Citations

Background: Alzheimer’s disease (AD) and cerebrovascular pathology are the two most common causes of dementia, frequently co-occurring in older people. Community-based neuropathology studies indicate that vascular disease accounts for approximately one-third of the population-attributable risk of dementia, controlling for other pathologies (including AD). The proportion with vascular disease as co-pathology is likely to be higher (50–70%). The most common vascular substrate is cerebral small vessel disease, which includes small artery fibrosis (arteriolosclerosis), vascular amyloid deposits (cerebral amyloid angiopathy), and monogenic forms of small vessel disease, the commonest being Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Post-stroke cognitive impairment following both ischemic stroke and intracerebral hemorrhage also contributes. Aims and Methods: In this World Stroke Organization (WSO) scientific statement, we assembled a multi-disciplinary international group of experts to review the vascular contribution to dementia, encompassing both vascular and neurodegenerative dementia. This statement has been reviewed and approved by the WSO executive. Results: We summarize the epidemiology, neuropathology, cognitive profile, clinical impact and management of vascular disease in dementia and discuss the recent VasCog-2-WSO diagnostic criteria. We consider the substantial overlap with clinical stroke and with AD dementia. We catalog transcriptomic and proteomic studies that have revealed novel candidate molecules ( COL4A1/4A2, HTRA1, TRIM47, FOXF2 ) as possible treatment targets. We appraise imaging-based biomarkers relevant to vascular disease and potential biochemical markers (vascular endothelial growth factor-A, placental growth factor, interleukin-6, matrix metalloproteinase-9, cathepsin-B). We highlight the potential for vascular interventions to treat not only vascular dementia but also the vascular component of neurodegenerative dementia. We review recent clinical trials targeting multiple pathways, including nitric oxide signaling, high blood pressure, the GABAergic system, angiogenic activity, microglial inhibition, PDE3 and PDE5 inhibition, as well as dietary supplementation with omega-3 fatty acids, s-equol and vitamin E. Finally, we consider upcoming opportunities and challenges relevant to vascular disease in dementia. Conclusion: The vascular contribution to dementia is i) substantial, ii) increasingly understood at molecular and mechanistic levels, iii) a source of potential treatment opportunities. Data Access Statement: no original data are presented in this document.

Stereotactic radiosurgery was associated with a higher obliteration rate compared with embolization in patients with eloquent brain arteriovenous malformations, whereas there was no evidence of a difference in functional outcomes or complications after adjustment.

BACKGROUND AND OBJECTIVES: Despite many publications about cavernous malformations (CMs), controversy remains regarding diagnostic and management strategies. To update evidence-based guidelines for the clinical management of brain and spinal cord CMs. METHODS: The Alliance to Cure CMs, the patient support group in the United States advocating on behalf of patients and research in CM, convened a multidisciplinary writing group comprising expert CM clinicians to help summarize the existing literature related to the clinical care of CM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and imaging standards, (4) neurosurgical considerations, and (5) neurological considerations. Building on prior evidence-based recommendations reflecting literature review through October 2014, the group conducted a systematic review of the more recent literature, identified references for mandatory citation, rated evidence, developed recommendations, and established consensus according to a prespecified protocol. Finally, the writing group outlined remaining knowledge gaps and controversies to guide future research. RESULTS: From 2672 publications published between October 1, 2014, and March 15, 2023, and meeting key word criteria, 234 were selected based on prearticulated criteria for mandatory consideration in evidence-based recommendations. Topic authors used these and other supporting references to summarize current knowledge and arrive at 53 management recommendations, with unanimous consensus based on a Delphi process. These were rated by class (strength of recommendation) and level (quality of evidence) per the American Heart Association/American Stroke Association criteria. Eighteen recommendations were class 1 (34%), class 2 in 31 (58%), and class 3 in 4 (8%). Three were level A (6%), 19 (36%) were level B, and 31 (58%) were level C. CONCLUSION: Current evidence supports prior and new recommendations for the management of CMs, but many reflect moderate classes and low levels, mandating further research to better inform clinical practice.

