Journal of Neurology, Neurosurgery, and Psychiatry最新文献

Background: Stroke remains a significant global health challenge, especially in low- and middle-income countries, despite advances in treatment and prevention. Understanding stroke trends is crucial for guiding prevention and healthcare strategies.

Methods: We analysed global data from the Global Burden of Disease Study 2021 on stroke incidence, prevalence, disability-adjusted life years and mortality from 1990 to 2021. The study focused on the major subtypes of stroke-ischaemic stroke (IS), intracerebral haemorrhage and subarachnoid haemorrhage-examining the effects of age, sex and sociodemographic index (SDI) on stroke outcomes. Decomposition analysis assessed the contributions of population growth, ageing and other factors to stroke burden. The Nordpred Prediction Model was used to forecast stroke trends from 2022 to 2046.

Results: From 1990 to 2021, global stroke incidence and deaths increased by 70.20% and 32.17%, respectively, driven by population ageing (45.3%) and growth (29.1%). However, age-standardised incidence and mortality rates declined by 21.78% and 39.10%, reflecting improvements in healthcare and risk factor control. IS saw the largest increase in crude incidence (87.97%), with regional disparities, especially in low-SDI countries. By 2046, global stroke incidence and mortality are projected to rise by 20.3% and 35.7%, primarily in low- and middle-SDI countries.

Conclusions: The global stroke burden is rising, particularly in low-SDI regions, due to ageing and population growth. Declines in age-standardised rates emphasise the importance of healthcare improvements. Region-specific strategies are needed to address the rising burden and reduce disparities in stroke outcomes.

Background: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, yet it remains under-recognised and misdiagnosed, which delays treatment, causes inaccurate prognosis and limits research opportunities. Imaging with 2-[¹⁸F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is a supportive DLB biomarker. We evaluated a multivariate, quantifiable metabolic network biomarker, termed DLB-related pattern (DLBRP), for its further clinical translation across centres and disease stages.

Methods: We analysed demographic, clinical and FDG PET imaging data of 1180 participants from 14 tertiary centres and two multicentre datasets. We included 379 DLB, 28 mild cognitive impairment-LB (MCI-LB), 195 dementia due to Alzheimer's disease (ADD), 172 MCI-AD without α-synuclein co-pathology (MCI-AD-S-), and 73 MCI-AD with α-synuclein co-pathology (S+) patients, along with a comparative group of 333 normal controls (NCs). From the scans, we calculated the expression of DLBRP, AD-related pattern (ADRP) and Parkinson's disease-related pattern (PDRP) and compared them across groups. DLBRP scores were correlated with clinical measurements.

Results: Across independent cohorts, DLBRP robustly distinguished DLB from NCs (sensitivity >89%, specificity >90%), and scores correlated with Unified Parkinson's Disease Rating Scale Part III and independently predicted Mini-Mental State Examination. DLBRP was elevated already in MCI-LB. In a small longitudinal dataset, we observed steady increases in DLBRP expression with scores exceeding the diagnostic threshold prior to dementia onset. DLBRP and PDRP discriminated DLB from ADD (sensitivity, 74%-90%; specificity, 80%). In MCI-AD groups, ADRP was expressed, whereas DLBRP and PDRP were increased only in MCI-AD-S+, although comparatively less than in MCI-LB.

Conclusions: This study demonstrates the value of DLBRP in diagnosing prodromal and manifest DLB and distinguishing them from their AD counterparts. While overlap between patterns may reflect actual co-pathology, this possibility cannot be accepted without thorough pathological confirmation. The current findings support the use of DLBRP in patient evaluation and in future trial design.

Background: Weight loss is a substantial non-motor feature of Parkinson's disease (PD) associated with worse clinical outcomes, but the underlying mechanisms remain poorly understood. Thus, we investigated the mechanisms of PD-related weight loss by examining the correlation between body composition and various plasma metabolites.

