Location-weighted versus Volume-weighted Mismatch at MRI for Response to Mechanical Thrombectomy in Acute Stroke.

Background A target mismatch profile can identify good clinical response to recanalization after acute ischemic stroke, but does not consider region specificities. Purpose To test whether location-weighted infarction core and mismatch, determined from diffusion and perfusion MRI performed in patients with acute stroke, could improve prediction of good clinical response to mechanical thrombectomy compared with a target mismatch profile. Materials and Methods In this secondary analysis, two prospectively collected independent stroke data sets (2012-2015 and 2017-2019) were analyzed. From the brain before stroke (BBS) study data (data set 1), an eloquent map was computed through voxel-wise associations between the infarction core (based on diffusion MRI on days 1-3 following stroke) and National Institutes of Health Stroke Scale (NIHSS) score. The French acute multimodal imaging to select patients for mechanical thrombectomy (FRAME) data (data set 2) consisted of large vessel occlusion-related acute ischemic stroke successfully recanalized. From acute MRI studies (performed on arrival, prior to thrombectomy) in data set 2, target mismatch and eloquent (vs noneloquent) infarction core and mismatch were computed from the intersection of diffusion- and perfusion-detected lesions with the coregistered eloquent map. Associations of these imaging metrics with early neurologic improvement were tested in multivariable regression models, and areas under the receiver operating characteristic curve (AUCs) were compared. Results Data sets 1 and 2 included 321 (median age, 69 years [IQR, 58-80 years]; 207 men) and 173 (median age, 74 years [IQR, 65-82 years]; 90 women) patients, respectively. Eloquent mismatch was positively and independently associated with good clinical response (odds ratio [OR], 1.14; 95% CI: 1.02, 1.27; P = .02) and eloquent infarction core was negatively associated with good response (OR, 0.85; 95% CI: 0.77, 0.95; P = .004), while noneloquent mismatch was not associated with good response (OR, 1.03; 95% CI: 0.98, 1.07; P = .20). Moreover, adding eloquent metrics improved the prediction accuracy (AUC, 0.73; 95% CI: 0.65, 0.81) compared with clinical variables alone (AUC, 0.65; 95% CI: 0.56, 0.73; P = .01) or a target mismatch profile (AUC, 0.67; 95% CI: 0.59, 0.76; P = .03). Conclusion Location-weighted infarction core and mismatch on diffusion and perfusion MRI scans improved the identification of patients with acute stroke who would benefit from mechanical thrombectomy compared with the volume-based target mismatch profile. Clinical trial registration no. NCT03045146 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Nael in this issue.

Perfusion Imaging and Clinical Outcome in Acute Ischemic Stroke with Large Core.

OBJECTIVE: Mechanical thrombectomy (MT) is not recommended for acute stroke with large vessel occlusion (LVO) and a large volume of irreversibly injured tissue ("core"). Perfusion imaging may identify a subset of patients with large core who benefit from MT. METHODS: We compared two cohorts of LVO-related patients with large core (>50 ml on diffusion-weighted-imaging or CT-perfusion using RAPID), available perfusion imaging, and treated within 6 hours from onset by either MT + Best Medical Management (BMM) in one prospective study, or BMM alone in the pre-MT era from a prospective registry. Primary outcome was 90-day modified Rankin Scale ≤2. We searched for an interaction between treatment group and amount of penumbra as estimated by the mismatch ratio (MMRatio = critical hypoperfusion/core volume). RESULTS: Overall, 107 patients were included (56 MT + BMM and 51 BMM): Mean age was 68 ± 15 years, median core volume 99 ml (IQR: 72-131) and MMRatio 1.4 (IQR: 1.0-1.9). Baseline clinical and radiological variables were similar between the two groups, except for a higher intravenous thrombolysis rate in the BMM group. The MMRatio strongly modified the clinical outcome following MT (pinteraction < 0.001 for continuous MMRatio); MT was associated with a higher rate of good outcome in patients with, but not in those without, MMRatio>1.2 (adjusted OR [95% CI] = 6.8 [1.7-27.0] vs 0.7 [0.1-6.2], respectively). Similar findings were present for MMRatio ≥1.8 in the subgroup with core ≥70 ml. Parenchymal hemorrhage on follow-up imaging was more frequent in the MT + BMM group regardless of the MMRatio. INTERPRETATION: Perfusion imaging may help select which patients with large core should be considered for MT. Randomized studies are warranted. ANN NEUROL 2021;90:417-427.

