Background: Endovascular thrombectomy (EVT) is standard of care for acute ischemic stroke. There is growing evidence that A Direct Aspiration first Pass Technique (ADAPT) is a safe, efficient and effective approach for EVT, offering several advantages. This study describes initial institutional experience in the use of a standardized aspiration only technique: CANADAPT. Methods: Single center prospective cohort study was performed on patients treated for large/medium vessel ischemic stroke. A sequential stepwise aspiration only technique was applied, CANADAPT, consisting of three maneuvers, A, B and C. The reperfusion success rate, number of passes, use of rescue technique, complication rate and procedural cost was determined. Results: 22 patients were included representing M1 (77%), M1/2 (9%), carotid-T (9%) and basilar (5%) occlusions. First pass recanalization was achieved in 50% of patients. A further 4 patients had successful reperfusion with a second pass (total 68% success). 7 patients had stent rescue technique (SOLUMBRA). Of these, 5 patients (22% of total) had successful reperfusion. The cost per procedure was $6,630 ± 1069 for CANADAPT, and $13,530 ± 2706 for SOLUMBRA. Conclusions: CANADAPT represents a standardized approach to aspiration only thrombectomy. This study demonstrates the safety, efficiency and efficacy of this technique in EVT.

Background: Obesity is increasingly implicated in the development of multiple sclerosis (MS), but its effect on disease disability is less well-established. This study aims to investigate the association between obesity and MS severity utilizing Mendelian Randomization (MR). Methods: Employing a two-sample MR setting, we examined the effects of various obesity measures and adiposity distribution metrics on MS severity. Genetic proxies for body mass index (BMI) were selected from a study of 806,834 participants, with MS severity determined from a genetic study of age-related MS severity scores in 12,584 individuals with MS. Results: The main analysis reveals an association between elevated BMI and increased MS severity (P = 0.03). This is supported by a significant effect of whole body fat (P = 0.04), aligning with the hypothesis that obesity exacerbates MS disability. Sensitivity analyses suggest minimal heterogeneity and bias, indicating a potential causal effect. Conclusions: Our findings suggest that obesity adversely influences long-term disability outcomes in MS. The convergence of this genetic evidence with some of the prior observational studies strengthens the argument for a causal relationship between obesity and MS severity. These insights highlight obesity as a potentially modifiable risk factor in managing MS, underscoring the importance of weight management in MS treatment strategies.

Background: Parkinson’s disease (PD) varies widely across individuals in terms of clinical manifestations and course of progression. We aimed to compare patterns of brain atrophy between PD clinical subtypes using longitudinally acquired brain MRIs. Methods: We used T1-weighted MRIs from Parkinson’s Progression Markers Initiative (PPMI) on 134 PD individuals and 60 healthy controls with at least two MRIs. Patients were classified into three clinical subtypes at de novo stage using validated subtyping criteria based on major motor and non-motor classifiers (early cognitive impairment, RBD, dysautonomia): mild-motor predominant (n=74), intermediate (n=44), and diffuse-malignant (n=16). Deformation-based morphometry (DBM) maps were calculated and mixed effect models were used to examine the interaction between PD subtypes and rate of atrophy across brain regions over time, controlling for sex and age at baseline. Results: Individuals with ‘diffuse malignant’ PD showed a significantly higher rate of atrophy across multiple brain regions, including lateral nucleus of the forebrain, precuneus, paracentral lobule, inferior temporal gyrus, fusiform gyrus, and lateral hemisphere of the cerebellum (FDR corrected p<0.05). Conclusions: We demonstrated an accelerated atrophy pattern within several brain regions in ‘diffuse malignant’ PD subtype. These findings suggest the presence of a more diffuse multidomain neurodegenerative process in a subgroup of people with PD, favoring the existence of diverse underlying pathophysiologies.

