Showing papers in "Nature Reviews Neurology in 2018"

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

Abstract: The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented

Neurofilaments as biomarkers in neurological disorders

Abstract: Neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. Reliable quantification and longitudinal follow-up of such damage are important for assessing disease activity, monitoring treatment responses, facilitating treatment development and determining prognosis. The neurofilament proteins have promise in this context because their levels rise upon neuroaxonal damage not only in the cerebrospinal fluid (CSF) but also in blood, and they indicate neuroaxonal injury independent of causal pathways. First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays had limited sensitivity. Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. This technological advancement has paved the way to investigate neurofilaments in a range of neurological disorders. Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. We also consider work needed to explore the value of this axonal damage marker in managing neurological diseases in daily practice.

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

Abstract: Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike

Tau-targeting therapies for Alzheimer disease.

Abstract: Alzheimer disease (AD) is the most common form of dementia. Pathologically, AD is characterized by amyloid plaques and neurofibrillary tangles in the brain, with associated loss of synapses and neurons, resulting in cognitive deficits and eventually dementia. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles, respectively. In the decades since Aβ and tau were identified, development of therapies for AD has primarily focused on Aβ, but tau has received more attention in recent years, in part because of the failure of various Aβ-targeting treatments in clinical trials. In this article, we review the current status of tau-targeting therapies for AD. Initially, potential anti-tau therapies were based mainly on inhibition of kinases or tau aggregation, or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting therapies in clinical trials are immunotherapies, which have shown promise in numerous preclinical studies. Given that tau pathology correlates better with cognitive impairments than do Aβ lesions, targeting of tau is expected to be more effective than Aβ clearance once the clinical symptoms are evident. With future improvements in diagnostics, these two hallmarks of the disease might be targeted prophylactically.

Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease.

Abstract: Research into dementia prevention is of paramount importance if the dementia epidemic is to be halted. Observational studies have identified several potentially modifiable risk factors for dementia, including hypertension, dyslipidaemia and obesity at midlife, diabetes mellitus, smoking, physical inactivity, depression and low levels of education. Randomized clinical trials are needed that investigate whether interventions targeting these risk factors can reduce the risk of cognitive decline and dementia in elderly adults, but such trials are methodologically challenging. To date, most preventive interventions have been tested in small groups, have focused on a single lifestyle factor and have yielded negative or modest results. Given the multifactorial aetiology of dementia and late-onset Alzheimer disease, multidomain interventions that target several risk factors and mechanisms simultaneously might be necessary for an optimal preventive effect. In the past few years, three large multidomain trials (FINGER, MAPT and PreDIVA) have been completed. The FINGER trial showed that a multidomain lifestyle intervention can benefit cognition in elderly people with an elevated risk of dementia. The primary results from the other trials did not show a statistically significant benefit of preventive interventions, but additional analyses among participants at risk of dementia showed beneficial effects of intervention. Overall, results from these three trials suggest that targeting of preventive interventions to at-risk individuals is an effective strategy. This Review discusses the current knowledge of lifestyle-related risk factors and results from novel trials aiming to prevent cognitive decline and dementia. Global initiatives are presented, including the World Wide FINGERS network, which aims to harmonize studies on dementia prevention, generate high-quality scientific evidence and promote its implementation.

CGRP as the target of new migraine therapies — successful translation from bench to clinic

Abstract: Treatment of migraine is on the cusp of a new era with the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are expected to receive approval for use in migraine headache in 2018 and 2019. CGRP-related therapies offer considerable improvements over existing drugs as they are the first to be designed specifically to act on the trigeminal pain system, they are more specific and they seem to have few or no adverse effects. CGRP receptor antagonists such as ubrogepant are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine attacks. As these drugs come into clinical use, we provide an overview of knowledge that has led to successful development of these drugs. We describe the biology of CGRP signalling, summarize key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatment, and synthesize what is known about the role of CGRP in the trigeminovascular system. Finally, we consider how the latest findings provide new insight into the central role of the trigeminal ganglion in the pathophysiology of migraine.