Methods: We enrolled 91 patients with PD and 47 healthy controls between July 2021 and October 2023. Body composition was evaluated using bioelectrical impedance analysis. Plasma metabolite profiling was conducted via mass spectrometry, including short-chain and medium-chain fatty acids, Krebs cycle intermediates, ketone bodies and phospholipids. Subsequently, alterations in body composition in PD and their association with plasma metabolites were assessed.

Results: Patients with PD had lower body weight (p=0.003), body mass index (BMI; p=0.001) and body fat mass (p<0.001) compared with controls. Metabolomic analyses revealed that, in patients with PD, glycolysis and Krebs cycle markers (lactic acid and succinic acid) were reduced, while ketone bodies (acetoacetic acid and 3-hydroxybutyric acid), amino acid catabolism-related markers (2-hydroxybutyric acid and 2-oxobutyric acid) and acetic acid were elevated. Notably, in patients with PD, acetoacetic acid and 3-hydroxybutyric acid negatively correlated with BMI. Phosphatidylcholine (40:2) was also elevated in PD and showed higher levels in individuals at more advanced Hoehn and Yahr stages.

Conclusions: PD-related fat loss was accompanied by a pattern of lower glycolytic activity and higher levels of lipid and amino acid metabolism-related metabolites, consistent with a potential shift in energy utilisation. These findings highlight metabolic pathways as potential targets for interventions to mitigate weight loss in PD.

Background: Higher vitamin D has consistently been associated with a lower multiple sclerosis (MS) risk, but some controversy remains about whether this is due to vitamin D itself or sunlight.

Methods: We conducted a prospective study among women participating in the Norwegian Mother, Father and Child Cohort Study, recruited in 2002-2008 and followed until 2022. We identified incident MS cases through data linkage with the Norwegian MS Registry. Total vitamin D intake from food and supplements was obtained from validated food frequency questionnaires completed in pregnancy. We estimated HRs for MS and 95% confidence intervals (CI) using Cox regression.

Results: Among 78 074 participants, 349 developed MS during follow-up. Their median daily vitamin D intake was 296 international units (IU) compared with 333 IU among women who did not develop MS. Higher total vitamin D intake was associated with a 42% lower MS risk (HR comparing top vs bottom quintile 0.58, 95% CI 0.38 to 0.89, p_trend<0.01). The results were similar when adjusting for age at delivery, total energy intake, pre-pregnancy body mass index and smoking. The associations were similar for vitamin D intake from food (HR for top vs bottom quintile 0.70, 95% CI 0.47 to 0.1.04, p_trend=0.02) and supplements (HR for ≥600 IU/day vs <200 IU/day 0.65, 95% CI 0.41 to 1.04, p_trend=0.01).

Conclusions: In this prospective study, higher vitamin D intake was associated with lower MS risk in women living in Norway, where there is insufficient sun-induced vitamin D production during most of the year. This supports the hypothesis that vitamin D itself modifies MS risk.

Background: Non-motor symptoms are highly prevalent in prodromal Parkinson's disease (PD); however, their impact on PD trajectory remains largely unexplored. We aimed to assess whether prevalent prodromal non-motor symptoms could predict future motor phenotype and time-to-PD diagnosis.

Methods: We studied the prodromal cohort of the ongoing Parkinson's Progression Markers Initiative (n=958), which prospectively assesses individuals with prodromal PD features (genetic: n=361, hyposmia: n=298, rapid eye movement behaviour disorder: n=136, combination: n=163) with up to 10 years of follow-up. The presence of prevalent prodromal symptoms was defined by evidence-based cut-off scores. In unmedicated or OFF-state PD converters (total n=52), binary logistic regression models established whether these predicted non-tremor-dominant (n=35) and tremor-dominant (n=17) motor phenotypes at diagnosis. Cox proportional hazards models determined whether identified prodromal symptoms predicted a shorter time-to-phenoconversion across all PD converters (n=59) and non-converters (n=343). Both models adjusted for age and sex.

