BackgroundMigraine, especially with aura (MA), increases the risk of brain white matter hyperintensities (WMH) and ischemic stroke. Altered microvascular function has been proposed as a shared underlying mechanism, potentially involving endothelial dysfunction. Visually-induced hemodynamic response describes the process by which cerebral blood flow is locally increased to meet the metabolic demands of neuronal activity and may serve as a surrogate measure of cerebral endothelial function. We investigated the relationship between visually-induced hemodynamic responseand WMH volume in middle-aged women with ischemic stroke or MA.MethodsWe cross-sectionally measured hemodynamic response using blood-oxygen-level-dependent (BOLD) fMRI upon visual stimulation on 7T-MRI, and WMH volume on 3T-MRI, in three groups of women aged 40-60 with: (I)ischemic stroke, (II)MA, and (III)no history of stroke or migraine. We assessed the associations between BOLD parameters in the posterior circulation (amplitude, time-to-peak [TTP], and time-to-baseline [TTB]) and WMH volume using multivariable linear regression within each group.ResultsWe included 87 women (mean age 51 years): (I)25 with ischemic stroke, (II)25 with MA, and (III)37 without stroke or migraine. Visually-induced hemodynamic response was similar across groups and not associated with WMH volume overall. However, lower amplitude was associated with higher deep WMH volume in those without stroke or migraine (adjusted-β= -0.28;95%CI = -0.53 to -0.02 mL), shorter TTB with greater periventricular WMH volume in women with MA (adjusted-β= -0.12;95%CI = -0.21 to -0.02 mL), and longer TTP with increased periventricular WMH volume in women with stroke (adjusted-β=0.22;95%CI = 0.06 to 0.40 mL).ConclusionsNo overall association was observed between visually-induced hemodynamic response and WMH volume. Exploratory findings suggest potential differences in hemodynamic response in the posterior circulation across groups, which require replication in larger datasets and confirmation in longitudinal studies to clarify their temporal or mechanistic relevance to WMH development.

Abstract Introduction Migraine increases the risk of ischemic stroke and cardiovascular disease in women, potentially due to systemic vascular dysfunction. We investigated whether migraine is associated with increased aortic stiffness and impaired cardiac function as markers of macrovascular dysfunction in middle-aged women with ischemic stroke. Methods This cross-sectional study included three groups of women aged 40–60 years with: (I) ischemic stroke, (II) ischemic stroke with migraine, and (III) no history of stroke or migraine. Aortic stiffness was measured by assessing aortic arch pulse wave velocity (arch PWV) using high-temporal 2D-phase contrast MRI. Cardiac function was evaluated through left ventricular measures, including stroke volume (SV), cardiac output (CO), and ejection fraction (EF), from two orthogonal cine biplane long-axis (2-/4-Chamber) acquisitions. Multivariable linear regression was used to estimate mean differences in arch PWV and left ventricular function, comparing groups 1 and 2 with group 3 as the reference. Results Among 118 included women (mean age 51 years [SD 5]), (I) 44 had ischemic stroke, (II) 44 had both ischemic stroke and migraine, and (III) 30 had no stroke or migraine. In the reference group (group III), mean (SD) values were 6.97 (1.05) m/s for arch PWV, 95.91 (15.82) mL for SV, 6.73 (1.61) L/min for CO, and 64.90 (5.96)% for EF. Comparisons of groups I and II with group III showed no statistically significant mean differences in arch PWV, SV, CO, or EF. Although mean arch PWV was slightly higher in group II (7.11 [1.53] m/s), the adjusted mean difference (-0.03 m/s; 95%CI: -0.60 to 0.54 m/s) was not statistically significant. Small, non-significant reductions in SV, CO, and EF were also observed in the ischemic stroke groups compared with the reference group. Conclusions The increased risk of ischemic stroke in middle-aged women with migraine was not associated with differences in arch PWV or left ventricular function in this cohort. We did not detect evidence that macrovascular dysfunction plays a key role in linking migraine and cardiovascular risk, supporting other studies that point to a potential role for microvascular dysfunction.