Sex differences in Alzheimer disease — the gateway to precision medicine

Abstract: Alzheimer disease (AD) is characterized by wide heterogeneity in cognitive and behavioural syndromes, risk factors and pathophysiological mechanisms. Addressing this phenotypic variation will be crucial for the development of precise and effective therapeutics in AD. Sex-related differences in neural anatomy and function are starting to emerge, and sex might constitute an important factor for AD patient stratification and personalized treatment. Although the effects of sex on AD epidemiology are currently the subject of intense investigation, the notion of sex-specific clinicopathological AD phenotypes is largely unexplored. In this Review, we critically discuss the evidence for sex-related differences in AD symptomatology, progression, biomarkers, risk factor profiles and treatment. The cumulative evidence reviewed indicates sex-specific patterns of disease manifestation as well as sex differences in the rates of cognitive decline and brain atrophy, suggesting that sex is a crucial variable in disease heterogeneity. We discuss critical challenges and knowledge gaps in our current understanding. Elucidating sex differences in disease phenotypes will be instrumental in the development of a 'precision medicine' approach in AD, encompassing individual, multimodal, biomarker-driven and sex-sensitive strategies for prevention, detection, drug development and treatment.

Antisense oligonucleotides: the next frontier for treatment of neurological disorders

Abstract: Antisense oligonucleotides (ASOs) were first discovered to influence RNA processing and modulate protein expression over two decades ago; however, progress translating these agents into the clinic has been hampered by inadequate target engagement, insufficient biological activity, and off-target toxic effects. Over the years, novel chemical modifications of ASOs have been employed to address these issues. These modifications, in combination with elucidation of the mechanism of action of ASOs and improved clinical trial design, have provided momentum for the translation of ASO-based strategies into therapies. Many neurological conditions lack an effective treatment; however, as research progressively disentangles the pathogenic mechanisms of these diseases, they provide an ideal platform to test ASO-based strategies. This steady progress reached a pinnacle in the past few years with approvals of ASOs for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy, which represent landmarks in a field in which disease-modifying therapies were virtually non-existent. With the rapid development of improved next-generation ASOs toward clinical application, this technology now holds the potential to have a dramatic effect on the treatment of many neurological conditions in the near future.

C9orf72 -mediated ALS and FTD: multiple pathways to disease

Abstract: The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression.

Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic.

Abstract: Biomarker discovery and development for clinical research, diagnostics and therapy monitoring in clinical trials have advanced rapidly in key areas of medicine - most notably, oncology and cardiovascular diseases - allowing rapid early detection and supporting the evolution of biomarker-guided, precision-medicine-based targeted therapies. In Alzheimer disease (AD), breakthroughs in biomarker identification and validation include cerebrospinal fluid and PET markers of amyloid-β and tau proteins, which are highly accurate in detecting the presence of AD-associated pathophysiological and neuropathological changes. However, the high cost, insufficient accessibility and/or invasiveness of these assays limit their use as viable first-line tools for detecting patterns of pathophysiology. Therefore, a multistage, tiered approach is needed, prioritizing development of an initial screen to exclude from these tests the high numbers of people with cognitive deficits who do not demonstrate evidence of underlying AD pathophysiology. This Review summarizes the efforts of an international working group that aimed to survey the current landscape of blood-based AD biomarkers and outlines operational steps for an effective academic-industry co-development pathway from identification and assay development to validation for clinical use.

Idiopathic REM sleep behaviour disorder and neurodegeneration - an update.

Abstract: So-called idiopathic rapid eye movement (REM) sleep behaviour disorder (RBD), formerly seen as a rare parasomnia, is now recognized as the prodromal stage of an α-synucleinopathy. Given the very high risk that patients with idiopathic RBD have of developing α-synucleinopathies, such as Parkinson disease (PD), PD dementia, dementia with Lewy bodies or multiple system atrophy, and the outstandingly high specificity and very long interval between the onset of idiopathic RBD and the clinical manifestations of α-synucleinopathies, the prodromal phase of this disorder represents a unique opportunity for potentially disease-modifying intervention. This Review provides an update on classic and novel biomarkers of α-synuclein-related neurodegeneration in patients with idiopathic RBD, focusing on advances in imaging and neurophysiological, cognitive, autonomic, tissue-specific and other biomarkers. We discuss the strengths, potential weaknesses and suitability of these biomarkers for identifying RBD and neurodegeneration, with an emphasis on predicting progression to overt α-synucleinopathy. The role of video polysomnography in providing quantifiable and potentially treatment-responsive biomarkers of neurodegeneration is highlighted. In light of all these advances, and the now understood role of idiopathic RBD as an early manifestation of α-synuclein disease, we call for idiopathic RBD to be reconceptualized as isolated RBD.