Diagnostic utility of T2*-weighted GRE in migraine with aura attack. The cortical veins sign.

OBJECTIVE: To evaluate the frequency, distribution, and clinical associations of the dilated appearance of cerebral cortical veins, termed cortical veins sign on T2*-weighted gradient recalled-echo (T2*-GRE) in the acute setting of migraine with aura attack in adult patients. METHODS: We conducted a retrospective analysis of 60 consecutive patients admitted for acute neurological symptoms with a final diagnosis of migraine with aura (42%) or probable migraine with aura (58%) who underwent emergency brain magnetic resonance imaging and 60 non-migrainous control adults. The cortical veins sign was defined as a marked hypo-intensity and/or an apparent increased diameter of at least one cortical vein. We examined the prevalence, the spatial distribution, and the associations of cortical veins sign with clinical characteristics of migraine with aura. RESULTS: We detected the cortical veins sign in 25 patients (42%) with migraine with aura, compared to none in the control group (p < 0.0001). The spatial distribution of cortical veins sign was characterised by the predominantly bilateral and posterior location. Presence of cortical veins sign was associated with increased severity of aura (p = 0.05), and shorter delay to MRI (p = 0.02). CONCLUSION: In the setting of acute neurological symptoms, the presence of cortical veins sign is frequent in patients with migraine with aura and can be detected with good reliability. This imaging marker may help clinicians identify underlying migraine with aura.

Mismatch Profile Influences Outcome After Mechanical Thrombectomy.

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) is the recommended treatment for acute ischemic stroke caused by anterior circulation large vessel occlusion. However, despite a high rate of reperfusion, the clinical response to successful MT remains highly variable in the early time window where optimal imaging selection criteria have not been established. We hypothesize that the baseline perfusion imaging profile may help forecast the clinical response to MT in this setting. METHODS: We conducted a prospective multicenter cohort study of patients with large vessel occlusion-related acute ischemic stroke treated by MT within 6 hours. Treatment decisions and the modified Rankin Scale evaluation at 3 months were performed blinded to the results of baseline perfusion imaging. Study groups were defined a posteriori based on predefined imaging profiles: target mismatch (TMM; core volume <70 mL/mismatch ratio >1.2 and mismatch volume >10 mL) versus no TMM or mismatch (MM; mismatch ratio >1.2 and volume >10 mL) versus no MM. Functional recovery (modified Rankin Scale, 0-2) at 3 months was compared based on imaging profile at baseline and whether reperfusion (modified Thrombolysis in Cerebral Infarction 2bc3) was achieved. RESULTS: Two hundred eighteen patients (mean age, 71±15 years; median National Institutes of Health Stroke Scale score, 17 [interquartile range, 12-21]) were enrolled. Perfusion imaging profiles were 71% TMM and 82% MM. The rate of functional recovery was 54% overall. Both TMM and MM profiles were independently associated with a higher rate on functional recovery at 3 months Adjusted odds ratios were 3.3 (95% CI, 1.4-7.9) for TMM and 5.9 (95% CI, 1.8-19.6) for MM. Reperfusion (modified Thrombolysis in Cerebral Infarction 2bc3) was achieved in 86% and was more frequent in TMM and MM patients. Reperfusion was associated with a higher rate of functional recovery in MM and TMM patients but not among those with no MM. CONCLUSIONS: In this cohort study, about 80% of the patients with a large vessel occlusion-related acute ischemic stroke had evidence of penumbra, regardless of infarction volume. Perfusion imaging profiles predict the clinical response to MT.

ASCOD Phenotyping of Stroke With Anterior Large Vessel Occlusion Treated by Mechanical Thrombectomy.

