Microvascular brain damage in middle-aged women with a history of migraine with aura and/or ischemic stroke.

Clinical Relevance of Cerebral Small Vessel Diseases.

Introduction: chronic kidney disease (CKD) coexists with microvascular brain damage. This cerebrorenal connection is considered to involve small vessel disease in both the kidney and brain, based on their hemodynamic similarities. Hypothesis: to evaluate the relationship between microvascular brain damage (white matter hyperintensities -WMH-, microbleeds -MB- and silent brain infarcts -SBI-), and glomerular filtration rate (GFR) in a cohort of ischemic stroke patients. Methods: patients were prospectively included in a multidisciplinary secondary stroke prevention program. Pre-stroke vascular risk factor profile and control were obtained from electronic medical records and the burden of microvascular brain damage was evaluated on admission MRI. For the purpose of the analysis three groups were defined according to GFR estimated by Cockroft-Gault formula: >60, 30-60 and <30 ml/min/1.73 m2. Periventricular and deep WMH were classified according to Fazekas scale as low grade (0-1) and high grade (2-3); MB and SBI (lacunar and non-lacunar) were analyzed as dichotomous variables. Exclusion criteria: TIA and patients without MRI. Results: 808 patients (mean age 77±11 years, 59% females) were included. GRF was inversely related to age (70±11, 83±6, 85±8 years; p 0.0001), female sex (48%, 69%, 66%; p 0.001), hypertension (76%, 89%, 91%; p 0.0001) and AF (16%, 21%, 34%; p 0.08) prevalence. Chronic microvascular brain damage burden was inversely related to e-GFR (table). Conclusion: decreased GFR indicates small vessel disease not only in the kidney but also in the brain. As small vessel disease is a systemic disorder, information about disease in one organ may suggest damage in the other.

Background: White-matter hyperintensities (WMH) and cerebral microbleeds (CMBs) are considered radiographic markers of small vessel disease (SVD). Literature on CMB and WMH prevalence and associated risk factors in young patients presenting with stroke is limited. We have reported high prevalence of both WMH and CMBs in our cohort of young stroke patients. The aim of this report is to better characterize independent determinants of WMH and CMBs in the same cohort Methods: Charts of consecutive patients ≤49 years of age admitted with a diagnosis of ischemic stroke (IS) or spontaneous intraparenchymal hemorrhage (IPH) between 01/06-02/10 were reviewed (n=146). Patients with interpretable T2*-GRE (104) and/or T2/FLAIR (107) sequences on MRI were eligible. WMH was graded according to the Age-Related White Matter Changes Scale, and cerebral volume using the Global Cortical Atrophy Scale. Using multivariable regression analysis, we compared baseline demographics and vascular risk factors between patients with MRI markers of SVD and those without. Results: CMBs were present in 17% and moderate-severe WMH in 27% of individuals. Male gender (OR 4.93 [95%CI 1.01, 24.1]), hypertension (HTN) (OR 8.84 [95%CI 1.76, 40.5]), moderate-severe WMH (OR 5.25 [95%CI 1.54, 17.9]), and IPH (OR 6.97 [95%CI 1.81, 26.8]) were independently associated with the presence of CMBs. CMBs (OR 4.27 [95% CI 1.35, 13.5]), HTN (OR 4.14 [95% CI 1.42, 12.1]), serum creatinine on admission (OR per 1 mg/dl increment: 3.02 [95% CI 1.14, 7.99]) and moderate-severe cortical atrophy (OR 6.26 [95% CI 1.40, 27.94]) were significantly associated with moderate-severe WMH. Conclusions: Our data suggest male gender, HTN, IPH and moderate-severe WMH are associated with CMBs, while HTN, CMBs, elevated serum creatinine and moderate-severe cortical atrophy are associated with moderate-severe WMH. The association of CMBs with higher WMH severity and IPH supports the notion that CMBs are an indicator of an advanced stage of SVD that is prone to bleeding. Further studies are needed to examine if presence of CMBs and/or WMH may impact outcomes after ischemic stroke in young adults.

