The Lindop Parkinson’s Disease Mobility Assessment (LPA) is a Parkinson’s disease (PD)-specific clinical scale. The LPA was designed to assess core functional mobility in rehabilitation, including gait and bed mobility. This study aimed to develop a Japanese version of the LPA and evaluate its validity and reliability in PD. Sixty-two people with PD participated in the validation analyses. The Japanese version of the LPA was developed through a standardized translation and cross-cultural adaptation process. Construct validity was examined using Spearman’s rank correlations between LPA scores and relevant clinical measures. Internal consistency was assessed using Cronbach’s alpha. Inter-rater reliability for video-based assessments was evaluated using intraclass correlation coefficients (ICCs) and quadratic weighted kappa coefficients. The total LPA score showed very strong correlations with the axial subscore, MDS-UPDRS Part 3, bradykinesia subscore, and Berg Balance Scale (Spearman’s rho = − 0.83, − 0.74, − 0.70, and 0.75, respectively; all FDR-adjusted p < 0.0001). Internal consistency was excellent for the total score, gait mobility section, and bed mobility section (Cronbach’s α = 0.95, 0.94, and 0.94, respectively). Inter-rater reliability was excellent for the total score (ICC [2, 1] = 0.97). Item-level agreement assessed using quadratic weighted kappa coefficients ranged from 0.46 to 1.00 (all p ≤ 0.009). The Japanese version of the LPA demonstrated good construct validity and excellent internal consistency and inter-rater reliability for the total score in assessing gait and bed mobility in PD. Further studies are needed to examine its responsiveness and applicability among individuals with more advanced functional impairment.
Neurodegenerative diseases have traditionally been classified by their predominant protein pathology. However, accumulating evidence reveals extensive molecular cross-talk between distinct pathological proteins, particularly in Alzheimer's disease (AD). This review examines cross-disease protein interactions and their implications for diagnosis and treatment. We systematically reviewed peer-reviewed literature published between 2020 and 2025, complemented by seminal earlier studies, examining molecular mechanisms of protein cross-seeding, clinical evidence of co-pathology, and emerging therapeutic strategies. Cross-seeding between amyloid-β (Aβ), tau, α-synuclein, and TDP-43 has been demonstrated in vitro and in vivo. Harmonized autopsy studies reveal that 91
Behavioral and cognitive symptoms are frequent in Alzheimer’s disease and dementia, and available pharmacological options offer limited benefit. Cannabinoid-based therapies have been proposed as alternatives, but evidence remains inconclusive. We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library through November 2025 for randomized controlled trials evaluating cannabinoids in Alzheimer’s disease or dementia. Primary outcomes were agitation measured by the Cohen–Mansfield Agitation Inventory (CMAI) and neuropsychiatric symptoms assessed by the Neuropsychiatric Inventory–Nursing Home version (NPI-NH). Secondary outcomes included cognition using the Mini-Mental State Examination (MMSE) and adverse events. Standardized Mean Differences (SMDs) and Risk Ratios (RRs) were synthesized using random-effects (REML) and Bayesian random-effects models. Risk of bias was evaluated with RoB 2, and certainty of evidence with GRADE. Nine trials (334 participants) met inclusion criteria. Cannabinoids did not improve CMAI (SMD –0.58, 95
Traditionally, Generalized Epilepsy (GE) is viewed as a thalamocortical network disorder; however, recent evidence highlights subcortical network involvement. This study aims to investigate volumetric changes in brainstem substructures (midbrain, pons, medulla oblongata) between GE patients and healthy controls using a multi-atlas-based segmentation method (MRICloud). Twenty patients with chronic GE and 20 age- and sex-matched healthy controls were included. High-resolution 3T T1-weighted 3D MPRAGE MRI scans were analyzed using the MRICloud platform. The brainstem was segmented into the midbrain, pons, and medulla oblongata. Data were analyzed using Analysis of Covariance (ANCOVA) models, with Age, Sex, and Total Intracranial Volume (ICV) entered as covariates. Significant volume reduction was observed in all brainstem structures in the GE group, even after adjusting for ICV and age (p < 0.001). Compared to controls, patients exhibited highly significant lower mean total volumes in the midbrain (8889 ± 216 vs. 9907 ± 248 mm³), pons (17087 ± 199 vs. 18323 ± 287 mm³), and medulla oblongata (5425 ± 104 vs. 5999 ± 144 mm³). The anatomical basis of GE may involve a structural process encompassing the brainstem and affecting deep brain structures. The detected volume reduction in the medulla oblongata could be associated with a potential disruption in cardiorespiratory regulation. Further prospective studies are needed to elucidate the link between this condition and Sudden Unexpected Death in Epilepsy (SUDEP) mechanisms.
