The 2022 update of the Canadian Stroke Best Practice Recommendations (CSBPR) for Acute Stroke Management, 7th edition, is a comprehensive summary of current evidence-based recommendations, appropriate for use by an interdisciplinary team of healthcare providers and system planners caring for persons with an acute stroke or transient ischemic attack. These recommendations are a timely opportunity to reassess current processes to ensure efficient access to acute stroke diagnostics, treatments, and management strategies, proven to reduce mortality and morbidity. The topics covered include prehospital care, emergency department care, intravenous thrombolysis and endovascular thrombectomy (EVT), prevention and management of inhospital complications, vascular risk factor reduction, early rehabilitation, and end-of-life care. These recommendations pertain primarily to an acute ischemic vascular event. Notable changes in the 7th edition include recommendations pertaining the use of tenecteplase, thrombolysis as a bridging therapy prior to mechanical thrombectomy, dual antiplatelet therapy for stroke prevention,1 the management of symptomatic intracerebral hemorrhage following thrombolysis, acute stroke imaging, care of patients undergoing EVT, medical assistance in dying, and virtual stroke care. An explicit effort was made to address sex and gender differences wherever possible. The theme of the 7th edition of the CSBPR is building connections to optimize individual outcomes, recognizing that many people who present with acute stroke often also have multiple comorbid conditions, are medically more complex, and require a coordinated interdisciplinary approach for optimal recovery. Additional materials to support timely implementation and quality monitoring of these recommendations are available at www.strokebestpractices.ca.

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.

Patients with neuropathic pain are heterogeneous in pathophysiology, etiology, and clinical presentation. Signs and symptoms are determined by the nature of the injury and factors such as genetics, sex, prior injury, age, culture, and environment. Basic science has provided general information about pain etiology by studying the consequences of peripheral injury in rodent models. This is associated with the release of inflammatory cytokines, chemokines, and growth factors that sensitize sensory nerve endings, alter gene expression, promote post-translational modification of proteins, and alter ion channel function. This leads to spontaneous activity in primary afferent neurons that is crucial for the onset and persistence of pain and the release of secondary mediators such as colony-stimulating factor 1 from primary afferent terminals. These promote the release of tertiary mediators such as brain-derived neurotrophic factor and interleukin-1β from microglia and astrocytes. Tertiary mediators facilitate the transmission of nociceptive information at the spinal, thalamic, and cortical levels. For the most part, these findings have failed to identify new therapeutic approaches. More recent basic science has better mirrored the clinical situation by addressing the pathophysiology associated with specific types of injury, refinement of methodology, and attention to various contributory factors such as sex. Improved quantification of sensory profiles in each patient and their distribution into defined clusters may improve translation between basic science and clinical practice. If such quantification can be traced back to cellular and molecular aspects of pathophysiology, this may lead to personalized medicine approaches that dictate a rational therapeutic approach for each individual.

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.

As COVID-19 continues, a safe, cost-effective treatment strategy demands continued inquiry. Chronic neuroinflammatory disorders may appear to be of little relevance in this regard; often indolent and progressive disorders characterized by neuroinflammation (such as Alzheimer’s disease (AD)) are fundamentally dissimilar in etiology and symptomology to COVID-19’s rapid infectivity and pathology. However, the two disorders share extensive pathognomonic features, including at membrane, cytoplasmic, and extracellular levels, culminating in analogous immunogenic destruction of their respective organ parenchyma. We hypothesize that these mechanistic similarities may extent to therapeutic targets, namely that it is conceivable an agent against AD’s immunopathy may have efficacy against COVID-19 and vice versa. It is notable that while extensively investigated, no agent has yet demonstrated significant therapeutic efficacy against AD’s cognitive and memory declines. Yet this very failure has driven the development of numerous agents with strong mechanistic potential and clinical characteristics. Having already approved for clinical trials, these agents may be an expedient starting point in the urgent search for an effective COVID-19 therapy. Herein, we review the overlapping Alzheimer’s/ COVID-19 targets and theorize several initial platforms.

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.

Timely diagnosis of brain death (BD) is critical as it prevents unethical and futile continuation of support of vital organ functions when the patient has passed. Furthermore, it helps with avoiding the unnecessary use of resources and provides early opportunity for precious organ donation. The diagnosis of BD is mainly based on careful neurological assessment of patients with an established underlying diagnosis of neurological catastrophe capable of causing BD.

Ancillary testing, however, is tremendously helpful in situations when the presence of confounders prevents or delays comprehensive neurological assessment. Traditionally, four-vessel digital subtraction angiography and computed tomography angiography have been used for blood flow (BF) examinations of the brain. The lack of BF in the intracranial arteries constitutes conclusive evidence that the brain is dead. However, there is an apparent discrepancy between the BF and sufficient cerebral perfusion; several studies have shown that in 15% of patients with confirmed clinical diagnosis of BD, BF is still preserved. In these patients, cerebral perfusion is significantly impaired. Hence, measurement of cerebral perfusion rather than BF will provide a more precise assessment of the brain function.

In this review article, we discuss a brief history of BD, our understanding of its complex pathophysiology, current Canadian guidelines for the clinical diagnosis of BD, and the ancillary tests-specifically CT perfusion of the brain that help us with the prompt and timely diagnosis of BD.

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.