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Importance Typical cysteine-altering NOTCH3 ( NOTCH3 cys ) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3 -SVD severity spectrum is needed and currently lacking. Objective To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3 -SVD severity spectrum. Design, Setting, and Participants A cohort study was performed in which the NOTCH3 -SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3 cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3 cys -positive cases from families with CADASIL; the validation set included 1713 NOTCH3 cys -positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3 cys -positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024. Main Outcomes and Measures Percentage of cases following the sequence of events of the NOTCH3 -SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level. Results The NOTCH3 -SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3 -SVD staging system. The NOTCH3 -SVD stages were associated with neuroimaging outcomes in the NOTCH3 cys -positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3 -SVD staging system captured disease progression and was associated with 18-year survival. Conclusions and Relevance The NOTCH3 -SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3 cys variant to patients with end-stage disease. The NOTCH3 -SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.

Asymptomatic high-grade carotid stenosis is an important therapeutic target for stroke prevention. For decades, the ACAS (Asymptomatic Carotid Atherosclerosis Study) and ACST (Asymptomatic Carotid Surgery Trial) trials provided most of the evidence supporting endarterectomy for patients with asymptomatic high-grade stenosis who were otherwise good candidates for surgery. Since then, transfemoral/transradial carotid stenting and transcarotid artery revascularization have emerged as alternatives to endarterectomy for revascularization. Advances in treatments against atherosclerosis have driven down the rates of stroke in patients managed without revascularization. SPACE-2 (Stent-Protected Angioplasty Versus Carotid Endarterectomy-2), a trial that included endarterectomy, stenting, and medical arms, failed to detect significant differences in stroke rates among treatment groups, but the study was stopped well short of its recruitment goal. CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) will be able to clarify whether revascularization by stenting or endarterectomy remains efficacious under conditions of intensive medical management. Transcarotid artery revascularization has a favorable periprocedural risk profile, but randomized trials comparing it to intensive medical management are lacking. Features like intraplaque hemorrhage on MRI and echolucency on B-mode ultrasonography can identify patients at higher risk of stroke with asymptomatic stenosis. High-grade stenosis with poor collaterals can cause hemispheric hypoperfusion, and unstable plaque can cause microemboli, both of which may be treatable risk factors for cognitive impairment. Evidence that there are patients with carotid stenosis who benefit cognitively from revascularization is presently lacking. New risk factors are emerging, like exposure to microplastics and nanoplastics. Strategies to limit exposure will be important without specific medical therapies.

Objectives: To evaluate the relationship between Framingham Stroke Risk Profile (FSRP) score and rate of white matter hyperintensity (WMH) progression and cognition. Methods: Consecutive patients enrolled in the Mayo Clinic Florida Familial Cerebrovascular Diseases Registry (2011-2020) with 2 brain-MRI scans at least 1 year apart were included. The primary outcome was annual change in WMH volume (cm3/year) stratified as fast versus slow (above vs. below median). Cognition was assessed using a Mini-Mental State Exam (MMSE, 0-30). FSRP score (0 to 8) was calculated by summing the presence of age 65 years or older, smoking, systolic blood pressure greater than 130 mmHg, diabetes, coronary disease, atrial fibrillation, left ventricular hypertrophy, and antihypertensive medication use. Linear and logistic regression analyses were performed to examine the association between FSRP and WMH progression, and cognition. Results: In all, 207 patients were included, with a mean age of 60±16 y and 54.6% female. FSRP scores risk distribution was: 31.9% scored 0 to 1, 36.7% scored 2 to 3, and 31.4% scored ≥4. The baseline WMH volume was 9.6 cm3 (IQR: 3.3-28.4 cm3), and the annual rate of WMH progression was 0.9 cm3/year (IQR: 0.1 to 3.1 cm3/year). A higher FSRP score was associated with fast WMH progression (odds ratio, 1.45; 95% CI: 1.22-1.72; P<0.001) and a lower MMSE score (23.6 vs. 27.1; P<0.001). There was a dose-dependent relationship between higher FSRP score and fast WMH progression (odds ratios, 2.20, 4.64, 7.86, 8.03 for FSRP scores 1, 2, 3, and ≥4, respectively; trend P<0.001). Conclusions: This study demonstrated an association between higher FSRP scores and accelerated WMH progression, as well as lower cognition.