Results: Prodromal anxiety and hyposmia were each associated with an increased risk of subsequent non-tremor-dominant PD, compared with other motor phenotypes (adjusted OR=4.45, 95% CI 1.34 to 15.27 and adjusted OR=3.90, 95% CI 1.01 to 15.16, respectively). Concurrent prodromal anxiety and hyposmia predicted an increased risk of PD phenoconversion over time (HR=4.93, 95% CI 2.71 to 8.98).

Conclusion: In this exploratory analysis, individuals with prodromal hyposmia and anxiety phenoconverted to PD sooner and more often had a non-tremor-dominant phenotype, potentially reflecting more widespread pathology or specific pathophysiology underlying these symptoms. This may improve phenotyping prodromal PD and stratifying poorer prognostic trajectories for earlier and more personalised management.

Background: Corticosteroid treatment of multiple sclerosis (MS) relapses is assumed to improve the speed of relapse recovery, without modifying long-term disability risk. We aimed to re-evaluate this assumption in a large cohort of individuals with MS.

Methods: Individuals with clinically definite MS and ≥3 Expanded Disability Status Scale (EDSS) measurements over ≥12 months were identified within the international neuroimmunology registry MSBase. Individuals were required to have ≥1 relapse, with complete information on relapse treatment, phenotype and severity for all documented relapses. The primary outcome was disability worsening confirmed over 12 months. The association of the cumulative number of steroid-treated and untreated relapses (as a time-varying exposure) with disability worsening was evaluated with Cox proportional hazards.

Results: In total, 3673 individuals met the inclusion criteria (71% female, mean age 38 years, mean disability EDSS step 2); 5809 relapses (4671 treated/1138 untreated) were captured (annualised relapse rate 0.19). Over the study period (total 30 175 person-years), 32.7% reached the outcome of confirmed disability worsening (median survival time 5.2 years). Non-treated relapses were associated with a higher risk of disability worsening (HR 1.72, 95% CI 1.57 to 1.88) than steroid-treated relapses (HR 1.50, 95% CI 1.43 to 1.57). This association was modified by the efficacy of disease-modifying therapy at the time of relapse.

Conclusions: Our results suggest that a lack of steroid treatment of MS relapses is associated with a higher risk of future disability worsening. Hence, corticosteroid treatment of MS relapses may impact not only the speed of recovery but also the severity of residual structural damage.

Background: Biallelic SH3TC2 variants lead to autosomal recessive Charcot-Marie-Tooth type 4C (CMT4C) which is typically demyelinating and associated with early-onset spinal deformities. Electrophysiology typically reveals a non-uniform conduction velocity (CV) slowing, a pattern traditionally linked to inflammatory neuropathies, potentially leading to diagnostic misinterpretation.

Objective and methods: Clinical and neurophysiological data from 19 patients belonging to 16 unrelated families with confirmed CMT4C were retrospectively collected across six neuromuscular reference centres in Brazil.

Results: Among the 19 patients, consanguineous parentage was found in 11 patients. Most patients exhibited symptom onset before age 10, and difficulty walking was the most common presenting symptom. A high rate of initial misdiagnosis was noted, with six patients initially diagnosed as inflammatory neuropathy. Proximal muscle weakness since initial assessment, present in 13 patients, and non-uniform CV slowing, present in all patients, contributed to this diagnostic misinterpretation.

Conclusion: This is the largest Brazilian cohort of patients with CMT4C to date. Key findings include frequent non-uniform CV slowing, excessive temporal dispersion and a high rate of misdiagnosis, often as acquired demyelinating neuropathy. Clinicians should be aware of the distinctive neurophysiological pattern of SH3TC2-related neuropathy to avoid misdiagnosis, unnecessary ancillary tests and treatment.

