Parkinson disease (PD) is the fastest growing neurological disorder globally and poses substantial management challenges owing to progressive disability, emergence of levodopa-resistant symptoms, and treatment-related complications. In this Review, we examine the current state of research into PD therapies and outline future priorities for advancing our understanding and treatment of the disease. We identify two main research priorities for the coming years: first, slowing the progression of the disease through the integration of sensitive biomarkers and targeted biological therapies, and second, enhancing existing symptomatic treatments, encompassing surgical and infusion therapies, with the goal of postponing complications and improving long-term patient management. The path towards disease modification is impeded by the multifaceted pathophysiology and diverse mechanisms underlying PD. Ongoing studies are directed at α-synuclein aggregation, complemented by efforts to address specific pathways associated with the less common genetic forms of the disease. The success of these efforts relies on establishing robust end points, incorporating technology, and identifying reliable biomarkers for early diagnosis and continuous monitoring of disease progression. In the context of symptomatic treatment, the focus should shift towards refining existing approaches and fostering the development of novel therapeutic strategies that target levodopa-resistant symptoms and clinical manifestations that substantially impair quality of life.

Diet is a modifiable lifestyle factor with a proven role in cardiovascular disease risk reduction that might also play an important part in cognitive health. Evidence from observational studies has linked certain healthy dietary patterns to cognitive benefits. However, clinical trials of diet interventions have demonstrated either null or, at best, small effects on cognitive outcomes. In this Review, we summarize the currently available evidence from observational epidemiology and clinical trials regarding the potential role of diet in the prevention of cognitive decline and dementia. We further discuss possible methodological limitations that might have hindered the ability of previous diet intervention trials to capture potential neuroprotective effects. Considering the overwhelming and continuously expanding societal, economic and health-care burden of Alzheimer disease and other dementias, future nutritional research must address past methodological challenges to accurately and reliably inform clinical practice guidelines and public health policies. Within this scope, we provide a roadmap for future diet intervention trials for dementia prevention. We discuss study designs involving both intensive personalized interventions - to evaluate pharmacokinetic and pharmacodynamic properties, establish neuroprotective thresholds, and test hypothesized biological mechanisms and effects on brain health and cognition through sensitive and precise biomarker measures - and large-scale, pragmatic public health interventions to study population-level benefits.

Traumatic brain injury (TBI) is a leading cause of long-term disability across the world. Evidence for the usefulness of imaging and fluid biomarkers to predict outcomes and screen for the need to monitor complications in the acute stage is steadily increasing. Still, many people experience symptoms such as fatigue and cognitive and motor dysfunction in the chronic phase of TBI, where objective assessments for brain injury are lacking. Consensus criteria for traumatic encephalopathy syndrome, a clinical syndrome possibly associated with the neurodegenerative disease chronic traumatic encephalopathy, which is commonly associated with sports concussion, have been defined only recently. However, these criteria do not fit all individuals living with chronic consequences of TBI. The pathophysiology of chronic TBI shares many similarities with other neurodegenerative and neuroinflammatory conditions, such as Alzheimer disease. As with Alzheimer disease, advancements in fluid biomarkers represent one of the most promising paths for unravelling the chain of pathophysiological events to enable discrimination between these conditions and, with time, provide prediction modelling and therapeutic end points. This Review summarizes fluid biomarker findings in the chronic phase of TBI (≥6 months after injury) that demonstrate the involvement of inflammation, glial biology and neurodegeneration in the long-term complications of TBI. We explore how the biomarkers associate with outcome and imaging findings and aim to establish mechanistic differences in biomarker patterns between types of chronic TBI and other neurodegenerative conditions. Finally, current limitations and areas of priority for future fluid biomarker research are highlighted.

Preservation of brain health is a worldwide priority. The traditional view is that the major threats to the ageing brain lie within the brain itself. Consequently, therapeutic approaches have focused on protecting the brain from these presumably intrinsic pathogenic processes. However, an increasing body of evidence has unveiled a previously under-recognized contribution of peripheral organs to brain dysfunction and damage. Thus, in addition to the well-known impact of diseases of the heart and endocrine glands on the brain, accumulating data suggest that dysfunction of other organs, such as gut, liver, kidney and lung, substantially affects the development and clinical manifestation of age-related brain pathologies. In this Review, a framework is provided to indicate how organ dysfunction can alter brain homeostasis and promote neurodegeneration, with a focus on dementia. We delineate the associations of subclinical dysfunction in specific organs with dementia risk and provide suggestions for public health promotion and clinical management.

The genetic architecture of multiple sclerosis (MS) is similar to that of coeliac disease, with human leukocyte antigen (HLA) being the greatest genetic determinant in both diseases. Furthermore, similar to the involvement of gluten in coeliac disease, Epstein-Barr virus (EBV) infection is now widely considered to be an important environmental factor in MS. The molecular basis for the HLA association in coeliac disease is well defined, and B cells have a clear role in antigen presentation to gluten-specific CD4 T cells. By contrast, the mechanisms underlying the HLA association of MS are unknown but accumulating evidence indicates a similar role of B cells acting as antigen-presenting cells. The growing parallels suggest that much could be learned about the mechanisms of MS by using coeliac disease as a model. In this Perspective article, we discuss the insights that could be gained from these parallels and consider the possibility of antiviral treatment against EBV as a therapy for MS that is analogous to the gluten-free diet in coeliac disease.