TREM2 - a key player in microglial biology and Alzheimer disease.

Abstract: Alzheimer disease (AD) is a debilitating dementia believed to result from the deposition of extracellular amyloid-β (Aβ)-containing plaques followed by the formation of neurofibrillary tangles. Familial AD typically results from mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 or presenilin 2. Variations in triggering receptor expressed on myeloid cells 2 (TREM2), one of several genes for which expression is restricted to microglia in the brain, have now been shown to increase the risk of developing late-onset AD. Microglia have been shown to respond to Aβ accumulation and neurodegenerative lesions, progressively acquiring a unique transcriptional and functional signature and evolving into disease-associated microglia (DAM). DAM attenuate the progression of neurodegeneration in certain mouse models, but inappropriate DAM activation accelerates neurodegenerative disease in other models. TREM2 is essential for maintaining microglial metabolic fitness during stress events, enabling microglial progression to a fully mature DAM profile and ultimately sustaining the microglial response to Aβ-plaque-induced pathology. Here, we review the current data detailing the role of TREM2 in microglial biology and AD.

Multidimensional communication in the microenvirons of glioblastoma.

Abstract: Glioblastomas are heterogeneous and invariably lethal tumours. They are characterized by genetic and epigenetic variations among tumour cells, which makes the development of therapies that eradicate all tumour cells challenging and currently impossible. An important component of glioblastoma growth is communication with and manipulation of other cells in the brain environs, which supports tumour progression and resistance to therapy. Glioblastoma cells recruit innate immune cells and change their phenotype to support tumour growth. Tumour cells also suppress adaptive immune responses, and our increasing understanding of how T cells access the brain and how the tumour thwarts the immune response offers new strategies for mobilizing an antitumour response. Tumours also subvert normal brain cells - including endothelial cells, neurons and astrocytes - to create a microenviron that favours tumour success. Overall, after glioblastoma-induced phenotypic modifications, normal cells cooperate with tumour cells to promote tumour proliferation, invasion of the brain, immune suppression and angiogenesis. This glioblastoma takeover of the brain involves multiple modes of communication, including soluble factors such as chemokines and cytokines, direct cell-cell contact, extracellular vesicles (including exosomes and microvesicles) and connecting nanotubes and microtubes. Understanding these multidimensional communications between the tumour and the cells in its environs could open new avenues for therapy.

Imaging tau and amyloid-β proteinopathies in Alzheimer disease and other conditions.

Abstract: Most neurodegenerative disorders are associated with aggregated protein deposits In the case of Alzheimer disease (AD), extracellular amyloid-β (Aβ) aggregates and intracellular tau neurofibrillary tangles are the two neuropathological hallmarks of the disease Aβ-PET imaging has already been approved for clinical use and is being used in clinical trials of anti-Aβ therapies both for patient recruitment and as an outcome measure These studies have shown that Aβ accumulation is a protracted process that can extend for more than 2 decades before the onset of clinical AD This Review describes how in vivo brain imaging of Aβ pathology has revolutionized the evaluation of patients with clinical AD by providing robust and reproducible statements of global or regional brain Aβ burden and enabling the monitoring of disease progression The role of selective tau imaging is discussed, focusing on how longitudinal tau and Aβ imaging studies might reveal the various effects (sequential and/or parallel, independent and/or synergistic) of these proteins on progression, cognition and other disease-specific biomarkers of neurodegeneration Finally, imaging studies are discussed in the context of elucidating the respective roles of Aβ and tau in AD and in advancing our understanding of the relationship and/or interplay between these two proteinopathies