BACKGROUND:Migraine increases the risk of ischemic stroke and white matter hyperintensities (WMH), especially in women. Underlying shared mechanisms may include endothelial activation and hypercoagulability. We assessed these markers in middle-aged women with and without migraine and ischemic stroke to explore their role in WMH development. METHODS:We cross-sectionally measured fibrinogen and von Willebrand factor antigen (VWF:Ag) levels as markers of endothelial activation, and factor (F)IX and FXI activity (FXI:C) as markers of hypercoagulability in four groups of women aged 40-60 years with (1)ischemic stroke, (2)migraine, (3)both ischemic stroke and migraine, and (4)no stroke or migraine. Multivariable linear regression estimated mean differences in coagulation factor levels between groups 1 and 3, with group 4 as the reference. RESULTS:Among 166 women (mean age:51 years), (1) 45 had ischemic stroke, (2) 38 had migraine, (3) 48 had both, and (4) 35 had no stroke or migraine. Mean fibrinogen, FIX, and FXI:C levels were similar in all groups compared with group 4. VWF:Ag levels were higher in the ischemic stroke with migraine group (170 [57]%; adjusted β = 31%; 95% CI = 6%-56%) compared with group 4, but not in the other groups. There was no association between coagulation factors and WMH volume in any group. CONCLUSIONS:In women with both stroke and migraine, VWF:Ag levels were increased, while fibrinogen, FIX, and FXI:C were not. This suggests that endothelial activation might be more relevant than a procoagulant state alone in the pathophysiology of ischemic stroke in women with migraine. Coagulation factors did not seem to be related to WMH volume, suggesting other mechanisms may be involved in their development.

BACKGROUND:Both patients with migraine with aura (MA) and patients with ischemic stroke have an increased risk of white matter hyperintensities (WMH) indicating structural microvascular brain damage. It is unclear whether other signs of microvascular damage are also more abundant in these patients, and whether patients with both conditions are more severely affected. METHODS:We included middle-aged women with a history of MA, ischemic stroke, or both, as well as age-matched female control participants without any neurological disease, from two cross-sectional MRI studies (CREW and WHISPER). We assessed WMH, enlarged perivascular spaces, cerebral microbleeds, lacunes, cortical superficial siderosis, parenchymal volume, and cortical atrophy, according to STRIVE criteria. A total small vessel disease (SVD) burden score was determined. We performed regression analyses to assess the association between a history of MA, stroke, or both and the different MRI markers, adjusted for vascular risk factors. RESULTS:We included 207 women (mean age: 51 years): 39 with MA, 67 with stroke, 62 with both MA and stroke, and 39 controls. MA was not associated with increased microvascular damage compared with controls. Stroke patients had more cerebellar WMH (OR = 7.9, 95% CI = 0.9-73.6), more cortical atrophy (β = 0.2, 95% CI = 0.0-0.4), and a lower parenchymal volume (β = -16.1, 95% CI = -30.7 to -1.4) than controls. There was no difference in the frequency of any of the SVD markers on 3 Tesla (3T)-MRI in patients with stroke with or without migraine. CONCLUSION:In our study, markers of microvascular cerebral damage were infrequent in middle-aged women with MA and healthy controls, while stroke was associated with more cerebellar WMH, decreased parenchymal volume, and cortical atrophy. We found no (supra-)additive effect of a history of migraine on the extent of microvascular brain damage in women with stroke.

Women with migraine, especially with aura (MA), have a higher risk of white matter hyperintensities (WMH) and ischemic stroke. We aimed to assess differences in stroke etiology between women with and without migraine and the impact of migraine on WMH volume in women with stroke. We included women aged 40–60 years with a history of ischemic stroke, migraine or both. Stroke etiology was categorized using the TOAST criteria. WMH volume was measured using 3D-FLAIR images. Presence or absence of cerebellar WMH was scored. We used regression analysis to assess differences between groups, with adjustments for age, BMI, hypertension and smoking status. We included 55 women with stroke, 55 with stroke and migraine, and 38 with MA. Women with stroke more often had a history of smoking than those with stroke and migraine (74

Introduction: Migraine symptoms are postulated to improve post-stroke. We aimed to determine post-stroke changes in patients with active migraine pre-stroke and explored the relation with stroke location and stroke-preventive medication use. Methods: Patients with active migraine who had an ischemic stroke were retrieved from three research-cohorts between 2014 and 2021. By an interview, we retrospectively investigated first-year post-stroke changes for those ischemic stroke patients that suffered from migraine pre-stroke. Associations between change in migraine frequency/intensity/aura (decrease, no change, increase), stroke location (posterior location vs. other), and use of secondary stroke preventive medication were assessed by ordinal regression with adjustment for confounders. Results: We included 78 patients (mean age 48 years, 86% women, 47% with aura). Change in migraine symptomatology was reported by 63 (81%) patients; 51 (81%) noticed a decrease in attack frequency (27 no attacks) and 12 (19%) an increase. Pain intensity change was reported by 18 (35%) patients (50% increase, 50% decrease). Aura symptomatology improved in 4 (11%). Reduced attack frequency was not related to posterior stroke (OR = 1.5, 95% CI: 0.6–3.9), or preventive medication (antiplatelets OR = 1.0, 95% CI: 0.2–3.7; coumarin OR = 2.7, 95% CI: 0.4–20.6). Conclusions: Most patients with active pre-stroke migraine experience improvement of their symptoms in the first year after ischemic stroke. This change does not seem to be related to secondary stroke preventive medication or posterior stroke location.

