Clinical neurology:

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.

AIM: The "2024 Guideline for the Primary Prevention of Stroke" replaces the 2014 "Guidelines for the Primary Prevention of Stroke." This updated guideline is intended to be a resource for clinicians to use to guide various prevention strategies for individuals with no history of stroke.

Recently a substantial body of biological evidence, converging data from biochemistry, neurophysiology, pharmacology, immunology, and neuroimaging has been collected to underpin the concept of continuum of affective disorders. Overall, it is comprised of two dimensions. One is clinical, which spans from major depressive disorder to bipolar spectrum, with mixed and sub-threshold states. The other dimension is causal, based mainly on evidence about the heterogenous etiological structure of mood disorders, including organic and exogenous brain disorders (such as multiple sclerosis, neurodegenerative diseases, intoxications) manifested in prodromal stages with affective disturbances, and "functional" or endogenous mood disorders. This Special Issue will explore the trait and state complex markers which define the continuum of affective disorders in both causal and clinical perspective.

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.

Abstract: The quotation, attributed to Confucius many centuries ago, in our opinion, applies to the evolving story of defining a primary surgical treatment for spontaneous intracerebral hemorrhage. The precise quote is: "Keep it simple and focus on what matters. Don't let yourself be overwhelmed." The evidence from multiple trials on intracerebral hemorrhage regarding mortality benefit and potential functional benefit directs us toward the simple task of evacuating the clot, similar to our prime focus on opening the artery in ischemic stroke. We need not be overwhelmed by questions about adjustments to patient selection, comparative techniques, and precision timing, for which we do not have conclusive data. We review the consensus results from the recent MISTIE trial (Minimally Invasive Surgery Plus Alteplase in ICH Evacuation) and ENRICH trial (Early Minimally Invasive Removal of Intracerebral Hemorrhage) and articulate remaining questions where further evidence is needed to challenge equipoise and define future practice.

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.

The revised biomarker framework for diagnosis and staging of Alzheimer's disease (AD) relies on amyloid beta (Aβ) and tau pathologies as core markers, and markers for adjacent pathophysiology, such as neurodegeneration and inflammation. Many of the core fluid biomarkers are phosphorylated tau (p-tau) fragments, with p-tau217 showing a prominent association with Aβ and tau. While positron emission tomography (PET) imaging is well established, plasma p-tau assays are newer and likely to reduce the use of expensive, and less accessible cerebrospinal fluid and PET imaging tests, thereby promoting wider access to AD screening. There is a need for greater understanding of how the various plasma p-tau species reflect different pathological processes of AD and how different immunoassays perform. This review surveys the available immunoassays and highlights their strengths and limitations in different contexts of use. Assays need to be standardized to maximize their impact on AD clinical research, and patient diagnosis and management. HIGHLIGHTS: Different plasma phosphorylated tau (p-tau) species reflect different pathological processes of Alzheimer's disease (AD), with p-tau231 showing the greatest association with the earliest increases in brain amyloid beta (Aβ) accumulation, while p-tau217 shows greater association with both brain Aβ and early tau pathology, and other p-tau and tau fragment species show greater association with later stages of brain tau pathology. Plasma p-tau217 has proven to be an excellent biomarker for AD pathology due to its close association with both brain Aβ and tau pathology, as well as its large dynamic range. Many different assays with varying performance exist for the same p-tau species, with mass spectrometry assays performing uniformly well, and several immunoassays achieving comparable performance. "Round robin" head-to-head studies have been performed to compare different assays for several key plasma biomarkers, including p-tau181 and p-tau217, but additional head-to-head studies are needed, especially for new analytes and for measuring performance in diverse populations. Plasma immunoassays have the potential to increase accessibility of early diagnostic testing for a broad population, including diverse historically under-represented and under-served populations, due to the potential to be implemented globally, including in primary care settings; however, further research is needed to validate the optimal cutoffs for each assay for real-world clinical usage. Eventually, clinical implementation of a two-step workflow may allow standalone use of plasma testing in certain contexts, minimizing the need for confirmation with costly and less accessible cerebrospinal fluid/positron emission tomography testing.