Cerebral small vessel disease: from a focal to a global perspective

Abstract: Cerebral small vessel disease (SVD) is commonly observed on neuroimaging among elderly individuals and is recognized as a major vascular contributor to dementia, cognitive decline, gait impairment, mood disturbance and stroke. However, clinical symptoms are often highly inconsistent in nature and severity among patients with similar degrees of SVD on brain imaging. Here, we provide a new framework based on new advances in structural and functional neuroimaging that aims to explain the remarkable clinical variation in SVD. First, we discuss the heterogeneous pathology present in SVD lesions despite an identical appearance on imaging and the perilesional and remote effects of these lesions. We review effects of SVD on structural and functional connectivity in the brain, and we discuss how network disruption by SVD can lead to clinical deficits. We address reserve and compensatory mechanisms in SVD and discuss the part played by other age-related pathologies. Finally, we conclude that SVD should be considered a global rather than a focal disease, as the classically recognized focal lesions affect remote brain structures and structural and functional network connections. The large variability in clinical symptoms among patients with SVD can probably be understood by taking into account the heterogeneity of SVD lesions, the effects of SVD beyond the focal lesions, the contribution of neurodegenerative pathologies other than SVD, and the interaction with reserve mechanisms and compensatory mechanisms.

Seizure prediction - ready for a new era

Abstract: Epilepsy is a common disorder characterized by recurrent seizures. An overwhelming majority of people with epilepsy regard the unpredictability of seizures as a major issue. More than 30 years of international effort have been devoted to the prediction of seizures, aiming to remove the burden of unpredictability and to couple novel, time-specific treatment to seizure prediction technology. A highly influential review published in 2007 concluded that insufficient evidence indicated that seizures could be predicted. Since then, several advances have been made, including successful prospective seizure prediction using intracranial EEG in a small number of people in a trial of a real-time seizure prediction device. In this Review, we examine advances in the field, including EEG databases, seizure prediction competitions, the prospective trial mentioned and advances in our understanding of the mechanisms of seizures. We argue that these advances, together with statistical evaluations, set the stage for a resurgence in efforts towards the development of seizure prediction methodologies. We propose new avenues of investigation involving a synergy between mechanisms, models, data, devices and algorithms and refine the existing guidelines for the development of seizure prediction technology to instigate development of a solution that removes the burden of the unpredictability of seizures.

Amyloid-β and tau complexity - towards improved biomarkers and targeted therapies

Abstract: Most neurodegenerative diseases are proteinopathies, which are characterized by the aggregation of misfolded proteins. Although many proteins have an intrinsic propensity to aggregate, particularly when cellular clearance systems start to fail in the context of ageing, only a few form fibrillar aggregates. In Alzheimer disease, the peptide amyloid-β (Aβ) and the protein tau aggregate to form plaques and tangles, respectively, which comprise the histopathological hallmarks of this disease. This Review discusses the complexity of Aβ biogenesis, trafficking, post-translational modifications and aggregation states. Tau and its various isoforms, which are subject to a vast array of post-translational modifications, are also explored. The methodological advances that revealed this complexity are described. Finally, the toxic effects of distinct species of tau and Aβ are discussed, as well as the concept of protein 'strains', and how this knowledge can facilitate the development of early disease biomarkers for stratifying patients and validating new therapies. By targeting distinct species of Aβ and tau for therapeutic intervention, the way might be paved for personalized medicine and more-targeted treatment strategies.

Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease?

Abstract: Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities.

Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

Abstract: The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly progressive course Pronounced weakness in axial and proximal muscle groups is a common feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects Central core disease (CCD), multi-minicore disease (MmD), centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital myopathies to be reported, and they still represent the main diagnostic categories However, these entities seem to belong to a much wider phenotypic spectrum To date, congenital myopathies have been attributed to mutations in over 20 genes, which encode proteins implicated in skeletal muscle Ca2+ homeostasis, excitation-contraction coupling, thin-thick filament assembly and interactions, and other mechanisms RYR1 mutations are the most frequent genetic cause, and CCD and MmD are the most common subgroups Next-generation sequencing has vastly improved mutation detection and has enabled the identification of novel genetic backgrounds At present, management of congenital myopathies is largely supportive, although new therapeutic approaches are reaching the clinical trial stage

Japanese encephalitis - the prospects for new treatments.