BACKGROUND: The temporal ordering of biomarkers for cerebral amyloid angiopathy (CAA) is important for their use in trials and for the understanding of the pathological cascade of CAA. We investigated the presence and abnormality of the most common biomarkers in the largest (pre)symptomatic Dutch-type hereditary CAA (D-CAA) cohort to date. METHODS: We included cross-sectional data from participants with (pre)symptomatic D-CAA and controls without CAA. We investigated CAA-related cerebral small vessel disease markers on 3T-MRI, cerebrovascular reactivity with functional 7T-MRI (fMRI) and amyloid-β 40 and amyloid-β 42 levels in cerebrospinal fluid. We calculated frequencies and plotted biomarker abnormality according to age to form scatterplots. RESULTS: We included 68 participants with D-CAA (59% presymptomatic, mean age, 50 [range, 26–75] years; 53% women), 53 controls (mean age, 51 years; 42% women) for cerebrospinal fluid analysis and 36 controls (mean age, 53 years; 100% women) for fMRI analysis. Decreased cerebrospinal fluid amyloid-β 40 and amyloid-β 42 levels were the earliest biomarkers present: all D-CAA participants had lower levels of amyloid-β 40 and amyloid-β 42 compared with controls (youngest participant 30 years). Markers of nonhemorrhagic injury (>20 enlarged perivascular spaces in the centrum semiovale and white matter hyperintensities Fazekas score, ≥2, present in 83% [n=54]) and markers of impaired cerebrovascular reactivity (abnormal BOLD amplitude, time to peak and time to baseline, present in 56% [n=38]) were present from the age of 30 years. Finally, markers of hemorrhagic injury were present in 64% (n=41) and only appeared after the age of 41 years (first microbleeds and macrobleeds followed by cortical superficial siderosis). CONCLUSIONS: Our results suggest that amyloid biomarkers in cerebrospinal fluid are the first to become abnormal in CAA, followed by MRI biomarkers for cerebrovascular reactivity and nonhemorrhagic injury and lastly hemorrhagic injury. This temporal ordering probably reflects the pathological stages of CAA and should be taken into account when future therapeutic trials targeting specific stages are designed.

Childhood adversity (CA), including childhood adverse life events, increases the risk for development of psychiatric disorders later in life. Both CA and psychiatric disorders are associated with structural brain changes and dysfunctional hypothalamic-pituitary-adrenal-axis. However, many studies investigated single diagnostic and single regions of interest of the brain, and did not take stress reactivity into account. We investigated associations of CA and cortisol levels with gray matter volume and cortical thickness, in a whole-brain manner. Primary analysis constituted of a transdiagnostic approach, followed by a moderation analysis to investigate the influence of diagnosis. Patients with stress-related and/or neurodevelopmental disorders and matched healthy controls underwent an magnetic resonance imaging scan, next to assessing hair cortisol levels and CA/life events. CA was reported by 62-72% of the patients versus 33% of the controls. Primary transdiagnostic linear regression analyses revealed that CA was not associated with gray matter volume, while childhood life events were associated with lower right thalamic volume. Hair cortisol was not associated with any lobe volume. None of the associations were moderated by diagnosis. In conclusion, CA is a risk factor that needs to be taken into account when investigating psychiatric disorders. Yet the relationship with structural brain changes and stress reactivity is less clear than postulated on the basis of more seed-based studies.