Background Rather than considering carotid stenting and endarterectomy to be rival procedures, they ought to be seen as complementary, with some patients more suited to one procedure over another. The respective patient populations best suited for optimal outcomes with stenting and endarterectomy differ substantially. Hence, the CREST‐2 (Carotid Revascularization, Endarterectomy Versus Stent Trial‐2) ( study was designed as 2 separate 2‐arm randomized trials run in parallel. One trial compares intensive medical management with and without stenting; the other, intensive medical management with and without endarterectomy. Each trial has a recruitment target of 1240 patients with ≥70% asymptomatic carotid stenosis, randomized 1:1 in each arm. To ensure patient safety and give stenting the best possible chance of demonstrating net benefits in stroke prevention, CREST‐2 adopted a rigorous procedure for evaluating, monitoring, and approving operators to enroll in the trial. The CREST‐2 Registry was established to allow for recent experience for applicant stent operators. Methods The CREST‐2 Registry is a prospective, multicenter, short‐term observational study of carotid stenting allowing use of multiple devices. Results The registry enrolled its first patient in September 2014, and as of October 2, 2023, a total of 9830 patients have been treated by 207 different stent operators from 103 different clinical centers. In this mixed cohort of asymptomatic (61.1% of the cohort) and symptomatic (38.9%) patients, the 30‐day stroke rate is 1.8% and the combined 30‐day stroke or death rate is 2.6%. At its peak in March 2016, the registry achieved an enrollment rate of 142 cases/month. As of October 20, 2023, a total of 104 patients remain to be enrolled in the CREST‐2 stenting trial. Conclusion The registry has facilitated assembly of a high‐performing team of stent operators for the CREST‐2 trial. With continued support of the many operators, we anticipate completing enrollment by the summer of 2024.

Introduction: Collateral cerebrovasculature is important for the survival of penumbral tissue in patients with large vessel occlusive (LVO) stroke, and adequate collateralization is associated with favorable outcomes. The presence of cerebral microbleeds (CMB) have been implicated in vessel wall remodeling and impaired vasoreactivity. We investigated whether the presence of deep and/or lobar CMB predicts poor collateral recruitment in patients with LVO stroke who underwent thrombectomy (MT). Methods: We performed a retrospective, single-center study of adults who presented with LVO stroke and had MT between January 2012-June 2020. CT angiography of head prior to MT was used to assess collateral status with poor status defined as ≤50% filling and good status as >50% filling. CMBs were assessed using T2*-weighted gradient echo or susceptibility weighted magnetic resonance images. Location of CMB was further characterized as deep vs. lobar using consensus definitions. Poor stroke outcome was defined as modified Rankin Scale (mRS) ≥3 at 90 days. Multivariable logistic regressions were performed to evaluate the associations between CMB, CMB types (lobar, deep, lobar+deep) and poor collaterals after adjusting for vascular risk factors. Results: Consecutive 151 subjects were included (mean age 68±15 years, 47% women), with a median NIHSS of 18. CMB were identified in 57 subjects (37.4%). Of these, 20.5% had lobar CMB, 5.3% had deep CMB and 11.9% had combined lobar & deep CMB. Patients with CMB had higher odds of having poor collaterals compared to those without CMB (OR 1.56, 95% CI 1.09-2.23, P=0.015). The association of CMB with poor collaterals was strongest in patients with combined lobar & deep CMB (OR 4.78, 95% CI 1.43-15.93, P=0.011), compared with those with exclusively deep CMB (OR 2.78, 95% CI 0.44-17.62, P=0.278) or lobar CMB (OR 0.52, 95% CI 0.19-1.38, P=0.188). Patients with poor collaterals were more likely to have poor outcome compared with those with good collaterals (48.4% vs. 31.0%, P=0.03). Conclusion: Cerebral microbleeds are independently associated with poor collateral recruitment when adjusted for traditional vascular risk factors. Further study is warranted to elucidate the differential effects of CMB types on collateral recruitment.