Advances in neurodegenerative diseases

Feng et al. unravel the structural basis of TDP-43 higher-order assemblies with mRNA and the structural changes leading to TDP-43 aggregation, which are associated with neurodegenerative diseases such as Amyotrophic Lateral Sclerosis.

Sleep-active physiological processes enhance overnight glymphatic clearance of Alzheimer’s disease biomarkers into plasma in humans, supporting the critical role of glymphatic function in Alzheimer’s pathophysiology and its potential as a therapeutic target.

Li et al. apply machine learning to longitudinal clinical notes to improve prediction of Alzheimer’s disease. They find that Alzheimer’s-related keywords occur more often in patients who later develop the disease, rising sharply before diagnosis and helping identify high-risk individuals.

Kopal et al. analyze MRI data from a Parkinson’s Disease cohort to assess how LRRK2 gene variants shape brain structure. They find that LRRK2-associated Parkinson’s Disease shows a milder and anatomically distinct pattern of neurodegeneration compared to non LRRK2-associated Parkinson’s Disease.

A genome-wide association study in Japanese patients with ALS identifies rs113161727 at the ADAM29-GPM6A locus as a modifier of age at onset and links it to GPM6A upregulation.

High-affinity ligands were developed that specifically bind aggregated TDP-43, are selective over common co-pathologies, and possess pharmacokinetic profiles suitable for PET imaging to visualize TDP-43 pathology in the brains of patients.

Candidate PET ligands targeting pathological TDP-43 aggregates are characterized by Vokali and colleagues in a series of human tissue, cell/animal model, and non-human primate experiments. Their preclinical data suggests favorable specificity and pharmacokinetic profiles of their two candidate tracers, which could translate into a disease-specific biomarker in TDP-43 proteinopathies.

The role of individual lipid species in Alzheimer’s disease (AD) is not fully understood. Here, the authors performed global lipidomics on post-mortem dorsolateral prefrontal cortex collected from 316 participants in the ROSMAP cohort including asymptomatic and symptomatic AD.

Genome-wide CRISPR/Cas9 screening reveals novel modulators of heparan sulfate proteoglycans that regulate cellular uptake of α-synuclein fibrils, including in human dopaminergic neurons.

Structural and biochemical analyses reveal Lewy-MSA hybrid α-synuclein filament fold in atypical pathological variant of MSA, linking distinct neuronal cytopathology to unique filament conformations and expanding structure-based classification.

MINT is a Python toolbox for multimodal data integration and community detection, offering cross-validation and modality selection optimization to identify biologically relevant subgroups and predict Alzheimer’s progression.

Gao et al. examine if napping patterns can predict individuals at risk for cognitive impairment. They find that among older adults, more morning naps are linked to a higher Alzheimer’s risk, while more early afternoon naps and less variability in nap duration are linked to lower levels of Alzheimer’s pathology.

This study characterised the landscapes and changes of RNA m6A in brains of individuals with or without Alzheimer’s disease, and revealed roles of a promoter antisense RNA next to MAPT in neuronal gene regulation that promote neuronal survival.

BPAN is a rare neurodegenerative disease caused by WDR45 mutations. Here, the authors discover that WDR45 can competitively displace G3BP1 from Caprin-1 to promote stress granule disassembly, a function that is disrupted by BPAN-associated WDR45 mutations.

Early expression of intraneuronal amyloid-β (not phospho-tau) and inflammatory and glycosylation pathway transcripts distinguish neocortical RORB⁺ and GAD1⁺ neurons selectively vulnerable to neurodegeneration in Alzheimer’s disease.

WM dysfunction observed in AD and MCI spatially correlates with specific genes enriched in biological processes related to synaptic function and development, mostly active in neurons and astrocytes.

Ex vivo stimulation of isolated monocytes and T cells from peripheral blood immune cells reveals distinct signatures of immune activation across different stages of Parkinson’s disease, including the prodromal stage.

Kverneng et al. assess the mitochondrial respiratory chain in skeletal muscle from persons with Parkinson’s disease. Their findings suggest the existence of a subpopulation with complex I deficiency and support the potential of extra-neural biomarkers for patient stratification.

Feizpour et al. assess the utility of a high-performing Alzheimer’s disease (AD) blood test to discriminate AD disease stages. The blood test reliably detects Intermediate and Advanced stages of disease, and while the test is less effective at distinguishing Advanced stage alone, it may reduce reliance on expensive brain scans.

Nunes et al. predict Huntington’s disease score by applying deep learning to readings from a wrist-worn sensor obtained over a 7 day period. Differences are seen in goal-directed movement that correlate with clinical score.