Review Articles

Early diagnosis of Alzheimer disease (AD) is crucial for efficient selection of clinical trial participants for drug development and ultimately for timely treatment of individuals with AD. Here, Claire Murphy examines the potential for olfactory and other sensory impairments as very early indicators of AD and considers the important questions that remain to be answered.

Pathogenic variants in POLG, which encodes the catalytic subunit of DNA polymerase γ, cause a spectrum of overlapping disease phenotypes. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG-related disorders, focusing particularly on the neurological manifestations.

In this Review, Handel and colleagues examine the contribution of thymic T cell selection to CNS autoimmune conditions and consider how a better understanding of this contribution could lead to novel therapeutic strategies for these conditions.

Premonitory symptoms of migraine can start hours to days before the onset of headache. In this Review, Karsan and Goadsby discuss the phenotypes of these premonitory symptoms and the insights that they provide into the neurobiology of migraine.

New technological advances in genomics have enabled the rapid discovery of hundreds of gene mutations linked to epilepsy. This Review considers the prospects for precision medicine in genetic epilepsies, the use of conventional and novel experimental models to unpick the complex pathogenic mechanisms of these diseases and the opportunities and challenges that face basic and clinical researchers.

Traumatic brain injury (TBI) susceptibility and outcomes are influenced by numerous factors, many relating to sex and gender. The authors review recent research exploring the influence of sex and gender in the TBI context, focusing particularly on marginalized populations.

Advances in biomarker research are aiding the development of targeted therapies and prevention strategies for Alzheimer disease (AD). In this Review, an international working group assesses the current status of blood-based AD biomarkers and outlines a roadmap for future research.

Prevention of dementia through moderation of risk factors presents a promising strategy to counter the rising dementia epidemic. In this Review, Kivipelto and colleagues discuss lifestyle-related risk factors for dementia, results from clinical trials of lifestyle interventions and new multinational initiatives that aim to identify and test effective dementia prevention strategies.

In this Review, the authors describe the current data detailing the role of triggering receptor expressed on myeloid cells (TREM2) in microglial biology and Alzheimer disease (AD), and discuss the possibility of targeting TREM2 as a treatment for AD.

In this Review, Khalil et al. consider how technological advances have enabled the detection of neurofilament proteins in the blood, and discuss how these proteins consequently have the potential to be easily measured biomarkers of neuroaxonal injury in various neurological conditions.

Lafora disease is an autosomal recessive, progressive myoclonus epilepsy caused by loss of function of laforin or malin, leading to impaired glycogen metabolism. The authors review the clinical and molecular features of Lafora disease and discuss current and emerging treatment options.

In this Review, the authors consider advances over the past decade that have set the stage for a resurgence in attempts to predict seizures in epilepsy, and they propose new avenues of investigation that combine mechanisms, models, data, devices and algorithms.

Advances in our understanding of the pathogenic mechanisms of spinocerebellar ataxias (SCAs) have resulted in the development of promising therapeutic strategies for these inherited neurodegenerative disorders. Here, Ashizawa and colleagues review the current progress and future challenges facing clinical trials of new therapies for the SCAs.

Repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Balendra and Isaacs review the pathological and mechanistic features of C9orf72-associated ALS and FTD, highlighting loss-of-function, gain-of-function and downstream mechanisms.

In this Review, the authors consider the evidence for the contribution of various factors to the pathogenesis of cerebral palsy, highlighting the complexities in its aetiology to inform translational research for the prevention of cerebral palsy.

Migraine is prevalent in the paediatric population and represents a major cause of disability. This Review outlines the epidemiology and natural history of paediatric migraine, discusses the recent landmark clinical trials of treatments for paediatric migraine and examines the best evidence-based interventions for this population in light of these new findings.

Glioblastomas remain one of the most aggressive and lethal tumours, with no effective treatments available. Here, Xandra Breakefield and colleagues examine the ways in which glioblastomas manipulate brain cells and immune cells in their environment to support tumour growth and the opportunities available for new therapies that disrupt these interactions.

In this Review, Ferretti et al. discuss the evidence for sex-related differences in Alzheimer disease symptoms, progression, risk factors and treatment, and consider how understanding sex differences is crucial in developing precision medicine.

This Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed Alzheimer disease with a focus on using spatial navigation as a diagnostic tool. Research gaps and future research priorities are also identified.

Non-rapid eye movement (NREM) sleep parasomnias are thought to derive from incomplete arousal from NREM sleep. Here, the authors present evidence for coexistence of sleep-like and wake-like brain activity in disorders of arousal, including confusional arousals, sleep terrors and sleepwalking.