Opinion

Kullmann et al. discuss the need for gene therapy in epilepsy and the challenges of translating experimental research into the clinic. Furthermore, they outline the potential for gene therapy strategies in pharmacoresistant epilepsy, ways to assess therapeutic efficacy, and the need to evaluate long-term safety data.

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.

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.

Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is an effective treatment for acute ischaemic stroke, although its use for patients with mild forms of this condition remains controversial. Here, Guerrero and Savitz outline the potential risks and benefits of rtPA in this patient population, and explain why they believe patients with mild ischaemic stroke should receive this treatment.

Despite recent advances in our understanding of the pathophysiology of mitochondrial disease, beneficial treatments for these disorders are lacking. In this Perspectives article, Pfeffer et al. retrospectively review data from clinical trials in mitochondrial disease, and find that many problems arise from publication bias and poor trial design. After discussing these issues, the authors make recommendations for the design of future treatment trials in mitochondrial diseases.

Uhthoff's phenomena are transient disturbances in neurological functioning that can be triggered by an increase in core body temperature in patients with multiple sclerosis (MS). In this article, Frohman et al. discuss the pathophysiological underpinnings of Uhthoff's phenomena, and highlight the importance of differentiating between these events and true MS exacerbations in the clinic.

The aim of palliative care is to improve the quality of life for patients with terminal illness, and also their families. In this Perspectives article, the author discusses the challenges specific to palliative care for patients with neurological disorders, and outlines new approaches to the care of these patients.

In this Perspectives article, Roozenbeek et al. discuss issues with epidemiological studies in traumatic brain injury (TBI) and variability in the definition of such injuries. They describe how changing epidemiological patterns have influenced mortality and outcomes following brain injury, and identify the need for standardized epidemiological monitoring in TBI.

Hypertension is highly prevalent, particularly in individuals over 60 years of age, and constitutes a major risk factor for stroke and dementia. Antihypertensive therapy in elderly individuals has, however, been limited owing to concerns over adverse effects of such therapies. In this Perspectives article, Sörös et al. emphasize that treatment of hypertension can markedly reduce stroke and dementia risk, and argue that antihypertensive therapy should be considered in all patients, irrespective of age.

Pathological changes underlying Alzheimer disease (AD) begin more than 10 years before clinical presentation, and the need for early therapeutic intervention is becoming increasingly recognized. Reisa Sperling and colleagues consider challenges to such an approach—including the difficulty of defining preclinical AD, and ethical issues associated with disclosing information on AD biomarker status to healthy individuals—and discuss possible ways to overcome these hurdles.

The neurovascular unit is a key concept in stroke medicine that for many years has been defined as the endothelial cells, neurons and glia surrounding cerebral capillaries. In this Perspectives article, the authors expand this concept to encompass more-distant circulation, smooth muscle cells and perivascular innervation. This 'neural vascular network' in turn points to new strategies for stroke therapy.

Immunotherapy targeting amyloid-β showed promise for treatment of Alzheimer disease (AD) in preclinical studies, but trials in humans have yielded disappointing results. In their Perspectives article, Liu and colleagues discuss adverse effects of amyloid-targeted therapies, which have limited treatment efficacy, and propose strategies to optimize the design of future therapeutic antibodies for AD.

The first-in-human phase I trial of stem cell transplantation for amyotrophic lateral sclerosis was approved by the FDA in 2009 and is ongoing. In their Perspectives article, Eva Feldman and colleagues, who are conducting the trial, discuss the preclinical research supporting this therapeutic approach, key aspects of the trial design to overcome translational issues, and ongoing challenges to address in future studies.

Clinical trials for amyotrophic lateral sclerosis have failed to yield a single new drug over the past 17 years. In their Opinion article, Gordon and Meininger provide insights into possible reasons for the lack of success, such as the heterogeneity of the disease, limitations of preclinical models, and the choice of clinical end points. They also present possible strategies to address the ongoing challenges, including appropriate dose selection and development of suitable biomarkers.

Many individuals with Parkinson disease (PD) adopt a sedentary lifestyle as a result of the motor and nonmotor complications associated with the disease. In this article, Speelman et al. discuss 10 reasons why exercise may be of benefit to patients with PD, suggesting that increased levels of physical activity can have disease-specific and, potentially, disease-modifying effects. The limitations and obstacles to changing the sedentary lifestyles of patients with PD are also discussed.

The considerable need for research on Alzheimer disease (AD) is complicated by the impaired capacity of patients with AD to provide informed consent to participate in research and the lack of well-defined policy guidelines on this issue. Scott Kim highlights the importance of distinguishing between capacity and authenticity when assessing the ability of a patient with AD to provide informed consent, and discusses how the role of surrogate decision-makers could be enhanced in this context.

Multiple system atrophy is characterized by a combination of parkinsonian, cerebellar, autonomic and pyramidal features, but recent data indicate that the clinical spectrum also includes nonmotor symptoms such as urinary disorders and orthostatic hypotension. Colosimo argues that neurologists and other specialists should be made aware that this neurodegenerative disease can manifest with nonmotor symptoms long before patients develop any overt motor disorder.

Labate et al. argue that benign mesial temporal lobe epilepsy (bMTLE)—defined as at least 24 months of seizure freedom with or without antiepileptic medication—has been under-recognized because of a bias in the literature towards refractory forms of epilepsy. Here, the authors discuss emerging concepts on bMTLE, some of which were formulated during an international workshop held in Italy.

MicroRNAs (miRNAs) seem to confer a novel layer of gene regulation, possibly fine-tuning the expression of ≈50% of genes in humans. Dysfunction of these short regulatory RNAs has been noted in various neurological disorders, including Alzheimer disease and Parkinson disease. Here, Junker and colleagues explore the possible involvement of miRNAs in multiple sclerosis, highlighting the therapeutic implications for this disease.

Protein misfolding and aggregation occur in most neurodegenerative disorders, but the concept of spreading and infectivity of aggregates in the CNS has, until recently, been confined to prion diseases such as Creutzfeldt–Jakob disease. New evidence suggests that prion-like spreading, involving proteins such as amyloid-β, tau, huntingtin and α-synuclein, can occur in other neurodegenerative disorders. In this article, Lee et al. discuss the underlying molecular mechanisms and consider the therapeutic implications of the new data.