Reviews & Analysis

The recent DOMINO-AD trial suggests that continued treatment with donepezil delays nursing home placement for patients with severe Alzheimer disease, but more work is needed to support strong conclusions about whether the benefits outweigh the costs.

Parkinson disease (PD) is now regarded as a mixed motor, nonmotor and multiorgan disorder rather than a pure movement disorder. Nonmotor symptoms (NMS) have underpinned this conceptual change, and new criteria for clinical and prodromal diagnosis of PD, incorporating a range of NMS, have recently been published.

Hepatitis E virus (HEV) is the causative agent of hepatitis E, and extrahepatic manifestations, including various types of neurological injury, have also been reported in individuals with HEV infection. The most common neurological manifestations are Guillain–Barré syndrome (GBS), neuralgic amyotrophy, and encephalitis and/or myelitis. In this article, the authors review the reported cases of HEV-associated neurological injury, discuss the possible pathogenic mechanisms, and outline future directions and research questions.

In Europe, use of intravenous tissue plasminogen activator (tPA) in patients older than 80 years is discouraged because these patients have been excluded from certain past clinical trials. A new retrospective, observational study shows that tPA can substantially improve functional outcome after ischaemic stroke in patients aged 80–89 years.

Whole-exome sequencing is a new tool for neuromuscular clinicians, and recent findings show that it improves the diagnosis of limb-girdle muscular dystrophy. The technique has a dual role as a tool for diagnosis and discovery in genetically heterogeneous neuromuscular diseases.

Many neurological disorders, from traumatic brain injury to Alzheimer disease, affect social cognition, yet deficits in social cognition can be difficult to detect and diagnose effectively. In this Review, Henry and colleagues provide an overview of the clinical contexts in which social cognitive dysfunction arises and consider how tests can be used to detect it. Through examples of four conditions in which social cognitive dysfunction arises, they demonstrate the appropriate tests to use, and consider their clinical application beyond these disorders.

The most-established risk factors for intracerebral haemorrhage (ICH) are lifestyle-related, but several studies have reported familial aggregation of ICH. An understanding of the role of genetic risk factors in ICH could provide insight into ICH aetiopathogenesis, and improve prevention and patient-tailored management of ICH. This Review discusses the evidence for a genetic component in ICH, taking into account the strength of evidence and functional relevance to ICH for each genetic variant.

Rupture of an unruptured intracranial aneurysm (UIA) is the most common cause of subarachnoid haemorrhage (SAH), and at least one in 20–30 adults is estimated to carry an asymptomatic UIA. However, the likelihood and epidemiology of UIA rupture and the associated risk factors are poorly understood. In this Perspectives article, Korja and Kaprio discuss possible misconceptions in the epidemiology of UIAs and SAH, and suggest options to improve the quality of future research.

A randomized, double-blind, phase III trial of generic glatiramer acetate has shown equivalent efficacy and safety compared with the approved formulation, Copaxone. The impact of approval of generic glatiramer acetate, however, will mainly depend on the pricing of the drug.

It is 40 years since the microtubule-associated protein tau was isolated and characterized, and 30 years since this protein was discovered to be abnormally hyperphoshorylated in the brains of patients with Alzheimer disease. To mark these important milestones, Iqbal and colleagues provide an overview of the pivotal discoveries in the tau research field over the past 40 years. They also review the current status of the field, focusing on the molecular biological insights that have established a key role for tau pathology in neurodegenerative disease, and the new therapeutic approaches that are emerging from this research.

Inflammation-driven synaptic dysfunction is emerging as a prominent pathogenic mechanism in multiple sclerosis (MS). Importantly, synaptic alterations and synaptic loss are potentially reversible, making them potential therapeutic targets. This Review draws on studies in patients with MS and in animal models of the disease to discuss the synaptic alterations in MS and the most promising drugs to restore synaptic function and intervene in the disease progression.

Harnessing self-protective pathways in the brain could protect against neurological disease, but pharmacological attempts at such an approach have failed. In this Review, Hess et al. consider the neurological potential of remote ischaemic conditioning (RIC), a procedure in which brief ischaemia induced by vascular occlusion in the limb activates self-protective pathways and protects distant organs against longer episodes of ischaemia. Clinical trials in cardiological settings have been successful, and trials in neurological conditions suggest that RIC is a feasible option for patients with ischaemic neurological conditions.

In a new study, one-quarter of individuals with a clinical diagnosis of mild to moderate Alzheimer dementia had no or only sparse neuritic amyloid plaques in their brains, and most were also at a low or an intermediate neurofibrillary tangle stage. The findings have enormous implications for clinical trials of anti-amyloid-β and anti-tau therapies.

Myoclonus is characterized by sudden, involuntary jerks, and can be caused by a variety of acquired and genetic disorders. Identification of the aetiology of myoclonus is paramount, because treatment should be based on the underlying disorder. The authors propose a novel eight-step diagnostic algorithm for myoclonus, incorporating—for the first time—next-generation sequencing. The algorithm should aid clinical decision-making and facilitate mechanism-based treatment.

Pneumonia impedes recovery from acute stroke and contributes to poor clinical outcomes. Two recent clinical trials demonstrate that antibiotics commonly used to treat stroke-associated pneumonia (SAP) neither reduce the frequency of pneumonia nor improve outcome after stroke when administered in a preventive manner. These findings necessitate fundamental reassessment of our current concepts of SAP.

A treatment trial of the monoclonal anti-amyloid antibody solanezumab showed slight benefits in people with dementia due to mild Alzheimer disease. Drug effects on several neuropsychological testing outcomes were statistically significant, but the effect sizes were unlikely to manifest as meaningful functional benefits. Here, we discuss the implications and possible molecular underpinnings.

The molecular mechanisms of neurodegeneration due to a repeat expansion in C9orf72, the most common cause of frontotemporal dementia and amyotrophic lateral sclerosis, are unknown. Three reports now link compromised nucleocytoplasmic transport to disease pathogenesis. Whether RNA structures or dipeptide repeat proteins are most toxic in humans remains open to question.

In our third and final installment from the MAGNIMS study group, Enzinger et al. consider how dramatic progress in MRI has enabled nonconventional structural imaging techniques to shed new light on the pathophysiology of multiple sclerosis. The authors discuss the present use of these techniques in the disease, and consider their future application to clinical research and practice.

The past decade of multiple sclerosis research has been marked by important advances in understanding the disease, a dramatic increase in the range of treatment options and a new spirit of data sharing in research for patient benefit. This progress has made personalized medicine in multiple sclerosis a realistic possibility.

CNS infections have severe manifestations, often leading to high mortality, but the CNS is usually not the primary target of pathogens, leaving a window of opportunity to prevent neuroinvasion. We must prioritize development of therapies to prevent neurological sequelae that cause long-lasting morbidity and disease burden on society.