevalence and incidence were found with higher dementia burden in African descendants. Previous neuropathological studies were conducted mostly in white participants in convenience samples. Further studies in diverse populations are important to foster the understanding of race differences in dementia pathology.

Public Health.

Background: The outcomes of extensive Genome-Wide Association Study (GWAS) data in Polygenic Risk Score (PRS) studies exhibit varying odds ratios (ORs), ranging from 1.13 (Bellenguez) to 1.34 (Kunkle).

Public Health.

Background: Hypertension is a midlife modifiable risk factor for dementia. Uncontrolled hypertension is related to brain damage that could result in cognitive impairment, and one way of evaluating uncontrolled hypertension through life is assessing left ventricular hypertrophy (LVH). Previous imaging studies have shown a relationship between LVH and cognitive impairment.

Public Health.

Background: Dementia prevalence in Latin America is higher in rural than urban areas. This discrepancy may be explained by inequities over the lifespan in access to health and educational services. However, there is no evidence of potential adverse long-standing effects of living in rural areas during childhood in current urban adults.

Biomarkers.

Background: Frailty, characterized by increased physical vulnerability, is associated with a higher incidence and severity of cognitive impairment and also a higher burden of neurodegenerative and cerebrovascular diseases. This study investigates the association between frailty and neurodegenerative and cerebrovascular pathologies.

Method: Cross-sectional analysis using clinical and neuropathological data from individuals aged 60 or older, enrolled in the Biobank for Aging Studies between 2004 and 2023.

Developing Topics.

Background: Caspase-cleaved tau can critically be involved in the pathogenesis and progression of Alzheimer's disease (AD), due to its ability to promote both misfolding and neurodegeneration, which ultimately leads to progressive cognitive impairment. Neuropathological studies show that caspase-cleaved tau species are abundant in AD brain neurons, yet show only a modest degree of co-occurrence with phospho-tau. This suggests that caspase-cleaved tau is an overlooked form of tau pathology that is related to the vulnerability and pathogenesis of AD.

Developing Topics.

Background: The Neuromodulatory Subcortical System (NSS) consists of nuclei exhibiting early vulnerability to tauopathies, including Alzheimer's Disease (AD). Within the NSS, there is a spectrum of vulnerability that becomes apparent in the earliest stages of AD, offering a chance to probe factors underlying vulnerability to AD.

Method: In this study, we applied bulk RNA sequencing in well-characterized postmortem human tissue from n = 22 cases at early (Braak 0-III) AD-tau stages to understand why this susceptibility gradient exists by examining two nuclei with very similar neurons but differing in their vulnerability to AD the locus coeruleus (LC) and substantia nigra (SN).

Alzheimer's Imaging Consortium.

Background: Neuropathological studies indicate that locus coeruleus(LC) volume decreases in Alzheimer's disease(AD) by 8% at each stage, (from Braak 0-1), whereas in normal aging, the LC remains unchanged. These changes make LC volumetry by neuroimaging a promising way to track AD progression even before symptoms appear. However, LC's small size and location make it prone to imaging artifacts.

Drug Development.

Background: Recruiting and retaining older adults for clinical trials is challenging, especially in low-resource settings. Such challenges led to a systematic exclusion of such participants from clinical trials, compromising the generalizability of the results obtained in high income countries.

Objective: Here we describe the strategies we used in the PROAME study for recruiting and retaining illiterate older adults from low socioeconomical levels in a non-pharmacological trial.

Dementia Care Research and Psychosocial Factors.

Background: Education is a recognized modifiable dementia risk factor. To boost cognitive reserve and reduce dementia risk in Brazil's vulnerable populations, we conceived a literacy program (PROAME trial) targeting low-educated adults, aiming to explore how executive function and individual differences influence program effectiveness.

Method: We screened 130 adults, with 108 meeting enrollment criteria.

Dementia Care Practice.