Ambulatory arterial stiffness index (AASI) is associated with microvascular damage in other organs, but the association with microvascular brain damage is unknown. The association of AASI with magnetic resonance imaging (MRI) markers of cerebral small vessel disease in 143 patients with lacunar stroke was investigated. We performed 24-hour ambulatory blood pressure monitoring and scored the presence of lacunes, white matter hyperintensities, perivascular spaces, and cerebral microbleeds on brain MRI. In logistic regression analyses, AASI was associated with white matter hyperintensities, but, after adjustment for age and sex, this association lost significance. AASI was not associated with lacunes, microbleeds, or perivascular spaces. Systolic and diastolic 24-hour blood pressure values were associated with lacunes, perivascular spaces, and microbleeds independent of age and sex. Despite its significance and growing interest as a possible prognostic and therapeutic target in (micro)vascular diseases, AASI seems to have no added value over standard 24-hour blood pressure in cerebral small vessel disease.

Cerebral amyloid angiopathy (CAA) is characteristically associated with magnetic resonance imaging (MRI) biomarkers of small vessel brain injury, including strictly lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. Although these neuroimaging markers reflect distinct pathophysiologic aspects in CAA, no studies to date have combined these structural imaging features to gauge total brain small vessel disease burden in CAA. To investigate whether a composite score can be developed to capture the total brain MRI burden of small vessel disease in CAA and to explore whether this score contributes independent and complementary information about CAA severity, defined as intracerebral hemorrhage during life or bleeding-related neuropathologic changes. This retrospective, cross-sectional study examined a single-center neuropathologic CAA cohort of eligible patients from the Massachusetts General Hospital from January 1, 1997, through December 31, 2012. Data analysis was performed from January 2, 2015, to January 9, 2016. Patients with pathologic evidence of CAA (ie, any presence of CAA from routinely collected brain biopsy specimen, biopsy specimen at hematoma evacuation, or autopsy) and available brain MRI sequences of adequate quality, including T2-weighted, T2*-weighted gradient-recalled echo, and/or susceptibility-weighted imaging and fluid-attenuated inversion recovery sequences, were considered for the study. Brain MRIs were rated for lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. All 4 MRI lesions were incorporated into a prespecified ordinal total small vessel disease score, ranging from 0 to 6 points. Associations with severity of CAA-associated vasculopathic changes (fibrinoid necrosis and concentric splitting of the wall), clinical presentation, number of intracerebral hemorrhages, and other imaging markers not included in the score were explored using logistic and ordinal regression. In total, 105 patients with pathologically defined CAA were included: 52 with autopsies, 22 with brain biopsy specimens, and 31 with pathologic samples from hematoma evacuations. The mean (range) age of the patients was 73 (71-74) years, and 55 (52.4%) were women. In multivariable ordinal regression analysis, severity of CAA-associated vasculopathic changes (odds ratio, 2.40; 95% CI, 1.06-5.45; P = .04) and CAA presentation with symptomatic intracerebral hemorrhage (odds ratio, 2.23; 95% CI, 1.07-4.64; P = .03) were independently associated with the total MRI small vessel disease score. The score was associated with small, acute, diffusion-weighted imaging lesions and posterior white matter hyperintensities in adjusted analyses. This study provides evidence of concept validity of a total MRI small vessel disease score in CAA. After further validation, this approach can be potentially used in prospective clinical studies.

