Reviews & Analysis

Huntington disease (HD)-like 2 (HDL2) is a rare HD phenocopy that seems to be confined to people with African ancestry. This Review summarizes our current knowledge of HDL2 and highlights the need for further studies of neurodegenerative diseases on the African continent.

Schizophrenia is a leading cause of global disability but lacks therapies that target all aspects of the disease. This Review summarizes our current understanding of the pathophysiological mechanisms underlying the disease, highlighting potential targets for new drug development.

Using integrative multiomics, a new study has shed light on the aetiology of ischaemic stroke. By probing the mechanisms underlying stroke, such approaches could aid the development of therapies and improve risk prediction and stratification, with the ultimate aim of developing personalized preventive and therapeutic strategies.

This Perspective proposes a tripartite model involving the amygdala, hippocampus and striatum as key structures underlying cognitive dysfunction in Parkinson disease. The authors explore the anatomical and functional relationships of the structures and summarize evidence of their involvement in the cognitive aspects of the disease.

Clinical boundaries between neurology and psychiatry hamper understanding of disorders with phenotypes that span these disciplines. In this Review, Peall et al. discuss rare genetic brain disorders with neurological and psychiatric phenotypes, and consider common underlying mechanisms that could be therapeutic targets.

A new study indicates that African American people with multiple sclerosis have higher markers of humoral disease pathology than white people with multiple sclerosis. However, apparent differences in pathophysiology between ethnic groups cannot be fully interpreted without more comprehensive studies that examine the effects of social inequality on disease.

Vascular cognitive impairment and dementia is the second most common cause of dementia after Alzheimer disease. In this Review, the authors examine the potential of key molecules in the pathophysiology as biomarkers of vascular cognitive impairment and dementia and consider the challenges of clinical translation.

The incidence of idiopathic intracranial hypertension is rapidly rising in line with global obesity rates. This Review summarizes evidence suggesting that the condition is not idiopathic but is instead related to systemic metabolic and hormonal perturbations and should thus be considered a metabolic disease.

This Review describes the emerging landscape of diagnostic, categorical and pharmacodynamic biomarkers for amyotrophic lateral sclerosis and considers the role of these biomarkers in the rapidly evolving landscape of new therapeutics for this condition.

New guidelines for designing controlled clinical trials for idiopathic intracranial hypertension (IIH) have been published. The design of such trials remains a challenge, as the heterogeneity of IIH necessitates different outcome measures for specific clinical presentations.

The limited success of amyloid-β-targeting therapies for Alzheimer disease has led to a shift in focus towards the tau protein. This Review provides an update on the initial trials of tau-targeting therapies, focusing particularly on immunotherapies, and considers future directions for these therapies.

The underlying cause of sporadic Alzheimer disease (AD) remains enigmatic, but an increased risk among spouses of people with AD has led to speculation of transmissibility. A mouse study now suggests that the transfer of microbiota could underlie this potential transmissibility, but the findings leave many questions unanswered.

Understanding of the pathogenetic mechanisms underlying cerebral malaria remains incomplete despite intense scrutiny. Hadjilaou et al. discuss potential treatment strategies targeting pathogen replication and clearance, host–pathogen interactions at the cerebrovasculature or leveraging host innate and adaptive immunity.

The term amyotrophic lateral sclerosis (ALS)–frontotemporal spectrum disorder encompasses a spectrum ranging from pure motor ALS to ALS with frontotemporal dementia. This Review focuses on the cognitive and behavioural impairments that are found in the mid-range of this spectrum.

Acquired neurocognitive impairment affects 30–50% of the 38 million people living with HIV worldwide. Here, the authors provide an overview of the proposed mechanisms of HIV-associated neurocognitive impairment and describe potential and emerging therapeutics and non-pharmacological interventions.

Here, the authors discuss evidence for the involvement of the cerebellum in Parkinson disease. They cover the anatomical connections between the cerebellum and basal ganglia and how functional and connectivity alterations observed in the cerebellum of people with the disease relate to specific clinical symptoms.

A new study indicates that although men and women are equally likely to experience cognitive impairment after acute ischaemic stroke, there are sex differences in particular cognitive domains. Whether these differences are directly linked to biological sex is uncertain, as many factors, including age and pre-stroke factors, could contribute to cognitive outcomes.

The amyotrophic lateral sclerosis exposome is the lifetime accumulation of environmental exposures that increase disease risk and affect progression. This Review summarizes the literature that has sought to characterize aspects of the amyotrophic lateral sclerosis exposome and considers potential mechanisms of exposure-induced toxicity.

The TRACK-TBI LONG study has shown that outcomes are highly variable in the 7 years after traumatic brain injury (TBI). Although many patients remain stable, almost one-third experience declines in cognitive, psychiatric and functional state. These findings suggest that TBI is a chronic disease and that its management should change accordingly.

Endemic parkinsonism occurs only in specific locations or populations. Here, Menšíková et al. describe clusters of endemic parkinsonism and highlight that those linked to neurotoxic environmental factors seem to be disappearing, while genetically determined clusters persist.