Abstract: Japanese encephalitis is a mosquito-borne disease that occurs in Asia and is caused by Japanese encephalitis virus (JEV), a member of the genus Flavivirus. Although many flaviviruses can cause encephalitis, JEV causes particularly severe neurological manifestations. The virus causes loss of more disability-adjusted life years than any other arthropod-borne virus owing to the frequent neurological sequelae of the condition. Despite substantial advances in our understanding of Japanese encephalitis from in vitro studies and animal models, studies of pathogenesis and treatment in humans are lagging behind. Few mechanistic studies have been conducted in humans, and only four clinical trials of therapies for Japanese encephalitis have taken place in the past 10 years despite an estimated incidence of 69,000 cases per year. Previous trials for Japanese encephalitis might have been too small to detect important benefits of potential treatments. Many potential treatment targets exist for Japanese encephalitis, and pathogenesis and virological studies have uncovered mechanisms by which these drugs could work. In this Review, we summarize the epidemiology, clinical features, prevention and treatment of Japanese encephalitis and focus on potential new therapeutic strategies, based on repurposing existing compounds that are already suitable for human use and could be trialled without delay. We use our newly improved understanding of Japanese encephalitis pathogenesis to posit potential treatments and outline some of the many challenges that remain in tackling the disease in humans.

Traumatic brain injury: sex, gender and intersecting vulnerabilities.

Abstract: Over the past decade, traumatic brain injury (TBI) has emerged as a major public health concern, attracting considerable interest from the scientific community, clinical and behavioural services and policymakers, owing to its rising prevalence, wide-ranging risk factors and substantial lifelong familial and societal impact. This increased attention to TBI has resulted in increased funding and advances in legislation. However, many questions surrounding TBI remain unanswered, including questions on sex and gender trends with respect to vulnerability to injury, presentation of injury, response to treatment, and outcomes. Here, we review recent research efforts aimed at advancing knowledge on the constructs of sex and gender and their respective influences in the context of TBI, and discuss methodological challenges in disentangling the differential impacts of these two constructs, particularly in marginalized populations.

Advances in therapy for spinal muscular atrophy: promises and challenges.

Abstract: Spinal muscular atrophy (SMA) is a devastating motor neuron disease that predominantly affects children and represents the most common cause of hereditary infant mortality. The condition results from deleterious variants in SMN1, which lead to depletion of the survival motor neuron protein (SMN). Now, 20 years after the discovery of this genetic defect, a major milestone in SMA and motor neuron disease research has been reached with the approval of the first disease-modifying therapy for SMA by US and European authorities - the antisense oligonucleotide nusinersen. At the same time, promising data from early-stage clinical trials of SMN1 gene therapy have indicated that additional therapeutic options are likely to emerge for patients with SMA in the near future. However, the approval of nusinersen has generated a number of immediate and substantial medical, ethical and financial implications that have the potential to resonate beyond the specific treatment of SMA. Here, we provide an overview of the rapidly evolving therapeutic landscape for SMA, highlighting current achievements and future opportunities. We also discuss how these developments are providing important lessons for the emerging second generation of combinatorial ('SMN-plus') therapies that are likely to be required to generate robust treatments that are effective across a patient's lifespan.

Spinocerebellar ataxias: prospects and challenges for therapy development

Abstract: The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding CAG repeats. Nucleotide-based gene-silencing approaches that target the first steps in the pathogenic cascade are one promising approach not only for polyglutamine SCAs but also for the many other SCAs caused by toxic mutant proteins or RNA. For these and other emerging therapeutic strategies, well-coordinated preparation is needed for fruitful clinical trials. To accomplish this goal, investigators from the United States and Europe are now collaborating to share data from their respective SCA cohorts. Increased knowledge of the natural history of SCAs, including of the premanifest and early symptomatic stages of disease, will improve the prospects for success in clinical trials of disease-modifying drugs. In addition, investigators are seeking validated clinical outcome measures that demonstrate responsiveness to changes in SCA populations. Findings suggest that MRI and magnetic resonance spectroscopy biomarkers will provide objective biological readouts of disease activity and progression, but more work is needed to establish disease-specific biomarkers that track target engagement in therapeutic trials. Together, these efforts suggest that the development of successful therapies for one or more SCAs is not far away.