BACKGROUND AND PURPOSE: Determining the mechanism of large vessel occlusion related acute ischemic stroke is of major importance to initiate a tailored secondary prevention strategy. We investigated using the atherosclerosis, small vessel disease, cardiac source, other cause, dissection (ASCOD) classification the distribution of the causes of large vessel occlusion related acute ischemic stroke treated by mechanical thrombectomy. METHODS: This was a predefined substudy of the FRAME (French Acute Multimodal Imaging to Select Patient for Mechanical Thrombectomy). Each patient underwent a systematic etiological workup including brain and vascular imaging, electrocardiogram monitoring lasting at least 24 hours and routine blood tests. Stroke mechanisms were systematically evaluated using the atherosclerosis, small vessel disease, cardiac source, other cause, dissection grading system at 3 months. We defined single potential cause by one cause graded 1 in a single domain, possible cause as a cause graded 1 or 2 regardless of overlap, and no identified cause without grade 1 nor 2 causes. RESULTS: A total of 215 patients (mean age 70±14; 50% male) were included. A single potential cause was identified in 148 (69%). Cardio-embolism (53%) was the most frequent, followed by atherosclerosis (9%), dissection (5%) and other causes (1%). Atrial fibrillation accounted for 88% of C1. Overlap between grade 1 causes was uncommon (3%). Possible causes were identified in 168 patients (83%) and 16 (7%) had no cause identified after the initial evaluation. CONCLUSIONS: Cardio-embolism, especially atrial fibrillation, was the major cause of large vessel occlusion related acute ischemic stroke. This finding emphasizes the yield of paroxysmal atrial fibrillation detection in those patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03045146.

Decreased frontal white-matter diffusion and improved cognitive flexibility after burr-hole surgery in moyamoya angiopathy.

BACKGROUND: In Moyamoya Angioplasty (MMA), increased apparent diffusion coefficient (ADC) in frontal white matter (WM) with a normal appearance has been associated with frontal hypoperfusion and executive dysfunction. Multiple burr-hole surgery enables the revascularization of large frontal areas. GOAL: To assess the effect of multiple burr-hole surgery on the ADC and cognitive functions in adults with MMA. METHODS: ADC was measured in 26 brain hemispheres of 14 consecutive adults with MMA (9 women, mean age ± SD: 38.1 ± 10.7 years) prior to and 6 months after burr-hole surgery. ADC was obtained from regions of interest located in frontal and posterior (temporo-occipital) normal-appearing WM. Ten patients had neuropsychological assessment that focused on executive and attentional functions before and after surgery. RESULTS: Anterior and posterior ADC values did not differ before surgery (815.8 ± 60.1 vs. 812.1 ± 35.3 mm2/s, p = 0.88). After surgery, frontal ADC was lower than prior to surgery (789.9 ± 64.5 vs. 815.8 ± 60.1 mm2/s; p <0.001) whereas no change occurred in posterior ADC (p = 0.31). Trail-making test part B median z-score increased from - 1.47 to - 0.21 (p = 0.018), suggesting improved cognitive flexibility. CONCLUSION: In adults with MMA, indirect revascularization with burr-hole is followed by a decrease of ADC in normal-appearing frontal WM and may have improved some executive functions in the flexibility process. Change in ADC may reflect the improvement in cerebral perfusion after surgery. The measuring of ADC may be a promising tool in exploring potentially reversible microstructural WM damage related to hypoperfusion and cognitive change in MMA.

Risk of Intracerebral Hemorrhage and Mortality After Convexity Subarachnoid Hemorrhage in Cerebral Amyloid Angiopathy.

