Review Articles

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.

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.

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.

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.

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.

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.

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.

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.