Exploring the neuromagnetic signatures of cognitive decline from mild cognitive impairment to Alzheimer's disease dementia

EBioMedicine, Journal Year: 2025, Volume and Issue: 114, P. 105659 - 105659

Published: March 29, 2025

Language: Английский

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Divergent patterns of healthy aging across human brain regions at single-cell resolution reveal links to neurodegenerative disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 1, 2023

Abstract Age is a major common risk factor underlying neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s and amyotrophic lateral sclerosis. Previous studies reported that chronological age correlates with differential gene expression across different brain regions. However, prior datasets have not disambiguated whether associations are due to changes in cell numbers and/or per cell. In this study, we leveraged single nucleus RNA-sequencing (snRNAseq) examine proportions transcriptomes four regions, each from 12 donors aged 20-30 years (young) or 60-85 (old). We sampled 155,192 nuclei two cortical regions (entorhinal cortex middle temporal gyrus) subcortical (putamen subventricular zone) relevant diseases the proliferative niche. found no cellular composition of healthy aging. Surprisingly, did find region has distinct aging signature, only minor overlap differentially associated genes Moreover, type shows age-associated changes, loss protein synthesis inhibitory neurons, axonogenesis excitatory neurons oligodendrocyte precursor cells, enhanced gliosis markers astrocytes disease-associated microglia, critical for neuron-glia communication. Importantly, type-specific enrichments nominated by disease genome-wide association (GWAS), such as apolipoprotein E ( APOE ), leucine-rich repeat kinase 2 LRRK2 ) microglia independent overall levels types. present data new resource which highlights, first, region- transcriptomic may contribute selective vulnerability and, second, provide context testing GWAS-nominated subtypes developing more targeted therapeutic strategies. The readily accessible without requirement extensive computational support public website, https://brainexp-hykyffa56a-uc.a.run.app/ Graphical *Created using Biorender.com Highlights Establishment atlas human Each exhibits unique aging-associated transcriptome signature Gene occur absence overt categorically types Neurological patterns specific

Language: Английский

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Neurophysiological trajectories in Alzheimer’s disease progression

eLife, Journal Year: 2024, Volume and Issue: 12

Published: March 28, 2024

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, progressive neurodegeneration cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, trajectories abnormal AD progression their relationship to decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) investigate long-range local synchrony across stages, estimated from resting-state magnetoencephalography. The increases delta-theta band decreases alpha beta bands showed changes throughout stages EBM. Decreases preceded both decline, indicating that frequency-specific neuronal abnormalities early manifestations pathophysiology. effects were greater than synchrony, a sensitivity connectivity metrics involving multiple regions brain. These results demonstrate evolution functional deficits along sequence progression.

Language: Английский

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Characterizing dysregulations via cell-cell communications in Alzheimer’s brains using single-cell transcriptomes

BMC Neuroscience, Journal Year: 2024, Volume and Issue: 25(1)

Published: May 13, 2024

Abstract Background Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting 44 million people worldwide, leading to cognitive decline, memory loss, and significant impairment in daily functioning. The recent single-cell sequencing technology has revolutionized genetic genomic resolution by enabling scientists explore the diversity of gene expression patterns at finest resolution. Most existing studies have solely focused on molecular perturbations within each cell, but cells live microenvironments rather than isolated entities. Here, we leveraged large-scale publicly available single-nucleus RNA human prefrontal cortex investigate cell-to-cell communication healthy brains their AD. We uniformly processed snRNA-seq with strict QCs labeled canonical cell types consistent definitions from BRAIN Initiative Cell Census Network. From ligand receptor expression, built high-confidence network signaling differences between AD brains. Results Specifically, first performed broad pattern analyses highlight that biologically related normal rely largely overlapping networks brain exhibits irregular inter-mixing pathways. Secondly, more cell-type-centric analysis found excitatory neurons significantly increased communications inhibitory neurons, while other non-neuronal globally decreased theirs all cells. Then, delved deeper signaling-centric view, showing pathways CSF, TGFβ, CX3C are dysregulated type microglia/PVM endothelial neuronal for WNT pathway. Finally, after extracting 23 known risk genes, our intracellular revealed strong connection extracellular genes APP, APOE, PSEN1 TREM2, ABCA1, APP astrocytes microglia neurons. Conclusions In summary, novel advances technologies, show cellular regulated cell-type-specific manner improper regulation linked giving mechanistic intra- inter-cellular picture

Language: Английский

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Viscous dynamics associated with hypoexcitation and structural disintegration in neurodegeneration via generative whole‐brain modeling

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(5), P. 3228 - 3250

Published: March 19, 2024

Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) lack mechanistic biophysical modeling in diverse, underrepresented populations. Electroencephalography (EEG) is a high temporal resolution, cost-effective technique for studying globally, but lacks models produces non-replicable results.