Intracerebral haemorrhage (ICH) is a devastating condition associated with high mortality and substantial residual disability among survivors. Effective treatments for the acute stages of ICH are limited. However, promising findings from randomized trials of therapeutic strategies, including acute care bundles that target anticoagulation therapies, blood pressure control and other physiological parameters, and trials of minimally invasive neurosurgical procedures have led to renewed optimism that patient outcomes can be improved. Currently ongoing areas of research for acute treatment include anti-inflammatory and haemostatic treatments. The implementation of effective secondary prevention strategies requires an understanding of the aetiology of ICH, which involves vascular and brain parenchymal imaging; the use of neuroimaging markers of cerebral small vessel disease improves classification with prognostic relevance. Other data underline the importance of preventing not only recurrent ICH but also ischaemic stroke and cardiovascular events in survivors of ICH. Ongoing and planned randomized controlled trials will assess the efficacy of prevention strategies, including antiplatelet agents, oral anticoagulants or left atrial appendage occlusion (in patients with concomitant atrial fibrillation), and optimal management of long-term blood pressure and statin use. Together, these advances herald a new era of improved understanding and effective interventions to reduce the burden of ICH.

Neuromyelitis optica (NMO) spectrum disorder (NMOSD) is a relapsing inflammatory disease of the CNS, characterized by the presence of serum aquaporin 4 (AQP4) autoantibodies (AQP4-IgGs) and core clinical manifestations such as optic neuritis, myelitis, and brain or brainstem syndromes. Some people exhibit clinical characteristics of NMOSD but test negative for AQP4-IgG, and a subset of these individuals are now recognized to have serum autoantibodies against myelin oligodendrocyte glycoprotein (MOG) - a condition termed MOG antibody-associated disease (MOGAD). Therefore, the concept of NMOSD is changing, with a disease spectrum emerging that includes AQP4-IgG-seropositive NMOSD, MOGAD and double-seronegative NMOSD. MOGAD shares features with NMOSD, including optic neuritis and myelitis, but has distinct pathophysiology, clinical profiles, neuroimaging findings (including acute disseminated encephalomyelitis and/or cortical encephalitis) and biomarkers. AQP4-IgG-seronegative NMOSD seems to be a heterogeneous condition and requires further study. MOGAD can manifest as either a monophasic or a relapsing disease, whereas NMOSD is usually relapsing. This Review summarizes the history and current concepts of NMOSD and MOGAD, comparing epidemiology, clinical features, neuroimaging, pathology and immunology. In addition, we discuss new monoclonal antibody therapies for AQP4-IgG-seropositive NMOSD that target complement, B cells or IL-6 receptors, which might be applied to MOGAD in the near future.

The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old therapeutic approaches that provide only symptomatic relief. To address this unmet need, an in-person symposium was held in Toronto, Canada, in November 2022 for international researchers and experts in MS and PD to discuss strategies for advancing DMT development. In this Roadmap article, we highlight discussions from the symposium, which focused on therapeutic targets and preclinical models, disease spectra and subclassifications, and clinical trial design and outcome measures. From these discussions, we propose areas for novel or deeper exploration in PD using lessons learned from therapeutic development in MS. In addition, we identify challenges common to the PD and MS fields that need to be addressed to further advance the discovery and development of effective DMTs.

Several major challenges, including an ageing population and declining workforce and the implementation of recent breakthrough therapies for Alzheimer disease, are prompting a necessary rethink of how people with neurodegenerative dementias are diagnosed and medically managed. Digital health technologies could play a pivotal part in this transformation, with new advances enabling the collection of millions of data points from a single individual. Possible applications include unobtrusive monitoring that aids early detection of disease and artificial intelligence-based health advice. To translate these advances to meaningful benefits for people living with a disease, technologies must be implemented within a system that retains the physician expert as a central figure in decision-making. This Perspective presents a new framework, termed the Digitized Memory Clinic, for the diagnostic pathway of neurodegenerative dementias that incorporates digital health technologies with currently available assessment tools, such as fluid and imaging biomarkers, in an interplay with the physician. The Digitized Memory Clinic will manage people across the entire disease spectrum, from the detection of risk factors for cognitive decline and the earliest symptoms to dementia, and will replace the present paradigm of a pure 'brick-and-mortar' memory clinic. Important ethical, legal and societal barriers associated with the implementation of digital health technologies in memory clinics need to be addressed. The envisioned Digitized Memory Clinic aims to improve diagnostics and enable precise disease-tracking prognostication for individuals with memory disorders and to open new possibilities, such as precision medicine for prevention and treatment.