Journal of Neurology最新文献

Early detection and monitoring of neurodegenerative processes in persons with multiple sclerosis (PwMS) is currently a major challenge. Optical coherence tomography angiography (OCTA) is an emerging method to visualize retinal vascular architecture. However, its use has mainly been investigated in relapsing MS. We evaluated OCTA as a possible complementary method in progressive MS (PMS) in a monocentric, retrospective, cross-sectional study. Eyes with evidence of optic neuritis were excluded from analysis. OCTA images acquired using a Spectralis OCT (Heidelberg Engineering) were analyzed with an established deep learning-based segmentation algorithm. After rigorous quality control, 85 eyes of 62 PwPMS were compared with 64 eyes of 43 age and gender-matched healthy controls (HC). The vessel density in the superficial vascular complex (VD_SVC (%)) was reduced in PMS compared to HC (p = 0.018). VD_SVC correlated negatively with age in PwPMS and HC. Using a Johnson-Neyman analysis, we identified that the disease duration influences the VD_SVC in PMS individuals < 57.5 years of age. PwPMS with disease duration > 10 years had reduced VD_SVC compared to subjects with ≤ 5 years of disease duration (p = 0.049) (corrected for age). Clinical disability (EDSS) negatively correlated with VD_SVC in PwPMS (β = -0.487, p = 0.010). These results suggest that OCTA might be suitable to detect retinal vascular changes in PwPMS. One consequence could be structured and harmonized OCTA investigations as part of routine clinical practice. External validation and longitudinal studies are necessary to further elaborate OCTA´s potential in monitoring PwPMS.

Objective: Our study aimed to determine the prevalence and clinical phenotypes of JAK2 pathogenic mutation carriers in the CNSR-III ischemic stroke (IS) cohort, and to develop a pre-test genetic screening model for identifying high-risk individuals.

Methods: We performed retrospective characterization of JAK2 pathogenic variants using targeted sequencing data in the CNSR-III cohort. Clinical and laboratory characteristics of JAK2 V617F mutation carriers and non-carriers were tested in a logistic regression model to identify key features. V617F screening score was developed to predict positive JAK2 V617F test results.

Results: 46 cases (0.4%, 46/10428) harbored the JAK2 V617F-exclusive mutation. Mutation carriers manifested significantly inferior functional outcomes following stroke relative to non-carriers (adjusted OR 2.74[1.07, 6.49]). Significant predictors of mutation status comprised elevated platelet count (PLT, OR 1.02[1.02, 1.03]), increased hemoglobin concentrations (HGB, OR 1.06 [1.04, 1.08]), and a reduced burden of traditional stroke risk factors, such as history of hypertension (OR 0.24[0.11, 0.52]), smoking history (OR 0.08[0.02, 0.24]), and body mass index (BMI, OR 0.8[0.75, 0.97]). We constructed the JAK2 V617F screening score, which efficiently discriminated between carriers and non-carriers (area under the ROC curve, AUC 0.98), achieving sensitivity of 85%, specificity of 94%, and accuracy of 94% for a cut-off score of 3 points. Internal validation confirmed robust performance, with a consistent AUC of 0.98.

Conclusions: Despite low prevalence (0.4%), JAK2 V617F mutation represents a clinically actionable stroke subtype with distinct pathophysiology. The prediction model offers a precision medicine approach, potentially reducing the need for comprehensive genetic testing.

Background: The hyperdense sinus sign (HDSS) is a readily identifiable non-contrast CT marker of acute thrombus in cerebral venous sinus thrombosis (CVST). We aimed to characterize HDSS associated features and prognostic significance.

Methods: Data from prospective multicenter CVST registries was analysed. HDSS was defined as attenuation > 70 Hounsfield units within a thrombosed venous structure. Baseline characteristics and outcomes were compared between patients with and without HDSS on admission CT. Multivariable logistic regression identified independent predictors of Excellent-Functional-Outcome (mRS 0-1) and remote seizures.

Results: Among 465 patients (mean age 41.9 ± 18.4 years; 64.3% female), 178 (38.3%) exhibited HDSS. Patients with HDSS had higher rates of oral contraceptives use (28% vs 18%, p = 0.009), seizures at presentation (23% vs 14%, p = 0.015), superior sagittal (45% vs 35%, p = 0.028) and transverse sinus involvement (78% vs 67%, p = 0.01), deep venous thrombosis (8% vs 2%, p = 0.003), cortical vein thrombosis (19% vs 9%, p = 0.004), and multisite occlusion (34% vs 22%, p = 0.002). Parenchymal lesions were more common in HDSS patients, including intracerebral hemorrhage (27% vs 13%, p < 0.001) and venous infarction (22% vs 11%, p = 0.004). On day-90, HDSS was associated with lower Excellent-Functional-Outcome rates (71% vs 82%, p = 0.022), higher rates of remote seizures (9% vs 3%, p = 0.001), and similar recanalization rates. HDSS independently predicted reduced odds of Excellent-Functional-Outcome (OR = 0.491 [0.261-0.926], p = 0.028) and increased remote seizures (OR = 2.693 [1.057-6.861], p = 0.038).

