Background and objectives: Clinical phenotypes of neuropathies associated with contactin-associated protein-1 (CASPR1) or isolated CASPR1/contactin-1 (CNTN1)-complex-IgG are not well characterized, and we aimed to describe the same.
Methods: Patient sera positive for CASPR1 or CASPR1/CNTN1-complex-IgG by cell-based assay (CBA) at Mayo Clinic Neuroimmunology Laboratory (January 1, 2010-May 31, 2024) was identified retrospectively and prospectively. Clinical and paraclinical data were collected. CASPR1/CNTN1-complex-IgG-positive sera were tested using tissue indirect immunofluorescence assay, murine teased nerve fibers, and ELISAs for CASPR1 and CNTN1 to elucidate antigenic targets. Patients were compared with CNTN1-IgG and NF155-IgG4 autoimmune nodopathy cohorts.
Results: Among 17 CASPR1 or isolated CASPR1/CNTN1-complex-IgG-seropositive patients identified, 14 had clinical data (CASPR1-IgG = 8 [50% males, median age 50 years], CASPR1/CNTN1-complex-IgG = 6 [67% males, median age 42 years]). Neuropathic pain was more common in CASPR1-IgG (88% vs 33%), while sensory ataxia was more frequent in CASPR1/CNTN1-complex-IgG cases (100% vs 75%). All showed primarily demyelinating electrophysiology (1 CASPR1/CNTN1-complex-IgG case presented as chronic inflammatory sensory polyradiculopathy). Intravenous immunoglobulin (IVIg) refractoriness occurred in 63% of CASPR1-IgG and 40% of CASPR1/CNTN1-complex-IgG. Rituximab was effective in 6 of 7 (86%) treated patients. One patient with CASPR1/CNTN1-complex-IgG who was refractory to multiple immunotherapies underwent allogenic hematopoietic stem cell transplant after which she was off immunotherapies and is in sustained remission for the past 10 years. CASPR1-IgG patients progressed faster to nadir than NF155-IgG4 (p = 0.003). CASPR1/CNTN1-complex-IgG patients had more frequent asymmetric onset (p = 0.009) and greater long-term disability than NF155-IgG4 (p = 0.035). Five of the 7 CASPR1-IgG patients had IgG4 antibodies, compared with 2 of the 5 CASPR1/CNTN1-complex-IgG patients. Four isolated CASPR1/CNTN1-complex-IgG sera tested positive by tissue immunofluorescence assay; 3 also bound paranodes on teased nerve fibers. CASPR1-IgG cases had higher titers compared with CASPR1/CNTN1-complex-IgG cases by CBA. Three of the 5 CASPR1/CNTN1-complex-IgG cases had CASPR1-IgG reactivity by ELISA, while the other 2 were negative by both CASPR1 and CNTN1 ELISA.
Discussion: CASPR1-IgG and CASPR1/CNTN1-complex-IgG neuropathies, though rare, usually have a rapidly progressive course. Both are frequently IVIg-refractory and respond to rituximab. Compared with NF155-IgG4 nodopathies, CASPR1-IgG exhibits faster progression, while some CASPR1/CNTN1-complex-IgG nodopathies can cause greater long-term disability.
Background and objectives: fMRI has proven useful in dissecting the neurobiological underpinnings of migraine. However, the existing evidence is limited by small samples, use of suboptimal statistical thresholds, and different methods of clinical data acquisition. Given these limitations, we hypothesized that a large, well-characterized sample would allow a clearer distinction between resting-state functional connectivity (rs-FC) alterations specific to migraine and those related to migraine subtypes.
Methods: Adults with migraine and age-matched and sex-matched healthy controls (HCs) underwent a single 3T rs-fMRI scan. We compared rs-FC between migraine and HCs, and across migraine subtypes, using multi-voxel pattern and seed-based analysis. General linear models and analysis of covariance tests with Bonferroni-adjusted cluster-wise family-wise error correction (pFWE-Bonferroni ≤0.001) were applied. rs-FC measures, expressed as Z scores, were also compared across migraine subtypes using general linear models (pBonferroni < 0.05).
Results: We analyzed rs-fMRI data from 264 participants with migraine (mean age 42 ± 12 years, 234 women) and 151 HCs (mean age 41 ± 11 years, 130 women). The multi-voxel pattern analysis identified significant rs-FC differences in a cluster within the bilateral middle cingulate cortex when comparing participants with migraine to HCs (pFWE-Bonferroni <0.001). The seed-based analysis revealed that participants with migraine had increased rs-FC between the cluster in the bilateral middle cingulate cortex and both the right lateral occipital cortex and bilateral occipital pole (both pFWE-Bonferroni <0.001), compared with HCs. Furthermore, increased rs-FC was identified between the limbic lobe and the right occipital pole (pFWE-Bonferroni = 0.0014) and precuneus (pFWE-Bonferroni <0.001). The cingulate-occipital rs-FC was consistently increased in participants with migraine, irrespective of the migraine subtype (pBonferroni <0.001). In addition, ictal participants who were scanned during attacks exhibited an increased hypothalamic rs-FC with the bilateral precuneus, compared with HCs (pBonferroni <0.001). No significant associations emerged between rs-FC and clinical features in migraine.
