Reviews & Analysis

Two recent studies leverage the same French population-based disease registry to describe real-world medication prescription patterns, patient characteristics and treatment effectiveness in people with schizophrenia. These studies also identify disparities in the health care and outcomes of these individuals compared with those of the general population.

Results from the phase III trials of the amyloid-targeting antibodies donanemab and solanezumab add further evidence that amyloid pathology is a key driver of cognitive decline in Alzheimer disease. The mixed results highlight important considerations for future trials and clinical practice.

Cholesterol has diverse roles in the brain, and precise regulation of cholesterol production and catabolism is essential for healthy brain function. This Review summarizes cholesterol regulation and function in the brain and discusses evidence of cholesterol dyshomeostasis in age-related neuropathology and a number of neurological diseases. In particular, the authors focus on Huntington disease and insights from rodent models.

Understanding of the psychiatric and behavioural consequences of traumatic brain injury (TBI) remains limited. In this Review, Li and colleagues highlight ways to progress research in this field and discuss neuropsychiatric sequelae of TBI that affect long-term health outcomes and functional recovery.

Two studies have confirmed previous observations that an inverse relationship exists between chronological age and focal white-matter inflammatory activity in individuals with multiple sclerosis, which could underlie the relative ineffectiveness of traditional disease-modifying therapies in older individuals.

Limbic-predominant age-related TDP43 encephalopathy (LATE) is a clinical entity characterized by amnestic dementia resembling Alzheimer disease. This Review focuses on the pathology, genetic risk factors and clinical features associated with pure LATE neuropathological change and LATE neuropathological change with coexisting pathologies.

The diagnosis of cerebral palsy is currently made on clinical observations only and does not consider aetiology or pathology. Here, van Eyk and colleagues review the current state of genomic testing in cerebral palsy and highlight the benefits of a ‘genotype-first’ approach for this group of disorders.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease classically thought to impact the motor system, but research is now investigating the contribution of non-motor symptoms. Here, the authors explore evidence that highlights the extent to which nutrition and metabolism might contribute to ALS pathogenesis, and discuss the effectiveness of modifying energy balance in ALS.

The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and European Academy of Neurology (EAN) joint consensus statement on vaccination in people with multiple sclerosis provides highly relevant clinical guidance on immunization strategies in today’s era of effective immunotherapies. Nevertheless, several open questions remain to be addressed.

Ditans are a recently developed drug class for the treatment of acute migraine. In this Review, the authors provide an overview of ditan development, from the initial rationale to the clinical studies that led to the recent FDA approval of the first ditan.

Smouldering inflammation encompasses all non-relapsing aspects of inflammatory pathobiology in multiple sclerosis. Here, Bittner and colleagues describe the mechanisms that underlie CNS-compartmentalized smouldering inflammation and review evidence indicating that immunometabolic reprogramming driven by the CNS tissue microenvironment shapes these inflammatory responses. Potential treatments are also discussed.

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.

Current approaches to classifying cognitive impairment in people living with HIV can overestimate disease burden and lead to ambiguity around disease mechanisms. In this Consensus Statement, the International HIV-Cognition Working Group have outlined six recommendations towards a new approach, intended to better represent changes in the spectrum of HIV disease in the modern era of antiretroviral therapy.

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.

Here, the authors offer their perspective on the roles of cell states in sustaining health and counteracting disease, and examine how cellular ageing might set the stage for pathological fate loss and neurodegeneration.

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.