Idiopathic normal pressure hydrocephalus (iNPH) is a treatable condition, but predicting shunt response remains challenging. Cerebrospinal fluid (CSF) biomarkers, including phosphorylated tau (p-tau181), have been suggested as potential predictors, although existing evidence is inconsistent. In this retrospective single-center study, we included 230 patients with probable or possible iNPH who underwent shunt surgery and had available CSF biomarker data for Amyloid beta42, total tau and phosphorylated tau 181. Patients were divided into two cohorts based on assay method (Innotest® and Elecsys®). The primary outcome was improvement in gait score. Secondary outcomes included cognition, continence, and overall clinical response. Predictive performance of CSF p-tau181 was evaluated using logistic regression and receiver operating characteristic (ROC) analyses. Mean CSF p-tau181 levels did not differ significantly between responders and non-responders in either cohort. In multivariable logistic regression analyses adjusted for age and sex, CSF p-tau181 was not associated with shunt response (Innotest®: OR 0.997 (0.972–1.024), p = 0.815; Elecsys®: OR 1.091 (0.910–1.419), p = 0.429). Findings were consistent across two CSF p-tau181 assay platforms, although the Elecsys® cohort was underpowered for calculating AUC with only 14 non-responders. Similar results were observed across secondary outcomes and after exclusion of patients with high CSF p-tau181 levels to reduce potential confounding by concomitant Alzheimer’s disease pathology. CSF p-tau181 does not demonstrate clinically meaningful predictive value for shunt response in patients with iNPH and cannot alone guide patient selection for shunt surgery. Future research should focus on multimodal approaches integrating clinical, radiological, and biochemical markers.
Subarachnoid hemorrhage (SAH) disproportionately affects young adults aged 15–49 years, yet prior global studies have rarely focused on this population and may obscure age-specific patterns by combining all-age data. We therefore quantified the global burden of SAH in young adults and explored disparities by sex and socio-demographic index (SDI) level. Using Global Burden of Disease 2021 data from 204 countries (1990–2021), we estimated the age-standardized incidence rates (ASIR), age-standardized prevalence rates, age-standardized death rates, and age-standardized disability-adjusted life-year (DALY) rates. Temporal trends were assessed using estimated annual percentage changes and age-period-cohort models. We further evaluated cross-country disparities by SDI, examined risk attribution using population attributable fractions, projected future burden to 2050 using Bayesian age-period-cohort models, and conducted an exploratory machine learning analysis with SHapley Additive exPlanations. In 2021, SAH caused 55,012 deaths and 3.19 million DALYs among young adults globally. Although the ASIR declined over time, the absolute burden remained substantial. High-SDI regions showed higher incidence, whereas lower-SDI regions bore a greater mortality and DALY burden. Males had a higher DALY burden, whereas females had higher prevalence. Metabolic risks were the leading contributors globally, while environmental and occupational risks remained more prominent in low-SDI settings. Projections suggested a continued decline in burden through 2050, although uncertainty widened after 2040. SAH in young adults represents a non-uniform burden-transition pattern, with declining age-standardized rates but persistent premature mortality and DALYs, higher incidence in high-SDI settings, and greater fatal and disabling burden in lower-resource settings. These findings support stronger metabolic-risk reduction in high-SDI settings and improved blood pressure screening, referral, and acute-care access in lower-resource regions. Age-stratified global assessment of SAH in 15-49-year-olds across 204 countries (1990-2021). Young-adult SAH showed a burden-transition pattern: declining age-standardized rates but persistent premature deaths and DALYs. High-SDI regions typically exhibit higher incidence but lowest mortality; metabolic risks account for ≈ 45
This study aimed to investigate the frequency of Restless Legs Syndrome (RLS) in pregnant women and its relationship with sleep quality and the questionnaire-defined risk of obstructive sleep apnea syndrome (OSAS). This cross-sectional study included 208 pregnant women, and RLS was diagnosed according to the International Restless Legs Syndrome Study Group criteria. RLS severity and disease-specific quality of life were evaluated using the International Restless Legs Syndrome Rating Scale (IRLS) and the Restless Legs Syndrome Quality of Life (RLS-QoL) questionnaire. Sleep quality and daytime sleepiness were assessed using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS), while the risk of OSAS was evaluated using the STOP-Bang and Berlin questionnaires. RLS was identified in 69 women (33.2