Background: Circadian rhythms are implicated in timing of stroke onset and infarct progression in adults, but this has not been studied in pediatric/young adult populations. Methods: We queried the RAPID Insights database from centers in USA for unique patients <25 years with a CTP (10/05/2018-09/29/2023) and a minimum ischemic core volume (defined as relative cerebral blood flow (rCBF) reduction of <30%) of >0 cc and minimum mismatch of >0 cc. Imaging time was subdivided into three epochs: Nigh (23:00 h-06:59 h), Day (07:00 h-14:59 h), and Evening (15:00 h-22:59 h). We analyzed age by pre-defined strata: <2 years, 2-5, 6-11, 12-18 and 19-25. Perfusion parameters (core, perfusion volume, mismatch ratio) were analyzed using descriptive statistics. Results: 836 patients were included; 52.3% were in the 19-25 category. Median ischemic cores were larger during the Night (23.0cc [10.0 – 58.0]) compared to Day (19.0cc [8.0-42.0]) or Evening (15.0cc [7.0-33.0]), p=0.009. There was a trend towards larger perfusion volumes in the Night epoch. In the 19-25 group, perfusion volumes were significantly larger at Night (127.5cc [51.5 – 203.5]) compared to Day (74.0cc [33.0 – 139.0]) or Evening (76.0cc [38.0 – 157.5]), with larger mismatch volumes at Night. Conclusions: This is the first study to demonstrate diurnal fluctuations in perfusion parameters in a predominantly pediatric cohort.

Background: Liquid biopsy represents a major development in cancer research, with significant translational potential. Similarly, the integration of multiple molecular platforms has yielded novel insights into disease biology and heterogeneity. We hypothesise that applying contemporary multi-omic approaches to liquid biopsies will improve the power of current models. Methods: We have compiled a cohort of 51 patients with glioblastoma, brain metastasis, and primary CNS lymphoma who underwent CSF sampling as part of clinical care. Cell free methylated DNA and shotgun proteomic profiling was obtained from the CSF of each patient and used to build tumour-specific classifiers. Integrated classifiers were compared with single platform classifiers using multiple approaches. Results: In this study, we show that the DNA methylation and protein profiles of cerebrospinal fluid can be combined to fully discriminate lymphomas from their major diagnostic counterparts with perfect AUCs of 1 (95% confidence interval 1-1) and 100% specificity. Each integrated lymphoma classifier significantly outperforms single-platform classifiers, suggesting synergistic biology is obtained using multiple molecular platforms. Conclusions: We present the most specific and accurate CNS lymphoma classifier to date by integrating the methylome and proteome of CSF. This has important implications for the future of cancer diagnostics and generates immediate utility for patients with CNS lymphoma.

Background: Meningiomas are the most common intracranial tumor with surgery, dural margin treatment, and radiotherapy as cornerstones of therapy. Response to treatment continues to be highly heterogeneous even across tumors of the same grade. Methods: Using a cohort of 2490 meningiomas in addition to 100 cases from the prospective RTOG-0539 phase II clinical trial, we define molecular biomarkers of response across multiple different, recently defined molecular classifications and use propensity score matching to mimic a randomized controlled trial to evaluate the role of extent of resection, dural marginal resection, and adjuvant radiotherapy on clinical outcome. Results: Gross tumor resection led to improved progression-free-survival (PFS) across all molecular groups (MG) and improved overall survival in proliferative meningiomas (HR 0.52, 95%CI 0.30-0.93). Dural margin treatment (Simpson grade 1/2) improved PFS versus complete tumor removal alone (Simpson 3). MG reliably predicted response to radiotherapy, including in the RTOG-0539 cohort. A molecular model developed using clinical trial cases discriminated response to radiotherapy better than standard of care grading in multiple cohorts (ΔAUC 0.12, 95%CI 0.10-0.14). Conclusions: We elucidate biological and molecular classifications of meningioma that influence response to surgery and radiotherapy in addition to introducing a novel molecular-based prediction model of response to radiation to guide treatment decisions.

