A phase III trial of obinutuzumab β shows striking efficacy in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder. The findings reinforce B cell depletion as a therapeutic principle while raising a more fundamental question: which B cell populations must be depleted, and how completely?
Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains primarily focused on diseases with complement-fixing pathogenic antibodies (such as myasthenia gravis and neuromyelitis optica spectrum disorder), a robust pipeline of emerging treatments holds promise for expanding complement-targeted therapies to a broader spectrum of autoimmune neurological diseases, such as multiple sclerosis and even neurodegenerative diseases such as Alzheimer disease or amyotrophic lateral sclerosis. This Review presents insights into complement biology as it relates to the development or initiation of autoimmune and possibly degenerative diseases affecting the central and peripheral nervous systems or muscle. The effects, merits, risks and challenges of marketed drugs or biologic agents in ongoing phase I-III clinical trials engineered to inhibit proximal or distal components of the complement cascade are also discussed. Anti-complement therapeutics are destined to change the treatment of autoimmune neurologic conditions in which the therapeutic landscape is now becoming crowded with biologic agents targeting other key autoimmunity factors.
Symptomatic treatment remains central to the clinical management of Alzheimer disease (AD), even as disease-targeted therapies emerge. This Review synthesizes current evidence for pharmacological and non-pharmacological symptomatic therapies targeting cognition, function and neuropsychiatric symptoms in AD. Non-pharmacological interventions, including cognitive training, physical exercise, cognitive stimulation therapy and multimodal lifestyle programmes, show small-to-moderate benefits, particularly in mild cognitive impairment, although implementation challenges persist. Established pharmacological treatments, notably cholinesterase inhibitors and memantine, deliver modest but significant benefits, with biomarker-stratified analyses suggesting the greatest benefit in individuals with confirmed AD pathology. Advances in muscarinic agonists, multitarget agents, neurotrophic modulators and repurposed drugs highlight emerging opportunities for broader symptomatic benefit. Neuropsychiatric symptoms remain highly prevalent and burdensome; personalized psychosocial interventions demonstrate meaningful reductions in agitation and depression, whereas atypical antipsychotics offer only modest efficacy with substantial safety concerns. Newer agents, including brexpiprazole for agitation and pimavanserin for psychosis, show promise but require careful interpretation of effect size and safety. Future progress will depend on biomarker-informed patient selection, integration of circuit-level measures, rational combination strategies spanning pharmacological and non-pharmacological modalities, and adoption of patient-centred outcomes. Symptomatic therapies will remain essential for improving quality of life in people with AD, even as disease-targeted therapies reshape disease trajectories.
Obesity is a global health issue, and cognitive impairment and elevated risk of dementia are emerging as important consequences. Clinical studies have documented that obesity over the life course is associated with cognitive decline, with midlife obesity carrying a particularly high risk. Evidence from both preclinical and clinical studies suggests that obesity has multiple pathophysiological effects on the brain, including hypothalamic dysregulation and disruptions in biological processes that affect the hippocampus and prefrontal cortex, such as metabolic, inflammatory and vascular dysfunction. In this Review, we summarize the global epidemiology of obesity and examine its clinical relevance as a risk factor for cognitive impairment and dementia. We also discuss the peripheral and central mechanisms through which obesity affects brain function and review obesity-related interventions that have been shown to improve cognition. We conclude by identifying crucial gaps in the existing clinical, translational and intervention-focused literature that warrant future investigation.
Regional variations in Lewy body ultrastructure do not differ between Parkinson disease and dementia with Lewy bodies, but variations in mitochondrial morphology do, according to new research.
A common mechanism of mutagenesis contributes to amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer disease, new research has shown.
Differences in structural brain asymmetry could be associated with age-related diseases such as Alzheimer disease, new research suggests.
Circular RNAs in the blood could be used as a highly sensitive biomarker for Alzheimer disease (AD), according to new research.
Menopause is under-recognized as a biological and sociocultural contributor to brain health, and scientific understanding of the impact that the menopausal transition has on the brain is minimal. This knowledge gap is particularly detrimental for women who live with neurological conditions. We lack sufficient data to understand the experience of women with established neurological conditions during perimenopause, the mechanisms associated with postmenopausal changes in disease course and how to improve management of neurological conditions in a sex-specific way. Furthermore, approximately two thirds of women experience cognitive concerns during the menopausal transition. Although earlier menopause is associated with a greater risk of cognitive decline, the influence of the menopausal transition on subsequent risk of neurological conditions remains unclear. In this Roadmap, we identify key areas in which research is limited and highlight historical and scientific challenges that have hindered progress in understanding brain health in the context of menopause. To address these challenges, we consider existing knowledge and propose priorities and future research directions to advance our understanding of the relationship between menopause and neurological health and disease.
A new study reports a CAR T cell therapy that concurrently targets the tumour and the pro-tumour microenvironment through a shared antigen. The new strategy could help to overcome key limitations of current therapies.
