Journal Article

The combination of brain glucose hypometabolism and hyperphosphorylated Tau (p-Tau) pathology is the strongest known clinical predictor of imminent cognitive decline, yet how these factors cooperate to drive dementia remains unknown. Here, we show that glucose hypometabolism synergizes with p-Tau to trigger neuronal loss through necroptosis. [...]

Subjective cognitive decline (SCD) refers to cognitive concerns that may occur with or without objective impairment on standardized testing. Studies suggest that SCD may be an early clinical marker of Alzheimer's disease and related dementias, and that it can predict future objective cognitive decline and progression to dementia. [...]

Isolated rapid eye movement sleep behavior disorder (iRBD) is a major prodromal marker of α-synucleinopathies, often preceding the clinical onset of Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. While wrist-worn actimeters hold significant potential for detecting RBD in large-scale screening efforts by capturing abnormal nocturnal movements, they require a reliable and efficient analysis pipeline. [...]

γ-Secretase is a pivotal membrane-embedded protease that cleaves more than 150 single-span membrane proteins within their transmembrane domains. While γ-secretase is involved in a wide range of physiological processes, it is best known for its critical role in Alzheimer's disease, where it cleaves a C-terminal fragment of the amyloid precursor protein into small aggregation-prone and neurotoxic peptides. [...]

Spinocerebellar Ataxia 27B (SCA27B) is a novel, frequent and likely treatable late-onset autosomal-dominant ataxia caused by GAA repeat-expansions in FGF14. For understanding disease evolution and imminent trial planning, metrics of the most widely used clinical outcome assessment (Scale for the Assessment and Rating of Ataxia/SARA), longitudinal progression and modifiers thereof are warranted.Multicentre intercontinental observational study (2015-2024) of 661 assessments from 219 patients with SCA27B (age: 68 ± 10 years; SARA: 9 ± 6 points) with item-level distribution-based analyses to characterise SARA metrics relative to ageing-related impairment in 390 healthy controls; and linear mixed-effects modelling to determine longitudinal progression and demographic or genetic modifiers.Ataxia severity in SCA27B as assessed by SARA was primarily attributable to gait, stance, and lower-limb impairment; other ataxia domains scored ≤1 SARA point in 79-94% of patients. [...]

Condensed biomolecular phases are fundamental compartments in cells and play intricate roles for cellular organization. Although often referred to as “membraneless organelles,” evidence has emerged that condensates associate with membranes through wetting interactions, which are physiologically important but not well understood. [...]

FUS is an RNA-binding protein mutated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive muscle weakness. We show in this work that a heterozygous knock-in mutation in the mouse Fus gene leads to cell-autonomous ultrastructural defects in skeletal muscle, with disruption of sarcomeres and mitochondria. [...]

Adults with Down syndrome (DS) have an increased risk of developing early Alzheimer disease. While our previous cross-sectional study investigated the blood proteome in the context of Alzheimer in DS, identifying CBLN4, CD14, C-X-C motif chemokine 17 (CXCL17), ectodysplasin A2 receptor (EDA2R), glial fibrillary acidic protein (GFAP), insulin-like growth factor binding protein-2 (IGFBP2), neurofilament light (NFL), SEPTIN3, and SPON1 as proteins of interest, longitudinal trajectories remain mostly unexplored. [...]

Hearing loss has been reported as a major, potentially modifiable risk factor for dementia and often co-occurs with tinnitus. Both conditions are prevalent and have been linked to brain health and cognitive decline. [...]

Stem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions, but limitations in reproducibility, maturation and cell-type diversity persist. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. [...]