Conclusions: HDSS identifies a CVST subgroup with more extensive thrombosis, greater parenchymal injury, and poorer outcomes, supporting its utility in early risk stratification.

Background: Gradual worsening in relapsing-remitting MS (RRMS) may precede the formal transition to secondary progressive MS (SPMS). We aimed to quantify self-reported gradual worsening, assess concordance with clinically recorded subtype, and identify baseline predictors of discordance.

Methods: We included 1640 participants with incident RRMS from a population-based study (2005-2019). A 2021 follow-up survey captured patient-reported gradual worsening. Clinical data, including Expanded Disability Status Scale (EDSS) scores and SPMS classification, were obtained from the Swedish MS registry. Discordance with clinically recorded subtype was modeled using logistic regression stratified by subtype. Time to EDSS 3 and EDSS 4 were summarized with Kaplan-Meier estimates within subtype by self-reported worsening, and secondary Cox proportional hazards models were fitted stratified by subtype with self-reported worsening as the exposure.

Results: Among participants classified as RRMS, 24% reported gradual worsening, while 23% of those classified as SPMS did not. Kaplan-Meier curves showed clear within-subtype separation by self-reported worsening, consistent with higher hazards of reaching EDSS 3 and EDSS 4 among those reporting worsening. In RRMS, older age and higher baseline EDSS were associated with self-reported gradual worsening despite RRMS classification. In SPMS, self-reported worsening preceded clinical classification by 4.1 years.

Conclusions: Patient-reported gradual worsening aligns with disability accumulation and may help identify progression earlier than subtype reclassification, supporting integration of structured patient reports into routine monitoring.

The diagnostic approach to subjects with early-onset dementia (EOD) is often challenging due to the broader range of possible etiologies as compared to late-onset dementia cases. Pathogenic variants in CSF1R gene have been increasingly reported in subjects with EOD, mostly clinically mimicking behavioral variant of frontotemporal dementia (bvFTD). Here we screened for variants in CSF1R gene in a large cohort of dementia patients consecutively referred for genetic analysis to an Italian tertiary center between 2005 and 2024 (n = 2163). Sequence of CSF1R gene was determined with next-generation sequencing through either a dedicated panel or whole-exome sequencing. Pathogenic variants or variants of uncertain significance with higher evidence of pathogenicity were found in four participants (one female); three of these were not previously reported. Clinical data were collected, including brain magnetic resonance imaging and neuropsychological assessment. Cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) protein were measured. A family history of dementia was present in one subject. Mean age at onset was 51.5. Seizures were the presenting symptom in two cases and later appeared in other two. Two subjects presented with behavioral disturbances, resembling early bvFTD. Neuropsychological assessment revealed executive and language impairment in most cases. Anterior-predominant atrophy, symmetric white-matter involvement, and serpentine calcifications were the most common imaging abnormalities. High CSF NfL levels were found in all cases, with two of them showing markedly elevated values. CSF1R-related disease should be considered in EOD subjects, especially those presenting with executive/language deficits, seizures, white matter involvement, and markedly elevated CSF NfL levels.

Background: Multiple Sclerosis (MS) severity is influenced by several factors. Understanding the impact of age at disease onset may help to better characterize clinical and disease features across age groups. This study aimed to characterize the clinical features and disability outcomes of late-onset MS (LOMS) and very late-onset MS (vLOMS), compared to adult-onset MS (AOMS).

Methods: We conducted an observational study using data from the MSBase registry and categorized patients based on age at MS onset: AOMS (18-39 years), transition onset (40-49 years), LOMS (50-59 years), and vLOMS (≥ 60 years). Disease progression was assessed using the 24 week confirmed disability progression, EDSS4 and 6 milestones, conversion to secondary progressive MS(SPMS), and the first progression independent of relapse activity (PIRA) event. Cox proportional hazard regression models were used to determine unadjusted hazard ratios(HR), and propensity score inverse probability of treatment weighting(PS-IPTW) balanced covariate distributions.

Results: Among 81,236 patients, 5.2% had LOMS and 1% had vLOMS. Primary progressive MS was more frequent in LOMS and vLOMS (21.7 and 24%, respectively). Patients with LOMS and vLOMS had a significantly increased risk of 24 week confirmed disability progression (HR:LOMS = 1.39, vLOMS = 1.80), EDSS 4 (HR:LOMS = 2.14, vLOMS = 2.95), EDSS 6 (HR:LOMS = 2.33, vLOMS = 6.33), SPMS (HR:LOMS = 1.62, vLOMS = 2.38), and first PIRA event (HR:LOMS = 2.12, vLOMS = 2.93).

Conclusion: LOMS and vLOMS exhibited a more progressive disease onset and higher disability milestones compared with AOMS.

Aims: Rivaroxaban has been approved for the primary prevention of stroke with non-valvular atrial fibrillation caused by one or more risk factors. However, the optimal antithrombotic therapy for secondary prevention of stroke in atrial fibrillation (AF) with ischemic stroke/transient ischemic attack (TIA) had been uncertain. We compared the safety and efficacy of novel oral anticoagulants. (NOACs) and Warfarin in treating AF with ischemic stroke.

