Showing papers in "Nature Reviews Neurology in 2021"

Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?

Abstract: Alzheimer disease (AD) is the most common form of neurodegenerative disease, estimated to contribute 60–70% of all cases of dementia worldwide. According to the prevailing amyloid cascade hypothesis, amyloid-β (Aβ) deposition in the brain is the initiating event in AD, although evidence is accumulating that this hypothesis is insufficient to explain many aspects of AD pathogenesis. The discovery of increased levels of inflammatory markers in patients with AD and the identification of AD risk genes associated with innate immune functions suggest that neuroinflammation has a prominent role in the pathogenesis of AD. In this Review, we discuss the interrelationships between neuroinflammation and amyloid and tau pathologies as well as the effect of neuroinflammation on the disease trajectory in AD. We specifically focus on microglia as major players in neuroinflammation and discuss the spatial and temporal variations in microglial phenotypes that are observed under different conditions. We also consider how these cells could be modulated as a therapeutic strategy for AD. Accumulating evidence indicates important roles for microglial activation and neuroinflammation in Alzheimer disease (AD). Here, Leng and Edison describe the interplay between microglial activation and AD-related pathologies and discuss how microglial priming and activation might influence the trajectory of AD.

Technology of deep brain stimulation: current status and future directions.

Abstract: Deep brain stimulation (DBS) is a neurosurgical procedure that allows targeted circuit-based neuromodulation. DBS is a standard of care in Parkinson disease, essential tremor and dystonia, and is also under active investigation for other conditions linked to pathological circuitry, including major depressive disorder and Alzheimer disease. Modern DBS systems, borrowed from the cardiac field, consist of an intracranial electrode, an extension wire and a pulse generator, and have evolved slowly over the past two decades. Advances in engineering and imaging along with an improved understanding of brain disorders are poised to reshape how DBS is viewed and delivered to patients. Breakthroughs in electrode and battery designs, stimulation paradigms, closed-loop and on-demand stimulation, and sensing technologies are expected to enhance the efficacy and tolerability of DBS. In this Review, we provide a comprehensive overview of the technical development of DBS, from its origins to its future. Understanding the evolution of DBS technology helps put the currently available systems in perspective and allows us to predict the next major technological advances and hurdles in the field.

Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies.

Abstract: Substantial progress has been made over the past two decades in detecting, predicting and promoting recovery of consciousness in patients with disorders of consciousness (DoC) caused by severe brain injuries. Advanced neuroimaging and electrophysiological techniques have revealed new insights into the biological mechanisms underlying recovery of consciousness and have enabled the identification of preserved brain networks in patients who seem unresponsive, thus raising hope for more accurate diagnosis and prognosis. Emerging evidence suggests that covert consciousness, or cognitive motor dissociation (CMD), is present in up to 15–20% of patients with DoC and that detection of CMD in the intensive care unit can predict functional recovery at 1 year post injury. Although fundamental questions remain about which patients with DoC have the potential for recovery, novel pharmacological and electrophysiological therapies have shown the potential to reactivate injured neural networks and promote re-emergence of consciousness. In this Review, we focus on mechanisms of recovery from DoC in the acute and subacute-to-chronic stages, and we discuss recent progress in detecting and predicting recovery of consciousness. We also describe the developments in pharmacological and electrophysiological therapies that are creating new opportunities to improve the lives of patients with DoC. In this Review, the authors discuss recent progress in the detection and prediction of recovery of consciousness in patients with disorders of consciousness caused by severe brain injuries. They describe the ongoing development of pharmacological and electrophysiological therapies designed to enhance recovery.

Applications of focused ultrasound in the brain: from thermoablation to drug delivery.

Abstract: Focused ultrasound (FUS) is a disruptive medical technology, and its implementation in the clinic represents the culmination of decades of research. Lying at the convergence of physics, engineering, imaging, biology and neuroscience, FUS offers the ability to non-invasively and precisely intervene in key circuits that drive common and challenging brain conditions. The actions of FUS in the brain take many forms, ranging from transient blood-brain barrier opening and neuromodulation to permanent thermoablation. Over the past 5 years, we have seen a dramatic expansion of indications for and experience with FUS in humans, with a resultant exponential increase in academic and public interest in the technology. Applications now span the clinical spectrum in neurological and psychiatric diseases, with insights still emerging from preclinical models and human trials. In this Review, we provide a comprehensive overview of therapeutic ultrasound and its current and emerging indications in the brain. We examine the potential impact of FUS on the landscape of brain therapies as well as the challenges facing further advancement and broader adoption of this promising minimally invasive therapeutic alternative.