Language: Английский

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Biophysical models applied to dementia patients reveal links between geographical origin, gender, disease duration, and loss of neural inhibition

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: April 11, 2024

Abstract Background The hypothesis of decreased neural inhibition in dementia has been sparsely studied functional magnetic resonance imaging (fMRI) data across patients with different subtypes, and the role social demographic heterogeneities on this remains to be addressed. Methods We inferred regional by fitting a biophysical whole-brain model (dynamic mean field realistic inter-areal connectivity) fMRI from 414 participants, including Alzheimer’s disease, behavioral variant frontotemporal dementia, controls. then investigated effect disease condition, clinical variables local inhibitory feedback, variable related maintenance balanced excitation/inhibition. Results Decreased feedback was modeling results patients, specific brain areas presenting neurodegeneration. This loss correlated positively years showed differences regarding gender geographical origin patients. correctly reproduced known disease-related changes connectivity. Conclusions suggest critical link between abnormal circuit-level excitability levels, grey matter observed reorganization connectivity, while highlighting sensitivity underlying mechanism patient population.

Language: Английский

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Personalized whole-brain neural mass models reveal combined Aβ and tau hyperexcitable influences in Alzheimer’s disease

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: May 4, 2024

Abstract Neuronal dysfunction and cognitive deterioration in Alzheimer’s disease (AD) are likely caused by multiple pathophysiological factors. However, mechanistic evidence humans remains scarce, requiring improved non-invasive techniques integrative models. We introduce personalized AD computational models built on whole-brain Wilson-Cowan oscillators incorporating resting-state functional MRI, amyloid-β (Aβ) tau-PET from 132 individuals the spectrum to evaluate direct impact of toxic protein deposition neuronal activity. This subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aβ tau effects impairment excitability increases with progression. The data-derived values strongly predict clinically relevant plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP) grey matter atrophy obtained through voxel-based morphometry. Furthermore, reconstructed EEG proxy quantities show hallmark electrophysiological alterations (theta band activity enhancement alpha reductions) which occur Aβ-positivity after limbic involvement. Microglial activation influences less definitive, potentially due neuroimaging limitations mapping neuroprotective vs detrimental phenotypes. Mechanistic brain can further clarify intricate neurodegenerative processes accelerate preventive/treatment interventions.

Language: Английский

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Different oscillatory mechanisms of dementia-related diseases with cognitive impairment in closed-eye state

NeuroImage, Journal Year: 2024, Volume and Issue: unknown, P. 120945 - 120945

Published: Nov. 1, 2024

Language: Английский

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Neuroprotection and Mechanism of Gas-miR36-5p from Gastrodia elata in an Alzheimer’s Disease Model by Regulating Glycogen Synthase Kinase-3β

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(24), P. 17295 - 17295

Published: Dec. 9, 2023

Alzheimer’s disease (AD) is currently the most common neurodegenerative disease. Glycogen synthase kinase 3β (GSK-3β) a pivotal factor in AD pathogenesis. Recent research has demonstrated that plant miRNAs exert cross-kingdom regulation on target genes animals. Gastrodia elata (G. elata) valuable traditional Chinese medicine significant pharmacological activity against diseases of central nervous system (CNS). Our previous studies have indicated G. elata-specific miRNA plays regulatory role for NF-κB signaling pathway mice. In this study, further bioinformatics analysis suggested Gas-miR36-5p targets GSK-3β. Through western blot, RT-qPCR, and assessments T-AOC, SOD, MDA levels, its neuroprotective effects an cell model. Furthermore, was detected murine brain tissues. The results Morris water maze test blot provided positive evidence reversing learning deficits hyperphosphorylation Tau mice, elucidating model following RNA administration. emphasizes as novel with properties by targeting Consequently, our findings provide insights into mechanisms underlying miRNA, presenting perspective treatment

Language: Английский

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Longitudinal resting-state EEG in amyloid-positive patients along the Alzheimer’s disease continuum: considerations for clinical trials

Alzheimer s Research & Therapy, Journal Year: 2023, Volume and Issue: 15(1)

Published: Oct. 19, 2023

To enable successful inclusion of electroencephalography (EEG) outcome measures in Alzheimer's disease (AD) clinical trials, we retrospectively mapped the progression resting-state EEG over time amyloid-positive patients with mild cognitive impairment (MCI) or dementia due to AD.Resting-state 21-channel was recorded 148 AD (MCI, n = 88; AD, 60). Two more recordings were available for all subjects. We computed whole-brain and regional relative power (i.e., theta (4-8 Hz), alpha1 (8-10 alpha2 (10-13 beta (13-30 Hz)), peak frequency, signal variability permutation entropy), functional connectivity values alpha corrected amplitude envelope correlation, phase lag index, weighted symbolic mutual information, inverted joint entropy). Whole-group linear mixed effects models used model development time. Group-wise analysis performed investigate potential differences change trajectories between MCI subgroups. Finally, estimated minimum sample size required detect different treatment 50% less deterioration, stabilization, improvement) on time, hypothetical trials 1- 2-year duration.Whole-group revealed significant global oscillatory slowing increased power, decreased power), strongest temporal parieto-occipital regions. Disease severity at baseline influenced measures' rates change, fastest deterioration reported patients. Only displayed a decrease frequency estimate that focusing patients, require 36 subjects per arm (2 arms, 1:1 randomization, 80% power) stabilizing effect power.Resting-state could facilitate early detection neuronal function Their sensitivity depends region-of-interest study population. Conventional spectral measures, particularly from regions, present sensitive monitoring markers.

Language: Английский

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