Background and Purpose- Convexity subarachnoid hemorrhage (cSAH) is an increasingly recognized presentation of cerebral amyloid angiopathy (CAA), usually revealed by transient symptoms, but data on its outcome are limited. We compared the risk of future intracerebral hemorrhage (ICH), cSAH, and death in patients with CAA after cSAH and after lobar ICH. Methods- Consecutive patients with probable CAA, based on the Boston criteria, presenting with cSAH (CAA-cSAH) or lobar ICH (CAA-ICH) were included. We obtained baseline clinical and magnetic resonance imaging data and follow-up information. Univariable and multivariable analyses were used to compare incidence rate for symptomatic ICH, symptomatic cSAH, and late-death (beyond 30 days) between patients with CAA-cSAH and CAA-ICH. Results- Among 105 patients (mean age, 76.7±7.5 years) enrolled, 44 participants presented with CAA-cSAH and 61 with CAA-ICH. The median follow-up was 22.2 months (interquartile range, 12.6-34.4). The symptomatic ICH rate (per person-year) was 10.5% (95% CI, 5.6-19.4) in patients with CAA-cSAH compared with 8.5% (95% CI, 4.4-16.4) in those with CAA-ICH (adjusted hazard ratio, 1.05; 95% CI, 0.32-3.43). The annual incidence rates of symptomatic cSAH (9.9% versus 3.8%; adjusted hazard ratio, 1.77; 95% CI, 0.43-7.28) and death (9.5% versus 17.8%; adjusted hazard ratio, 0.56; 95% CI, 0.22-1.43) were not significantly different between patients with CAA-cSAH and those with CAA-ICH. Conclusions- Patients with CAA-related cSAH have a poor outcome, with similar high risk of future ICH and long-term mortality than CAA patients after lobar ICH. Our findings may have important prognostic implication and guide management of patients with cSAH in CAA.

Subarachnoid and Subdural Hemorrhages in Lobar Intracerebral Hemorrhage Associated With Cerebral Amyloid Angiopathy.

Background and Purpose- Identifying underlying cerebral amyloid angiopathy (CAA) in patients with intracerebral hemorrhage (ICH) has important clinical implication. Convexity subarachnoid hemorrhage (cSAH) and subdural hemorrhage (SDH) are computed tomography features of CAA-related ICH. We explored whether cSAH and SDH could be additional magnetic resonance imaging markers of CAA in lobar ICH survivors. Methods- We analyzed data from consecutive patients with acute lobar ICH associated with CAA (CAA-ICH) or not attributed to CAA (non-CAA-ICH). Magnetic resonance imaging scans were analyzed for cSAH, SDH, and markers of small vessel disease. The associations of cSAH and SDH with the diagnosis of probable CAA based on the modified Boston criteria were explored using multivariable models. Results- We included 165 patients with acute lobar ICH (mean age 70±13 years): 72 patients with CAA-ICH and 93 with non-CAA-ICH. Patients with CAA-ICH had a higher prevalence of cSAH (73.6% versus 39.8%; P<0.001) and SDH (37.5% versus 21.5%; P=0.02) than non-CAA-ICH. In multivariate logistic regression analysis, the presence of cSAH was independently associated with CAA-ICH (odds ratio, 2.97; 95% CI, 1.26-6.99; P=0.013), whereas there was no association between SDH and CAA-ICH. Conclusions- Among survivors of acute lobar ICH, the presence of cSAH is associated with the magnetic resonance imaging-based diagnosis of CAA. Further studies should investigate whether cSAH help improve the sensitivity of magnetic resonance imaging for in vivo diagnosis of CAA.

Enlarged perivascular spaces and florbetapir uptake in patients with intracerebral hemorrhage.