Multiple sclerosis (MS) is a major, immune-mediated, demyelinating disease and the major cause of non-traumatic disability in young adults. Susceptibility to disease is controlled by a variety of interacting features that include genetic and notably environmental factors. One of these risk factors appears to be the occurrence of traumatic brain injury. In a follow-on to previous analysis of head injury-induced risk factors for MS, analysis of Swedish Registry data of MS and matched controls demonstrates enhanced susceptibility to MS, notably when stratified for the presence of HLA-DRB1*15.01, absence of HLA-A*02.01 and occurrence of smoking, which are known risk factors, the risk of MS increases to OR 65.4 (95% CI 8.35 to 512). This can be mechanistically supported by a number of routes whereby brain injury can lead to expression of autoantigenic targets, or damage-related release of neuroantigens that could generate a novel autoantigenic response in draining lymph nodes following glymphatic/meningeal lymphatic drainage. These may be different from other mechanisms that are relevant to susceptibility due to human leucocyte antigen expression and smoking.

Background: Previous proteomic work has identified the somatodendritic protein MAP2 as a new candidate cerebrospinal fluid (CSF) biomarker for amyotrophic lateral sclerosis (ALS).

Methods: We measured CSF levels of MAP2 and neurofilament light chain (NFL) in a retrospective cohort of 251 patients with ALS and 108 neurological controls (NCs).

Results: Patients with ALS had a higher median CSF MAP2 level compared with NCs, leading to an area under the curve (AUC) of 0.7080 (p<0.0001). They also had a higher median CSF NFL level (p<0.0001), resulting in an excellent diagnostic performance (AUC=0.9641; p<0.0001). Among patients with ALS, CSF MAP2 correlated with disease progression rate (DPR) (r=0.3099; p<0.0001) and was negatively associated with survival (HR=3.174). CSF NFL also correlated with DPR (r=0.4936; p<0.0001) and was negatively associated with survival (HR=2.759). The association of MAP2 with DPR was independent from NFL (p=0.0037). Stratifying patients based on median levels of both biomarkers resulted in significant differences in median survival times (low NFL/low MAP2, 66 months; high NFL/low MAP2 and vice versa, 35 months; high NFL/high MAP2, 26 months; p<0.0001). MAP2 was also associated with genetic status in patients with ALS, as patients with no mutations in C9ORF72 or in SOD1, as well as C9ORF72-positive ones, had higher median levels compared with NCs (p<0.0001), while patients with SOD1 mutations did not significantly differ from NCs (p>0.9999).

Conclusions: Our study shows that the somatodendritic protein MAP2 is a promising candidate CSF biomarker for ALS.

Background: Synapses are essential for cognitive processes, and synaptic dysfunction is a hallmark of Alzheimer's disease (AD). Beta (β)-synuclein, a homologue of alpha-synuclein, is a presynaptic phosphoprotein abundantly expressed in the brain. It has emerged as a promising candidate biomarker for synaptic dysfunction. However, its role in longitudinal clinical progression has not been fully elucidated. This study investigated the associations of serum β-synuclein levels with AD pathologies, cognitive performance and progression to dementia.

Methods: We examined 474 participants from the AD Neuroimaging Initiative cohort with serum β-synuclein measurements. 233 participants also had corresponding cerebrospinal fluid (CSF) AD pathology data. Multiple linear regressions, linear mixed-effects models and Cox proportional hazards models were applied to explore the associations of serum β-synuclein level with CSF AD pathologies, cognition and dementia risk.

Results: Higher serum β-synuclein levels were associated with greater CSF phosphorylated tau181 and total tau levels and lower β-amyloid (1-42) levels. Serum β-synuclein predicted worse baseline cognitive performance and a longitudinal decline in AD Assessment Scale-Cognitive Subscale 13, Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes scores. Participants with higher serum β-synuclein levels showed a greater progression to dementia over 84 months compared with those with lower levels. Furthermore, even after adjusting for AD pathologies, elevated β-synuclein levels were associated with increased risk of dementia.

Conclusions: Our findings underscore serum β-synuclein as a promising biomarker for AD progression and cognitive decline. Further research is warranted to clarify its role in the pathogenesis of AD and validate its utility in clinical settings.