Maternal immune activation and neuroinflammation in human neurodevelopmental disorders.

Abstract: Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring. The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs). Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring. In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene-environment interface during NDD pathogenesis. For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways. In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome. We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic 'priming' of offspring microglia and postnatal immune-brain crosstalk. The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms.

Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease.

Abstract: Progressive multifocal leukoencephalopathy (PML) is a devastating CNS infection caused by JC virus (JCV), a polyomavirus that commonly establishes persistent, asymptomatic infection in the general population. Emerging evidence that PML can be ameliorated with novel immunotherapeutic approaches calls for reassessment of PML pathophysiology and clinical course. PML results from JCV reactivation in the setting of impaired cellular immunity, and no antiviral therapies are available, so survival depends on reversal of the underlying immunosuppression. Antiretroviral therapies greatly reduce the risk of HIV-related PML, but many modern treatments for cancers, organ transplantation and chronic inflammatory disease cause immunosuppression that can be difficult to reverse. These treatments - most notably natalizumab for multiple sclerosis - have led to a surge of iatrogenic PML. The spectrum of presentations of JCV-related disease has evolved over time and may challenge current diagnostic criteria. Immunotherapeutic interventions, such as use of checkpoint inhibitors and adoptive T cell transfer, have shown promise but caution is needed in the management of immune reconstitution inflammatory syndrome, an exuberant immune response that can contribute to morbidity and death. Many people who survive PML are left with neurological sequelae and some with persistent, low-level viral replication in the CNS. As the number of people who survive PML increases, this lack of viral clearance could create challenges in the subsequent management of some underlying diseases.

Neurological infection with SARS-CoV-2 - the story so far.

Abstract: As the COVID-19 pandemic developed and neurological manifestations were reported, concern grew that SARS-CoV-2 might directly invade neuronal cells. However, research throughout the year to address this concern has revealed a different story with inflammatory processes at its centre.

Prodromal Parkinson disease subtypes - key to understanding heterogeneity.

Abstract: In Parkinson disease (PD), pathological processes and neurodegeneration begin long before the cardinal motor symptoms develop and enable clinical diagnosis. In this prodromal phase, risk and prodromal markers can be used to identify individuals who are likely to develop PD, as in the recently updated International Parkinson and Movement Disorders Society research criteria for prodromal PD. However, increasing evidence suggests that clinical and prodromal PD are heterogeneous, and can be classified into subtypes with different clinical manifestations, pathomechanisms and patterns of spatial and temporal progression in the CNS and PNS. Genetic, pathological and imaging markers, as well as motor and non-motor symptoms, might define prodromal subtypes of PD. Moreover, concomitant pathology or other factors, including amyloid-β and tau pathology, age and environmental factors, can cause variability in prodromal PD. Patients with REM sleep behaviour disorder (RBD) exhibit distinct patterns of α-synuclein pathology propagation and might indicate a body-first subtype rather than a brain-first subtype. Identification of prodromal PD subtypes and a full understanding of variability at this stage of the disease is crucial for early and accurate diagnosis and for targeting of neuroprotective interventions to ensure efficacy.

Improving clinical trial outcomes in amyotrophic lateral sclerosis

Abstract: Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s - a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.