Migraine with aura (MWA) is a risk factor for stroke, but the mechanisms underlying this association remain unclear. Our aim was to assess the association between MWA and cerebral small-vessel disease (CSVD) ischemic stroke after adjustment for vascular risk factors in a population of young patients hospitalized for a first-ever ischemic stroke. Patients aged 18-54years consecutively hospitalized for a first-ever acute ischemic stroke at the neurovascular unit of our university hospital between January 2017 and July 2021 were included in this retrospective cohort study. CSVD lesions were assessed and classified according to ASCOD (Atherosclerosis, Small-Vessel Disease, Cardiac pathology, Others causes, Dissection) classification criteria. In total, 646 patients were included (median (SD) age, 44.03 (9.01)years; 61.8% male) including 115 patients with MWA and 110 patients with migraine without aura (MWoA). Grade S1, potentially causal, CSVD lesions were significantly less frequent in patients with MWA (odds ratio (OR) = 0.35, 95% cofdence interval (CI) = 0.13-0.95, p = 0.048) compared to non-migraine patients in univariate analysis. Logistic regression adjusting for vascular risk factors showed no significant association of CSVD of any grade (S1, S2 or S3 vs. S0) with migraine: OR = 0.78, 95% CI = 0.48-1.28, p = 0.34; MWoA: OR = 0.81, 95% CI = 0.42-1.47, p = 0.51; and MWA: OR = 0.84, 95% CI = 0.43-1.56, p = 0.60, as well as no association of grade S1 CSVD lesions with migraine: OR = 0.91, 95% CI = 0.40-1.92, p = 0.81; MWoA: OR = 1.11, 95% CI = 0.42-2.64, p = 0.81; and MWA: OR = 0.72, 95% CI = 0.20-1.98, p = 0.56. In a retrospective study including almost 650 young adults hospitalized for a first ischemic stroke, MWA was not associated with CSVD cause of stroke after adjustment for vascular risk factors.

Sometimes migraine aura changes from attack to attack, raising the question of whether the change is heralding an ischemic stroke or an unusual aura. Differentiating unusual migraine aura from the onset of an acute ischemic stroke in patients with migraine with aura (MwA) can be challenging. The aim of this cohort study was to assess clinical characteristics that help distinguish between MwA and minor stroke in patients with a previous history of MwA who presented with suspicion of stroke. We interviewed patients with MwA and ischemic stroke (MwA + IS) and patients with MwA and unusual aura, but without ischemic stroke (MwA - IS) from a tertiary hospital using a structured questionnaire. We assessed how symptoms of ischemic stroke or unusual aura differed from usual, that is, the typical aura in each patient. Stroke or exclusion of stroke was verified by multimodal magnetic resonance imaging. Seventeen patients with MwA + IS and twelve patients with MwA - IS were included. New focal neurological symptoms (13/17 [76%] vs. 3/12 [25%]), change of the first symptom (10/17 [59%] vs. 1/12 [8%]), and absence of headache (6/15 [40%] vs. 2/10 [20%]) were more often reported during ischemic stroke. The physical examination was normal in 8/17 (47%) MwA + IS and in 6/12 (50%) MwA - IS patients. In 5/17 (29%) patients with MwA + IS, there were unequivocal physical signs suggestive of stroke such as persistent visual loss, ataxia, or paresis. There are clues from the history that might help identify stroke in patients with MwA with changed aura symptoms. These might be particularly useful in patients presenting without physical findings suggestive of stroke.

Total small vessel disease burden and brain network efficiency in cerebral amyloid angiopathy

Hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA) may contribute to the development of mixed cerebral microbleeds (CMBs). Recently, the total small vessel disease (SVD) scores for HA and CAA were proposed, which are determined by a combination of MRI markers to reflect overall severity of these microangiopathies. We investigated whether or not total HA-SVD and CAA-SVD scores could be used to predict overlap of HA and CAA in patients with mixed CMBs. Fifty-three subjects with mixed CMBs were retrospectively analyzed. MRI markers (CMBs, lacunes, perivascular space, white matter hyperintensity [WMH] and cortical superficial siderosis [cSS]) were assessed. The HA-SVD score and CAA-SVD score were obtained for each subject. Anterior or posterior WMH was also assessed using the age-related white matter changes scale. The two scores were positively correlated (ρ= 0.449, p < 0.001). The prevalence of lobar dominant CMB distribution (p < 0.001) and lacunes in the centrum semiovale (p < 0.001) and the severity of WMH in the parieto-occipital lobes (p = 0.004) were significantly higher in the high CAA-SVD score group. cSS was found in four patients with high CAA-SVD score who showed lobar-dominant CMB distribution and severe posterior WMH. Mixed CMBs are mainly due to HA. Assessing both two scores may predict the overlap of HA and CAA in individuals with mixed CMBs. Patients with a high CAA-SVD score may have some degree of advanced CAA, especially when lobar predominant CMBs, severe posterior WMH, lobar lacunes, or cSS are observed.

