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Mitochondrial membrane protein-associated neurodegeneration (MPAN) from the neurodegeneration with brain iron accumulation (NBIA) family is a rare neurodegenerative disease marked by α-synuclein aggregation, brain iron accumulation, and midbrain dopaminergic neuron degeneration.The mechanisms driving neuron vulnerability remain unclear. Our study aimed to develop a patient-derived disease model replicating key pathologies of patient brains.We generated induced pluripotent stem cell-derived midbrain dopaminergic neurons from MPAN patients and examined ultrastructural and biochemical markers of pathology.MPAN patient neurons displayed α-synuclein aggregation, axonal swellings, iron accumulation, and severe membrane destruction. [...]

Genome-wide association study of Parkinson's disease (PD) identified common variants associated with lysosomal mechanism, including TMEM175, SCARB2, and CTSB. We investigated the association between common and rare variants across populations using cohorts from the Global Parkinson's Genetics Program (GP2) (33,733 cases and 18,703 controls from ten ancestries). [...]

Aging and accumulation of α-synuclein (α-syn) oligomers in the brain are indisputably linked to Parkinson’s disease (PD). Using an inducible α-syn oligomer mouse model, we demonstrate that the induction of PD-associated α-syn oligomers for the same time span caused PD-associated symptoms only in aged, but not in young mice. [...]

Pressure overload first leads to compensated hypertrophy and secondary to heart failure. m6A-RNA methylation is a fast process for the adaptation of cell composition. [...]

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific treatment, of which molecular mechanisms remain poorly understood. To identify potential biomarkers and therapeutic targets, we applied Mendelian randomization to examine over 2,500 proteins measured in plasma and, uniquely, cerebrospinal fluid, in relation to magnetic resonance imaging (MRI) markers of cSVD in more than 40,000 individuals. [...]

Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets.We collected data from 55 cohorts with a combined sample size of 732,564 participants (87 % European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). [...]

Neuronal aggregates of Tau are a hallmark of Alzheimer's disease (AD), but more than half of the patients exhibit additional TDP-43 inclusions, while some have co-aggregates of the two proteins. The presence of such co-aggregates is associated with increased disease severity, although whether there is a causal relationship remains unclear. [...]

Predicting functional recovery after ischemic stroke is vital for guiding clinical care. This study investigated whether lesion network mapping (LNM), a technique for modeling symptom-specific brain networks, can improve outcome prediction of functional recovery up to one-year post-stroke.We pooled data from two prospective stroke cohorts (1000Plus and PROSCIS-B; N = 565). [...]

To compare cerebellar transcranial direct current stimulation (tDCS)-induced electric field strengths between individuals with spinocerebellar ataxia type 3 (SCA3) and healthy controls and to identify factors that underlie the variability in field strength.MRI scans from 68 SCA3 mutation carriers spanning the disease spectrum and 37 healthy adults were used to reconstruct tetrahedral volume meshes of the head. Electric field simulations of midline cerebellar tDCS were performed with the buccinator muscle, frontopolar region, and lower neck as reference electrode positions. [...]

In genetic amyotrophic lateral sclerosis (ALS), the clinical phenotypes, disease progression and neurofilament light chain (NfL) levels are incompletely characterized.In a total cohort of 1988 ALS patients, a subcohort of genetic ALS linked to C9orf72 (n = 137), SOD1 (n = 54), TARDBP (n = 27), and FUS (n = 19) was investigated. The phenotypes of onset region, propagation and motor neuron involvement were analyzed according to the OPM classification. [...]