Reviews & Analysis

Growing evidence indicates a central role for meningeal inflammation in driving multiple sclerosis (MS) pathology. In this Review, the authors summarize current knowledge regarding structural, cellular and molecular changes to the meninges in MS and discuss the clinical and therapeutic implications.

Patients with Duchenne muscular dystrophy show clinically relevant phenotypic variability, despite sharing the same primary biochemical defect (dystrophin deficiency). In this Review, the authors provide an overview of the current evidence on Duchenne muscular dystrophy genetic modifiers that contribute to this variability.

Astrocytes are essential for neuronal survival and function in the CNS but, under pathological conditions, they can adopt potentially harmful reactive states. This Review highlights how ‘omics’ technologies can enable the functional characterization of defined reactive astrocyte states in various pathological scenarios.

Neurological diseases associated with specific pathogenic gene variants can show considerable phenotypic variation. This Review explores the mechanisms that underlie this phenomenon, including environmental, genetic and epigenetic factors that influence the expressivity and penetrance of pathogenic variants.

In this Review, the authors discuss the ways in which single-cell and spatially resolved transcriptomics are contributing to our understanding of the pathophysiology of neurological conditions. They also discuss the limitations and possible future directions of these technologies.

Some patients with Parkinson disease (PD) present with mostly non-motor symptoms. Here, Chaudhuri et al. discuss the evidence for CNS abnormalities in noradrenergic function in these individuals. Recognition of this noradrenergic subtype of PD might ultimately lead to subtype-specific treatments and personalized medicine.

Here, the authors summarize current knowledge regarding mechanisms of remyelination and remyelination failure in multiple sclerosis and animal models of the disease and discuss strategies to overcome the translational roadblock in the field of remyelination-promoting therapies.

Bruton tyrosine kinase inhibitors are an emerging treatment for multiple sclerosis. Krämer et al. consider the evidence that central nervous system-penetrant Bruton tyrosine kinase inhibitors might target both peripheral immune cells and compartmentalized inflammation and discuss promising preliminary results of clinical trials of these agents in multiple sclerosis.

In the field of Alzheimer disease genetics, a lack of ancestral diversity in study cohorts is limiting progress. Here, the authors summarize our current knowledge of Alzheimer disease genetics in populations across the world and highlight efforts to increase cohort diversity.

This Review highlights how two discoveries — expression of α7 nicotinic acetylcholine receptors (α7nAChRs) by astrocytes and a correlation between astrocytic α7nAChR overexpression and amyloid-β pathology — are bridging the gap between the cholinergic and amyloid cascade hypotheses of Alzheimer disease pathogenesis.

In this Review, the authors discuss recent efforts to predict disease onset, treatment response and disease outcome in individuals with psychosis. They cover genetic, biological, clinical and environmental predictive factors and assess whether the variation in outcomes is attributable to differences in the pathophysiology of psychosis.

Chronic neuropathic pain is a leading cause of disability that remains therapeutically challenging. Here, Fiore et al. review the immune mechanisms that contribute to the resolution of chronic neuropathic pain. Contributions of the gut microbiome and specialized pro-resolving mediators are also discussed, along with potential therapeutic strategies.

Wilson et al. review our current knowledge of the extracellular proteostasis system that protects the brain from the pathological consequences of extracellular protein aggregation. They discuss growing evidence that impairment of this system contributes to neuronal death in neurodegenerative diseases.

This article reviews key pathogenic mechanisms underlying the development of CNS autoimmunity, focusing on the role of autoantibodies that target neuronal and/or glial cell-surface antigens. The authors consider novel therapeutic approaches based on knowledge of the immunopathogenesis of autoimmune CNS disorders.

In this Review, the authors provide an overview of the evidence indicating that multiple sclerosis is a rare complication of infection with the Epstein–Barr virus and discuss the mechanisms that could underlie this association.

Here, Sven Bölte and colleagues consider the effects of sex and gender on neurodevelopmental conditions. They discuss the available epidemiological, behavioural, neurobiological and endocrinological evidence and highlight the importance of further research in this area.

Here, Timothy Steiner and Lars Stovner discuss the progression of migraine epidemiology over the last seven decades and question the apparent increase in migraine prevalence over time.

Facioscapulohumeral muscular dystrophy is caused by aberrant expression of the transcription factor DUX4. Tihaya, Mul and colleagues describe advances in the development of targeted treatments for facioscapulohumeral muscular dystrophy and discuss potential clinical trial outcome measures as well as molecular and imaging biomarkers.