Fatigue is a severely disabling symptom that can substantially impair quality of life and employment prospects, and has serious socioeconomic consequences. Different individual and disease-related variables interact to generate this complex symptom, leading to clinical heterogeneity. We currently lack a common understanding and definition of fatigue and its origins, thereby impeding professional exchange among disciplines regarding diagnosis and underlying pathophysiology. To aid the development of a common language that encapsulates the heterogeneity of fatigue, we propose a taxonomy consisting of neurogenic, myogenic and systemic clusters. Each cluster comprises the same five distinct concepts and their phenotypic expression. The interplay between multifactorial pathophysiological mechanisms might vary between diseases and over time, and additional factors such as comorbidities can modulate fatigue. Understanding this complexity is essential to improve both the diagnostic process and the development of targeted therapeutic interventions. In this Review, we compare the clinical and pathophysiological characteristics of a range of neurological and non-neurological diseases within predefined clusters of fatigue origin. We propose an integrative model for fatigue of different origin and over time based on the interplay of genetics and epigenetics, immunological changes, structural and functional brain abnormalities, and behavioural alterations. Large research consortia will be required to tackle the methodological shortcomings that currently hamper our understanding of fatigue and to initiate large longitudinal cohort studies with multidimensional readouts to further explore and address this burdensome symptom.

Cognitive impairment in people with Parkinson disease (PD) imposes a substantial societal burden: PD affects over 1% of the population aged 65 years and older, and 24-31% of individuals with this condition develop dementia and another 26% present with mild cognitive impairment. Given the increasing prevalence of PD in light of an ageing population, the challenge of PD-associated cognitive impairment is likely to intensify. In this Review, we highlight the latest research advances in PD-associated cognitive impairment, emphasizing emerging mechanistic insights and new biomarkers. We outline the epidemiology and natural history of cognitive decline in PD, focusing on prodromal stages and the closely related spectrum of Lewy body dementia. We discuss key pathophysiological factors and mechanisms, including aggregation and prion-like propagation of α-synuclein; co-pathologies; synaptic dysfunction; genetics; neuroinflammation; mitochondrial dysfunction; oxidative stress; microbiome alterations; degeneration of cholinergic and monoaminergic systems; autonomic dysfunction; altered neuronal network activity; and glymphatic impairment. We consider how advances in fluid and neuroimaging biomarkers, together with preclinical disease models and pathological studies, are providing insights into these mechanisms. A deeper understanding of the multifaceted pathophysiology of PD-associated cognitive impairment will help us to explain the heterogeneity of cognitive profiles and disease progression in PD, providing a foundation for personalized disease-modifying treatments.

Prevention of Alzheimer disease (AD) is a medical challenge owing to its complex pathogenesis, which involves amyloid-β (Aβ) and tau aggregation, neuroinflammation and progressive neurodegeneration. Development of disease-specific biomarkers has transformed our ability to detect AD pathology early, enabling more accurate diagnosis, monitoring and the development of targeted disease-modifying therapies. Consequently, primary and secondary prevention of AD have become feasible goals. In this Perspective, we examine current and emerging pharmacological strategies for the prevention of AD, particularly the use of existing anti-Aβ therapies and emerging anti-tau approaches, among people at risk of AD or in the earliest, presymptomatic stages of the disease. We highlight the key challenges in implementing prevention trials, discuss ongoing prevention trials and their implications, and consider the potential and challenges of translation into clinical practice. Implementation of preventative strategies, supported by biomarker-guided patient selection and innovative trial designs, has the potential to substantially delay or prevent the cognitive decline caused by AD. Success would fundamentally transform the AD therapeutic landscape, reducing the socioeconomic burden of dementia and preserving cognitive function in ageing populations worldwide.

According to the MS International Federation, the global prevalence of multiple sclerosis (MS) is increasing, although regional variations have been reported, which could provide valuable insights into MS pathophysiology. As we highlight in this Review, the prevalence of MS in Latin America is comparatively low, possibly owing at least in part to the unique genetic and environmental characteristics of this region. Latin America has experienced centuries of admixture between Native American Indian populations and people from other parts of the world, including Europe and - to a lesser extent - Africa. Moreover, certain environmental factors in the Southern Hemisphere might contribute to this reduced MS prevalence. The McDonald criteria are considered to be a useful tool to diagnose MS in Latin America, although it is important to exclude regional diseases that can mimic MS. MS research is burgeoning in the region, and increasing numbers of Latin American patients are participating in randomized clinical trials. In addition, real-world data from national and regional MS registries are helping us to understand the distinct features of the disease in Latin America.

