Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma.

The sub-ventricular zone (SVZ) is the most well-characterized neurogenic area in the mammalian brain. We previously showed that in 65% of patients with glioblastoma (GBM), the SVZ is a reservoir of cancer stem-like cells that contribute to treatment resistance and the emergence of recurrence. Here, we build a single-nucleus RNA-sequencing-based microenvironment landscape of the tumor mass and the SVZ of 15 patients and two histologically normal SVZ samples as controls.

Basic Science and Pathogenesis.

Background: The recent European-ancestry based genome-wide association study (GWAS) of Alzheimer disease (AD) by Bellenguez2022 has identified 75 significant genetic loci, but only a few have been functionally mapped to effector gene level. Besides the large-scale RNA expression, protein and metabolite levels are key molecular traits bridging the genetic variants to AD risk, and thus we decided to integrate them into the genetic analysis to pinpoint key proteins and metabolites underlying AD etiology. Few studies have generated more than one layer of post-transcriptional phenotypes, limiting the scale of biological translation of disease modifying treatments.

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: The Apolipoprotein E ε4 (APOE-ε4) allele is common in the population, but acts as the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Despite the strength of the association, there is notable heterogeneity in the population including a strong modifying effect of genetic ancestry, with the APOE-ε4 allele showing a stronger association among individuals of European ancestry (EUR) compared to individuals of African ancestry (AFR). Given this heterogeneity, we sought to identify genetic modifiers of APOE-ε4 related to cognitive decline leveraging APOE-ε4 stratified and interaction genome-wide association analyses (GWAS).

Basic Science and Pathogenesis.

Background: "SuperAgers" are older adults (ages 80+) whose cognitive performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary aging are underexplored in large, racially diverse cohorts. Using eight cohorts, we investigated the frequency of APOE genotypes in SuperAgers compared to middle-aged and older adults.

Basic Science and Pathogenesis.

Background: Murine studies have identified blood proteins that influence brain aging, but translating these findings to humans remains challenging. We used an innovative approach to investigate whether genetically predicted blood levels of proteins linked to brain aging in animal models are associated with cognitive performance in individuals at risk of Alzheimer's disease (AD) [Figure 1].

Method: Through systematic review, we identified 13 circulating proteins with an aging/rejuvenating effect on the mouse brain.

Basic Science and Pathogenesis.

Background: Amyloid PET imaging is a promising biomarker to track the accumulation of parenchymal amyloid beta (Aβ) deposits in the brain. Recent large-scale genome-wide association studies (GWAS) reported common risk factors associated with amyloidosis, suggesting that this endophenotype is driven by genetic variants. We hypothesized that genes with multiple variants with deleterious effect are associated with Aβ accumulation.

Basic Science and Pathogenesis.

Background: Genome-wide association studies (GWAS) have identified numerous genetic variants associated with Alzheimer's disease (AD) risk, but genetic variation in the onset and progression of AD pathology is less understood. Accumulation of amyloid-β (Aβ) in the brain is a key pathological hallmark of AD beginning 10 - 20 years prior to cognitive symptoms. We investigated the genetic basis of variation in age at onset (AAO) of brain Aβ by comparing the performance of polygenic scores (PGSs) based on AD risk and resilience with a Aβ-AAO trait-specific PGS.

Basic Science and Pathogenesis.

Background: Clear sex differences exist in AD and PD. Several studies examined genetic regulations for AD phenotypes and gene expression data in a sex-specific manner, identifying some differences between males and females. In contrasts, although proteins are final effectors of most physiological pathways and important drug targets, sex-specific regulations for proteins remain vastly understudied.

Clinical Manifestations.

Background: The multisite SuperAging Research Initiative (SRI) was established in 2021 to identify resilience and resistance factors promoting cognitive healthspan through a harmonized multidisciplinary protocol with prospective data collection. The designation of SuperAger is reserved for individuals age 80+ with episodic memory performance that is at least average for those 2-3 decades younger. Research studies of this relatively uncommon phenotype allow for investigations of fundamental importance to the neurobiology of brain aging, resilience, resistance, and avoidance of cognitive decline related to "average aging" and more severe impairments associated with Alzheimer's and related dementias (ADRD).

Clinical Manifestations.

Background: Practice effects (PEs) on cognitive tests are improvements in performance from repeated testing. We and others have shown that reductions in PEs on standard tests administered annually are associated with neurodegenerative disease. Using mobile technology, cognition can be assessed at much higher frequencies than standard in-clinic assessments.

Biologically plausible gated recurrent neural networks for working memory and learning-to-learn.

The acquisition of knowledge and skills does not occur in isolation but learning experiences amalgamate within and across domains. The process through which learning can accelerate over time is referred to as learning-to-learn or meta-learning. While meta-learning can be implemented in recurrent neural networks, these networks tend to be trained with architectures that are not easily interpretable or mappable to the brain and with learning rules that are biologically implausible.

Increasing hub disruption parallels dementia severity in autosomal dominant Alzheimer's disease.

Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer's disease (AD). Computational simulations and animal experiments have hinted at the theory of activity-dependent degeneration as the cause of this hub vulnerability. However, two critical issues remain unresolved.

Age- and sex-related differences in social competence and emotion labeling in pre-adolescence.

Identification of facial expressions is important to navigate social interactions and associates with developmental outcomes. It is presumed that social competence, behavioral emotion labeling and neural emotional face processing are related, but this has rarely been studied. Here, we investigated these interrelations and their associations with age and sex, in the YOUth cohort (1055 children, 8-11 years old).

Human pluripotent stem cell-derived microglia shape neuronal morphology and enhance network activity in vitro.

