Reviews & Analysis

Traumatic brain injury (TBI) is increasingly recognized as a risk factor for dementia. New data provide further support for this association and demonstrate the influence of age at injury and injury severity on dementia risk after TBI, revealing that even mild TBI increases dementia risk in those aged ≥65 years.

The past year has seen some extraordinary activity in clinical amyotrophic lateral sclerosis (ALS) research. Two trials were completed, with negative results, but the discovery of novel ALS-associated genes, and body fluid and imaging biomarkers warrants cautious optimism. Here, we provide a snapshot of some of the main findings in 2014.

The short-term safety and efficacy of IFN-β in patients with multiple sclerosis are well established, but less is known about this drug when taken over years and decades. Sormani and Bruzzi discuss the difficulties associated with designing studies of the long-term treatment effects of IFN-β. They then present techniques that have been employed to minimize potential sources of bias. The authors conclude that long-term use of IFN-β reduces clinical progression, but important questions relating to mortality warrant further investigation.

The notion that the classic motor features of Parkinson disease (PD) are preceded by a prodrome has received renewed interest in the past decade. A recent study corroborates previous findings that smell loss and constipation are signifiers of nigral degeneration. But can we really predict who is going to get PD?

The recent TOPIC trial found that teriflunomide could prevent relapses in patients with clinically isolated syndrome (CIS). Many other multiple sclerosis (MS) therapies are effective for CIS, because CIS is the first clinical manifestation of MS for most patients. Questions remain over the utility of future trials like TOPIC.

Despite a growing emphasis on biomarkers in research into Alzheimer disease (AD) and Parkinson disease (PD), there is little consensus as to which biomarkers are most effective. In this Review, Lleó and colleagues discuss cerebrospinal fluid (CSF) biomarkers for AD and PD, with a particular emphasis on applicability to clinical trials. Compared with AD, less is known about CSF biomarkers in PD, and the authors highlight several areas for further research.

LDL-lowering drugs are widely recommended for the secondary prevention of vascular events in patients who have experienced a stroke or transient ischaemic attack. As a new study illustrates, however, lipid management among this group remains inadequate, possibly placing patients at unnecessary risk of stroke recurrence.

The network between mitochondia is in a constant state of flux, with organelles fusing and separating in response to cellular metabolic demands. Disturbances to mitochondrial fusion and fission have been observed in several human diseases, and in this Review, Florence Burté and colleagues discuss how the mitochondrial network might play a crucial part in neurodegeneration. The authors focus on major protein mediators of mitochondrial dynamics, including optic atrophy protein and the mitofusins, and trace the involvement of mitochondrial dynamics in autosomal dominant optic atrophy, Charcot–Marie–Tooth disease and other disorders.

After decades of near neglect, the importance of exercise for patients with Parkinson disease is being increasingly supported by recent studies in experimental animal models and controlled clinical trials. Now, an inverse relationship between physical activity and disease burden has been demonstrated in a large cohort study.

Despite the promise that many potential neuroprotective treatments for Parkinson disease (PD) have shown in preclinical studies, the benefits have not been replicated in recent clinical trials. In this Review, Athauda and Foltynie discuss the reasons for this 'failure to translate', and propose strategies to avoid such eventualities in the future, including improved trial design and repositioning of existing drugs. They also review the most promising drugs that are currently in preclinical development or clinical testing for their neuroprotective properties in PD.

Neuromyelitis optica spectrum disorders (NMOSD) can mimic multiple sclerosis (MS). Avoiding misdiagnosis is crucial, because some disease-modifying drugs for MS can aggravate NMOSD, causing blindness and paraplegia. A recent study reports that misdiagnosis of NMOSD as MS occasionally occurs, and that a two-step antibody assay could improve differential diagnosis.

Disruption of circadian rhythms in neurodegenerative disorders not only contributes to morbidity and poor quality of life, but could also be involved in driving the disease process itself. Restoration of circadian rhythmicity via behavioural or pharmacological interventions might, therefore, slow down disease progression. In this Review, Videnovic and colleagues provide an overview of the circadian system, and summarize current understanding of the dysfunction of circadian rhythms in Alzheimer disease, Parkinson disease and Huntington disease.

Despite a wealth of data generated by neuroimaging research in Parkinson disease (PD), no imaging techniques are currently recommended for routine clinical use. In this Review, Marios Politis assesses the various PET, single-photon emission CT, MRI and other imaging modalities that could aid the differential diagnosis and assessment of patients with PD. He then looks to the future of neuroimaging, including newly developed radioligands and combined-modality approaches, and discusses how research and clinical practice might better address the needs of patients.

After brain injuries, microglia and macrophages can aid or hinder tissue repair depending on polarization toward specific cell phenotypes. This Perspectives article describes the phenotypic dynamics and different functions of these cells after acute CNS injury and argues that therapeutic approaches should focus on subtle adjustment of the balance between their phenotypes.

Glioblastoma is the most common primary brain tumour in adults, but—unlike many other cancers—no blood-based biomarkers are available for differential diagnosis, estimation of prognosis or monitoring of treatment response in glioblastoma. New research has detected three proteins with potential clinical value in the blood of patients with glioblastoma.

The knowledge of imaging and fluid biomarkers gained from longitudinal observational studies of Alzheimer disease has recently been translated to a cross-sectional study of randomly selected, cognitively unimpaired elderly individuals. This is the first time that a two-feature biomarker classification system has been applied to a population-based cohort.

Clinical exome sequencing (CES) is becoming a standard tool for molecular diagnosis of genetic disorders, with a diagnostic yield of approximately 25%. New studies demonstrate the favourable diagnostic yield of CES for both early-onset and adult-onset neurogenetic disorders. These studies demonstrate the strengths, limitations and potential of CES in neurology practice.

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a common and severe adverse effect of cytostatic drugs that can limit dose and choice of chemotherapy, and can lead to delay or discontinuation of cytostatic treatment. Most drugs that are in use for neuropathic pain have failed to alleviate CIPNP in clinical trials. Here, Sisignano et al. review the mechanisms through which the most commonly used cytostatic drugs cause CIPNP, and suggest mechanism-based treatment options.

Genome-wide association studies (GWASs) are uncovering genetic variants that are associated with the risk of stroke, and with specific stroke subtypes. In this Review, Markus and Bevan explore the implications of these associations for predictive testing, clinical management and new therapeutic approaches, as well as insights into stroke pathophysiology. They also outline considerations for future studies, so as to maximize the potential of GWASs.

Epidemiological evidence strongly suggests that circulatory levels of 25-hydroxyvitamin D below 50 nmol/l are associated with cognitive impairment and the development of dementia. A number of biochemical mechanisms could explain these effects; however, interventional studies to date have revealed disappointingly little.