Restless legs syndrome (RLS) and periodic limb movements (PLMs) are increasingly recognized as risk factors for cerebrovascular and cardiovascular diseases, particularly stroke. Conversely, stroke can precipitate or exacerbate the symptoms of RLS and PLMs. This Review explores the shared pathophysiological mechanisms linking RLS and PLMs to cerebrovascular pathology, highlighting a bidirectional relationship. We discuss mechanisms including neurotransmitter dysregulation, autonomic dysfunction, inflammation, oxidative stress, hypoxia and genomic and proteomic factors. Furthermore, we summarize emerging evidence and provide new insights on the potential clinical relevance of RLS in cerebrovascular risk assessment and management.

Accumulating evidence indicates that Alzheimer disease (AD) is caused by dysregulated microglial phagocytosis. The main risk factor for AD is age, and ageing reduces microglial phagocytosis of amyloid-β (Aβ) plaques, while increasing microglial phagocytosis of synapses and neurons. Most of the known genetic risk for AD can be linked to microglial phagocytosis, including ABCA1, ABI3, ACE, ADAM17, APOE, APP, BIN1, BLNK, CD2AP, CD33, CLU, CR1, CTSB, CTSH, EED, GRN, INPP5D, LILRB2, PICALM, PLCG2, PSEN1, PTK2B, SIGLEC11, SORL1, SPI1, TMEM106B and TREM2. Moreover, the only disease-modifying treatments for AD - anti-Aβ antibodies - work by increasing microglial phagocytosis of Aβ aggregates. Microglial phagocytosis of Aβ via TREM2, LRP1, CD33, TAM receptors and anti-Aβ antibodies appears to reduce AD pathology by pruning and compacting plaques, restricting subsequent tau pathology, whereas microglial phagocytosis of synapses and neurons seems detrimental in the later stages of AD, via complement, P2Y receptor and TREM2. However, the roles of microglial phagocytosis in AD are complex and multifaceted, and improved treatments are likely to require a deeper understanding of these roles.

Expansion of simple DNA repeats causes over 45 human, predominantly neurodegenerative, inherited disorders. Huntington disease is a fatal, inherited, neurodegenerative disease caused by a CAG repeat expansion in the huntingtin gene (HTT), resulting in a toxic polyglutamine tract in the huntingtin protein. The disease leads to progressive motor, cognitive and psychiatric decline, primarily resulting from loss of medium spiny neurons in the striatum. Although Huntington disease has long been viewed as a consequence of age-dependent toxicity from mutant huntingtin, genome-wide association studies have identified genetic modifiers, mostly DNA repair genes, that significantly influence disease onset and progression. These findings point to somatic CAG repeat expansions in affected tissues as a key pathological mechanism. This emerging paradigm suggests that disease progression is not solely protein-driven but also shaped at the DNA level, a mechanism that is shared among other repeat expansion disorders. Therapeutically, this discovery opens new opportunities: interventions to limit somatic repeat expansion might be effective across multiple repeat expansion diseases and, when combined with disease-specific approaches, such as huntingtin lowering in Huntington disease, might offer more effective and longer-lasting clinical benefits than either strategy in isolation. This approach also poses challenges, determining the optimal point for therapeutic intervention and how best to establish phenotypic improvement in clinical trials when the target tissue is the brain.

Multiple sclerosis (MS) is among the most common causes of disability in the young and, despite the advent of highly effective disease-modifying therapies, remains an incurable disease. Prevention of MS before the onset of demyelination is a feasible, albeit ambitious, goal. Currently, preventive interventions with adequate evidence of efficacy are lacking, and evaluating such interventions with traditional trial designs is challenging. Additionally, the high frequency and low effect sizes of putative MS risk factors, a limited window of opportunity to intervene, and the relatively low incidence of MS in the general population make prevention studies conceptually and practically difficult. Nevertheless, studies in radiologically isolated syndrome have generated momentum within the MS prevention space, and novel trial designs offer the potential for reimagining traditional randomized controlled trials. In this Perspective, we discuss the challenges in developing and testing preventive interventions in MS and, drawing on progress in other diseases, we propose strategies and solutions. We discuss pragmatic approaches to risk stratification and illustrate the importance of considering statistical power and outcome definitions. Prevention studies require careful thought with respect to risk stratification, communication, intervention and outcomes but, given the current knowledge, the time to set up and start MS prediction and prevention studies is now.