PHACE syndrome is a rare neurocutaneous disorder defined by the association of large segmental infantile hemangiomas of the head and neck with malformations of the posterior fossa, cerebral and cervical arteries, heart, eyes, and ventral midline structures. Although facial hemangiomas are often the presenting feature, the cerebrovascular, neurodevelopmental, and airway manifestations are responsible for the greatest long-term morbidity. A systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching PubMed, Web of Science, EMBASE, and PsycINFO. After removal of duplicates and screening of 308 records, five studies meeting the inclusion criteria were retained for qualitative synthesis. We additionally present the case of a now 12-year-old girl with PHACE syndrome characterized by a left V1-distribution facial hemangioma, ocular abnormalities, multiple cerebrovascular venous and arterial malformations, neonatal intraventricular hemorrhage with hydrocephalus, and a subsequently diagnosed dural arteriovenous fistula requiring repeated embolization. The five included studies collectively describe epidemiology and early supportive care needs, long-term health outcomes and quality of life into adulthood, airway hemangioma prevalence and management, and the clinical spectrum of infantile hemangiomas with minimal or arrested growth (IH-MAG) as a cutaneous marker of PHACE syndrome. Across studies, cerebrovascular arteriopathy (72–91
Whether spontaneous cervical artery dissection (sCeAD), the leading cause of ischemic stroke in young adults, represents the manifestation of unrecognized hereditary connective tissue disorders (HCTDs) and whether HCTDs have a major impact in the epidemiology of the disease is a matter of ongoing debate. We aimed at determining the frequency of clinically relevant genetic variants (CRGVs) in a cohort of unselected sCeAD patients by targeted next-generation sequencing (NGS) approach. We designed a high-throughput sequencing panel to identify variants in 38 candidate genes associated with arterial dissection or aneurysm and screened patients with apparently sporadic sCeAD, consecutively referred to one comprehensive stroke center from August 2020 to December 2025. The frequency of known disease-causing and pertinent variants of uncertain significance (VUS) was calculated. Then, we performed a systematic review of all studies evaluating the prevalence of monogenic disorders among sCeAD patients up to December 2025. Among 183 patients (males, 51.3
Frontotemporal dementia (FTD) is a leading cause of early-onset dementia in individuals under 65. Despite its significant burden, a comprehensive synthesis of its global prevalence is lacking. We conducted a systematic review and meta-analysis to estimate the worldwide prevalence of FTD. We systematically searched multiple databases for epidemiological studies on FTD prevalence published up to October 31, 2025. Meta-analysis was performed using a random-effects model. Subgroup analyses were conducted by geographic region, age range, and diagnostic criteria era. We systematically searched multiple databases for epidemiological studies on FTD prevalence published up to October 31, 2025. Meta-analysis was performed using a random-effects model. Subgroup analyses were conducted by geographic region, age range, and diagnostic criteria era. A total of 21 studies, encompassing 38,656, 516 individuals, were included. The pooled global prevalence of FTD was 30 cases per 100,000 population (0.03
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system with a complex etiology involving genetic and environmental factors. Maternal diabetes during pregnancy has been hypothesized to influence offspring MS risk through intrauterine metabolic programming, yet the evidence remains inconclusive. To systematically review and meta-analyze the association between maternal diabetes and the risk of MS in offspring. A systematic literature search was conducted across PubMed, Scopus, Web of Science, and Embase, identifying 427 records. After removing 188 duplicates, 239 records were screened, 38 full-text reports were assessed for eligibility, and 4 studies met the inclusion criteria. Pooled risk ratios (RR) were calculated using both common-effect and random-effects models. Heterogeneity was assessed using the I² statistic, and publication bias was evaluated using Egger’s and Begg’s tests. The studies, published between 2009 and 2026, were conducted in Denmark, the USA (two studies), and Norway, utilizing diverse designs including nationwide register-based cohorts and a case-control study. The common-effect model yielded a pooled RR of 1.42 (95
Smoking is a well-established environmental risk factor for multiple sclerosis (MS), yet its impact on disability progression remains incompletely understood, with conflicting evidence across studies. This review evaluated smoking and clinical outcomes in MS. Disability progression was the primary outcome; disability severity, imaging, relapse recovery, functional status, and patient-reported outcomes were secondary outcomes. A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. PubMed, Scopus, Web of Science, and the Cochrane Library were searched from inception through the 4th of March 2026. Eighteen studies were included. Smoking was not significantly associated with increased EDSS (SMD = 0.09, 95