Background: We observed subarachnoid cerebrospinal fluid (CSF) hyperintensities at non-contrast 7-tesla (T) fluid-attenuated inversion recovery (FLAIR) MRI, frequently topographically associated with cortical superficial siderosis (cSS), in participants with cerebral amyloid angiopathy (CAA). To systemically evaluate these CSF hyperintensities we investigated their frequency and anatomical and temporal relationship with cSS on 7T and 3T MRI in hereditary Dutch-type CAA (D-CAA), sporadic CAA (sCAA), and non-CAA controls. Methods: CAA participants were included from two prospective natural history studies and non-CAA controls from a 7T study in healthy females and females with ischemic stroke. CSF hyperintensities were scored by two independent observers. Results: We included 38 sCAA participants (mean age 72y), 50 D-CAA participants (mean age 50y) and 44 nonCAA controls (mean age 53y, 15 with stroke). In total 27/38 (71 %, 95 %CI 56-84) sCAA and 23/50 (46 %, 95 % CI 33-60) D-CAA participants had subarachnoid CSF hyperintensities at baseline 7T. Most (96 %) of those had cSS, in 54 % there was complete topographical overlap with cSS. The remaining 46 % had & GE;1 sulcus with CSF hyperintensities without co-localizing cSS. None of the healthy controls and 2/15 (13 %, 95 %CI 2-41, 100 % cSS overlap) of the stroke controls had CSF hyperintensities. In 85 % of the CAA participants CSF hyperintensities could retrospectively be identified at 3T. Of the 35 CAA participants with follow-up 7T after two years, 17/35 (49 %) showed increase and 6/35 (17 %) decrease of regional CSF hyperintensities. In 2/11 (18 %) of participants with follow-up who had baseline CSF hyperintensities without overlapping cSS, new cSS developed at those locations. Conclusions: Subarachnoid CSF hyperintensities at 7T FLAIR MRI occur frequently in CAA and are associated with cSS, although without complete overlap. We hypothesize that the phenomenon could be a sign of subtle plasma protein or blood product leakage into the CSF, resulting in CSF T1-shortening.

Early life stress (ELS) alters the excitation-inhibition-balance (EI-balance) in various rodent brain areas and may be responsible for behavioral impairment later in life. The EI-balance is (amongst others) influenced by the switch of GABAergic transmission from excitatory to inhibitory, the so-called "GABA-switch". Here, we investigated how ELS affects the GABA-switch in mouse infralimbic Prefrontal Cortex layer 2/3 neurons, using the limited-nesting-and-bedding model. In ELS mice, the GABA-switch occurred already between postnatal day (P) 6 and P9, as opposed to P15-P21 in controls. This was associated with increased expression of the inward chloride transporter NKCC1, compared to the outward chloride transporter KCC2, both of which are important for the intracellular chloride concentration and, hence, the GABA reversal potential (Erev). Chloride transporters are not only important for regulating chloride concentration postsynaptically, but also presynaptically. Depending on the Erev of GABA, presynaptic GABAA receptor stimulation causes a depolarization or hyperpolarization, and thereby enhanced or reduced fusion of glutamate vesicles respectively, in turn changing the frequency of miniature postsynaptic currents (mEPSCs). In accordance, bumetanide, a blocker of NKCC1, shifted the Erev GABA towards more hyperpolarized levels in P9 control mice and reduced the mEPSC frequency. Other modulators of chloride transporters, e.g. VU0463271 (a KCC2 antagonist) and aldosterone -which increases NKCC1 expression-did not affect postsynaptic Erev in ELS P9 mice, but did increase the mEPSC frequency. We conclude that the mouse GABA-switch is accelerated after ELS, affecting both the pre- and postsynaptic chloride homeostasis, the former altering glutamatergic transmission. This may considerably affect brain development.

Background: Women are more affected by stroke than men. This might, in part, be explained by sex differences in stroke pathophysiology. The hemostasis system is influenced by sex hormones and associated with female risk factors for stroke, such as migraine. Aim: To systematically review possible sex differences in hemostatic related factors in patients with ischemic stroke in general, and the influence of migraine on these factors in women with ischemic stroke. Results: We included 24 studies with data on sex differences of hemostatic factors in 7247 patients with ischemic stroke (mean age 57–72 years, 27–57% women) and 25 hemostatic related factors. Levels of several factors were higher in women compared with men; FVII:C (116% ± 30% vs. 104% ± 30%), FXI (0.14 UI/mL higher in women), PAI-1 (125.35 ± 49.37 vs. 96.67 ± 38.90 ng/mL), D-dimer (1.25 ± 0.31 vs. 0.95 ± 0.24 μg/mL), and aPS (18.7% vs. 12.0% positive). In contrast, protein-S (86.2% ± 23.0% vs. 104.7% ± 19.8% antigen) and P-selectin (48.9 ± 14.4 vs. 79.1 ± 66.7 pg/mL) were higher in men. Most factors were investigated in single studies, at different time points after stroke, and in different stroke subtypes. Only one small study reported data on migraine and hemostatic factors in women with ischemic stroke. No differences in fibrinogen, D-dimer, t-PA, and PAI-1 levels were found between women with and without migraine. Conclusion: Our systematic review suggests that sex differences exist in the activation of the hemostatic system in ischemic stroke. Women seem to lean more toward increased levels of procoagulant factors whereas men exhibit increased levels of coagulation inhibitors. To obtain better insight in sex-related differences in hemostatic factors, additional studies are needed to confirm these findings with special attention for different stroke phases, stroke subtypes, and not in the least women specific risk factors, such as migraine.

