Reviews & Analysis

Huntington disease is a neurodegenerative disorder caused by pathological expansion of the huntingtin (HTT) gene, and no disease-modifying therapies are currently available. Two new studies demonstrate different genetic approaches to targeting the toxic Htt transcript Htt1a in knockin mouse models of Huntington disease, which might inform future strategies to lower mutant HTT in humans.

Heckmann and colleagues critically appraise the literature on amyotrophic lateral sclerosis (ALS) and other motor neuron diseases in Africa, highlighting knowledge gaps and barriers to patient care. They also consider potential ALS mimics that are prevalent in this region and assess the evidence for a link between HIV infection and ALS.

Multiple sclerosis is marked by considerable prognostic uncertainty, and no unified framework currently exists to guide the integration of diverse prognostic factors. To address this gap, a MAGNIMS consortium proposes a multiaxial model, incorporating the overall burden of damage, the topography of injury and the capacity for compensation.

Migraine treatments that target calcitonin gene-related peptide (CGRP) are widely used, but questions remain regarding their mechanisms and sites of action. Re-examination of the effects of CGRP in the trigeminovascular system has now refined our understanding of nociceptive CGRP signalling and underscores the importance of early therapeutic intervention.

This Review outlines how the neural extracellular matrix (ECM) regulates synaptic function, memory and cognitive flexibility, and how its remodelling can contribute to both acute and chronic CNS disorders. The authors highlight emerging ECM-targeted therapies and technologies that could enable new treatments and biomarkers for neurological disorders.

The apolipoprotein E ε3 Christchurch variant provides remarkable resilience against Alzheimer disease by limiting tau propagation and suppressing neuroinflammation. New research reveals that this protection extends to the periphery, where ‘lipid-loaded’ extracellular vesicles stabilize the blood–brain barrier, which offers a novel systemic mechanism for developing potent disease-modifying therapies.

Twenty years after UK Biobank was established, the incidence of dementia among participants is set to rise rapidly. In this Perspective, Matthews et al. highlight how UK Biobank has advanced dementia research in its first 20 years and consider how future developments will leverage increasing incidence to further advance understanding of dementias.

Post-COVID-19 condition (PCC), also known as long COVID, is a heterogeneous condition marked by persistent symptoms following acute SARS-CoV-2 infection. This Review summarizes the spectrum of neurological and psychological symptoms in people with PCC and explores the proposed underlying mechanisms and current and future treatment approaches.

The prevalence of dementia is rising in low-income and middle-income countries, but access to advanced diagnostic and research tools such as neuroimaging remains severely restricted in these regions. This Review highlights the potential of low-field MRI as an accessible alternative to conventional imaging in resource-limited settings.

This Review explores how reciprocal brain–heart interactions can cause dysfunction in one of these organs to adversely affect the other. The authors discuss clinical conditions, such as Takotsubo syndrome and stroke–heart syndrome, in which these interactions are particularly prominent and address sex and gender differences in brain–heart interactions.

In this Review, the authors outline the physiology and innervation of the lower urinary tract and sexual organs and discuss various aspects of urogenital dysfunction in CNS (brain and spinal cord) disorders. Advances in the management of urogenital dysfunction in patients with neurological disorders are also discussed.

Delirium presents a major challenge in intensive care and postoperative settings; however, the pathophysiology is poorly understood. In this Perspective, Nedergaard and colleagues examine the evidence for impaired glymphatic flow as a central mechanism in the development of delirium and discuss potential strategies to mitigate delirium risk.

Impairment of episodic memory — the ability to recollect personal experiences — is an early symptom of Alzheimer disease (AD) and profoundly affects life participation and independence. This Review introduces the circuit utilization framework, which posits that episodic memory impairment in AD includes a regainable component stemming from suboptimal utilization of brain circuits.

Spreading depression is a slowly propagating wave of mass depolarization that successively engulfs contiguous brain regions, causing transient neuronal hyperexcitability at its leading edge, followed by complete but reversible neuronal silence lasting minutes. Here, the authors present an evidence-based view of spreading depression as a probable cause of characteristic neurological signs and symptoms in numerous neurological conditions.

Organoids provide a useful model to capture the heterogeneity of brain tumours. Here, the authors assess current methodologies for generating organoids from various types of brain tumour and discuss how these models have enhanced mechanistic insight into tumour initiation, progression and resistance to treatment, moving towards precision medicine.

Clinical diagnostic criteria for Parkinson disease (PD) have limitations, but no validated biomarker-based diagnostic framework currently exists. In this Review, Tolosa et al. examine progress towards biomarker-based diagnosis of PD, focusing on α-synuclein seed amplification assays alongside molecular, imaging and genetic markers.

Low-income and middle-income countries and other under-represented populations remain largely excluded from Parkinson disease research despite the growing disease burden. Here the authors detail diversity gaps across Parkinson disease research and outline priority actions to address them.

This Review explores how individual-level and neighbourhood-level social factors, including income, education, health-care access and neighbourhood deprivation, contribute to disparities in cognitive and neurobehavioural outcomes in people with epilepsy. The authors propose a new framework that integrates biological and social factors to better explain the heterogeneity of these outcomes.

Translation of evidence about dementia risk into effective public health policy is a challenge. In this Consensus Statement, Demnitz-King and colleagues present 56 policy recommendations for dementia prevention, providing policymakers with a foundation for designing and implementing evidence-based dementia prevention strategies, prioritizing clear communication, targeted intervention and sustained research investment.

Freezing of gait (FOG) is among the most debilitating symptoms of Parkinson disease. This Consensus Statement from the International Consortium for Freezing of Gait presents new guidelines for the definition and assessment of FOG, with the aim of harmonizing the study and management of the condition.