Background: Currently there are no disease modifying treatment for Synucleinopathies including Parkinson’s disease Dementia (PDD). Carrying a mutation in the GBA gene (beta-glucocerebrosidase/ GCAse) is a leading risk factor for synucleinopathies. Raising activity GCAse lowers α-synuclein levels in cells and animal models. Ambroxol is a pharmacological chaperone for GCAse and can raise GCAse levels. Our goal is to test Ambroxol as a disease-modifying treatment in PDD. Methods: We randomized fifty-five individuals with PDD to Ambroxol 1050mg/day, 525mg/day, or placebo for 52 weeks. Primary outcome measures included safety, Alzheimer’s disease Assessment Scale-cognitive (ADAS-Cog) subscale and the Clinician’s Global Impression of Change (CGIC). Secondary outcomes included pharmacokinetics, cognitive and motor outcomes and and plasma and CSF biomarkers. Results: Ambroxol was well tolerated. There were 7 serious adverse events (SAEs) none deemed related to Ambroxol. GCase activity was increased in white blood cells by ~1.5 fold. There were no differences between groups on primary outcome measures. Patients receiving high dose Ambroxol appeared better on the Neuropsychiatric Inventory. GBA carriers appeared to improve on some cognitive tests. pTau 181 was reduced in CSF. Conclusions: Ambroxol was safe and well-tolerated in PDD. Ambroxol may improve biomarkers and cognitive outcomes in GBA1 mutation carrie.rs Ambroxol improved some biomarkerss. ClinicalTrials.gov NCT02914366

Background: Adherence to healthy lifestyle behaviours or to prescribed medication requires perseverance with stamina, and this is captured by Grit, a non-cognitive trait defined as perseverance and passion for long-term goals. Despite predicting cognitive decline and physical, emotional, and social functioning, Grit remains poorly understood and its neural substrates are unknown in cognitive aging. Methods: Ninety-five cognitively unimpaired older adults with a family history of Alzheimer’s disease were recruited through the PREVENT-AD longitudinal cohort. Participants completed tests that assess grit and conscientiousness and underwent resting-state functional magnetic resonance imaging (fMRI). Multivariate pattern analyses (MVPA), a rigorous data-driven whole-brain approach, were used to examine if resting-state functional connectivity of connectome-wide voxels were associated with grit scores, controlling for age, sex, APOE ε4 carriership, mean displacement, and conscientiousness. Results: Our analyses identified two large (≥54 voxels) and statistically significant (p<0.01 corrected for family-wise error) clusters in the right ventrolateral prefrontal cortex and the left orbitofrontal cortex underlying grit. Conclusions: Being the first to identify functional neural correlates supporting grit in the aging population while accounting for the variance of conscientiousness, our study provides unique insights into the construct which has important applications in adherence to clinical and empirical neurological interventions as well as in successful aging.

Background: Despite the limited successes of recent amyloid-targetting biologics, the need for a new pathogenesis mechanistic model of Alzheimer’s disease (AD) is a continuing priority, to facilitate improved rational drug design. Methods: To devise a new AD model, we performed an extensive, comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic–molecular mechanisms of cytokine-mediated and amyloid-beta (Aβ)-mediated neurotoxicities in AD. Results: A new model of AD has been devised: In response to pathogen-/damage-associated molecular pattern-stimulating events (e.g., infection, trauma, ischaemia), Aβ is released as an early responder cytokine triggering an innate immunity cascade in which Aβ exhibits immunomodulatory/antimicrobial duality. However, Aβ’s antimicrobial properties result in a misdirected cytotoxic attack upon “self” neurons, arising from the electrophysiological similarities between neurons and bacteria in terms of transmembrane potential and anionic charges on outer membrane macromolecules. The subsequent breakdown products (amyloid-ganglioside complexes) released from the damaged neurons diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic, self-perpetuating disease cycle. In short, AD occurs because Aβ cannot differentiate neurons from bacteria. Conclusions: An innovative new model of AD has been devised, recognizing Aβ as a physiologically oligomerizing cytokine and conceptualizing AD as brain-centric autoimmune disorder of innate immunity.

