Reviews & Analysis

New biologics are rapidly opening up target-specific therapeutic opportunities for myasthenia gravis (MG) — an autoimmune disease caused by antibodies against neuromuscular junction proteins. Two recent trials have now demonstrated the efficacy and tolerability of the complement C5 inhibitor zilucoplan and the FcRn inhibitor rozanolixizumab in patients with generalized MG.

A new study using the UK Biobank database has shown that people with epilepsy are at an increased risk of developing dementia. The results demonstrate that this risk is multiplied in individuals who also have high cardiovascular risk, highlighting the importance of addressing modifiable cardiovascular risk factors.

In this Perspective, Owolabi et al. propose strategies to improve brain health and address the growing global burden of neurological disorders. They present a new framework — the neurological quadrangle — which aims to provide equitable and effective surveillance, prevention, acute care and rehabilitation of neurological disorders globally.

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.

A new study examining trends in postmortem neuropathology results over the past 25 years provides important insights into secular trends in dementia risk. The results suggest that improvements in both cardiovascular health and cognitive reserve underlie the reduced risk.

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.

A study of more than 350,000 individuals has shown that multisite chronic pain is strongly correlated with elevated risk of dementia, decreased cognitive function and reduced hippocampal volume. Further study of these relationships and their potential underlying mechanisms is required and could inform the development of interventions to prevent or slow dementia.

Results from a phase III trial have set zavegepant as the first intranasal gepant to be approved by the FDA for the acute treatment of migraine. The therapeutic benefits were modest, however, and more work is needed to address unmet treatment needs.

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.

An artificial intelligence-based tool can turn low-resolution clinical MRI scans into high-resolution 3D objects suitable for research studies. The new approach opens up the possibility of secondary analysis of large clinical MRI datasets to answer disease-relevant questions, although further work to automate scan annotation will be required.

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.

A new study, drawing on data from national biobanks, adds to the growing evidence that exposure to common viral pathogens increases the risk of Alzheimer disease and other neurodegenerative diseases. These findings might provide insights into the initiating factors that lead to neurodegeneration.

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.

In this Perspective, Edwards and colleagues present their opinion that functional neurological disorder is categorically different from feigning and malingering. They discuss clinical, epidemiological and experimental evidence in support of this view.

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.