IntroductionThe mechanisms subtending the increased stroke risk in migraine with aura (MA) are not fully understood. Our study aims to evaluate if the clinical profile in stroke patients with MA differentiates from those without MA.MethodsWe retrieved the prospective registered electronic clinical dossiers of adult patients younger than 60 years with acute ischemic stroke admitted in four hospitals between January 2016 and June 2022. Patients were classified by the history of MA (MA+ and MA–).ResultsWe identified 851 stroke patients (59 MA+, 6.9%). Compared to MA−, MA+ patients were characterized by younger age (44.0 ± 10.6 vs 50.1 ± 8.2 years), female sex (59.3% vs 29.0%), and affected by cryptogenic (OR 2.594 95% CI 1.483–4.537), and cerebellar stroke (OR 3.218 95% CI 1.657–6.250; p ≤ 0.001 for all comparisons). After adjusting for age and sex, MA+ patients presented less frequently hypertension (OR 0.349 95% CI 0.167–0.470; p=0.005) and dyslipidemia (OR 0.523 95% CI 0.280–0.974; p = 0.041). After adjusting also for risk factors, the MA+ group had less frequently symptomatic large vessel stenosis (OR 0.126 95% CI 0.017–0,924; p = 0.042) and clinical atherosclerosis (OR 0.103 95% CI 0.014–0.761; p = 0.026), while intima–media thickness did not differ (p = 0.395).DiscussionCryptogenic and cerebellar stroke and fewer vascular risk factors and clinical atherosclerosis seem to characterize stroke patients with MA.

Effects of Genetic Variants on Stroke Risk.

Prevalence of ischemic stroke and atrial fibrillation in young patients with migraine national inpatient sample analysis

Cerebral small vessel disease is an important cause for both ischaemic stroke and intracranial haemorrhage. To date, knowledge on the impact of small vessel disease on the clinical course in stroke patients treated with oral anticoagulation for atrial fibrillation is limited. Registry-based prospective observational study of 320 patients (aged 78.2 ± 9.2 years) treated with anticoagulation following atrial fibrillation stroke. Patients underwent standardised magnetic-resonance-imaging assessing measures of small vessel disease, including cerebral microbleeds and white matter hyperintensities. Median follow-up was 754 (interquartile range = [708-828]) days. Using adjusted logistic and Cox regression, we assessed the association of imaging measures with clinical outcome including recurrent ischaemic stroke, intracranial haemorrhage and death and assessed disability (modified Rankin Scale). Overall, recurrent ischaemic stroke was more common than intracranial haemorrhage (22 versus 8, respectively). Cerebral microbleeds were related to an increased risk of the composite endpoint (ischaemic stroke, intracranial haemorrhage, death: odds ratio (OR) 2.05, 95% confidence interval (CI) 1.27-3.31; P = 0.003), as were white matter hyperintensities (OR 2.00, 95%CI 1.23-3.27, P = 0.005). This was also true in time-to-event analysis (cerebral microbleeds: HR 2.31, 95%CI 1.39-3.52; P < 0.001; white matter hyperintensities: HR 1.99, 95%CI 1.20-3.17; P = 0.007). Both measures were associated with an increased risk for recurrent ischaemic stroke (cerebral microbleeds: HR 4.42, 95%CI 1.07-18.20; P = 0.04; white matter hyperintensities: HR 5.27, 95%CI 1.08-25.79, P = 0.04) and intracranial haemorrhage (cerebral microbleeds: HR 2.43, 95%CI 1.04-5.69; P = 0.04; white matter hyperintensities: HR 2.57, 95%CI 1.11-5.98, P = 0.03). Furthermore, confluent white matter hyperintensities were associated with increased disability (OR 4.03; 95%CI 2.16-7.52; P < 0.001) and mortality (HR 1.81, 95%CI 1.04-3.14, P = 0.04). In atrial fibrillation stroke patients treated with oral anticoagulation, small vessel disease is associated with an unfavourable outcome. The presence of microbleeds indicated a risk higher for recurrent ischaemic stroke than for intracranial haemorrhage.