Teleneurology and mobile technologies: the future of neurological care

Abstract: Neurological disorders are the leading cause of global disability. However, for most people around the world, current neurological care is poor. In low-income countries, most individuals lack access to proper neurological care, and in high-income countries, distance and disability limit access. With the global proliferation of smartphones, teleneurology - the use of technology to provide neurological care and education remotely - has the potential to improve and increase access to care for billions of people. Telestroke has already fulfilled this promise, but teleneurology applications for chronic conditions are still in their infancy. Similarly, few studies have explored the capabilities of mobile technologies such as smartphones and wearable sensors, which can guide care by providing objective, frequent, real-world assessments of patients. In low-income settings, teleneurology can increase the capacity of local care systems through professional development, diagnostic support and consultative services. In high-income settings, teleneurology is likely to promote the expansion and migration of neurological care away from institutions, incorporate systems of asynchronous communication (such as e-mail), integrate clinicians with diverse skill sets and reach new populations. Inertia, outdated policies and social barriers - especially the digital divide - will slow this progress at considerable cost. However, a future increasingly will be possible in which neurological care can be accessed by anyone, anywhere. Here, we examine the emerging evidence regarding the benefits of teleneurology for chronic conditions, its role and risks in low-income countries and the promise of mobile technologies to measure disease status and deliver care. We conclude by discussing the future trends, barriers and timing for the adoption of teleneurology.

The current role of MRI in differentiating multiple sclerosis from its imaging mimics

Abstract: MRI red flags proposed over a decade ago by the European Magnetic Resonance Network in MS (MAGNIMS) have guided clinicians in the diagnosis of multiple sclerosis (MS). However, the past 10 years have seen increased recognition that vascular disease can coexist and possibly interact with MS, improvements in the reliability of ways to differentiate MS from novel antibody-mediated CNS disorders (such as anti-aquaporin-4 antibody and myelin-oligodendrocyte glycoprotein antibody-associated diseases) and advances in MRI techniques. In this Review, MAGNIMS updates the imaging features that differentiate the most common mimics of MS, particularly age-related cerebrovascular disease and neuromyelitis optica, from MS itself. We also provide a pragmatic summary of the clinically useful MRI features that distinguish MS from its mimics and discuss the future of nonconventional techniques that have identified promising disease-specific features.

The complex aetiology of cerebral palsy.

Abstract: Cerebral palsy (CP) is the most prevalent, severe and costly motor disability of childhood. Consequently, CP is a public health priority for prevention, but its aetiology has proved complex. In this Review, we summarize the evidence for a decline in the birth prevalence of CP in some high-income nations, describe the epidemiological evidence for risk factors, such as preterm delivery and fetal growth restriction, genetics, pregnancy infection and other exposures, and discuss the success achieved so far in prevention through the use of magnesium sulfate in preterm labour and therapeutic hypothermia for birth-asphyxiated infants. We also consider the complexities of disentangling prenatal and perinatal influences, and of establishing subtypes of the disorder, with a view to accelerating the translation of evidence into the development of strategies for the prevention of CP.

Advances in meningioma genetics: novel therapeutic opportunities.

Abstract: Meningiomas currently are among the most frequent intracranial tumours. Although the majority of meningiomas can be cured by surgical resection, ∼20% of patients have an aggressive clinical course with tumour recurrence or progressive disease, resulting in substantial morbidity and increased mortality of affected patients. During the past 3 years, exciting new data have been published that provide insights into the molecular background of meningiomas and link sites of tumour development with characteristic histopathological and molecular features, opening a new road to novel and promising treatment options for aggressive meningiomas. A growing number of the newly discovered recurrent mutations have been linked to a particular clinicopathological phenotype. Moreover, the updated WHO classification of brain tumours published in 2016 has incorporated some of these molecular findings, setting the stage for the improvement of future therapeutic efforts through the integration of essential molecular findings. Finally, an additional potential classification of meningiomas based on methylation profiling has been launched, which provides clues in the assessment of individual risk of meningioma recurrence. All of these developments are creating new prospects for effective molecularly driven diagnosis and therapy of meningiomas.