PURPOSE: Enlarged perivascular spaces in the centrum semiovale (CSO-EPVS) have been linked to cerebral amyloid angiopathy (CAA). To get insight into the underlying mechanisms of this association, we investigated the relationship between amyloid-ß deposition assessed by 18F-florbetapir PET and CSO-EPVS in patients with acute intracerebral hemorrhage (ICH). METHODS: We prospectively enrolled 18 patients with lobar ICH (suggesting CAA) and 20 with deep ICH (suggesting hypertensive angiopathy), who underwent brain MRI and 18F-florbetapir PET. EPVS were assessed on MRI using a validated 4-point visual rating scale in the centrum semiovale and the basal ganglia (BG-EPVS). PET images were visually assessed, blind to clinical and MRI data. We evaluated the association between florbetapir PET positivity and high degree (score> 2) of CSO-EPVS and BG-EPVS. RESULTS: High CSO-EPVS degree was more common in patients with lobar ICH than deep ICH (55.6% vs. 20.0%; p = 0.02). Eight (57.1%) patients with high CSO-EPVS degree had a positive florbetapir PET compared with 4 (16.7%) with low CSO-EPVS degree (p = 0.01). In contrast, prevalence of florbetapir PET positivity was similar between patients with high vs. low BG-EPVS. In multivariable analysis adjusted for age, hypertension, and MRI markers of CAA, florbetapir PET positivity (odds ratio (OR) 6.44, 95% confidence interval (CI) 1.32-38.93; p = 0.03) was independently associated with high CSO-EPVS degree. CONCLUSIONS: Among patients with spontaneous ICH, high degree of CSO-EPVS but not BG-EPVS is associated with amyloid PET positivity. The findings provide further evidence that CSO-EPVS are markers of vascular amyloid burden that may be useful in diagnosing CAA.

Research Progresses in Understanding the Pathophysiology of Moyamoya Disease.

BACKGROUND: The pathogenesis of moyamoya disease (MMD) is still unknown. The detection of inflammatory molecules such as cytokines, chemokines and growth factors in MMD patients' biological fluids supports the hypothesis that an abnormal angiogenesis is implicated in MMD pathogenesis. However, it is unclear whether these anomalies are the consequences of the disease or rather causal factors as well as these mechanisms remain insufficient to explain the pathophysiology of MMD. The presence of a family history in about 9-15% of Asian patients, the highly variable incidence rate between different ethnic and sex groups and the age of onset support the role of genetic factors in MMD pathogenesis. However, although some genetic loci have been associated with MMD, few of them have been replicated in independent series. Recently, RNF213 gene was shown to be strongly associated with MMD occurrence with a founder effect in East Asian patients. However, the mechanisms leading from RNF213 mutations to MMD clinical features are still unknown. SUMMARY: The research on pathogenic mechanism of MMD is in its infancy. MMD is probably a complex and heterogeneous disorder, including different phenotypes and genotypes, in which more than a single factor is implicated. KEY MESSAGE: Since the diagnosis of MMD is rapidly increasing worldwide, the development of more efficient stratifying risk systems, including both clinical but also biological drivers became imperative to improve our ability of predict prognosis and to develop mechanism-tailored interventions.

Acute Convexity Subarachnoid Hemorrhage Related to Cerebral Amyloid Angiopathy: Clinicoradiological Features and Outcome.

BACKGROUND: The specificities of acute convexity subarachnoid hemorrhage (cSAH) related to cerebral amyloid angiopathy (CAA) and its evolution are not well known. We aimed to describe the clinicoradiological pattern, the magnetic resonance imaging (MRI) evolution, and the risk of recurrent bleeding in such patients. METHODS: Among consecutive patients with an acute nontraumatic cSAH, subjects with available MRI who meet the modified Boston criteria for probable CAA were included. Review of medical records, MRI findings, and follow-up data was performed. RESULTS: Twenty-three patients (14 women; mean age ± standard deviation: 75.9 ± 7.3 years) were included. cSAH was revealed by transient focal neurological episodes (TFNEs) in 18 of 23 (78.3%) patients. In all patients, acute cSAH appeared as a sulcal fluid-attenuated inversion recovery hyperintensity and GRE T2 hypointensity. Cortical superficial siderosis and cortical microbleeds, respectively, were observed in 21 (91.3%) and 20 (86.9%) patients. Twenty patients (87%) had available follow-up data with a mean duration of 29.8 ± 20.2 months. Recurrent TFNEs occurred in 40% of patients. Acute cSAH evolved into cortical superficial siderosis in all patients. New subarachnoid bleedings defined by recurrent acute cSAH (n = 8) or extension of siderosis (n = 14) were detected in 83.3% of the patients. Lobar intracerebral hemorrhage (ICH) occurred in 7 patients (35%). CONCLUSION: CAA-related cSAH has a specific pattern defined by a high prevalence of TFNEs and cortical superficial siderosis, with a high risk of recurrent bleeding, either cSAH or lobar ICH. The systematic evolution from cSAH to focal cortical superficial siderosis reveals data on siderosis physiopathology.