Diagnosis and management of migraine in ten steps

Abstract: Migraine is a disabling primary headache disorder that directly affects more than one billion people worldwide. Despite its widespread prevalence, migraine remains under-diagnosed and under-treated. To support clinical decision-making, we convened a European panel of experts to develop a ten-step approach to the diagnosis and management of migraine. Each step was established by expert consensus and supported by a review of current literature, and the Consensus Statement is endorsed by the European Headache Federation and the European Academy of Neurology. In this Consensus Statement, we introduce typical clinical features, diagnostic criteria and differential diagnoses of migraine. We then emphasize the value of patient centricity and patient education to ensure treatment adherence and satisfaction with care provision. Further, we outline best practices for acute and preventive treatment of migraine in various patient populations, including adults, children and adolescents, pregnant and breastfeeding women, and older people. In addition, we provide recommendations for evaluating treatment response and managing treatment failure. Lastly, we discuss the management of complications and comorbidities as well as the importance of planning long-term follow-up. In this Consensus Statement, which is endorsed by the European Headache Federation and the European Academy of Neurology, an expert panel provides recommendations for the diagnosis and management of migraine to support clinical decision-making by general practitioners, neurologists and headache specialists.

The effects of the COVID-19 pandemic on people with dementia.

Abstract: The COVID-19 pandemic has posed unique risks to people with Alzheimer disease and dementia. Research from 2020 has shown that these people have a relatively high risk of contracting severe COVID-19, and are also at risk of neuropsychiatric disturbances as a result of lockdown measures and social isolation.

Peripheral and central immune system crosstalk in Alzheimer disease - a research prospectus.

Abstract: Dysregulation of the immune system is a cardinal feature of Alzheimer disease (AD), and a considerable body of evidence indicates pathological alterations in central and peripheral immune responses that change over time. Considering AD as a systemic immune process raises important questions about how communication between the peripheral and central compartments occurs and whether this crosstalk represents a therapeutic target. We established a whitepaper workgroup to delineate the current status of the field and to outline a research prospectus for advancing our understanding of peripheral-central immune crosstalk in AD. To guide the prospectus, we begin with an overview of seminal clinical observations that suggest a role for peripheral immune dysregulation and peripheral-central immune communication in AD, followed by formative animal data that provide insights into possible mechanisms for these clinical findings. We then present a roadmap that defines important next steps needed to overcome conceptual and methodological challenges, opportunities for future interdisciplinary research, and suggestions for translating promising mechanistic studies into therapeutic interventions.

Developing the ATX(N) classification for use across the Alzheimer disease continuum.

Abstract: Breakthroughs in the development of highly accurate fluid and neuroimaging biomarkers have catalysed the conceptual transformation of Alzheimer disease (AD) from the traditional clinical symptom-based definition to a clinical–biological construct along a temporal continuum. The AT(N) system is a symptom-agnostic classification scheme that categorizes individuals using biomarkers that chart core AD pathophysiological features, namely the amyloid-β (Aβ) pathway (A), tau-mediated pathophysiology (T) and neurodegeneration (N). This biomarker matrix is now expanding towards an ATX(N) system, where X represents novel candidate biomarkers for additional pathophysiological mechanisms such as neuroimmune dysregulation, synaptic dysfunction and blood–brain barrier alterations. In this Perspective, we describe the conceptual framework and clinical importance of the existing AT(N) system and the evolving ATX(N) system. We provide a state-of-the-art summary of the potential contexts of use of these systems in AD clinical trials and future clinical practice. We also discuss current challenges related to the validation, standardization and qualification process and provide an outlook on the real-world application of the AT(N) system. The AT(N) system is a classification scheme based on biomarkers that reflect the core pathophysiological features of Alzheimer disease. This Perspective outlines the conceptual framework and clinical importance of the AT(N) system and considers its potential expansion to incorporate biomarkers for additional pathophysiological mechanisms.

Cycles in epilepsy.

Abstract: Epilepsy is among the most dynamic disorders in neurology. A canonical view holds that seizures, the characteristic sign of epilepsy, occur at random, but, for centuries, humans have looked for patterns of temporal organization in seizure occurrence. Observations that seizures are cyclical date back to antiquity, but recent technological advances have, for the first time, enabled cycles of seizure occurrence to be quantitatively characterized with direct brain recordings. Chronic recordings of brain activity in humans and in animals have yielded converging evidence for the existence of cycles of epileptic brain activity that operate over diverse timescales: daily (circadian), multi-day (multidien) and yearly (circannual). Here, we review this evidence, synthesizing data from historical observational studies, modern implanted devices, electronic seizure diaries and laboratory-based animal neurophysiology. We discuss advances in our understanding of the mechanistic underpinnings of these cycles and highlight the knowledge gaps that remain. The potential clinical applications of a knowledge of cycles in epilepsy, including seizure forecasting and chronotherapy, are discussed in the context of the emerging concept of seizure risk. In essence, this Review addresses the broad question of why seizures occur when they occur.