Background: Microglia, the resident immune cells of the central nervous system, play a critical role in maintaining neuronal health, but are often overlooked in traditional neuron-focused in vitro models.

New Method: In this study, we developed a novel co-culture system of human pluripotent stem cell (hPSC)-derived microglia and neurons to investigate how hPSC-derived microglia influence neuronal morphology and network activity. Using high-content morphological analysis and multi-electrode arrays (MEA), we demonstrate that these microglia successfully incorporate into neuronal networks and modulate key aspects of neuronal function.

BioMedGraphica: An All-in-One Platform for Biomedical Prior Knowledge and Omic Signaling Graph Generation.

Artificial intelligence (AI) is revolutionizing scientific discovery because of its super capability, following the neural scaling laws, to integrate and analyze large-scale datasets to mine knowledge. Foundation models, large language models (LLMs) and large vision models (LVMs), are among the most important foundations paving the way for general AI by pre-training on massive domain-specific datasets. Different from the well annotated, formatted and integrated large textual and image datasets for LLMs and LVMs, biomedical knowledge and datasets are fragmented with data scattered across publications and inconsistent databases that often use diverse nomenclature systems in the field of AI for Precision Health and Medicine (AI4PHM).

Functional network disruption in cognitively unimpaired autosomal dominant Alzheimer's disease: a magnetoencephalography study.

Understanding the nature and onset of neurophysiological changes, and the selective vulnerability of central hub regions in the functional network, may aid in managing the growing impact of Alzheimer's disease on society. However, the precise neurophysiological alterations occurring in the pre-clinical stage of human Alzheimer's disease remain controversial. This study aims to provide increased insights on quantitative neurophysiological alterations during a true early stage of Alzheimer's disease.

Single-Nucleus Atlas of Cell-Type Specific Genetic Regulation in the Human Brain.

Genetic risk variants for common diseases are predominantly located in non-coding regulatory regions and modulate gene expression. Although bulk tissue studies have elucidated shared mechanisms of regulatory and disease-associated genetics, the cellular specificity of these mechanisms remains largely unexplored. This study presents a comprehensive single-nucleus multi-ancestry atlas of genetic regulation of gene expression in the human prefrontal cortex, comprising 5.

Altered lipid profile and reduced neuronal support in human induced pluripotent stem cell-derived astrocytes from adrenoleukodystrophy patients.

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder resulting from pathogenic variants in the ABCD1 gene that primarily affects the nervous system and is characterized by progressive axonal degeneration in the spinal cord and peripheral nerves and leukodystrophy. Dysfunction of peroxisomal very long-chain fatty acid (VLCFA) degradation has been implicated in ALD pathology, but the impact on astrocytes, which critically support neuronal function, remains poorly understood. Fibroblasts from four ALD patients were reprogrammed to generate human-induced pluripotent stem cells (hiPSC).

Linking the gut microbiome to host DNA methylation by a discovery and replication epigenome-wide association study.

Microbiome influences multiple human systems, but its effects on gene methylation is unknown. We investigated the relations between gene methylation in blood and the abundance of common gut bacteria profiled by 16s rRNA gene sequencing in two population-based Dutch cohorts: LifeLines-Deep (LLD, n = 616, discovery) and the Netherlands Twin Register (NTR, n = 296, replication). In LLD, we also explored microbial pathways using data generated by shotgun metagenomic sequencing (n = 683).

Endosomal sorting protein SNX4 limits synaptic vesicle docking and release.

Sorting nexin 4 (SNX4) is an evolutionary conserved organizer of membrane recycling. In neurons, SNX4 accumulates in synapses, but how SNX4 affects synapse function remains unknown. We generated a conditional SNX4 knock-out mouse model and report that SNX4 cKO synapses show enhanced neurotransmission during train stimulation, while the first evoked EPSC was normal.

The Utility of Long-Read Sequencing in Diagnosing Early Onset Parkinson's Disease.

Objective: Variants in PRKN and PINK1 are the leading cause of early-onset autosomal recessive Parkinson's disease, yet many cases remain genetically unresolved. We previously identified a 7 megabases complex structural variant in a pair of monozygotic twins using Oxford Nanopore Technologies (ONT) long-read sequencing. This study aims to determine if ONT long-read sequencing can detect a second variant in other unresolved early-onset Parkinson's disease (EOPD) cases with 1 heterozygous PRKN or PINK1 variant.

Alzheimer's disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain.

Introduction: While there may be microbial contributions to Alzheimer's disease (AD), findings have been inconclusive. We recently reported an AD-associated CD83(+) microglia subtype associated with increased immunoglobulin G4 (IgG4) in the transverse colon (TC).

Methods: We used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments to explore this association.

Analysis of exonic deletions in a large population study provides novel insights into NRXN1 pathology.

The NRXN1 locus is a hotspot for non-recurrent copy number variants and exon-disrupting NRXN1 deletions have been associated with increased risk of neurodevelopmental disorders in case-control studies. However, corresponding population-based estimates of prevalence and disease-associated risk are currently lacking. Also, most studies have not differentiated between deletions affecting exons of different NRXN1 splice variants nor considered intronic deletions.

Meis transcription factors regulate cardiac conduction system development and adult function.

Aims: The Cardiac Conduction System (CCS) is progressively specified during development by interactions among a discrete number of Transcriptions Factors that ensure its proper patterning and the emergence of its functional properties. Meis genes encode homeodomain transcription factors (TFs) with multiple roles in mammalian development. In humans, Meis genes associate with congenital cardiac malformations and alterations of cardiac electrical activity, however the basis for these alterations has not been established.