Background: Neurological complications following vaccinations have been described before, but the rates of neurological complications, and their variation by ethnicity, following COVID-19 vaccine are not well-known. Methods: We conducted a population-based cohort study of Ontarians aged 18 years and over who received their first COVID-19 vaccine, and followed them for six weeks to estimate the incidence of neurological events, ascertained using validated case definitions based on ICD-10 codes. Ethnicity was defined using last name surname algorithm. We used multivariable logistic regression models, adjusting for age, sex, and vaccine-type to evaluate ethnic differences. Results: In the included 10,063,466 Ontario residents, incidence of GBS (n=72), CVST (n=52) and transverse myelitis (n=25) after first COVID-19 vaccine was rare. The crude rate of ischemic stroke (240/1,000,000 people) was the highest followed by Bell’s palsy (54/1,000,000). Compared to the general population, the adjusted odds of ischemic stroke and Bell’s palsy were lower in Chinese (aORBell’s 0.62; 0.39-0.98 and a ORischemic stroke 0.74; 0.59-0.91) and South Asians (aORBell’s 0.83; 0.52-1.31 and aORischemic stroke 0.84; 0.65-1.08). Conclusions: The incidence of neurological events following COVID-19 vaccine is low, and it varies by ethnicity. Our findings should encourage vaccination against COVID-19 in all ethnic groups.

Background: Historical studies of myelitis associated with rheumatologic disease may have featured patients with unrecognized aquaporin-4 (AQP4)-IgG seropositive neuromyelitis optica spectrum disorder (NMOSD) or MOG-IgG associated disease (MOGAD). Methods: Cases with rheumatologic disease and myelitis unrelated to multiple sclerosis (MS) seen at Johns Hopkins between 2018-2023 were identified by medical record query and chart review. Descriptive statistics were used to compare AQP4-IgG seropositive to seronegative subjects. Results: Of 234 patients screened, 190 were excluded (144 did not have inflammatory myelopathy, 46 had MS), resulting in a cohort of 44 patient (43 female, mean age 45 years [SD±14]). Twenty patients (45%) had AQP4-IgG seropositive NMOSD, 1 (2%) MOGAD, 20 (45%) other myelitis, and 3 (7%) AQP4-IgG seronegative NMOSD. AQP4-IgG seropositive subjects were more likely to have longitudinally extensive central cord lesions than seronegative patients. Most (n=43; 98%) were tested for serum AQP4-IgG, and 20 (46%) were positive by cell-based assay (CBA) or enzyme-linked immunosorbent assay. Of 24 AQP4-IgG seronegative patients, 8 were tested only by ELISA/unknown assay. Serum MOG-IgG was positive in 2/18 subjects. Conclusions: AQP4-IgG seropositive NMOSD was common in this cohort of patients with rheumatologic disease and myelitis, with the caveat that several seronegative cases were never tested with gold-standard CBA.

Background: We evaluated vorasidenib (VOR), a dual inhibitor of mIDH1/2, in patients with mIDH1/2 glioma (Phase 3; NCT04164901). Methods: Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (age ≥12; Karnofsky Performance Score ≥80; measurable non-enhancing disease; surgery as only prior treatment; not in immediate need of chemoradiotherapy). Patients were stratified by 1p19q status and baseline tumor size and randomized 1:1 to VOR 40 mg or placebo (PBO) daily in 28-day cycles. Endpoints included imaging-based progression-free survival (PFS), time to next intervention (TTNI), tumor growth rate (TGR), health-related quality of life (HRQoL), neurocognition and seizure activity. Results: 331 patients were randomized (VOR, 168; PBO, 163). The median age was 40.0 years. 172 and 159 patients had histologically confirmed oligodendroglioma and astrocytoma, respectively. Treatment with VOR significantly improved PFS and TTNI. Median PFS: VOR, 27.7 mos; PBO, 11.1 mos (P=0.000000067). Median TTNI: VOR, not reached; PBO, 17.8 mos (P=0.000000019). Treatment with VOR resulted in shrinkage of tumor volume. Post-treatment TGR: VOR, -2.5% (95% CI: -4.7, -0.2); PBO, 13.9% (95% CI: 11.1, 16.8). HRQoL and neurocognition were preserved and seizure control was maintained. VOR had a manageable safety profile. Conclusions: VOR was effective in mIDH1/2 diffuse glioma not in immediate need of chemoradiotherapy.

