Reviews & Analysis

The past few years have seen the identification of a growing number of risk factors for Alzheimer disease (AD). In this Perspectives article, the authors discuss the evidence for a bidirectional relationship between disrupted sleep patterns and amyloid-β accumulation, and the potential implications for disease progression in AD.

A population-based study of babies who were exposed to antiepileptic drugs (AEDs) in utero revealed impairment of fine motor and social skills as early as 6 months of age. Such neurocognitive changes were independent of breastfeeding status at 18 months, suggesting that breastfeeding can be recommended in women receiving AEDs.

Medulloblastomas can be categorized into four molecular subgroups. A new report shows, for the first time, that these tumours remain in the same subgroup at relapse, and the molecular subgroup influences the pattern of relapse. These findings indicate that this developmentally defined classification is robust, although its relationship to prognosis remains uncertain.

A key challenge to improving the design of clinical trials in Huntington disease (HD) has been the limited data on the natural history of HD. A recent prospective longitudinal study has provided important information in this regard, which could be useful for future translation of disease-modifying therapies for early-stage HD.

According to a new systematic review, placebo treatment in clinical trials of migraine prophylaxis results in responder rates ranging from 0–56%, probably owing to variable combinations of spontaneous improvement and genuine placebo effects. Clinicians who treat patients with migraine should be aware of the potential nonspecific effects of any treatment modality.

In this Review, Paul Matthews and colleagues outline the potential benefits of a stratified approach to health-care delivery in neurology, including reduced risk of adverse events from medicines, and lower treatment costs. They provide examples of neurological diseases in which stratified medicine is already improving treatment, and consider challenges to implementation of these approaches.

Subarachnoid haemorrhage (SAH) has a high case fatality. In addition to neurological injury occurring at the time of haemorrhage, delayed neurological deterioration can occur days later owing to processes such as cerebral vasospasm and microthrombosis, which culminate in delayed cerebral ischaemia. R. Loch Macdonald reviews the pathophysiology of these delayed complications of SAH, and outlines existing treatments and drugs in development for this indication.

Gilles de la Tourette syndrome (GTS) is often perceived as the 'swearing disease', yet coprolalia affects only 10–15% of individuals with this condition. As highlighted in a new study, GTS has many phenotypes, some of which are sex-related. Could gender—that is, culturally established roles—also affect the phenotype?

Increasing evidence suggests that Parkinson disease (PD) should be included on the growing list of diseases associated with vitamin D insufficiency. A recent study reconfirms this association and supports the monitoring of vitamin D concentrations in patients with PD. The conundrum of causality regarding this association, however, remains unanswered.

Primary cilia are hair-like, non-motile sensory organelles that are found on the surface of almost all cells in vertebrates. Defects in these organelles can lead to a wide array of disorders known as ciliopathies. In this Review, Valente et al. focus on ciliopathies with major neurological involvement, describing their clinical features and known pathogenetic mechanisms, and discussing the possible aetiologies of associated brain malformations.

Survivors of critical illness can experience substantial morbidity long after the event. Recent findings provide further support that long-term cognitive impairment is frequent in these patients, and that in many cases, delirium due to encephalopathy has a causal role in its development.

Currently approved multiple sclerosis (MS) treatments mainly target the peripheral immune system, thereby reducing relapse rates and MRI markers of inflammation. A recent phase III trial indicates that laquinimod, a new orally active immunomodulator, has a CNS-intrinsic mode of action that is independent of effects on the peripheral immune response.

Increasing use of brain monitoring via continuous EEG in intensive care units has revealed that subclinical seizures are common among adults and children with acute brain injury. Subclinical seizures are associated with worse outcomes, but whether their prompt detection and treatment improves outcomes remains a pressing clinical question.

Effective treatments are lacking for most neurological disorders, and progress in developing new therapeutic agents has been frustratingly slow. Howells and colleagues explore the barriers to the development of treatments for these conditions, focusing predominantly on the stroke field. They highlight the current deficiencies and conflicts of interest in preclinical and clinical research, and suggest ways in which scientific rigour might be improved.

Chronic cerebrospinal venous insufficiency (CCSVI) has been proposed as a cause of multiple sclerosis (MS). However, two new studies found a very low overall prevalence of definite CCSVI, and no association with MS. The data confirm that the ultrasound findings of CCSVI are extremely variable, subjective, and based on major methodological flaws.

Prion-like propagation of pathogenic proteins has been suggested to underlie several neurodegenerative diseases. In this Perspectives article, Braak et al. posit that progressive lesions in amyotrophic lateral sclerosis (ALS) spread through cell-to-cell transfer of 43-kDA transactive response DNA-binding protein, mainly through cortical neuronal projections to other brain areas and the spinal cord. This model could have important implications for our understanding of ALS and approach to treatment.

Notable failures of amyloid-β-targeted therapies in late-stage clinical trials for Alzheimer disease (AD) suggest the need for a reassessment of the amyloid cascade hypothesis of AD pathology. Here, Giacobini and Gold discuss the limitations of focusing on amyloid-β, and suggest a shift towards tau-directed therapy. They outline the rationale for such an approach and summarize results in animal models that show promise for translation to the clinic.

Rodent models of nerve injury are frequently used to study peripheral nerve regeneration, but translating the findings to clinical applications has been difficult, in part because in axons in humans generally need to regenerate over much longer distances, leaving the distal nerves and muscle tissue denervated for long periods of time. In this Review, Scheib and Höke discuss the challenges and advances in the study of peripheral nerve regeneration, and suggest that chronic rodent models of nerve injury more closely mimic the chronic denervation condition that is commonly present in human nerve injuries.

Current approaches to rehabiliation of motor and language function after stroke focus on compensation rather than repair of the underlying damage, often with limited clinical benefit. Here, Steven Small and colleagues propose a new model for poststroke therapy that aims to rebuild brain circuits underlying the impaired functional domains. They describe experience with action observation therapy, which harnesses the putative mirror neuron system in humans to improve motor performance and language skills.

In addition to difficulties in movement, patients with Parkinson disease (PD) exhibit changes in somatosensory function, which might contribute substantially to disability by interfering with signals that are required for the preparation and execution of voluntary movement. In this article, Conte et al. review the evidence for disrupted tactile, nociceptive, thermal and proprioceptive sensations in PD, and the effects of dopaminergic therapy and deep brain stimulation on these sensations.