Sleep disruption in Alzheimer disease has long been viewed as a downstream consequence of amyloid and tau. Two new studies show that glia-mediated mechanisms involving microglia and astrocytic aquaporin 4, rather than amyloid plaque burden, disrupt sleep and are potential targets to prevent Alzheimer disease-related sleep loss.
Hereditary white matter disorders, encompassing leukodystrophies and genetically determined leukoencephalopathies, are a heterogeneous group of conditions characterized by white matter signal abnormalities on neuroimaging. An increasing number of these disorders are now associated with defects in genes that encode proteins involved in transcription, RNA processing and translation. Pathogenic variants in these genes disrupt fundamental processes of the central dogma yet manifest primarily as neurological diseases, often presenting with diverse clinical and radiological features. Although many of these conditions have been recognized for over a decade, their underlying pathophysiological mechanisms and the selective vulnerability of the CNS and myelin remain incompletely understood. Here we provide a comprehensive overview of white matter disorders arising from defects in protein biosynthesis pathways. We summarize known disease-causing genes and their molecular consequences and associated clinical and radiological phenotypes, and highlight emerging mechanistic themes and therapeutic strategies across this expanding class of disorders.
Contemporary management of multiple sclerosis is based on the clinical course descriptors of relapsing-remitting, secondary progressive and primary progressive. However, recognition is growing in the field that these clinical course descriptors do not capture the full disease spectrum of multiple sclerosis or reflect the underlying biological mechanisms of disease, and that biologically informed course descriptors are needed. In this Roadmap, participants in an International Advisory Committee on Clinical Trials in Multiple Sclerosis workshop discuss the problems with the existing course descriptors, highlight considerations for developing new course descriptors and propose a roadmap for transitioning towards a more dynamic, biologically informed description of the multiple sclerosis disease course.
People with Lewy body disease exhibit heterogeneous clinical symptoms, diverse patterns of neurodegeneration on imaging and variable Lewy body pathology at post-mortem. The brain-first versus body-first (BvB) model provides a unifying framework that may account for much of this variability. According to the BvB model, Lewy pathology originates either in autonomic nerves of the gut or other peripheral neurons (body first) or in the olfactory bulb with subsequent spread to the limbic system (brain first). Both subtypes are thought to begin largely outside the CNS, possibly triggered by exogenous factors such as infectious agents or toxins. The model is supported by several observations. First, some individuals develop autonomic dysfunction and sleep disorders years before diagnosis, whereas other individuals experience these symptoms only after diagnosis. Second, in people with prodromal sleep disorders, cardiac sympathetic denervation precedes nigrostriatal degeneration by approximately a decade, whereas in individuals without sleep disorders, these systems degenerate in the opposite sequence. Third, post-mortem studies often reveal bottom-up or top-down gradients of Lewy pathology, consistent with body-first versus olfactory-first origins. This Review provides a critical appraisal of the BvB model, highlighting supporting evidence and current limitations. The article also considers implications for diagnostics, therapy and prevention, and outlines key avenues for future research.
Ebola virus disease is associated with a broad range of long-term neurological sequalae, a new study reports.
With accelerating development of treatments for ataxias, biomarkers are needed as end-points in clinical trials. The Ataxia Global Initiative MRI Biomarkers Working Group has published recommendations for the use of MRI measures as end-points in clinical trials in the most common forms of ataxia.
Adaptive deep brain stimulation (DBS) promises to revolutionize the treatment of Parkinson disease with neuromodulation, and regulatory approval has enabled its use in clinical practice. This Clinical Outlook considers the principles behind adaptive DBS, current clinical recommendations and practical considerations in its implementation, as well as remaining challenges.
Artificial intelligence (AI) applications in neurology have reached an inflection point. Despite US Food and Drug Administration approval of numerous algorithms in neuroimaging, neurophysiology, genetics and chatbots, their real-world impact remains limited. This disconnect between research promise and clinical reality represents a gap in understanding how to translate AI algorithms into clinical benefit for patients globally. In this Perspective, we examine the challenges that prevent clinical AI use in neurology moving beyond pilot studies towards meaningful clinical impact. We consider the steps required in the process of translation, including research, validation of AI models, regulatory approval pathways and clinical implementation. We discuss implementation of AI models as stand-alone products versus embedded platforms, and the requirements for sustainable deployment. Beyond traditional clinical decision support tools, we examine paraclinical applications of AI, including chatbots and ambient voice documentation. We recommend expanding capacity for prospective validation and scaling by implementing and validating technologies across multiple sites and countries, which requires infrastructure from long-term partnerships. Neurology must shift from asking whether AI can work to understanding how to use it safely at scale.
Artificial intelligence is foreshadowed to revolutionize healthcare. Headache care is no exception, with applications in diagnostics, disease forecasting and treatment optimization. Still, a considerable gap remains between optimism and technological advancements on one side and clinically adopted and evidence-based solutions on the other.
The diagnosis and management of disorders of consciousness (DoC) currently relies on complex multimodal assessments by experienced multidisciplinary teams, which are often unavailable in non-specialist care settings. Artificial-intelligence-based approaches could aid DoC prognostication and care in such settings, as well as yielding new mechanistic and therapeutic insights into DoC.