B cells in multiple sclerosis - from targeted depletion to immune reconstitution therapies.

Abstract: Increasing evidence indicates the involvement of B cells in the pathogenesis of multiple sclerosis (MS), but their precise roles are unclear. In this Review, we provide an overview of the development and physiological functions of B cells and the main mechanisms through which B cells are thought to contribute to CNS autoimmunity. In MS, abnormalities of B cell function include pro-inflammatory cytokine production, defective B cell regulatory function and the formation of tertiary lymphoid-like structures in the CNS, which are the likely source of abnormal immunoglobulin production detectable in the cerebrospinal fluid. We also consider the hypothesis that Epstein-Barr virus (EBV) is involved in the B cell overactivation that leads to inflammatory injury to the CNS in MS. We also review the immunological effects - with a focus on the effects on B cell subsets - of several successful therapeutic approaches in MS, including agents that selectively deplete B cells (rituximab, ocrelizumab and ofatumumab), agents that less specifically deplete lymphocytes (alemtuzumab and cladribine) and autologous haematopoietic stem cell transplantation, in which the immune system is unselectively ablated and reconstituted. We consider the insights that these effects on B cell populations provide and their potential to further our understanding and targeting of B cells in MS.

Hypomyelinating leukodystrophies - unravelling myelin biology.

Abstract: Hypomyelinating leukodystrophies constitute a subset of genetic white matter disorders characterized by a primary lack of myelin deposition. Most patients with severe hypomyelination present in infancy or early childhood and develop severe neurological deficits, but the clinical presentation can also be mild with onset of symptoms in adolescence or adulthood. MRI can be used to visualize the process of myelination in detail, and MRI pattern recognition can provide a clinical diagnosis in many patients. Next-generation sequencing provides a definitive diagnosis in 80-90% of patients. Genes associated with hypomyelination include those that encode structural myelin proteins but also many that encode proteins involved in RNA translation and some lysosomal proteins. The precise pathomechanisms remain to be elucidated. Improved understanding of the process of myelination, the metabolic axonal support functions of myelin and the proposed contribution of myelin to CNS plasticity provide possible explanations as to why almost all patients with hypomyelination experience slow clinical decline after a long phase of stability. In this Review, we provide an overview of the hypomyelinating leukodystrophies, the advances in our understanding of myelin biology and of the genes involved in these disorders, and the insights these advances have provided into their clinical presentations and evolution.

Circadian rhythms in neurodegenerative disorders.

Abstract: Endogenous biological clocks, orchestrated by the suprachiasmatic nucleus, time the circadian rhythms that synchronize physiological and behavioural functions in humans. The circadian system influences most physiological processes, including sleep, alertness and cognitive performance. Disruption of circadian homeostasis has deleterious effects on human health. Neurodegenerative disorders involve a wide range of symptoms, many of which exhibit diurnal variations in frequency and intensity. These disorders also disrupt circadian homeostasis, which in turn has negative effects on symptoms and quality of life. Emerging evidence points to a bidirectional relationship between circadian homeostasis and neurodegeneration, suggesting that circadian function might have an important role in the progression of neurodegenerative disorders. Therefore, the circadian system has become an attractive target for research and clinical care innovations. Studying circadian disruption in neurodegenerative disorders could expand our understanding of the pathophysiology of neurodegeneration and facilitate the development of novel, circadian-based interventions for these disabling disorders. In this Review, we discuss the alterations to the circadian system that occur in movement (Parkinson disease and Huntington disease) and cognitive (Alzheimer disease and frontotemporal dementia) neurodegenerative disorders and provide directions for future investigations in this field. In this Review, Nassan and Videnovic discuss the alterations to the circadian system that occur in neurodegenerative disorders and highlight future directions for research in the field, including opportunities for the development of circadian-based therapeutic interventions.

The human connectome in Alzheimer disease - relationship to biomarkers and genetics.