Discussion: The identified rs-FC alterations between the middle cingulate cortex and occipital regions might represent a migraine-specific trait, suggesting an integration of nociceptive and visual processing. This discovery provides novel insights into the neurobiological underpinnings of migraine and proposes that altered cingulate-occipital rs-FC might serve as a potential biomarker for migraine.
Background and objectives: Previous studies have indicated an increased risk of cerebrovascular and coronary events shortly after cancer diagnosis. However, whether cancer affects mortality outcomes after stroke and myocardial infarction (MI) remains unclear. We aimed to investigate the relationship between cancer diagnosis and mortality after stroke and MI.
Methods: Using linked nationwide databases from Taiwan, we conducted a population-based cohort study including 3 cohorts of patients with first-time ischemic stroke, hemorrhagic stroke, and MI between 2011 and 2019. The primary outcome was 90-day mortality, with follow-up beginning at the index stroke (for ischemic and hemorrhagic stroke cohorts) and MI (for the MI cohort) event date for all patients. Odds ratios (ORs) of 90-day mortality associated with all cancers combined and 15 cancer types were estimated through propensity score matching for potential confounding variables. Excess mortality rates (between patients with cancer and matched controls) were analyzed across time intervals after cancer diagnosis, stratified by age group, cancer stage, and cancer type.
Results: Overall, 440,664, 159,606, and 228,993 patients were included in ischemic stroke (mean age, 70.1 years; 40.7% female), hemorrhagic stroke (mean age, 65.4 years; 36.5% female), and MI (mean age, 67.8 years; 29.7% female) cohorts, respectively. Compared with matched controls, patients with cancer had higher risks of 90-day mortality in ischemic stroke (OR 2.71, 95% CI 2.63-2.79), hemorrhagic stroke (OR 2.20, 95% CI 2.11-2.29), and MI (OR 1.63, 95% CI 1.57-1.69). Across 3 cohorts, substantial variations existed among cancer types, with aggressive malignancies (e.g., pancreatic cancer) consistently presenting the highest risks. Excess mortality rates were highest during the first postdiagnosis year and declined progressively thereafter. This temporal pattern was consistent across age groups and cancer stages, with excess mortality rates highest among patients aged 18-59 years and those with stage 4 disease. Despite variability among cancer types, excess mortality typically peaked within 2 years.
Discussion: This population-based study showed that patients with cancer had higher risks of mortality after stroke and MI, with substantial variations by cancer type, although cause-specific mortality data were lacking. Excess mortality rates peaked shortly after diagnosis, particularly for early-onset cancer and advanced disease.
Background and objectives: Cerebral adrenoleukodystrophy (CALD) is a common manifestation of adrenoleukodystrophy (ALD) in men. Early detection of CALD lesions through MRI screening is critical to allow for therapeutic action preventing severe disability and death. While the frequency of brain MRI monitoring has been addressed by international recommendations, no consensus currently exists regarding which MRI sequences should be used in a real-world setting for screening and follow-up of CALD lesions. The aim of this study was to establish guidelines for the MRI protocol in clinical practice and to identify priority sequences for research use, thereby promoting intercenter harmonization.
Methods: A modified Delphi procedure was used to achieve consensus on MRI protocols for ALD screening, lesion monitoring, and research applications among experts with experience in brain imaging in ALD. Questionnaires allowed experts to indicate whether they considered sequences as core, optional, or research, or to express agreement (5-point scale ranging from completely disagree to completely agree) with specific statements. Topics where no agreement was reached were discussed during online consensus meetings.
Results: Thirty experts from 9 countries participated and agreed that the core screening protocol for ALD in adults and children should include at least 3D T1-weighted, spin-echo T2-weighted, 3D fluid-attenuated inversion recovery, and diffusion-weighted imaging (DWI). Postcontrast T1-weighted imaging should be performed systematically in specific clinical scenarios. Experts supported using DWI alongside the Loes score and postcontrast imaging to assess lesion progression. A research protocol was defined, prioritizing diffusion tensor imaging, MR perfusion, and quantitative volumetric analyses.
Discussion: This international project harmonizes the ALD MRI protocol, thus offering a practical framework to screen and monitor lesions, which will improve clinical decision making. It also identifies MRI sequences that should be prioritized in future research. Future research on MRI in ALD should focus on topics where no consensus has yet been reached in this project.
