Reviews & Analysis

In this Review, Wiendl et al. consider how the study of rare but paradigmatic neuroimmunological diseases, including Susac syndrome, Rasmussen encephalitis and narcolepsy type 1, is providing fundamental insights into disease mechanisms that can be applied to more complex, heterogeneous neuroimmunological diseases such as multiple sclerosis.

Results of two recent studies by Messoud Ashina and colleagues demonstrate that infusion of two different potassium channel openers can trigger migraine in humans; one of the compounds also triggered aura in patients diagnosed with migraine with aura. The findings highlight the importance of human experimental models in migraine research.

Several childhood disorders, including infantile colic and cyclical vomiting syndrome, are thought to be related to migraine. In this Perspective, Gelfand and Abu-Arafeh present evidence for each of these disorders to be considered as part of a ‘childhood migraine syndrome’.

In patients with progressive multiple sclerosis, the presence of active inflammation is associated with improved efficacy of anti-inflammatory therapies. However, the frequency of active inflammation in this patient population is unknown, and is the subject of a new study.

The numeric clinical staging scheme in the 2018 NIA–AA research framework reflects the concept that symptoms of Alzheimer disease sit on a continuum rather than falling into distinct clinical categories. A recent study operationalized these clinical stages to evaluate their utility but found limitations in their application.

Despite the declining incidence of variant Creutzfeldt–Jakob disease, prion diseases remain a threat to public health. In this Review, Suvankar Pal and colleagues provide an up-to-date overview of the transmission of prion diseases in human populations and argue that CJD surveillance is still vital.

Chronic traumatic encephalopathy (CTE) is presumed to be associated with a clinical condition termed traumatic encephalopathy syndrome (TES). A new set of research diagnostic criteria for TES might be an improvement over previous guidelines, but many questions surrounding the putative link between head impacts, CTE neuropathology and neurobehavioural symptoms remain unanswered.

The failure to identify disease-modifying therapies for amyotrophic lateral sclerosis (ALS) could relate to the prevailing motor neuron-centric view of this neurodegenerative disorder. This Review considers the evidence for involvement of non-neuronal cells — in particular, microglia, astrocytes and oligodendrocytes — in ALS pathogenesis.

In this Review, Berg et al. summarize current understanding of prodromal Parkinson disease and consider the prodrome in the context of the clinical and pathological heterogeneity of the disease. They explore the possibility that prodromal Parkinson disease can be classified into subtypes.

Biomarkers that predict conversion from isolated REM sleep behaviour disorder to Parkinson disease are urgently needed. A new study finds that detection of misfolded α-synuclein in the cerebrospinal fluid is a good marker of conversion risk, but an inability to predict the timeline of progression might limit its utility.

In this Review, Wei and Goadsby discuss the pathophysiology of cluster headache, the treatments available and their mechanisms, and the insights being provided by results from trials of emerging treatments, which indicate mechanistic differences between episodic and chronic cluster headache.

Apolipoprotein E (APOE) is the most abundant apolipoprotein in the brain, where it is primarily expressed and secreted by astrocytes and microglia. APOE seems to exert immunomodulatory effects in an isoform-dependent way, and a new study indicates that the APOE isoform dictates the glycosylation state and secretion of this apolipoprotein.

In this Review, the authors provide an overview of the evidence for daily, multi-day and yearly cycles in epileptic brain activity. They also discuss advances in our understanding of the mechanisms underlying these cycles and the potential clinical applications of this knowledge.

Microglia are the first immune cells to encounter a developing primary brain tumour and have both tumour-supporting and antitumour effects. Here, Keane et al. consider the emerging evidence indicating that tumour-associated macrophages and microglia influence tumour initiation and progression as well as responses to therapy.

Impairments in prospective memory — that is, memory for future intentions, such as remembering to take medications — are observed in many neurological disorders. Henry reviews the manifestations and neural bases of prospective memory deficits and provides algorithms to guide evaluation and treatment.

In this Perspective, the authors discuss the steps necessary to achieve predictive modelling of neurological diseases with human induced pluripotent stem cells, including applications to diagnosis and prognosis in the context of a precision medicine paradigm.

A recent report in Nature Cancer proposes that glioblastoma can be stratified into four functional subgroups on the basis of pathway inference from single-cell or bulk gene expression data. The analysis disclosed a pathway-based subgroup of glioblastoma that depends on oxidative phosphorylation and could potentially be targeted with mitochondrial metabolism inhibitors.

The incidence and severity of Guillain–Barré syndrome (GBS) are increased in low-income and middle-income countries (LMIC) by distinct geographic, economic and environmental factors. Here, Papri and colleagues highlight the most important challenges and knowledge gaps relating to GBS in LMIC.

A recent study reports an improvement in migraine symptoms during a COVID-19 lockdown in the Netherlands. The findings suggest that lifestyle changes can substantially alter the course of migraine, opening the door for greater use of behavioural interventions alongside existing pharmacological therapies.

Assessment of the long-term effectiveness of disease-modifying therapies in multiple sclerosis is plagued by methodological issues, but statistical methods continue to evolve. Use of a novel approach has highlighted the importance of accounting for cumulative exposure to disease-modifying therapies when assessing the long-term effects of treatment on disability accumulation.