Reviews & Analysis

Vascular and neurodegenerative pathologies are known to co-occur in Alzheimer disease, and were recently proposed to drive progression to dementia through independent pathways. A new study provides evidence in support of this hypothesis, by showing dissociation between the pathologies and regional brain metabolism. But might the two pathways converge?

The concept of lysosomal storage disorders (LSDs) has existed for over 50 years, but our understanding of the causes and pathobiology of these diseases have come to light only recently, following advances in genetic technology. In this Review, Rose-Mary Boustany summarizes current understanding of known LSDs, highlighting existing treatment approaches for patients with these often devastating disorders, and outlining the barriers to development of novel therapies.

Quantitative sensory testing (QST) is being used increasingly in the research environment to measure somatosensory responses, both in patients with pain disorders and in normal individuals. A recent consensus meeting on the use of QST in clinical practice provides recommendations for the implementation of QST in patient diagnosis and monitoring.

Intracerebral haemorrhage is the most serious complication of intravenous thrombolysis in ischaemic stroke, and whether thrombolysis can be performed in patients receiving anticoagulants is an unresolved issue. Data from a large European registry now confirms that thrombolysis in some patients receiving warfarin is as safe as in non-anticoagulated patients.

Determination of prognosis in patients with status epilepticus (SE)—a life-threatening state of ongoing or repetitive seizures—is difficult, and current outcome prediction scales do not take into account novel outcome markers, such as EEG and imaging findings. Here, Sutter et al. review the available data on major prognostic determinants of outcome in SE, and propose a novel paradigm for assessment of these predictive factors over the course of the seizure.

The pathophysiological processes underlying onset and progression of amyotrophic lateral sclerosis (ALS) remain poorly understood. Unlike conventional imaging techniques, which provide information only at a gross structural level, advanced imaging modalities have shed light on the microstructural changes that accompany this disease. Eva Feldman and colleagues describe how advanced neuroimaging studies have delineated key factors, such as white matter tract integrity and brain metabolism, that are altered in ALS, and consider how such insights could aid diagnosis and treatment.

As the range of therapeutic options for multiple sclerosis (MS) continues to expand, the ability to select the most appropriate treatment for each patient becomes increasingly important. In this Review, Sormani and De Stefano assess the studies that have attempted to classify patients with MS on the basis of their response to IFN-β treatment. The authors also discuss the development and use of scoring systems that combine different clinical and MRI markers to aid definition of an early response to this drug.

The majority of patients with multiple sclerosis (MS) will at some point experience the progressive form of the disease, involving relentless functional decline and axonal degeneration. No cure for progressive MS is currently available, and clinical trials in this patient population are problematic. Koch and colleagues describe current limitations of trials in progressive MS, such as lack of suitable outcome measures, and present approaches to address these challenges.

Recently developed criteria for diagnosis of mild cognitive impairment due to Alzheimer disease make use of clinical and biomarker information. A new study reports that these criteria apply in both community and research settings; however, results from the community-based cohort conflict with a proposed biomarker-based model of disease progression.

A recent study has used whole-exome sequencing, an 'extreme trait' design and imaging genetics to identify coding variants associated with hippocampal volume loss in Alzheimer disease. The research highlights the utility of next-generation sequencing and association studies involving quantitative traits for discovery of disease-related variants in neurodegeneration.

Data on the incidence of synucleinopathies and tauopathies are limited, and a recently published study has attempted to address this deficit. Confirmation of these proteinopathies currently relies on pathological findings at autopsy, but the new findings raise the possibility of diagnosis during life in some cases.

Over the past 15 years, the contribution of genetic factors to development of Parkinson disease has been increasingly recognized. In their Review, Trinh and Farrer summarize the latest findings in this field, highlighting overlapping results from diverse genetics studies. Together, the genes identified suggest a key role for impaired vesicle and mitochondrial dynamics in neurons, which could represent promising targets for novel therapies in Parkinson disease.

Mitochondrial diseases are a complex and clinically heterogeneous group of disorders, which— together with our poor understanding of the underlying pathology—makes their diagnosis difficult. Here, DiMauro et al. review current knowledge of defects of the mitochondrial respiratory complex that lead to neurological mitochondrial disorders, outlining diagnostic clues for each disorder, and discussing current therapeutic approaches for these often devastating diseases.

Elderly patients represent a growing proportion of individuals with malignant glioma, but are often excluded from trials owing to their poor prognosis. In a new study, researchers have investigated molecular markers of glioma specifically in elderly patients—are these markers of clinical use?

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.

Chronic low back pain (CLBP) is a highly prevalent and debilitating disorder. Despite progress in understanding the aetiology of CLBP in recent years, this knowledge has not been translated into decreased prevalence or new therapies. In this Review, Morlion discusses interventional pain management, as well as surgical and pharmacotherapy approaches, and reviews the current evidence for the efficacy of these treatments in CLBP.

Huntington disease is caused by a CAG repeat expansion in the huntingtin gene. A repeat length of 35 CAGs has long been accepted as the cut-off point beyond which the expansion becomes pathological, but recent findings indicate that intermediate expansions (27–35 repeats) are associated with either a distinct behavioural phenotype or an endophenotype.

In this Review, Reindl et al. discuss a range of CNS disorders that are known to be associated with autoantibodies against myelin oligodendrocyte glycoprotein (MOG). They examine the experimental evidence for a role for MOG autoantibodies in the pathogenesis of demyelinating CNS disorders such as multiple sclerosis and acute disseminated encephalomyelitis, and explore the potential of MOG to function as a biomarker in these diseases.

Prion diseases are rare, clinically heterogeneous, rapidly progressive and invariably fatal. Late diagnosis and difficulties in adequately assessing disease progression are major obstacles to development and evaluation of treatments. The recent validation of a new outcome measure for therapeutic trials in prion disease represents a substantial advance in this field.

Alzheimer disease (AD)-associated loci identified by genome-wide association studies (GWAS) only partly explain the genetic risk for this common neurodegenerative dementia. A recent GWAS of an alternative phenotype—cerebrospinal fluid tau levels—has uncovered new genetic variants that might further account for risk of AD and provide novel pathophysiological insights.