Background: Patients with an acute ischemic stroke (AIS) are selected to receive reperfusion therapy using either computed tomography (CT-CTA) or magnetic brain imaging (MRI). The aim of this study was to compare CT and MRI as the primary imaging modality for AIS patients undergoing EVT. Methods: Data for AIS patients between January 2018 and January 2021 were extracted from two prospective multicenter EVT cohorts: the ETIS registry in France (MRI) and the OPTIMISE registry in Canada (CT). Demographics, procedural data and outcomes were collected. We assessed the association of qualifying imaging (CT vs. MRI) with time metrics and functional outcome. Results: From January 2018 to January 2021, 4059 patients selected by MRI and 1324 patients selected by CT were included in the study. Demographics were similar between the two groups. The median imaging-to-arterial puncture time was 37 minutes longer in the MRI group. Patients selected by CT had more favorable 90-day functional outcomes (mRS 0-2) as compared to patients selected by MRI (48.5% vs 44.4%; adjusted OR (aOR), 1.54, 95%CI 1.31 to 1.80, p<0.001). Conclusions: Patients with AIS undergoing EVT who were selected with MRI as opposed to CT had longer imaging-to-arterial-puncture delays and worse functional outcomes at 90 days.

Background: Cerebral venous thrombosis (CVT)most commonly affects younger women. Diagnosis may be delayed due to its distinct presentation and demographic profile compared to other stroke types. Methods: We examined delays to diagnosis of CVT in the SECRET randomized trial and TOP-SECRET parallel registry. Adults diagnosed with symptomatic CVT within <14 days were included. We examined time to diagnosis and number of health care encounters prior to diagnosis and associations with demographics, clinical and radiologic features and functional and patient-reported outcomes (PROMS) at days 180&365. Results: Of 103 participants, 68.9% were female; median age was 45 (IQR 31.0-61.0). Median time from symptom onset to diagnosis was 4 (1-8) days. Diagnosis on first presentation to medical attention was made in 60.2%. The difference in time to diagnosis for single versus multiple presentations was on the order of days (3[1-7] vs. 5[2-11.75], p=0.16). Women were likelier to have multiple presentations (OR 2.53; 95% CI1.00-6.39; p=0.05) and longer median times to diagnosis (5[2-8]days vs. 2[1-4.5] days; p=0.005). However, this was not associated with absolute or change in functional, or any patient reported, outcome measures (PROMs) at days 180&365. Conclusions: Diagnosis of CVT was commonly delayed; women were likelier to have multiple presentations. We found no association between delayed diagnosis and outcomes.

Background: Adults with congenital heart disease (ACHD) are at risk for stroke and dementia. We report baseline and Year 1 results from an ongoing study assessing brain health in people with moderate- and great-complexity ACHD. Methods: Participants aged ≥18 undergo baseline and Year-3 brain MRI/MRA and annual cognitive assessment (MoCA, NIH Toolbox-Cognitive Battery (NIH-TB)). Results: Of 93 participants to date, 79 (85%) have completed Year 1 follow-up. At baseline, the great-complexity group had lower MoCA (26.32 vs. 27.38; p=0.04) and NIH-TB scores (total composite 45.63 vs. 52.80; p=0.002) than the moderate-complexity group. Year-1 testing showed numerical improvements across cognitive batteries in both groups. More participants with great-complexity ACHD had white matter hyperintensities (WMH; 72% vs. 55%; p=0.21) and cerebral microbleeds (CMBs; 72% vs. 54%; p=0.17) on baseline neuroimaging, but differences were not significant. Conclusions: Baseline neuroimaging shows a greater-than-expected burden for age of CMB and WMH in the context of previous cardiac surgery. Baseline cognitive performance was worse with great-complexity ACHD. Improved cognitive battery performance across both subgroups at Year-1 suggests a practice effect. Repeat neuroimaging will be performed in Year-3 and cognitive performance is reassessed annually.

Background: Stroke simulation-based training has been associated with improved stroke quality metrics. The purpose of this study was to assess whether high-fidelity acute stroke simulation participation led to better knowledge retention one month post simulation in off-service residents. Methods: Off-service residents were provided with non-mandatory pre-simulation pre-reading on stroke. Immediately before stroke simulation, they completed a questionnaire to test their knowledge on a set of 8 questions related to stroke. Immediately post-stroke simulation, they were provided with a debrief including teaching on stroke. After the debrief and one month later, they completed the same questionnaire again. Results: There were a total of 16 off-service resident participants. Wilcoxon signed ranks test was performed. There was a significant difference between pre-simulation and immediate post-simulation scores on the knowledge retention questionnaire (p = 0.008). There was a significant difference between pre-simulation and one-month post-simulation on the knowledge retention questionnaire (p = 0.007). There was no difference between immediate post-simulation and one-month post-simulation on the knowledge retention questionnaire (p = 0.77). Conclusions: Participants performed better on the questionnaire after the simulation, and this improved performance was retained at one month. This is the first study to demonstrate delayed knowledge retention in stroke simulation literature.