Abstract Introduction The impact of multiple feeding arteries on clinical outcomes of cerebral arteriovenous malformations (AVMs) is not well understood. This study aims to compare outcomes between AVMs with multiple versus single feeding arteries. Patients and Methods Data from the Multicenter International Study for Treatment of Brain AVMs (MISTA) consortium were analyzed. Propensity score matching (PSM) was used to balance cohorts. Subgroup analysis was conducted for ruptured and unruptured AVMs and different treatment options, and multivariable logistic regression was applied to assess the impact of feeding artery origin. Results Among 953 patients, 661(69.4%) had multiple feeding arteries, and 292 (30.6%) had a single feeding artery. After PSM, which included 422 matched patients (211 in each group), the differences in obliteration rates (68.7% vs 74.8%, OR 0.73, 95% CI: 0.48–1.12, p = 0.16) and symptomatic complications (15.6% vs 11.8%, OR 1.37, 95% CI: 0.78–2.41, p = 0.25) were not significant. Subgroup analysis comparing ruptured and unruptured AVMs and different treatment options showed no significant differences across all subgroups. Multivariable analysis identified PICA feeders as significantly associated with increased odds of all complications (OR 7.33, 95% CI: 2.14–25.1, p = 0.002). Discussion and Conclusion AVMs with a single feeding artery were more likely to present with rupture, but no significant differences in obliteration rates or complications were observed between the groups after PSM. These findings suggest that while the number of feeding arteries may influence the initial presentation, it does not appear to impact overall treatment success or patient prognosis. Further prospective studies are needed to confirm these findings.

Background: Arteriovenous malformations (AVMs) are complex vascular anomalies with a high risk of hemorrhage and neurological deficits, especially when located in eloquent brain regions. The eloquence of an AVM location is a critical factor in the treatment planning, influencing both the risk of complications and long-term functional outcomes. This study aims to compare outcomes between eloquent and non-eloquent AVMs. Methods: This multicenter, retrospective study utilized data from the Multicenter International Study for Treatment of Brain AVMs (MISTA) consortium. Patients with eloquent and non-eloquent AVMs were compared on baseline characteristics, angiographic outcomes, and functional outcomes using the modified Rankin Scale (mRS). Propensity score weighting (IPTW) was applied to adjust for confounding variables. Results: The study included 1013 patients, with 498 (49.2%) AVMs located in eloquent regions and 515 (50.8%) in non-eloquent regions. In unadjusted analysis, eloquent AVMs had lower complete obliteration rates (67.6% vs 79.5%, OR: 0.53, 95% CI: 0.39–0.72, p < 0.001) and higher complication rates (24.5% vs 19.0%, OR: 1.38, 95% CI: 1.02–1.86, p = 0.03) compared to non-eloquent AVMs. After IPTW adjustment, eloquent AVMs continued to show significantly higher odds of overall complications (OR: 1.68, 95% CI: 1.12–2.52, p = 0.01) and symptomatic complications (OR: 1.77, 95% CI: 1.12–2.80, p = 0.01). Secondary analysis within the eloquent group indicated that embolization was linked to an elevated risk of complications. Surgery and radiosurgery showed comparable functional outcomes at last follow-up and complications rates with higher complete obliteration rates in surgery. Conclusion: AVMs in eloquent brain areas present higher risks of complications and lower obliteration rates, emphasizing the need for cautious, individualized treatment planning. Within the eloquent group, embolization increased the risk of complications, while surgery and radiosurgery showed comparable functional outcomes at last follow-up and complication rates with higher complete obliteration rates in surgery. These findings highlight the importance of location in AVM management and support further research focusing on comparing treatment strategies for AVMs in eloquent brain areas.

