Reviews & Analysis

The term ‘rapidly progressive dementia’ (RPD) describes a cognitive disorder with fast progression, leading to dementia within a relatively short time. This Review discusses the wide range of RPD aetiologies, as well as the diagnostic approach and treatment options.

In this Review, Coyne and Rothstein discuss disruptions to the nuclear pore complex and nucleocytoplasmic transport, which are emerging as pathological mechanisms in multiple neurodegenerative diseases, and consider the effects of these changes on cellular function and their potential for therapeutic targeting.

Analysis of brain images taken before and after infection with SARS-CoV-2 suggests that even mild COVID-19 is associated with brain structure alterations and cognitive impairment. However, the clinical implications for individuals are unclear and further studies are needed to assess the generalizability of the findings and whether the effects are long-lasting.

A recent publication reveals progressive, dose-dependent ventricular enlargement in the brains of patients with early Alzheimer disease who were treated with the FDA-approved drug aducanumab. Aducanumab joins a growing list of anti-amyloid-β therapies for which there is evidence that they cause accelerated neurodegeneration; extended follow-up studies are required to determine whether aducanumab causes progressive brain damage.

In this Review, the authors discuss how various immunotherapies for neuroimmunological diseases interact with vaccination responses, including responses to SARS-CoV-2 vaccinations, and the implications for the safe and effective use of vaccines in patients with these diseases.

Consensus is growing that intervention in the very early stages of Alzheimer disease is necessary for disease modification. Here, the authors discuss the challenges of recruiting asymptomatic or mildly symptomatic participants for clinical trials, focusing on ‘trial-ready’ cohorts as a potential solution.

In this Review, the authors highlight the growing recognition that disruptions in cellular metabolism can be both a cause and a consequence of epileptic seizures and discuss how this emerging science might be exploited to develop innovative therapeutic strategies.

In this Perspectives article, David Fischer and colleagues present a stepwise conceptual framework for neuroprognostication after severe brain injury, with the aim of providing structure and guidance to supplement clinical judgement and direct future investigation.

Post-traumatic stress disorder (PTSD) is one of the few neuropsychiatric disorders for which the timing and cause of onset are understood, facilitating research into the underlying mechanisms. In this Review, Ressler and colleagues examine the neurobiology of PTSD, highlighting new insights from omics studies and discussing future directions of research.

In this Review, the authors discuss recessive ataxias with ganglionopathy or polyneuropathy — particularly Friedreich ataxia and RFC1-associated cerebellar ataxia, neuropathy, vestibular areflexia syndrome — including the possible shared pathogenic mechanisms between these diseases and therapeutic advances.

Some individuals accumulate high levels of Alzheimer disease neuropathological changes without showing symptoms of the disease. Here, the authors review the insights that have been gained from post mortem studies of such ‘resilient’ individuals and discuss the implications for risk prediction and the development of therapeutic interventions.

The mechanistic contribution of cerebrovascular dysfunction to neurodegenerative diseases is difficult to determine. New single-cell transcriptomic analyses of human brain microvessels have identified transcriptomic signatures along the arteriovenous axis and transcriptional changes in the cerebrovasculature in Alzheimer disease and Huntington disease. This approach could advance our understanding of brain health and disease.

Use of a proteomics approach has demonstrated that changes in protein expression association with Alzheimer disease are not always reflected in changes in RNA levels, highlighting the importance of directly studying proteomic changes to a full understanding of Alzheimer disease pathogenesis.

Glioblastoma is one of the most treatment-resistant CNS malignancies, and the tumour inevitably recurs, usually in or near the resection cavity. Here, the authors discuss local therapies for glioblastoma, examining treatment of the resection cavity and other direct approaches to the tumour.

This Perspective highlights the importance of integrating cultural factors into dementia research and care. Focusing on minoritized groups in the USA, the authors explore the effects of culture on clinical evaluation, dementia risk, research and study recruitment, and caregiving practices.

A new case series describes a cohort of individuals with severe psychiatric presentations who were diagnosed with ‘possible’ or ‘probable’ autoimmune encephalitis on the basis of neurological examination. Many participants improved after treatment with immunotherapy, highlighting the importance of fostering a closer relationship between the fields of neurology and psychiatry.

Microglia are involved in many brain disorders, yet little is known about how genetic variants impact microglial function. A new study combined genome-wide association study data with the microglial transcriptomes of the same participants to reveal functional variants underlying brain disorders. This information will help to further mechanistic studies into disease-associated microglial changes.

The largest genome-wide association study of amyotrophic lateral sclerosis to date has identified new risk loci and provided insight into factors that influence susceptibility to the disease, highlighting the possibility that disease risk and disease progression are influenced by separate factors, with therapeutic implications.

In this Review, the authors discuss the involvement of astrocytes and microglia in the pathophysiology of progressive multiple sclerosis and consider current and future therapeutic approaches that directly target glial cells.

In vivo imaging biomarkers for early diagnosis and monitoring of Parkinson disease (PD) are important for the development of new therapies. The authors review recent advances in brain and retinal imaging in PD, focusing particularly on multimodal approaches with applications at the prodromal stage.