Methods: Seven databases were searched from inception up to December 2024 for studies comparing NOACs and Warfarin in AF with ischemic stroke. 7 randomized controlled trials (RCTs) and 9 cohort studies with 128,808 patients were included. A random-effects model or fix effects model was used.

Results: Pooled results showed that the NOACs are superior to Warfarin in the prevention of stroke or systemic embolism (RR 0.90, 95%CI [0.82,1.0], P = 0.04) and all-cause mortality (RR 0.83, 95%CI [0.76,0.92], P = 0.0003). As well as NOACs has lower risk in total bleeding (RR 0.79, 95%CI [0.76,0.83], P < 0.00001), fatal bleeding (RR0.64, 95% CI [0.54,0.76], P < 0.00001), hemorrhagic stroke (RR0.50, 95%CI [0.43,0.58], P < 0.00001), and intracranial bleeding (RR 0.49, 95%CI [0.36,0.65], P < 0.00001) than Warfarin.

Conclusion: In the secondary prevention with AF related to ischemic stroke, NOACs showed potential advantages over Warfarin in the incidence of stroke or systemic embolism, all-cause mortality, total bleeding, fatal bleeding, hemorrhagic stroke, and intracranial bleeding.

Background: Only a few longitudinal studies, with follow-up duration up to 3.6 years, have assessed the substrates of relapses and disability in aquaporin-4 (AQP4) IgG-positive neuromyelitis optica spectrum disorders (NMOSD), primarily focusing on clinical and conventional MRI variables.

Objective: We evaluated the association of clinical and MRI measures, including a comprehensive multimodal advanced MRI protocol, with key long-term clinical outcomes in AQP4 IgG-positive NMOSD patients over a median follow-up of 8.5 years (interquartile range [IQR] = 3.5; 13.3).

Methods: Forty-six NMOSD patients and 77 healthy controls underwent 3T brain MRI. In patients, neurological evaluations were collected at baseline and every six months. Time to first relapse and 6-month confirmed disability worsening (6m-CDW) were recorded. Lesion volume and topography, global and regional brain volumes, normal-appearing white matter and gray matter fractional anisotropy and mean diffusivity, choroid plexus volume, enlarged perivascular spaces number and glymphatic system function were assessed.

Results: During the follow-up, 30% patients experienced at least one clinical relapse, while 22% had 6m-CDW. Higher number of previous attacks (hazard ratio [HR] = 1.17, 95%-confidence interval [CI] = 1.04; 1.32) and presence of anterior optic pathway lesions (HR = 4.92, 95%-CI = 1.12; 21.852) were risk factors independently associated with a shorter time to a first clinical relapse; lower thalamic volume was marginally associated (HR = 0.93, 95%-CI = 0.87; 1.00). Presence of cervical cord lesions (HR = 3.93, 95%-CI = 1.16; 13.31) and lower normalized cortical volume (HR = 0.94, 95%-CI = 0.89;0.99) were risk factors independently associated with a shorter time to 6m-CDW; higher number of previous attacks contributed marginally (HR = 1.19, 95% = 0.99; 1.43). High efficacy treatments (HETs) delayed time to first relapse and 6m-CDW.

Conclusions: Previous attacks, optic nerve/spinal cord involvement, cortical/thalamic atrophy and the use of HETs associate with long-term outcomes in NMOSD.

Background and objectives: Age at onset is a key determinant of disease course in the general Parkinson's disease (PD) population, but its influence among GBA-PD remains undetermined. This study investigates whether age at onset affects cognitive decline in GBA-PD patients and compares symptoms between GBA-PD and nonGBA-PD groups, stratified by age of onset.

Methods: In this multicentric cross-sectional study, PD patients were stratified into early onset (< 50 years), intermediate onset (50-60 years), and late onset (> 60 years). Demographic-clinical data and scores of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment (MoCA), Scales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT), and Beck Depression Inventory (BDI-II) were compared using ANCOVA. The effects of age of onset, GBA1 status, and their interaction were investigated. External validation on cognition was performed using data from the PPMI cohort.

Results: We analyzed 80 GBA-PD and 236 nonGBA-PD patients. Among GBA-PD, late-onset patients exhibited worse axial scores (p = 0.037), while early-onset had more severe motor complications (p = 0.007) and dysautonomia (p = 0.012). Age of onset and GBA1 status did not influence MoCA scores. Conversely, GBA1 status independently affected MDS-UPDRS parts I and II (p < 0.001 and p = 0.019, respectively) and BDI-II scores (p = 0.002). Analysis on the external dataset (PPMI) showed late-onset PD had lower MoCA scores (p < 0.001) and confirmed GBA1 status did not influence cognition.

Discussion: In the first decade of PD, cognitive decline is mainly age and duration dependent, irrespective of GBA1 genotype. Early onset does not increase cognitive risk in GBA-PD, supporting its relevance for counseling and treatment planning.