Prediction of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage Using Cerebral Blood Flow Velocities and Cerebral Autoregulation Assessment.

BACKGROUND: The risk of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) is associated with large cerebral artery vasospasm, but vasospasm is not a strong predictor for DCI. Assessment of cerebral autoregulation with transcranial Doppler (TCD) may improve the prediction of DCI. The aim of this prospective study was to assess the value of TCD-derived variables to be used alone or in combination for prediction of DCI. METHODS: We included consecutive patients with low-grade aneurysmal SAH within 4 days of aneurysm rupture. Cerebral autoregulation was evaluated using the moving correlation coefficient Mx calculated from spontaneous fluctuations of cerebral blood flow velocities and arterial blood pressure. Transcranial color-coded sonography was performed to assess large artery vasospasm. RESULTS: Thirty patients (19 women and 11 men; mean age ± SD 44.7 ± 12.1 years) were included. Twenty (66.7%) patients had vasospasm. DCI occurred in six (20%) patients after a median delay of 10 days (range 8-13 days). Cerebral autoregulation was impaired at baseline and at day 7 and then returned to normal at day 14. Neither cerebral autoregulation impairment nor large artery vasospasm alone was associated with DCI. In contrast, the combination of large artery vasospasm with worsening impairment of cerebral autoregulation from baseline to day 7 was significantly correlated to subsequent DCI (p = 0.007). CONCLUSIONS: Early deterioration of cerebral autoregulation was strongly predictive of DCI in patients with large artery vasospasm after low-grade SAH. Our results suggest that consideration to both cerebral blood flow velocities and cerebral autoregulation may improve the prediction of DCI.

Number of passes and outcome of endovascular treatment of anterior circulation large core ischemic stroke: insights from the Endovascular Treatment in Ischemic Stroke (ETIS) registry.

BACKGROUND: The effect of multiple attempts on the outcome of endovascular treatment (EVT) of anterior circulation large ischemic core (LIC) stroke has not been fully explored. METHODS: We analyzed data from the Endovascular Treatment in Ischemic Stroke (ETIS) registry, a prospective, observational, multicenter study of acute ischemic stroke patients treated with EVT at 21 centers in France between January 1, 2015 and June 31, 2023. We included patients with proximal intracranial occlusion and LIC defined as Alberta Stroke Program Early CT Score (ASPECTS) of 0-5 up to 24 hours after last being seen well. We divided patients according to the number of passes with successful reperfusion (modified Thrombolysis In Cerebral Infarction (mTICI) ≥2b) into seven groups, according to the corresponding number of passes. We compared them to the group of patients with unsuccessful reperfusion. RESULTS: A total of 1235 patients with LIC constituted the study cohort. The rate of a modified Rankin Scale (mRS) score of 0 to 3 at 90 days was significantly higher for the one-pass successful recanalization category compared to no recanalization (48.1% vs 17.2%; adjusted OR (aOR) 7.99, 95% CI 4.30 to 14.8, P<0.001) and remained so even after six or more attempts (27.7% vs 17.2%; aOR 3.59, 95% CI 1.37 to 9.39, P=0.009). The rate of symptomatic intracranial hemorrhage was lower for successful recanalization up to two passes (11.1% vs 18.8%; aOR 0.36, 95% CI 0.18 to 0.69, P=0.002) without any significant differences for a higher number of passes. CONCLUSION: In anterior circulation LIC patients, successful reperfusion, even after six passes, is associated with favorable clinical outcomes with no increased hemorrhagic risk when compared to unsuccessful reperfusion.

Prevalence and characteristics of vascular cognitive impairment in a European cohort of adult patients with Moyamoya angiopathy.