Subjective cognitive decline (SCD) is a transitional state between objective cognitive impairment and cognitively intact mental status, providing a critical window for implementing preventive interventions to delay objective cognitive decline. We aimed to develop a predictive model for SCD progression in older adults with mild cognitive impairment (MCI). This model will facilitate the identification of risk factors and establishment of targeted interventions for community-based SCD management. Data from the China Health and Retirement Longitudinal Study (CHARLS) was utilized in this study, extracting 18 indicators. Potential predictors selected through univariate Cox regression and LASSO regression analyses were sequentially incorporated into a multivariable Cox regression model. A nomogram was constructed to establish a predictive model. Model validation encompassed Area Under Curve (AUC) metrics for discriminative capacity, complemented by quantitative assessments using calibration curve analysis for precision verification and decision curve analysis (DCA) for clinical utility evaluation. A total of 1099 older adults with SCD were included in the final analysis, of whom 114 (10.3
Cryptococcal meningitis (CM) is one of the most devastating opportunistic infections in people living with HIV and typically occurs in patients with advanced immunosuppression. Ischemic stroke is an uncommon manifestation and rarely represents the initial presentation. We report a 28-year-old man with an 11-year history of HIV infection who presented with acute right-sided hemiparesis despite a relatively preserved CD4 count (302 cells/mm³). Brain magnetic resonance imaging demonstrated an acute infarction of the left internal capsule with communicating hydrocephalus. Cerebrospinal fluid analysis revealed lymphocytic pleocytosis, elevated protein, low glucose, positive cryptococcal antigen, and culture-confirmed Cryptococcus neoformans. The patient was treated with amphotericin B and fluconazole, resulting in marked clinical improvement. This case demonstrates that CM may present as acute ischemic stroke in HIV-infected patients despite a relatively preserved CD4 count and the absence of classical meningeal manifestations. Early cerebrospinal fluid evaluation and prompt antifungal therapy are essential to avoid delayed diagnosis and improve neurological outcomes.
Unawareness of chorea is well-known in Huntington’s disease (HD). This study investigated unawareness for the whole gamut of motor impairments in daily life, which has not been explored previously. Data from 71 consecutive patients with stage I or II HD were assessed retrospectively. The motor section of UHDRS; the total functional capacity; a short battery of cognitive tests; the SANS and SAPS scales for negative and positive psychiatric symptoms; the Hamilton scales for depression (HAM-D) and anxiety (HAM-A); and a semi-structured questionnaire to assign motor anosognosia on a scale from 0 (fully aware) to 3 (severely unaware), were administered. Twenty-seven (38
Holmes tremor is a low-frequency movement disorder combining rest, postural and intention tremor, developing weeks to months after lesions involving the brainstem, thalamus, or cerebellothalamic pathways. We report an acute-onset Holmes-like tremor following an isolated precentral cortical ischemic stroke. A 68-year-old man presented with acute right-sided facial and upper limb weakness and aphasia, with rapid clinical improvement. Within 24 hours, he developed rhythmic low-frequency pronation–supination movements of the right hand and forearm, present at rest and enhanced during posture and voluntary movement. EEG showed no epileptiform discharges or cortical correlates, and lacosamide produced no clinical benefit. Multichannel surface polygraphy and accelerometry demonstrated relatively regular oscillations at approximately 3 Hz at rest and 3.5–4 Hz during action, supporting a Holmes-like tremor phenotype. Brain MRI revealed acute ischemic lesions confined to the left precentral cortex, without involvement of the thalamus, brainstem, basal ganglia, or cerebellum. The tremor resolved within days and did not recur at 1-month follow-up. This case is unusual because of the acute onset, isolated precentral cortical lesions, distal predominance of tremor, and spontaneous remission. The absence of prior tremor, the close temporal relationship with the new infarct, and complete recovery suggest that the acute cortical lesion was the most likely trigger. The cortical localization is consistent with network-based models suggesting that Holmes tremor may arise from disruption of a distributed motor circuit rather than a single anatomical structure. The rapid resolution supports the hypothesis of a transient functional network disturbance rather than a stable oscillatory circuit dysfunction.
