15th Anniversary

Advances in neurology over the past 15 years have transformed the treatment of a number of conditions but have also raised new questions and challenges.

Following extensive progress in the treatment of relapsing multiple sclerosis, the major challenge in the field is now to develop effective therapies for progressive forms of multiple sclerosis. As the first signs of success emerge, now is the time to consider the research needed to move the field forward.

Despite the strong treatment effects of mechanical thrombectomy in acute ischaemic stroke, penumbral tissue loss before recanalization and ischaemia–reperfusion injury after diminish functional outcomes and call for adjunct treatments. Classical neuroprotection strategies could consequently be revived, but novel treatment targets are also emerging through mechanistic research.

The introduction of therapies for spinal muscular atrophy (SMA) has rapidly changed the clinical landscape, transforming SMA from a lethal to a treatable disease. This transformation has driven further advances, from population screening imperatives to novel treatment delivery approaches, while uncovering health disparities and fuelling debate regarding drug pricing.

Despite the development of many new anti-seizure drugs over the past two decades, around one-third of individuals with epilepsy are without effective treatment. This pharmacoresistance is poorly understood, but new treatments targeting epileptogenesis instead of seizures have shown potential in animal models and are now being translated into the clinic.

Despite negative findings from numerous clinical trials of potential disease-modifying therapies for Alzheimer disease, amyloid remains the most compelling therapeutic target. Advances in biomarker methods now enable accurate monitoring of Alzheimer disease progression from the earliest stages of the disease. We must therefore redouble efforts to find an effective treatment.

In this Perspective, Pezzini and Padovani critique the evidence for neurological manifestations of COVID-19, including epidemiological, neuropathological and neuroimaging data, and highlight the need for further work to establish whether SARS-CoV-2 is responsible for these symptoms.

Acute respiratory distress syndrome is a common occurrence in COVID-19, an infectious disease caused by the coronavirus SARS-CoV-2. In this article, the authors consider how lung innervation might crosstalk with the immune system to modulate lung function and influence outcomes in COVID-19.

In this Review, Cristino, Bisogno and Di Marzo outline the biology of cannabinoids, the endocannabinoid system and the expanded endocannabinoid system and discuss the involvement of these systems and the therapeutic potential of cannabinoids across the spectrum of neurological disease.

Potential disease-modifying therapies for Alzheimer disease have mostly targeted brain accumulation of amyloid-β, but this approach has yet to provide substantial clinical benefits. The authors consider the reasons for this failure and suggest alternative strategies, including modification of risk factors.

Here, Sweeney and colleagues focus on advanced neuroimaging evidence of blood–brain barrier (BBB) breakdown in several neurodegenerative disorders. The role of the ageing cerebrovascular system in neurodegeneration and dementia and the implications of BBB dysfunction for treatment and drug delivery are also discussed.

Lifestyle and environmental factors, some which are potentially modifiable, have important roles in the risk of multiple sclerosis (MS), and some of these risk factors, such as Epstein–Barr virus infection, smoking and obesity in adolescence, interact with genetic risk factors. Here, Olsson and colleagues summarize recent data on modifiable environmental and lifestyle factors in MS, with a focus on gene–environment interactions.

Despite highly effective combination antiretroviral therapies, the prevalence of HIV-associated neurocognitive disorder (HAND) has not reduced. To date, clinical trials of HAND therapies have been unsuccessful, calling for better understanding of HAND pathogenesis to develop more-effective treatment strategies. In this Review, Justin McArthur and colleagues discuss recent proceedings in understanding the immunopathogenesis of HAND, drawing from human studies and animal models.

After brain injuries, microglia and macrophages can aid or hinder tissue repair depending on polarization toward specific cell phenotypes. This Perspectives article describes the phenotypic dynamics and different functions of these cells after acute CNS injury and argues that therapeutic approaches should focus on subtle adjustment of the balance between their phenotypes.

As a response to accumulation of debris and abnormally folded proteins during neurodegeneration, microglia multiply and adopt a chronically activated state. This process, referred to as priming, makes microglia susceptible to a secondary inflammatory stimulus, often arising from a systemic disorder with an inflammatory component, such as diabetes. Primed microglia react to the secondary inflammatory stimulus with an exaggarated response, which can further exacerbate neurodegeneration.

The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer disease (AD). Guojun Bu and colleagues describe the pathogenic links between Apo-E4 and neurodegeneration, including amyloid-β-dependent mechanisms and impairment of neurovascular function. The authors suggest potential strategies to target Apo-E, which could provide important additions to therapeutic options for AD.

Over the past few decades, considerable progress has been made in understanding the mechanisms underlying the relapsing–remitting stage of multiple sclerosis (MS), but the disease processes that drive progressive MS remain largely unresolved. In this Review, Lassmann and colleagues explore the current state of knowledge on the pathophysiology of progressive MS, and present a pathogenetic concept for this phase of the disease that involves oxidative stress and mitochondrial injury.

Relatively little is known about the mechanisms and processes that lead to the generation of seizures in patients with epilepsy, and this lack of knowledge hampers the development of treatments and cures. In this article, Vezzani et al. provide an overview of the involvement of inflammatory mediators in epileptic seizures. Gaining insights into the role of inflammation should yield new molecular targets for the design of antiepileptic drugs.

The early detection of Alzheimer disease might be critical to the effectiveness of disease-modifying drugs, when such therapies become available. In this Review, Blennowet al. examine the use of cerebrospinal fluid and plasma biomarkers in the early diagnosis of this neurodegenerative disorder. The authors also explore roles for cerebrospinal fluid biomarkers in Alzheimer disease clinical trials.

Alterations in the levels and activities of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), have been described in various neurodegenerative disorders, most notably Huntington disease. In this article, Zuccato and Cattaneo review the current knowledge about the involvement of BDNF in these diseases and critically assess whether BDNF treatment would be a beneficial and feasible therapeutic approach in the clinic.

Mitochondrial dysfunction and oxidative stress have been strongly implicated in the pathogenesis of Parkinson disease (PD), and the products of several PD-associated genes become localized to the mitochondria under certain conditions. In this article, Henchcliffe and Beal review recent developments in mitochondrial biology that have contributed to our understanding of the disease process in PD, and they discuss how this knowledge might aid in the development of 'mitochondrial therapies' for PD.

The use of brain stimulation for the treatment of neurological diseases such as chronic pain, Parkinson's disease, stroke and epilepsy has attracted growing attention. In this article, Fregni and Pascual-Leone review the recent literature regarding the use of two noninvasive brain stimulation techniques: repetitive transcranial magnetic stimulation and transcranial direct current stimulation. The authors discuss the underlying principles and present examples illustrating the therapeutic potential of these two techniques.

Investigations into the mechanisms underlying neurodegenerative disease have tended to focus largely on neuronal abnormalities, but it is becoming increasingly evident that astrocytes are important players in these and other neurological disorders. In this Review, the authors describe the normal roles of astrocytes in the brain, and discuss how animal models have provided important insights into the consequences of astrocyte dysfunction.

MRI has a pivotal role in the diagnosis of CNS disorders but has only recently been applied to diseases of the peripheral nervous system. Martin Bendszus and Guido Stoll discuss how MRI is being used to assess peripheral nerve lesions in experimental and clinical contexts, including recent advances in the development of novel contrast media.