INTRODUCTION: Moyamoya angiopathy (MMA) is associated with a high risk of stroke, but it is also increasingly recognized as leading to cognitive impairment. The aim of this study was to determine the prevalence, nature, and severity of vascular cognitive impairment no dementia (VCIND) in adults with MMA and to identify clinical and imaging factors associated with VCIND. METHODS: We conducted a retrospective study of consecutive adult patients with MMA followed in two tertiary hospitals (Toulouse and Paris Lariboisiere). All patients underwent neuropsychological assessment and brain magnetic resonance imaging (MRI). VCIND was defined as at least two variables of the same cognitive process with z-scores of < 2 standard deviations, regardless of the cognitive domain, that do not interfere in everyday life. Baseline demographic, clinical, and imaging data were compared between patients with and without VCIND. RESULTS: A total of 102 patients (mean age 43 years; 65% women) were included. Thirty-four patients (33.3%) had VCIND. VCIND was mild in 20/34 (59%), moderate in 8/34 (23%), and severe in 6/34 (18%) patients. Executive function was the most widely affected (25.5%), followed by attention and processing speed (24.8%). In univariable analyses, VCIND was associated with ischemic stroke at diagnosis and the presence of ischemic lesions on MRI. CONCLUSIONS: VCIND is highly prevalent in adults with MMA. Executive functions and processing speed are predominantly affected. These findings may guide clinicians in their evaluation of patients with MMA. Further research should assess the effect of revascularization therapies on cognitive functions.

MRI hypoperfusion as a determinant of cognitive impairment in adults with Moyamoya angiopathy.

INTRODUCTION: In Moyamoya angiopathy (MMA), mechanisms underlying cognitive impairment remain debated. We aimed to assess the association of cognitive impairment with the degree and the topography of cerebral hypoperfusion in MMA. METHODS: A retrospective analysis of neuropsychological and perfusion MRI data from adults with MMA was performed. Ischemic and haemorrhagic lesion masks were created to account for cerebral lesions in the analysis of cerebral perfusion. Whole brain volume of hypoperfused parenchyma was outlined on perfusion maps using different Tmax thresholds from 4 to 12 s. Regional analysis produced mean Tmax values at different regions of interest. Analyses compared perfusion ratios in patients with and without cognitive impairment, with multivariable logistic regression analysis to identify predictive factors. RESULTS: Cognitive impairment was found in 20/48 (41.7%) patients. Attention/processing speed and memory were equally impaired (24%) followed by executive domain (23%). After adjustment, especially for lesion volume, hypoperfused parenchyma volume outlined by Tmax > 4 s or Tmax > 5 s thresholds was an independent factor of cognitive impairment (OR for Tmax > 4 s = 1.06 [CI 95% 1.008-1.123]) as well as attention/processing speed (OR for Tmax > 4 s = 1.07 [CI 95% 1.003-1.133]) and executive domains (OR for Tmax > 5 s = 1.08 [CI 95% 1.004-1.158]). Regarding cognitive functions, patients with processing speed and flexibility impairment had higher frontal Tmax compared to other ROIs and to patients with normal test scores. DISCUSSION: Cerebral hypoperfusion emerged as an independent factor of cognitive impairment in MMA particularly in attention/processing speed and executive domains, with a strong contribution of frontal areas. CONCLUSION: Considering this association, revascularization surgery could improve cognitive impairment.

Prevalence and characterization of cerebral small vessel disease in young adults with intracerebral hemorrhage.

BACKGROUND AND AIMS: Cerebral small vessel disease (CSVD) is the main cause of intracerebral hemorrhage (ICH) in older individuals but has not been systematically studied in younger people. We aimed to evaluate the prevalence and characteristics of CSVD in young adults with symptomatic ICH. METHODS: We conducted a cohort study of consecutive adults aged 18-50 years with non-traumatic ICH. All patients were evaluated with brain and vascular imaging. Using validated imaging markers (cerebral microbleeds (CMBs), white matter hyperintensities and/or lacunes), patients were categorized as having CSVD-related ICH or non-CSVD-related ICH. Factors associated with CSVD were evaluated using multivariable analyses. CSVD subtypes were characterized using pre-specified criteria. RESULTS: Of 146 young adults with ICH (mean age = 37.7), CSVD was present in 41 patients (28.1%; 95% confidence interval (CI) = 21.0-36.1). In multivariable analysis, older age, male sex, and hypertension were independently associated with the presence of CSVD. Deep perforator arteriopathy (48.8%) and mixed CSVD (31.7%) were the most common CSVD subtypes. CONCLUSION: Our results suggest that CSVD is a frequent cause of ICH in young adults and provide new insights into the characterization of the disease. These findings may have important implications since the treatment and management differ from other causes of ICH.