Background Brain arteriovenous malformations (AVMs) are abnormal connections between feeding arteries and draining veins, associated with significant risks of haemorrhage, seizures and other neurological deficits. Preoperative embolization is commonly used as an adjunct to microsurgical resection, with the aim of reducing intraoperative complications and improving outcomes. However, the efficacy and safety of this approach remain controversial. Methods This study is a subanalysis of the Multicenter International Study for Treatment of Brain AVMs consortium. We retrospectively analysed 486 patients with brain AVMs treated with microsurgical resection between January 2010 and December 2023. Patients were divided into two groups: those who underwent microsurgery alone (n=245) and those who received preoperative embolization, followed by microsurgery (n=241). Propensity score matching was employed, resulting in 288 matched patients (144 in each group). The primary outcomes were rates of complete AVM obliteration and functional outcomes (measured by the modified Rankin Scale (mRS)). Secondary outcomes included complication rates, mortality, hospital length of stay and postsurgical rupture. Results After matching, the complete obliteration rate was 97% with no significant difference between the microsurgery-only group and the preoperative embolization group (p=0.12). The proportion of patients with an mRS score of 0–2 at the last follow-up was similar in both groups (83% vs 84%; p=0.67). The median hospital stay was significantly longer for the embolisation group (9 days vs 7 days; p=0.017). Complication rates (24% vs 22%; p=0.57) and mortality rates (4.9% vs 2.1%; p=0.20) were comparable between the two groups. No significant differences were observed in postsurgical rupture, recurrence or retreatment rates. Conclusions In this large multicentre study, preoperative embolization did not significantly improve AVM obliteration rates, functional outcomes or reduce complications compared with microsurgery alone.

Background: Two National Cancer Institute-funded pharmacovigilance programs have identified 49 serious hematology-related ADRs since 1998. The programs, called RADAR (Research on Adverse Drug events and Reports) and then SONAR (Southern Network on Adverse Reactions) involve &gt; 50 institutions and &gt; 75 co-investigators worldwide. The work builds on three prior studies evaluating “Davids and Goliaths” in medical oncology and in cardiology (PLOS One, eClinicalMedicine, and Journal of Scientific and Professional Integrity). Here we review the hematology focused safety investigations of RADAR/SONAR. Methods: Data were based on initial safety signals being identified by a RADAR/SONAR co-investigator. Then, case-series were derived. Collaborations with basic scientists allowed for basic science correlative studies. Results were disseminated primarily as Brief Report in the literature and Black Box warnings on the related drug. In some instances, studies identified hematologic toxicities that prevent FDA from approving a submitted drug application. Results: sADRs were frequently identified based on very small case series, including ticlopidine-and clopidogrel associated thrombotic thrombocytopenic purpura (22 and 10 patients, respectively), thalidomide- and lenalidomide-associated venous thromboembolism (9 and 5 patients, respectively), rituximab-associated progressive multi-focal leukoencephalopathy (22 patients), peginesatide-associated fatal anaphylaxis (5 patients), and COVID-19 vaccine associated immune thrombocytopenia (1 patient). Meta-analyses provided data for epoetin- and darbepoetin-associated mortality among cancer patients and lenalidomide- and thalidomide-associated venous thromboembolism. Following the onset of the COVID-19 pandemic, RADAR/SONAR investigated social media and pre-prints (COVID-19 vaccine associated cerebral vein thrombosis and immune thrombocytopenia). Time from FDA approval to sADR discovery was a median of 5 years (range, 0 months (thalidomide-associated venous thromboembolism) to 34 years (ciprofloxacin-associated neuropsychiatric toxicity). Basic science correlative studies identified ADAMTS13 autoantibodies (ticlopidine), leachates that developed in a multi-dose vial (peginesatide), anti-red blood cell antibodies (epoetin-associated pure red cell aplasia), and high-risk genes (fluoroquinolones and rituximab). Overall, RADAR/SONAR studies are estimated to have saved over 1 million lives and also resulted in overall payments to the Department of Justice of $1.5 billion (related to marketing of unsafe drugs). Discussion: RADAR/SONAR has proven to be a very important adjunct to FDA and pharmaceutical manufacturer-led safety investigations for hematology, paralleling the success in medical oncology and in cardiology. Going forward, independent centers of excellence for safety-focused investigations such as the CERSI network and the SENTINEL network (both are NIH funded) should be broadened to include a hematology-focused safety center.