Abstract: The pathology of Alzheimer disease (AD) damages structural and functional brain networks, resulting in cognitive impairment. The results of recent connectomics studies have now linked changes in structural and functional network organization in AD to the patterns of amyloid-β and tau accumulation and spread, providing insights into the neurobiological mechanisms of the disease. In addition, the detection of gene-related connectome changes might aid in the early diagnosis of AD and facilitate the development of personalized therapeutic strategies that are effective at earlier stages of the disease spectrum. In this article, we review studies of the associations between connectome changes and amyloid-β and tau pathologies as well as molecular genetics in different subtypes and stages of AD. We also highlight the utility of connectome-derived computational models for replicating empirical findings and for tracking and predicting the progression of biomarker-indicated AD pathophysiology.

Stroke in Africa: profile, progress, prospects and priorities.

Abstract: Stroke is a leading cause of disability, dementia and death worldwide. Approximately 70% of deaths from stroke and 87% of stroke-related disability occur in low-income and middle-income countries. At the turn of the century, the most common diseases in Africa were communicable diseases, whereas non-communicable diseases, including stroke, were considered rare, particularly in sub-Saharan Africa. However, evidence indicates that, today, Africa could have up to 2-3-fold greater rates of stroke incidence and higher stroke prevalence than western Europe and the USA. In Africa, data published within the past decade show that stroke has an annual incidence rate of up to 316 per 100,000, a prevalence of up to 1,460 per 100,000 and a 3-year fatality rate greater than 80%. Moreover, many Africans have a stroke within the fourth to sixth decades of life, with serious implications for the individual, their family and society. This age profile is particularly important as strokes in younger people tend to result in a greater loss of self-worth and socioeconomic productivity than in older individuals. Emerging insights from research into stroke epidemiology, genetics, prevention, care and outcomes offer great prospects for tackling the growing burden of stroke on the continent. In this article, we review the unique profile of stroke in Africa and summarize current knowledge on stroke epidemiology, genetics, prevention, acute care, rehabilitation, outcomes, cost of care and awareness. We also discuss knowledge gaps, emerging priorities and future directions of stroke medicine for the more than 1 billion people who live in Africa.

The neuroanatomical-functional paradox in spinal cord injury.

Abstract: Although lesion size is widely considered to be the most reliable predictor of outcome after CNS injury, lesions of comparable size can produce vastly different magnitudes of functional impairment and subsequent recovery. This neuroanatomical–functional paradox is likely to contribute to the many failed attempts to independently replicate findings from animal models of neurotrauma. In humans, the analogous clinical–radiological paradox could explain why individuals with similar injuries can respond differently to rehabilitation. We describe the neuroanatomical–functional paradox in the context of traumatic spinal cord injury (SCI) and discuss the underlying mechanisms of the paradox, including the concepts of lesion-affected and recovery-related networks. We also consider the various secondary complications that further limit the accuracy of outcome prediction in SCI and provide suggestions for how to increase the predictive, translational value of preclinical SCI models. In this Perspective, the authors discuss the mechanisms underlying the complex relationship between lesion size and functional recovery after spinal cord injury, highlighting various complications that can limit the accuracy of outcome prediction in patients and in animal models.

Aducanumab and the FDA - where are we now?

Abstract: The amyloid antibody aducanumab is currently undergoing review by the FDA. The treatment would be the first disease-modifying drug to be approved for Alzheimer disease; however, a medical advisory committee recently convened by the FDA did not recommend approval, raising questions about whether the existing evidence of efficacy is sufficient.

Non-neuronal cells in amyotrophic lateral sclerosis - from pathogenesis to biomarkers.

Abstract: The prevailing motor neuron-centric view of amyotrophic lateral sclerosis (ALS) pathogenesis could be an important factor in the failure to identify disease-modifying therapy for this neurodegenerative disorder. Non-neuronal cells have crucial homeostatic functions within the CNS and evidence of involvement of these cells in the pathophysiology of several neurodegenerative disorders, including ALS, is accumulating. Microglia and astrocytes, in crosstalk with peripheral immune cells, can exert both neuroprotective and adverse effects, resulting in a highly nuanced range of neuronal and non-neuronal cell interactions. This Review provides an overview of the diverse roles of non-neuronal cells in relation to the pathogenesis of ALS and the emerging potential of non-neuronal cell biomarkers to advance therapeutic development.