Safety and Efficacy of ApTOLL in Patients With Ischemic Stroke Undergoing Endovascular Treatment: A Phase 1/2 Randomized Clinical Trial.

Importance: ApTOLL is a TLR4 antagonist with proven preclinical neuroprotective effect and a safe profile in healthy volunteers. Objective: To assess the safety and efficacy of ApTOLL in combination with endovascular treatment (EVT) for patients with ischemic stroke. Design, Setting, and Participants: This phase 1b/2a, double-blind, randomized, placebo-controlled study was conducted at 15 sites in Spain and France from 2020 to 2022. Participants included patients aged 18 to 90 years who had ischemic stroke due to large vessel occlusion and were seen within 6 hours after stroke onset; other criteria were an Alberta Stroke Program Early CT Score of 6 to 10, estimated infarct core volume on baseline computed tomography perfusion of 5 to 70 mL, and the intention to undergo EVT. During the study period, 4174 patients underwent EVT. Interventions: In phase 1b, 0.025, 0.05, 0.1, or 0.2 mg/kg of ApTOLL or placebo; in phase 2a, 0.05 or 0.2 mg/kg of ApTOLL or placebo; and in both phases, treatment with EVT and intravenous thrombolysis if indicated. Main Outcomes and Measures: The primary end point was the safety of ApTOLL based on death, symptomatic intracranial hemorrhage (sICH), malignant stroke, and recurrent stroke. Secondary efficacy end points included final infarct volume (via MRI at 72 hours), NIHSS score at 72 hours, and disability at 90 days (modified Rankin Scale [mRS] score). Results: In phase Ib, 32 patients were allocated evenly to the 4 dose groups. After phase 1b was completed with no safety concerns, 2 doses were selected for phase 2a; these 119 patients were randomized to receive ApTOLL, 0.05 mg/kg (n = 36); ApTOLL, 0.2 mg/kg (n = 36), or placebo (n = 47) in a 1:1:√2 ratio. The pooled population of 139 patients had a mean (SD) age of 70 (12) years, 81 patients (58%) were male, and 58 (42%) were female. The primary end point occurred in 16 of 55 patients (29%) receiving placebo (10 deaths [18.2%], 4 sICH [7.3%], 4 malignant strokes [7.3%], and 2 recurrent strokes [3.6%]); in 15 of 42 patients (36%) receiving ApTOLL, 0.05 mg/kg (11 deaths [26.2%], 3 sICH [7.2%], 2 malignant strokes [4.8%], and 2 recurrent strokes [4.8%]); and in 6 of 42 patients (14%) receiving ApTOLL, 0.2 mg/kg (2 deaths [4.8%], 2 sICH [4.8%], and 3 recurrent strokes [7.1%]). ApTOLL, 0.2 mg/kg, was associated with lower NIHSS score at 72 hours (mean difference log-transformed vs placebo, -45%; 95% CI, -67% to -10%), smaller final infarct volume (mean difference log-transformed vs placebo, -42%; 95% CI, -66% to 1%), and lower degrees of disability at 90 days (common odds ratio for a better outcome vs placebo, 2.44; 95% CI, 1.76 to 5.00). Conclusions and Relevance: In acute ischemic stroke, 0.2 mg/kg of ApTOLL administered within 6 hours of onset in combination with EVT was safe and associated with a potential meaningful clinical effect, reducing mortality and disability at 90 days compared with placebo. These preliminary findings await confirmation from larger pivotal trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04734548.