Background: Only limited data exist on the potential benefit of prehospital video-based teletriage for patients with acute stroke. Methods: During a 6-month period, all patients from a defined geographical catchment area with a 911 call for acute stroke were screened by the paramedic team on site. Those with known symptom onset of <6h underwent video-based teletriage for transfer to either the closest tertiary (for suspected LVO occlusion) or to the closest secondary stroke centers. Patients referred for thrombectomy by same the secondary stroke centers without teletriage during the same period served as control. Results: Overall, 33 patients were teletriaged and 23 (70%) were bypassed to the tertiary center. Of the latter, 13 (median NIHSS 19) underwent thrombectomy (+/- iv thrombolysis). During the same period, 22 patients (median NIHSS 17) were referred for thrombectomy without teletriage. The median time from 911 to thrombectomy was 129 [IQR 51] min after teletriage, as compared to 196 [74] min in controls (p=0.015). The median NIHSS at 24h was 6 in the teletriage group versus 14.5 in controls (p=0.07). Conclusions: Video-based prehospital teletriage for acute stroke is feasible, reliably identifies patients without LVO stroke and significantly improves the delay between stroke alert and thrombectomy in eligible LVO stroke patients.

Background: After a transient ischemic attack (TIA) or minor stroke, the long-term risk of subsequent stroke is uncertain. Methods: Electronic databases were searched for observational studies reporting subsequent stroke during a minimum follow-up of 1 year in patients with TIA or minor stroke. Unpublished data on number of stroke events and exact person-time at risk contributed by all patients during discrete time intervals of follow-up were requested from the authors of included studies. This information was used to calculate the incidence of stroke in individual studies, and results across studies were pooled using random-effects meta-analysis. Results: Fifteen independent cohorts involving 129794 patients were included in the analysis. The pooled incidence rate of subsequent stroke per 100 person-years was 6.4 events in the first year and 2.0 events in the second through tenth years, with cumulative incidences of 14% at 5 years and 21% at 10 years. Based on 10 studies with information available on fatal stroke, the pooled case fatality rate of subsequent stroke was 9.5% (95% CI, 5.9 – 13.8). Conclusions: One in five patients is expected to experience a subsequent stroke within 10 years after a TIA or minor stroke, with every tenth patient expected to die from their subsequent stroke.

Background: All patients with drug-resistant focal epilepsy, should undergo an evaluation to determine if non-medical options, including surgical intervention, are appropriate. This evaluation involves a thorough work-up, typically including some or all of neuropsychological evaluation, prolonged video EEG monitoring, and advanced neuroimaging. The utility of genetic testing as part of this evaluation has not been thoroughly investigated. Methods: In this retrospective study, we reviewed the charts of pediatric patients referred for epilepsy surgery evaluation over a 5-year period. We extracted and analyzed results of genetic testing as well as clinical, EEG, and neuroimaging data. Results: 125 patients were referred for epilepsy surgical evaluation, 86 of whom had some form of genetic testing. Of these, 18 had a pathogenic or likely pathogenic variant identified. Genes affected included NPRL3, TSC2, KCNH1, CHRNA4, SPTAN1, DEPDC5, SCN2A, ARX, SCN1A, DLG4, and ST5. One patient had ring chromosome 20, one a 7.17p12 duplication, and one a 15q13 deletion. A specific medical therapy choice was allowed due to genetic diagnosis in three patients who did not undergo surgery. Conclusions: Obtaining a molecular diagnosis may dramatically alter management in children with drug-resistant focal epilepsy. Genetic testing should be incorporated as part of standard investigations in the pre-surgical work-up of such patients.