Background and objectives: Neurofibrillary tangles (NFTs) progressively damage gray matter in Alzheimer disease (AD). Resulting cortical microstructural alterations might not be detectable using macrostructural metrics but may be studied using isotropic water diffusion, as it reflects extracellular free water content. The aim of this study was to examine the effect of NFTs on cortical microstructure by investigating whether cortical free water increases as a function of tau load. We also investigated whether phosphorylated tau in blood plasma also indicated cortical microstructural abnormalities.
Methods: For this cross-sectional study, we sampled participants with T1 MRI, multishell diffusion-weighted MRI, amyloid PET ([18F]AZD4694), tau PET, and plasma phosphorylated tau 217+ (p-tau217) from the Translational biomarkers in Aging and Dementia cohort at McGill University; participants were recruited between 2017 and 2024. We used the Neurite Orientation Dispersion and Density Imaging algorithm to calculate isotropic free water images ("free water"). FreeSurfer was used to calculate cortical thickness in the entorhinal, fusiform, inferior temporal, and middle temporal gyri regions of interest ("meta-ROI"); Automatic Segmentation of Hippocampal Subfields was used to calculate hippocampal volumes. We grouped participants by amyloid PET positivity (A), plasma p-tau217 positivity (T1), and tau PET positivity (T2). We performed voxel-wise correlation analyses between free water and these proteinopathy markers, as well as ROI-based analyses in the meta-ROI.
Results: A total of 303 participants (mean age 67 years, 58.7% female) were included in this study (168 cognitively normal individuals, 43 with mild cognitive impairment, 23 with AD dementia, 68 not diagnosed). Tau PET was positively correlated with free water in gray matter predominantly in the temporal lobe (partial R2 = 0.39, p < 0.001), and the correlation of p-tau217 with the meta-ROI free water was entirely mediated by tau PET (p < 0.001). In addition, medial temporal and hippocampal free water was negatively correlated with Montreal Cognitive Assessment scores in the A-T1+ and A+T2+ groups. The strongest ROI-based multilinear models for predicting temporal gray matter and hippocampal tau PET burden used both cortical thickness and free water as predictors (temporal gray matter partial R2 = 0.62; hippocampal partial R2 = 0.64).
Discussion: In AD-relevant regions, increased free water correlates with tau load independently of macrostructural metrics or amyloid load. Free water may serve as an imaging marker for microstructural changes in gray matter resulting from NFT accumulation, complementary to macrostructural metrics.
Background and objectives: Although etiology is considered central to outcomes in status epilepticus (SE), previous studies often lacked standardized classification and adjustment for confounders, particularly withdrawal of life-sustaining treatment (WLST). This study examined the association between SE etiology, mortality, and neurologic recovery using the International League Against Epilepsy (ILAE) classification while accounting for confounders and WLST.
Methods: This 2-center observational study included adults (≥18 years) with SE treated at the University Hospitals of Basel and Geneva from 2015 to 2023. Etiologies were classified as acute symptomatic, remote symptomatic-unprovoked, progressive CNS disorders, epilepsy without additional triggers, or cryptogenic. Demographics, SE type, SE severity score, Charlson Comorbidity Index, treatment data, complications, and WLST were assessed. The primary outcome was in-hospital mortality; secondary outcomes were 30-day mortality and recovery to premorbid neurologic function at discharge. Associations were assessed using Poisson regression with robust error variance, adjusted for age, nonconvulsive SE (NCSE) with coma, comorbidity, and center.
Results: Among 967 patients (median age 67 years, interquartile range 54-78; 46.5% female), SE was terminated in 95%, with 48.5% of patients recovering to premorbid function. Acute symptomatic SE accounted for 34.2%, remote symptomatic SE for 27.6%, SE due to progressive CNS disorders for 14.4%, epilepsy without additional triggers for 16.7%, and cryptogenic SE for 7.1%. In-hospital and 30-day mortality were 7.9% and 13.9%, respectively, while 48.5% recovered to premorbid function. Etiology was associated with neurologic recovery, with intracranial hemorrhage (relative risk [RR] 0.49, 95% CI 0.35-0.67) and acute symptomatic SE (RR 0.71, 95% CI 0.60-0.83) being associated with reduced likelihood of recovery, whereas known epilepsy was associated with increased likelihood of recovery (RR 1.40, 95% CI 1.23-1.60). NCSE with coma (11.9%) was independently associated with higher in-hospital and 30-day mortality and reduced recovery across all ILAE etiology groups. WLST did not significantly alter these associations.
Discussion: Etiology was associated with neurologic recovery but not with short-term mortality after adjustment for confounders and WLST. By contrast, NCSE with coma showed the strongest association with adverse outcomes. This suggests that while etiology informs prognosis for recovery, SE type, particularly NCSE with coma, is the more critical determinant of survival.
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