The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014–2019; 2019–2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them. Responding to the needs of researchers within the CCNA teams, a unique sample of 1173 deeply phenotyped patients with various forms of dementia was accrued and studied over eight years (COMPASS-ND). In the second phase of funding (2019–2024), a national dementia prevention program (CAN-THUMBS UP) was set up. In a short time, this prevention program became a member of the World Wide FINGERS prevention consortium. In this article, the challenges, successes, and impacts of CCNA in Canada and internationally are discussed. Short-term deliverables have occurred, along with considerable promise of impacts in the longer term. The creation of synergy, networking, capacity building, engagement of people with lived experience, and economies of scale have contributed to the considerable success of CCNA by all measures. CCNA is evidence that an organized “centrally-organized” approach to dementia research can catalyze important progress nationally and yield significant and measurable results.

Background Arteriovenous malformations (AVMs) are uncommon cerebral lesions that can cause significant neurological complications. Surgical resection is the gold standard for treatment, but endovascular embolization and stereotactic radiosurgery (SRS) are viable alternatives. Objective To compare the outcomes of endovascular embolization versus SRS in the treatment of AVMs with Spetzler-Martin grades I–III. Methods This study combined retrospective data from 10 academic institutions in North America and Europe. Patients aged 1 to 90 years who underwent endovascular embolization or SRS for AVMs with Spetzler-Martin grades I–III between January 2010 and December 2023 were included. Results The study included 244 patients, including 84 who had endovascular embolization and 160 who had SRS. Before propensity score matching (PSM), complete obliteration at the last follow-up was achieved in 74.5% of the SRS group compared with 57.8% of the embolization group (OR=0.47; 95% CI 0.26 to 0.48; P=0.01). After propensity score matching, SRS still achieved significantly higher occlusion rates at last follow-up (78.9% vs 55.3%; OR=0.32; 95% CI 0.12 to 0.90; P=0.03). Hemorrhagic complications were higher in the embolization group than in the SRS group, although this difference did not reach statistical significance after PSM (13.2% vs 2.6%; OR=5.6; 95% CI 0.62 to 50.47; P=0.12). Similarly, re-treatment rate was higher in the embolization group (10.5% vs 5.3%; OR=2.11; 95% CI 0.36 to 12.31; P=0.40) compared with the SRS group. Conclusion Our findings indicate that SRS has a significantly higher obliteration rate at last follow-up compared with endovascular embolization. Also, SRS has a higher tendency for fewer hemorrhagic complications and lower re-treatment rate. Further prospective studies are needed.

OBJECTIVE Cerebral revascularization surgery (CRS) has been used to prevent stroke in children with sickle cell disease (SCD) and cerebral vasculopathy (e.g., moyamoya syndrome). While results suggest that it may be an effective treatment, surgical indications have not been well defined. This study sought to determine indications for offering revascularization surgery in centers with established sickle cell programs in the US. METHODS Three sequential surveys utilizing the Delphi methodology were administered to neurosurgeons participating in the Stroke in Sickle Cell Revascularization Surgery study. Respondents were presented with clinical scenarios of patients with SCD and varying degrees of ischemic presentation and vasculopathy, and the group’s agreement to offer surgical revascularization was measured. Consensus was defined as ≥ 75% similar responses. RESULTS The response rate to all 3 surveys was 100%. Seventeen neurosurgeons from 16 different centers participated. The presence of moyamoya collaterals (MMCs) and arterial stenosis matching an ischemic distribution yielded the strongest recommendations to offer surgery. There was consensus to offer revascularization in the presence of MMCs and at least 50% arterial stenosis matching an ischemic distribution. In contrast, there was no consensus to offer revascularization with 50%–70% stenosis not matching an ischemic presentation in the absence of MMCs. The presence of the ivy sign in the distribution of the stenotic artery also contributed to the consensus to offer surgery in certain scenarios. CONCLUSIONS There were several clinical scenarios that attained consensus to offer surgery; the strongest was moderate to severe arterial stenosis that matched the distribution of ischemic presentation in the presence of MMCs. Radiological findings of decreased cerebral flow or perfusion also facilitated attaining consensus to offer surgery. The findings of this study reflect expert opinion about questions that deserve prospective clinical research. Determination of indications for CRS can guide clinical practice and aid the design of prospective studies.