The importance of ongoing international surveillance for Creutzfeldt-Jakob disease.

Abstract: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, fatal and transmissible neurodegenerative disease associated with the accumulation of misfolded prion protein in the CNS. International CJD surveillance programmes have been active since the emergence, in the mid-1990s, of variant CJD (vCJD), a disease linked to bovine spongiform encephalopathy. Control measures have now successfully contained bovine spongiform encephalopathy and the incidence of vCJD has declined, leading to questions about the requirement for ongoing surveillance. However, several lines of evidence have raised concerns that further cases of vCJD could emerge as a result of prolonged incubation and/or secondary transmission. Emerging evidence from peripheral tissue distribution studies employing high-sensitivity assays suggests that all forms of human prion disease carry a theoretical risk of iatrogenic transmission. Finally, emerging diseases, such as chronic wasting disease and camel prion disease, pose further risks to public health. In this Review, we provide an up-to-date overview of the transmission of prion diseases in human populations and argue that CJD surveillance remains vital both from a public health perspective and to support essential research into disease pathophysiology, enhanced diagnostic tests and much-needed treatments.

The case for low-level BACE1 inhibition for the prevention of Alzheimer disease.

Abstract: Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease-modifying therapies targeting amyloid-β plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as β-secretase 1) reduce the production of amyloid-β peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non-progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this Perspective, we discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform 'go-no-go' decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention.

White matter injury in infants with intraventricular haemorrhage: mechanisms and therapies

Abstract: Intraventricular haemorrhage (IVH) continues to be a major complication of prematurity that can result in cerebral palsy and cognitive impairment in survivors. No optimal therapy exists to prevent IVH or to treat its consequences. IVH varies in severity and can present as a bleed confined to the germinal matrix, small-to-large IVH or periventricular haemorrhagic infarction. Moderate-to-severe haemorrhage dilates the ventricle and damages the periventricular white matter. This white matter injury results from a constellation of blood-induced pathological reactions, including oxidative stress, glutamate excitotoxicity, inflammation, perturbed signalling pathways and remodelling of the extracellular matrix. Potential therapies for IVH are currently undergoing investigation in preclinical models and evidence from clinical trials suggests that stem cell treatment and/or endoscopic removal of clots from the cerebral ventricles could transform the outcome of infants with IVH. This Review presents an integrated view of new insights into the mechanisms underlying white matter injury in premature infants with IVH and highlights the importance of early detection of disability and immediate intervention in optimizing the outcomes of IVH survivors.

Can we learn lessons from the FDA’s approval of aducanumab?

Abstract: On 7 June 2021, aducanumab was granted accelerated approval for the treatment of Alzheimer disease (AD) by the FDA on the basis of amyloid-lowering effects considered reasonably likely to confer clinical benefit. This decision makes aducanumab the first new drug to be approved for the treatment of AD since 2003 and the first drug to ever be approved for modification of the course of AD. Many have questioned how scientific evidence, expert advice and the best interests of patients and families were considered in the approval decision. In this article, we argue that prior to approval, the FDA and Biogen's shared interpretation of clinical trial data - that high-dose aducanumab was substantially clinically effective - avoided conventional scientific scrutiny, was prominently advanced by patient representative groups who had been major recipients of Biogen funds, and raised concerns that safeguards were insufficient to mitigate regulatory capture within the FDA. Here, we reflect on events leading to the FDA's decision on 7 June 2021 and consider whether any lessons can be learned for the field.

Apparent changes in the epidemiology and severity of multiple sclerosis.

Abstract: Multiple sclerosis (MS) is an immunological disease that causes acute inflammatory lesions and chronic inflammation in the CNS, leading to tissue damage and disability. As awareness of MS has increased and options for therapy have come into use, a large amount of epidemiological data have been collected, enabling studies of changes in incidence and disease course over time. Overall, these data seem to indicate that the incidence of MS has increased, but the course of the disease has become milder, particularly in the 25 years since the first disease-modifying therapies (DMTs) became available. A clear understanding of these trends and the reasons for them is important for understanding the factors that influence the development and progression of MS, and for clinical management with respect to prevention and treatment decisions. In this Review, we consider the evidence for changes in the epidemiology of MS, focusing on trends in the incidence of the disease over time and trends in the disease severity. In addition, we discuss the factors influencing these trends, including refinement of diagnostic criteria and improvements in health-care systems that have increased diagnosis in people with mild disease, and the introduction and improvement of DMT.

