Reviews & Analysis

Amyloid-β (Aβ) and tau come in a variety of forms and assembly states, not all of which are toxic. In this Review, Polanco and colleagues explain the clinical and therapeutic implications of this new understanding while highlighting the physiological and pathogenetic roles of Aβ and tau.

Parkinson disease (PD) affects up to 10 million people worldwide and is clinically diagnosed. Molecular phenotyping of patient samples might help to corroborate diagnosis, and a new study suggests that blood-based gene expression profiling might distinguish between patients with PD and those without. However, experience suggests that additional replication is needed.

Cognitive ageing is a complex public health, social and economic problem that demands a bold response — a paradigm shift that leads science and society to view brain health across the lifespan of every individual as critically important. Implementation of 'Life's Simple 7' is a laudable step in that direction.

Two decades after antisense oligonucleotides (ASOs) were initially identified as agents capable of modulating RNA processing and protein expression, the first antisense oligonucleotide (ASO) therapies have now been approved for the treatment of neurological disease. Here, Rinaldi and Wood discuss our current understanding of ASO pharmacology, and the future prospects for ASO-mediated treatment of neurological disease

Idiopathic rapid eye movement (REM) sleep behavioural disorder (RBD) is now recognized as an early marker of α-synucleinopathies. Here, Högl and colleagues review potential biomarkers for RBD and summarize the evidence for a prodromal stage, which might enable disease-modifying intervention. In light of these advances, they reconceptualize idiopathic RBD as isolated RBD.

A compelling need exists for a more reliable risk evaluation of natalizumab- associated progressive multifocal leukoencephalopathy (PML). A new report proposes a refined protocol that uses updated patient-based data and cumulative risk evaluation to provide an improved assessment of the annual risk of PML for patients positive for JC virus.

Inadequate remyelination is central to degeneration and disability in patients with multiple sclerosis (MS); however, all currently approved therapies for MS are primarily immunomodulatory. Here, Martin Stangel and colleagues review our current knowledge of remyelination in MS, discuss results from clinical trials of remyelination-enhancing therapies, and evaluate the opportunities for future regenerative treatments.

The causes of migraine remain unknown despite the high prevalence and societal burden of this disorder. Here, the authors highlight how advances in imaging and genetic studies of migraine provide insights into the underlying mechanisms of this disorder; furthermore, they discuss the potential for genetic and imaging biomarkers to improve our ability to prevent and treat migraine attacks.

Patients with prodromal Parkinson disease (PD) are most likely to respond to disease-modifying strategies. To date, cognitive impairment has been viewed as a complication of late-stage disease, but a longitudinal analysis of data from the Rotterdam cohort raises the possibility that such impairments are also associated with prodromal PD.

The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer immunotherapy, but these agents carry a high risk of immune-related adverse events. Here, the authors introduce the mechanisms of action of ICIs and review their adverse effects on the CNS, which result in conditions such as paraneoplastic neurological syndromes and multiple sclerosis.

Sadnicka and colleagues present task-specific dystonia in the context of motor skill learning in health. Their framework integrates established risk factors for task-specific dystonia with mechanisms of motor skill learning, to indicate how disrupted neural representations of motor skills might arise.

In recently published guidelines on the diagnosis and treatment of cerebral venous thrombosis, the European Stroke Organization has applied a rigorous evidence-based methodology, following the GRADE system. However, the guidelines provide many weak recommendations, reflecting the fact that more high-quality evidence from multicentre observational and experimental studies is needed.

Exercise and physical therapy are important adjunct interventions to improve gait and balance impairments in patients with Parkinson disease (PD), as these features are inadequately treated by current pharmacological and surgical treatments. Here, Mak and colleagues discuss the long-term effects of exercise and physical therapy for PD, possible risks, recommendations for clinical practice, and emerging treatment approaches.

Fatigue, defined as extreme and persistent mental and/or physical tiredness, weakness or exhaustion, frequently occurs as a challenging symptom or comorbidity in many neurological diseases. In this Review, Penner and Paul discuss the definitions and manifestations of fatigue, focusing on its pathophysiological background, assessment strategies, and current treatment options.

PET is a versatile imaging technique that is advancing our understanding of cerebrovascular disease and intracerebral pathophysiology. In this Review, Evans and colleagues describe mechanistic insights from PET studies relating to the metabolic pathophysiology of carotid atherosclerosis, salvageable penumbra after stroke, and neuroinflammatory changes associated with small vessel disease and vascular cognitive impairment.

In the ongoing search for new and better migraine treatments, human models have a key role in the discovery of novel targets for antimigraine drugs. This Review summarizes existing experimental models of migraine in humans, and describes the development and use of these models in the identification of key molecular pathways, biomarkers and drug targets.

The Lancet Commission on Dementia Prevention, Intervention, and Care has evaluated current evidence on dementia management, including the measures that can be taken to reduce an individual's risk of dementia. However, further intervention trials and evaluation in real-world settings are needed to alter dementia incidence globally.

Preventing the misfolding, aggregation, accumulation and propagation of α-synuclein — pivotal mechanisms that contribute to neurodegeneration in Parkinson disease (PD) and other synucleinopathies — is the ultimate goal of research into neuroprotective therapy. Now, exenatide, a glucagon-like peptide-1 (GLP-1) agonist, has been reported to ameliorate the severity of motor symptoms associated with PD.

Genome engineering tools, including targeted gene editing and gene regulation, are becoming available to correct the mutations that cause neuromuscular disorders such as muscular dystrophy, spinal muscular atrophy and myotonic dystrophy. This Review summarizes the genome engineering strategies that are under preclinical evaluation for the treatment of degenerative neuromuscular disorders, focusing on the tools that show the greatest potential for clinical translation.

Increasing evidence suggests that Alzheimer disease (AD) is not simply a CNS disorder, but involves interactions between systemic and brain-related factors. Wang and colleagues review the role of amyloid-β (Aβ) in AD, highlighting systemic abnormalities linked to Aβ metabolism and discussing how these abnormalities might influence central pathways of Aβ production and clearance.