Brain

Abstract Familial forms of ALS are potential candidates for gene-directed therapies, but many recently identified genes remain poorly characterized. Here, we provide a comprehensive clinical, neuropathological, and biochemical description of fALS caused by the heterozygous p.R15L missense mutation in the gene CHCHD10. Using a cross-sectional study design, we evaluated five affected and nine unaff…

Abnormal amyloid β and microtubule-associated protein are two intimately related proteinopathies central to the pathophysiology of Alzheimer disease (AD). Both are often accompanied by cholesterol dysmetabolism and/or altered transport of this neutral lipid in carriers of the APOEε4 (apolipoprotein E gene epsilon 4 allele), a causal gene for early-onset (familial) AD and the most important geneti…

This scientific commentary refers to ‘Benchmarking long-read sequencing approaches to resolve facioscapulohumeral dystrophy locus complexity’ by Tardy et al. (https://doi.org/10.1093/brain/awag029).

Dementia in Lewy body diseases (LBD) is common and arises through heterogeneous and incompletely understood pathways. Evidence suggests contributions from genetic factors, including APOE ε4 genotype, co-pathology including concomitant Alzheimer's disease pathology and hypoperfusion related to orthostatic hypotension. However, the relative impact of these factors remains unclear. To address this, …

Genome-wide association studies (GWAS) have identified over 230 genetic variants associated with susceptibility to multiple sclerosis (MS) and one genome-wide significant variant associated with progression of MS. Environmental risk factors, such as vitamin D deficiency and obesity, have also been implicated in MS pathogenesis. Statistical approaches building on these genetic data, such as Mendel…

Reported prevalence estimates of Lewy body pathology (LBP) vary widely, often without considering brain regional distributions or demographic influences. Large, population-representative autopsy cohorts are needed to provide estimates and clarify the distribution and clinical implications of LBP. Neuropathological, genetic, and clinical data were pooled from nine community- or population-based br…

Approximately 10% of clinically unimpaired individuals with abnormal amyloid (A+; preclinical Alzheimer's disease) have "divergent" cortical tau pathology (A+TCortical+), defined as greater than expected tau in cortical regions relative to medial temporal lobe and/or cortical asymmetry on tau PET in addition to or instead of traditional medial temporal lobe tau burden. Although these A+TCortical+…

Familial hemiplegic migraine (FHM) is a severe autosomal dominant subtype of migraine with aura, characterized by transient motor weakness during attacks. Known genes (CACNA1A, ATP1A2, SCN1A, PRRT2) account for fewer than 20% of genetically diagnosed cases. To identify novel genetic contributors to FHM, we performed whole-genome linkage analysis and partial exome sequencing in a four-generation p…

This scientific commentary refers to ‘Empathy motivation is preserved following amygdala damage’ by Scheffer et al. (https://doi.org/10/1093/brain/awag074).

The onset of epilepsy in adulthood occurs most commonly after 55 years of age. Given the ageing global population, this disorder represents an increasing burden on healthcare and society. The bidirectional link between epilepsy and dementia is a focus of intense research with underlying tau pathology highlighted as a potential mechanistic link. In this review, we examine the evidence for tau-rela…

This scientific commentary refers to ‘Cognition in multiple sclerosis within the modern diagnostic and treatment era’ by Sumowski et al. (https://doi.org/10.1093/brain/awaf446).

The USA, UK and other countries have announced major cuts to overseas development aid. Coughlan et al. describe the possible consequences for global neurology research, and the potential effects of these cuts on people living with neurological diseases in some of the world's poorest countries.

This scientific commentary refers to ‘Biological classification of memory clinic patients’ by Mastenbroek et al. (https://doi.org/10.1093/brain/awaf411).

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which there is no cure. While the precise etiology of ALS remains elusive, growing evidence suggests a pathogenic role for human endogenous retrovirus-K (HERV-K) in ALS. Expression of HERV-K subtype HML-2 envelope protein in neurons causes neurotoxicity in vitro and induces ALS-like symptoms in mice. We investigate…

Efforts to predict schizophrenia risk using biological data have been hampered by the heterogeneity of current "clinical-high-risk" (CHR-P) criteria, which pool phenomenologically and biologically distinct syndromes under a single label. In particular, the field has focused almost exclusively on ultra-high-risk (UHR) symptoms, while cognitive basic symptoms (COGDIS)-despite their close alignment …

Functional neurological disorder (FND) presents disabling symptoms that fluctuate, migrate across systems, and yet routinely show preserved structural integrity-features that can frustrate diagnosis and patient education. Crucially, these symptoms are genuine and reflect altered brain regulation across multiple systems rather than tissue damage or conscious control. This paper offers a clinically…

The symbol for DNA is all around us, on advertising and in the news. Yet it is almost always drawn incorrectly. Elizabeth Fisher explains how it should be depicted, and why it is important that we get the famous double helix right.

A hexanucleotide (GGGGCC) repeat expansion in C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), resulting in reduced C9orf72 mRNA and protein expression. C9orf72 is highly expressed in the cerebellum and growing evidence implicates C9orf72-associated cerebellar pathology across neurodegenerative disorders including AL…

This scientific commentary refers to ‘Granulocyte and astrocyte markers distinguish MOG antibody disease and neuromyelitis optica from multiple sclerosis’ by Furlan et al. (https://doi.org/10.1093/brain/awaf345).

Pathological forms of TAR-binding protein 43 (TDP-43), involving its aberrant mislocalization to the cytoplasm, inclusion formation, hyperphosphorylation and fragmentation, are present in ∼45-50% frontotemporal dementia (FTD) and Alzheimer's disease individuals, and most (97%) amyotrophic lateral sclerosis (ALS) cases. Hence, identifying mechanisms that induce TDP-43 pathology are central to neur…