Identification of clinically relevant biomarkers of epileptogenesis - a strategic roadmap.

Abstract: Onset of many forms of epilepsy occurs after an initial epileptogenic insult or as a result of an identified genetic defect. Given that the precipitating insult is known, these epilepsies are, in principle, amenable to secondary prevention. However, development of preventive treatments is difficult because only a subset of individuals will develop epilepsy and we cannot currently predict which individuals are at the highest risk. Biomarkers that enable identification of these individuals would facilitate clinical trials of potential anti-epileptogenic treatments, but no such prognostic biomarkers currently exist. Several putative molecular, imaging, electroencephalographic and behavioural biomarkers of epileptogenesis have been identified, but clinical translation has been hampered by fragmented and poorly coordinated efforts, issues with inter-model reproducibility, study design and statistical approaches, and difficulties with validation in patients. These challenges demand a strategic roadmap to facilitate the identification, characterization and clinical validation of biomarkers for epileptogenesis. In this Review, we summarize the state of the art with respect to biomarker research in epileptogenesis and propose a five-phase roadmap, adapted from those developed for cancer and Alzheimer disease, that provides a conceptual structure for biomarker research.

Mind the gap: from neurons to networks to outcomes in multiple sclerosis.

Abstract: MRI studies have provided valuable insights into the structure and function of neural networks, particularly in health and in classical neurodegenerative conditions such as Alzheimer disease. However, such work is also highly relevant in other diseases of the CNS, including multiple sclerosis (MS). In this Review, we consider the effects of MS pathology on brain networks, as assessed using MRI, and how these changes to brain networks translate into clinical impairments. We also discuss how this knowledge can inform the targeting of MS treatments and the potential future directions for research in this area. Studying MS is challenging as its pathology involves neurodegenerative and focal inflammatory elements, both of which could disrupt neural networks. The disruption of white matter tracts in MS is reflected in changes in network efficiency, an increasingly random grey matter network topology, relative cortical disconnection, and both increases and decreases in connectivity centred around hubs such as the thalamus and the default mode network. The results of initial longitudinal studies suggest that these changes evolve rather than simply increase over time and are linked with clinical features. Studies have also identified a potential role for treatments that functionally modify neural networks as opposed to altering their structure.

Mechanism-based criteria to improve therapeutic outcomes in progressive multiple sclerosis.

Abstract: In contrast to the multiple disease-modifying therapies that are available for relapsing–remitting multiple sclerosis (MS), the therapeutic options for progressive MS (PMS) are limited. Recent advances in our understanding of the neuroimmunology of PMS, including the mechanisms that drive slowly expanding lesions, have fuelled optimism for improved treatment of this condition. In this Review, we highlight the commonly observed neuropathology of PMS and discuss the associated mechanisms of CNS injury. We then apply this knowledge to formulate criteria for therapeutic efficacy in PMS, beginning with the need for early treatment owing to the substantial neuropathology that is already present at the initial clinical presentation. Other requirements include: antagonism of neuroaxonal injury mediators such as pro-inflammatory microglia and lymphocytes; remediation of oxidative stress resulting from iron deposition and mitochondrial dysfunction; and promotion of neuroprotection through remyelination. We consider whether current disease-modifying therapies for relapsing–remitting MS meet the criteria for successful therapeutics in PMS and suggest that the evidence favours the early introduction of sphingosine 1-phosphate receptor modulators. Finally, we weigh up emerging medications, including repurposed generic medications and Bruton’s tyrosine kinase inhibitors, against these fundamental criteria. In this new therapeutic era in PMS, success depends collectively on understanding disease mechanisms, drug characteristics (including brain penetration) and rational use. Despite substantial progress in the development of disease-modifying therapies for multiple sclerosis (MS), the therapeutic options for progressive MS (PMS) remain limited. The authors present criteria for therapeutic success in PMS and consider the extent to which current drugs meet these criteria.