BACKGROUND AND OBJECTIVES: Mounting evidence points to a strong connection between cardiovascular risk during middle age and brain health later in life. The American Heart Association's Life's Essential 8 (LE8) constitutes a research and public health construct capturing key determinants of cardiovascular health. However, the overall effect of the LE8 on global, clinically relevant metrics of brain health is still unknown. We tested the hypothesis that worse LE8 profiles are associated with higher composite risk of the most important clinical endpoints related to poor brain health.

Knowledge on the genetic basis of Parkinson's disease has grown tremendously since the discovery of the first monogenic form, caused by a mutation in α-synuclein, and with the subsequent identification of multiple other causative genes and associated loci. Genetic studies provide insights into the phenotypic heterogeneity and global distribution of Parkinson's disease. By shedding light on the underlying biological mechanisms, genetics facilitates the identification of new biomarkers and therapeutic targets. Several clinical trials of genetics-informed therapies are ongoing or imminent. International programmes in populations who have been under-represented in Parkinson's disease genetics research are fostering collaboration and capacity-building, and have already generated novel findings. Many challenges remain for genetics research in these populations, but addressing them provides opportunities to obtain a more complete and equitable understanding of Parkinson's disease globally. These advances facilitate the integration of genetics into the clinic, to improve patient management and personalised medicine.

CONCLUSIONS: Our findings suggest that, like other forms of epilepsy, genetic predisposition plays an essential role in PSE. These results underscore the need for future studies to elucidate the mechanisms underlying PSE development and to identify novel therapeutic avenues.

OBJECTIVES: Spinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene has recently been recognized as a common cause of late-onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4-aminopyridine in a cohort of 102 patients bearing GAA repeat expansions.

Obstructive sleep apnea (OSA) is a sleep disorder with well-known metabolic consequences. The relationship between OSA and bone health, especially osteoporosis, remains poorly understood. Given that both OSA and osteoporosis are highly prevalent chronic conditions with significant public health implications, this study aims to investigate the association of OSA with bone health and osteoporosis. A systematic search of PubMed, Embase and Cochrane Library was conducted from inception to November 22, 2022. Fifteen studies comprising 158,273 individuals were included. The presence of OSA correlated negatively with bone mineral density on meta-analysis (pooled correlation = -0.30; 95 % CI, -0.42 to -0.17; N = 8). Individuals with OSA had poorer bone mineral density scores (mean difference = -0.58, 95 % CI, -1.15 to -0.01; N = 8), and significantly higher risk of developing osteoporosis (adjusted odds ratio = 2.18; 95 % CI, 1.14 to 4.16; N = 4). Notably, both body mass index (BMI) and age were not significant effect modulators in the correlation of OSA and bone density. These findings suggest that OSA is associated with diminished bone health, and it is severity-dependent. Further studies are required to determine if treatment of OSA may have the potential to mitigate these risks.

Narcolepsy type 1 (NT1) is a sleep-wake disorder in which people typically experience excessive daytime sleepiness, cataplexy and other sleep-wake disturbances impairing daily life activities. NT1 symptoms are due to hypocretin deficiency. The cause for the observed hypocretin deficiency remains unclear, even though the most likely hypothesis is that this is due to an auto-immune process. The search for autoantibodies and autoreactive T-cells has not yet produced conclusive evidence for or against the auto-immune hypothesis. Other mechanisms, such as reduced corticotrophin-releasing hormone production in the paraventricular nucleus have recently been suggested. There is no reversive treatment, and the therapeutic approach is symptomatic. Early diagnosis and appropriate NT1 treatment is essential, especially in children to prevent impaired cognitive, emotional and social development. Hypocretin receptor agonists have been designed to replace the attenuated hypocretin signalling. Pre-clinical and clinical trials have shown encouraging initial results. A better understanding of NT1 pathophysiology may contribute to faster diagnosis or treatments, which may cure or prevent it.