Background and Purpose: Women have worse outcomes than men after stroke. Differences in presentation may lead to misdiagnosis and, in part, explain these disparities. We investigated whether there are sex differences in clinical presentation of acute stroke or transient ischemic attack. Methods: We conducted a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Inclusion criteria were (1) cohort, cross-sectional, case-control, or randomized controlled trial design; (2) admission for (suspicion of) ischemic or hemorrhagic stroke or transient ischemic attack; and (3) comparisons possible between sexes in >= 1 nonfocal or focal acute stroke symptom(s). A random-effects model was used for our analyses. We performed sensitivity and subanalyses to help explain heterogeneity and used the Newcastle-Ottawa Scale to assess bias. Results: We included 60 studies (n=582 844; 50% women). In women, headache (pooled odds ratio [OR], 1.24 [95% CI, 1.11-1.39]; I-2=75.2%; 30 studies) occurred more frequently than in men with any type of stroke, as well as changes in consciousness/mental status (OR, 1.38 [95% CI, 1.19-1.61]; I-2=95.0%; 17 studies) and coma/stupor (OR, 1.39 [95% CI, 1.25-1.55]; I-2=27.0%; 13 studies). Aspecific or other neurological symptoms (nonrotatory dizziness and non-neurological symptoms) occurred less frequently in women (OR, 0.96 [95% CI, 0.94-0.97]; I-2=0.1%; 5 studies). Overall, the presence of focal symptoms was not associated with sex (pooled OR, 1.03) although dysarthria (OR, 1.14 [95% CI, 1.04-1.24]; I-2=48.6%; 11 studies) and vertigo (OR, 1.23 [95% CI, 1.13-1.34]; I-2=44.0%; 8 studies) occurred more frequently, whereas symptoms of paresis/hemiparesis (OR, 0.73 [95% CI, 0.54-0.97]; I-2=72.6%; 7 studies) and focal visual disturbances (OR, 0.83 [95% CI, 0.70-0.99]; I-2=62.8%; 16 studies) occurred less frequently in women compared with men with any type of stroke. Most studies contained possible sources of bias. Conclusions: There may be substantive differences in nonfocal and focal stroke symptoms between men and women presenting with acute stroke or transient ischemic attack, but sufficiently high-quality studies are lacking. More studies are needed to address this because sex differences in presentation may lead to misdiagnosis and undertreatment.

In this study we tested the hypothesis i) that age-dependent shifts in the excitation-inhibition balance of prefrontal neurons are accelerated by early life stress, a risk factor for the etiology of many psychiatric disorders; and if so, ii) that this process is exacerbated by genetic forebrain-specific downregulation of the mineralocorticoid receptor, a receptor that was earlier found to be a protective factor for negative effects of early life stress in both rodents and humans. In agreement with the literature, an age-dependent downregulation of the excitation-inhibition balance was found both with regard to spontaneous and evoked synaptic currents. The age-dependent shift in spontaneous excitatory relative to inhibitory currents was significantly accelerated by early life stress, but this was not exacerbated by reduction in mineralocorticoid receptor expression. The age-dependent changes in the excitation-inhibition balance were mirrored by similar changes in receptor subunit expression and morphological alterations, particularly in spine density, which could thus potentially contribute to the functional changes. However, none of these parameters displayed acceleration by early life stress, nor depended on mineralocorticoid receptor expression. We conclude that, in agreement with the hypothesis, early life stress accelerates the developmental shift of the excitation-inhibition balance but, contrary to expectation, there is no evidence for a putative protective role of the mineralocorticoid receptor in this system. In view of the modest effect of early life stress on the excitation-inhibition balance, alternative mechanisms potentially underlying the development of psychiatric disorders should be further explored.