Rho kinase (ROCK) is a well-known downstream effector of Rho and plays an important role in various physiopathological processes. In this study, we aim to investigate the correlation between ROCK and microvascular damage in rat brain subjected to middle cerebral artery occlusion (MCAO) and reperfusion, and to elucidate the mechanisms underlying the microvascular damage. ROCK and matrix metalloproteinase 9 (MMP9) mRNA levels were determined by real time quantitative PCR, Laminin was detected by immunofluorescence and Blood Brain Barrier (BBB) permeability was examined by Evans Blue (EB) in rat MCAO models. We observed similar patterns of changes in ROCK expression, brain EB content, and Laminin expression at different time points after brain ischemia. Statistical analysis further confirmed a significant linear correlation of ROCK expression with the onset of microvascular damage in brain. Furthermore, the ROCK inhibitor fasudil decreased brain EB content but increased Laminin expression. These results provide strong evidence that ROCK mediates microvascular damage. In addition, we found that fasudil could significantly inhibit MMP9 expression induced by ischemia. Thus, our findings suggest that ROCK promotes microvascular damage by upregulating MMP9 and reveal ROCK as a promising therapeutic target for stroke.

Background: Enlarged perivascular spaces (PVS), a marker of cerebral small vessel disease (SVD), are considered to increase the risk of stroke. However, there is limited data on the benfits and harms of antithrombotic agents in patients with PVS. We assessed the association of PVS with the risk of hemorrhagic or ischemic events in patients receiving antithrombotic agents. Methods: This is an investigator-initiated, prospective, multicenter observational study that enrolled patients with cerebrovascular or cardiovascular diseases who were taking oral antithrombotic agents from 52 hospitals across Japan between 2016 and 2019. All participants underwent baseline multimodal MRI. The MRI scans were centrally evaluated for radiologic indicators related to SVD, including white matter hyperintensities (WMH), cerebral microbleeds (CMBs), lacunes, basal ganglia enlarged-perivascular spaces (BGPVS), cortical superficial siderosis, using a visual scale. The outcomes included major bleeding, intracranial hemorrhage, ischemic events, ischemic stroke, and mortality. Results: Of the analyzed 5,250 patients (1,736 women; median age 73 [IQR 66–79] years), antiplatelets and anticoagulants were administered at baseline in 3,948 (75.2%) and 1,565 (29.8%), respectively. During a median 2 (IQR1.8–2.0) years, 278 ischemic events, 197 ischemic strokes, 93 major bleeding, 55 intracranial hemorrhage, and 217 deaths were observed. The distribution of BGPVS was as follows: 0 BGPVS in 475 patients (9.4%), 1-10 BGPVS in 2615 patients (51.6%), and 11+ BGPVS in 1975 patients (39.9%). A higher BGPVS burden was associated with older age, a lower proportion of women, higher rates of hypertension and smoking, lower eGFR values, and a higher prevalence of lacunes, CMBs, and WMH. A higher burden of BGPVS was associated with a higher risk of major bleeding (1–10 BGPVS: adjusted hazard ratio (aHR) 1.49, [95% confidence interval CI 0.76–7.92], 11+ BGPVS: aHR 3.27 [1.09–11.57] versus 0 BGPVS; p trend = 0.035) and ischemic stroke (1–10 BGPVS: aHR 1.79 [0.90–3.57], 11+ BGPVS: aHR 2.39 [1.19–4.81]; p trend = 0.014). In contrast, higher BGPVS burden was not significantly associated with an increased risk of ischemic events, intracranial hemorrhage, or mortality. Conclusions: A higher burden of BGPVS was associated with an increased risk of ischemic stroke and major bleeding in patients taking antithrombotic medication and might be useful in clinical decision making.