Complex regional pain syndrome - phenotypic characteristics and potential biomarkers.

Abstract: Complex regional pain syndrome (CRPS) is a pain condition that usually affects a single limb, often following an injury. The underlying pathophysiology seems to be complex and probably varies between patients. Clinical diagnosis is based on internationally agreed-upon criteria, which consider the reported symptoms, presence of signs and exclusion of alternative causes. Research into CRPS biomarkers to support patient stratification and improve diagnostic certainty is an important scientific focus, and recent progress in this area provides an opportunity for an up-to-date topical review of measurable disease-predictive, diagnostic and prognostic parameters. Clinical and biochemical attributes of CRPS that may aid diagnosis and determination of appropriate treatment are delineated. Findings that predict the development of CRPS and support the diagnosis include trauma-related factors, neurocognitive peculiarities, psychological markers, and local and systemic changes that indicate activation of the immune system. Analysis of signatures of non-coding microRNAs that could predict the treatment response represents a new line of research. Results from the past 5 years of CRPS research indicate that a single marker for CRPS will probably never be found; however, a range of biomarkers might assist in clinical diagnosis and guide prognosis and treatment.

Assessing treatment outcomes in multiple sclerosis trials and in the clinical setting.

Abstract: Increasing numbers of drugs are being developed for the treatment of multiple sclerosis (MS). Measurement of relevant outcomes is key for assessing the efficacy of new drugs in clinical trials and for monitoring responses to disease-modifying drugs in individual patients. Most outcomes used in trial and clinical settings reflect either clinical or neuroimaging aspects of MS (such as relapse and accrual of disability or the presence of visible inflammation and brain tissue loss, respectively). However, most measures employed in clinical trials to assess treatment effects are not used in routine practice. In clinical trials, the appropriate choice of outcome measures is crucial because the results determine whether a drug is considered effective and therefore worthy of further development; in the clinic, outcome measures can guide treatment decisions, such as choosing a first-line disease-modifying drug or escalating to second-line treatment. This Review discusses clinical, neuroimaging and composite outcome measures for MS, including patient-reported outcome measures, used in both trials and the clinical setting. Its aim is to help clinicians and researchers navigate through the multiple options encountered when choosing an outcome measure. Barriers and limitations that need to be overcome to translate trial outcome measures into the clinical setting are also discussed.

Protecting the ischaemic penumbra as an adjunct to thrombectomy for acute stroke

Abstract: After ischaemic stroke, brain damage can be curtailed by rescuing the ‘ischaemic penumbra’ — that is, the severely hypoperfused, at-risk but not yet infarcted tissue. Current evidence-based treatments involve restoration of blood flow so as to salvage the penumbra before it evolves into irreversibly damaged tissue, termed the ‘core’. Intravenous thrombolysis (IVT) can salvage the penumbra if given within 4.5 h after stroke onset; however, the early recanalization rate is only ~30%. Direct removal of the occluding clot by mechanical thrombectomy considerably improves outcomes over IVT alone, but despite early recanalization in > 80% of cases, ~50% of patients who receive this treatment do not enjoy functional independence, usually because the core is already too large at the time of recanalization. Novel therapies aiming to ‘freeze’ the penumbra — that is, prevent core growth until recanalization is complete — hold potential as adjuncts to mechanical thrombectomy. This Review focuses on nonpharmacological approaches that aim to restore the physiological balance between oxygen delivery to and oxygen demand of the penumbra. Particular emphasis is placed on normobaric oxygen therapy, hypothermia and sensory stimulation. Preclinical evidence and early pilot clinical trials are critically reviewed, and future directions, including clinical translation and trial design issues, are discussed. Despite advances in the treatment of ischaemic stroke, functional outcomes are still suboptimal in many patients. Baron discusses approaches to further limit the spread of brain ischaemia by ‘freezing’ the penumbra — that is, the at-risk but not yet infarcted tissue.