Psychosis and agitation are among the most distressing neuropsychiatric symptoms (NPSs) of Alzheimer's disease (AD), linked to faster disease progression and earlier admission to nursing homes. While nonpharmacological treatments may alleviate mild behavioral symptoms, more severe syndromes often require pharmacological intervention. Brexpiprazole is the only medication approved for agitation in AD, although its limited clinical efficacy has raised criticism. No drugs have been approved for treating psychosis in AD, highlighting the critical need for new, effective, and safe treatments. Recent studies have elucidated part of the neurobiological basis of NPSs in the AD brain, offering insights for testing repurposed and novel drugs. We conducted a comprehensive nonsystematic literature review, aiming to provide a critical overview of both current treatments and emerging pharmacological interventions under clinical development for treating psychosis and agitation in AD. Additionally, we present strategies to optimize the clinical development of new drug candidates. We identify three promising compounds that are currently in phase 3 trials: xanomeline-trospium for AD psychosis, and dextromethorphan-bupropion and dexmedetomidine for agitation in AD. We propose that biomarkers linked to the neuropsychiatric traits of AD patients should be identified in dedicated studies and then included in phase 2 dose-range-finding studies with novel compounds to establish biological engagement. Furthermore, phase 3 placebo-controlled studies should be carried out in AD biomarker-confirmed subjects with narrower cognitive impairment ranges and precise NPS severity at screening. Alternative study designs, such as sequential phase approaches, may also be adopted.

BACKGROUND: Major depressive disorder (MDD) and frailty impose substantial health and economic burdens. MDD is recognized as a significant risk factor for frailty, but the genetic associations between these conditions remain unclear. This study investigates the genetic correlation, shared pleiotropic loci, causal relationships, and comorbid genes between MDD and frailty.

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BACKGROUND: Paroxysmal atrial fibrillation (PAF) is strongly associated with ischemic stroke. Continuous cardiac implantable electronic devices (CIEDs) can assess PAF episodes over prolonged periods. Studies that attempted to find a temporal association between PAF and ischemic stroke were inconclusive. Thus, we performed a systematic review and meta-analysis to assess this relationship.

AIM: Neuroinflammation is an important causal factor for a variety of psychiatric disorders. We previously reported increased cerebrospinal fluid interleukin-6 levels in patients with schizophrenia and major depressive disorder. The present study aimed to examine the possible association of interleukin-6 levels with anxiety and frustration, negative valence symptoms shared in various psychiatric disorders.

Cerebral small vessel disease (cSVD) refers to the age-dependent pathological processes involving the brain small vessels and leading to vascular cognitive impairment, intracerebral hemorrhage, and acute lacunar ischemic stroke. Despite the significant public health burden of cSVD, disease-specific therapeutics remain unavailable due to the incomplete understanding of the underlying pathophysiological mechanisms. Recent advances in neuroimaging acquisition and processing capabilities as well as findings from cSVD animal models have revealed critical roles of several age-dependent processes in cSVD pathogenesis including arterial stiffness, vascular oxidative stress, low-grade systemic inflammation, gut dysbiosis, and increased salt intake. These factors interact to cause a state of endothelial cell dysfunction impairing cerebral blood flow regulation and breaking the blood brain barrier. Neuroinflammation follows resulting in neuronal injury and cSVD clinical manifestations. Impairment of the cerebral waste clearance through the glymphatic system is another potential process that has been recently highlighted contributing to the cognitive decline. This review details these mechanisms and attempts to explain their complex interactions. In addition, the relevant knowledge gaps in cSVD mechanistic understanding are identified and a systematic approach to future translational and early phase clinical research is proposed in order to reveal new cSVD mechanisms and develop disease-specific therapeutics.