Background: The COVID-19 pandemic in Ethiopia posed additional challenges to an already strained mental health service. Eka Kotebe Hospital, the second-largest mental health facility with a capacity of 175 beds, was transformed into a dedicated COVID-19 treatment center, leaving mental health service users, especially vulnerable elderly patients with cognitive impairments, without adequate support. I had the challenge to implement alternatives to provide mental health services coverage to underserved elderly population.

Sex and the Clock: Exploring Sex Differences in Chronotype and Circadian Preferences Among Cognitively Healthy Older Adults.

This study aimed to compare objective circadian rest-activity-rhythm (RAR) measures with self-reported circadian behavior and morning-evening preference in cognitively healthy older men and women. A total of 129 participants (ages 65-90) completed the Horne & Ostberg Morning-Eveningness Questionnaire (MEQ) and the Circadian Type Inventory (CTI) to assess their morning-evening preference and circadian traits, including rigidity, vigor, languidness, and flexibility. These subjective measures were compared to objective actigraphy data from a sub-cohort of 70 individuals who wore actigraphy watches for 24 hours a day over a 7-day period.

Hypertension may associate with cerebral small vessel disease and infarcts through the pathway of intracranial atherosclerosis.

Hypertension, a major modifiable risk factor for cardiovascular diseases, is linked to late-life neurocognitive disorders such as vascular dementia and Alzheimer's disease (AD). This study explores the associations between hypertension, intracranial atherosclerotic disease (ICAD), cerebral small vessel disease (cSVD), and Alzheimer's disease neuropathologic change (ADNC) in a large community-based autopsy study. This cross-sectional study used data from the Biobank for Aging Studies of the University of São Paulo Medical School.

Comprehensive mapping of synaptic vesicle protein 2A (SV2A) in health and neurodegenerative diseases: a comparative analysis with synaptophysin and ground truth for PET-imaging interpretation.

Synaptic dysfunction and loss are central to neurodegenerative diseases and correlate with cognitive decline. Synaptic Vesicle Protein 2A (SV2A) is a promising PET-imaging target for assessing synaptic density in vivo, but comprehensive mapping in the human brain is needed to validate its biomarker potential. This study used quantitative immunohistochemistry and Western blotting to map SV2A and synaptophysin (SYP) densities across six cortical regions in healthy controls and patients with early-onset Alzheimer's disease (EOAD), late-onset Alzheimer's disease (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-GRN).

Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics.

The development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNA-seq and ATAC-seq in Alzheimer's disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), analyzing 41 participants and ∼1 million cells (RNA + ATAC) from three brain regions varying in vulnerability and pathological burden. We identify 32 shared, disease-associated cell types and 14 that are disease specific.

Health literacy, but not memory, is associated with hippocampal connectivity in adults with low levels of formal education.

Introduction: The influence of hippocampal connectivity on memory performance is well established in individuals with high educational attainment. However, the role of hippocampal connectivity in illiterate populations remains poorly understood.

Methods: Thirty-five illiterate adults were administered a literacy assessment (Test of Functional Health Literacy in Adults [TOFHLA]), structural and resting state functional magnetic resonance imaging, and an episodic memory test (Free and Cued Selective Reminding Test).

The Association Between Neuropathological Lesions and Body Mass Index Is Independent of Cognitive Abilities.

Background: The association of moderate and severe dementia with low body mass index (BMI) is well described, but weight decline seems to also occur in individuals with preclinical neuropathologies. Considering that up to one-fifth of individuals with normal cognition meet the criteria for a dementia-related neuropathological diagnosis, autopsy studies are key to detecting preclinical neurodegenerative and cerebrovascular diseases that could be underlying weight changes.

Objective: We investigated the association between dementia-related brain lesions and BMI and evaluated whether the cognitive function was a mediator of this association.

Don't die like me: Which proteins are responsible for the selective neuronal vulnerability within the substantia nigra?

A hallmark of Parkinson's disease is the specific degeneration of dopaminergic neurons in the substantia nigra pars compacta. Interestingly, not all of these neurons are affected to the same extent. Studies revealed that neurons located more ventrally within the substantia nigra pars compacta have a higher prevalence to degenerate than those located in the dorsal tier.