Supplementary Material for: Cerebral Microbleeds Are Not Associated with Long-Term Cognitive Outcome in Patients with Transient Ischemic Attack or Minor Stroke

<b><i>Background:</i></b> Cerebral microbleeds have been related to cerebrovascular disease and dementia. They occur more frequently in patients with ischemic stroke than in the general population, but their relation to cognition in these patients is uncertain, particularly in the long run. We examined the relationship between microbleeds in patients with a transient ischemic attack (TIA) or minor ischemic stroke, and cognitive performance 4 years later. <b><i>Methods:</i></b> Participants were recruited from a prospective multicenter cohort of patients with a TIA or minor ischemic stroke (n = 397). They underwent magnetic resonance imaging (MRI), including a T2*-weighted sequence, within 3 months after their ischemic event. Microbleeds, atrophy, lacunae and white matter hyperintensities (WMH) were rated visually. Cognitive status was examined in 94% of all patients who were still alive after a mean interval of 3.8 years by the Dutch version of the Telephone Interview for Cognitive Status (TICS; n = 280) or by an Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) obtained from a close relative if a TICS could not be obtained (n = 48). The relationship between presence of microbleeds and TICS or IQCODE score was assessed with linear regression analyses adjusted for age, sex, educational level and time interval between MRI and cognitive evaluation. <b><i>Results:</i></b> The mean age was 65 ± 12 years at inclusion. The vascular event at inclusion was a TIA in 170 patients (52%) and a minor ischemic stroke in 155 patients (47%). Microbleeds were present in 11.6% of the patients. Patients with microbleeds were significantly older than patients without microbleeds (70 ± 9 vs. 64 ± 12 years), more often had hypertension, and had more cerebral atrophy, WMH and lacunae on MRI (all p < 0.05). The mean TICS score was 35.3 ± 5.9 for patients with microbleeds (n = 29) and 34.6 ± 5.2 for patients without microbleeds (n = 251); the adjusted mean difference (95% CI) was 1.69 (-0.01 to 3.38). The total IQCODE score was 66.0 ± 10.8 for patients with microbleeds (n = 9) and 63.1 ± 12.9 for patients without microbleeds (n = 39); the adjusted mean difference was 2.43 (-7.55 to 12.41). The relative risk (adjusted for age) for abnormal cognitive performance when having microbleeds was 1.19 (95% CI: 0.63-2.26). Subcortical atrophy was associated with lower TICS score [standardized regression coefficient β: -0.12 (-0.23 to 0.00); p = 0.04] and with lower IQCODE score [0.51 (0.19-0.83); p = 0.00]. The adjusted mean difference of IQCODE scores between patients with and those without a lacunar infarct was 0.39 (0.12-0.65; p = 0.01). <b><i>Conclusions:</i></b> In this sample of patients with a recent TIA or minor ischemic stroke, microbleeds were not associated with cognitive performance 4 years later. Apparently, this association is different from other markers of small vessel disease

Supplementary Material for: Diagnostic Accuracy of CT Perfusion Imaging for Detecting Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

<b><i>Background:</i></b> The aim of the current study was to determine the sensitivity and specificity of CT perfusion (CTP) for the detection of ischemic stroke<b> </b>by performing a systematic review and meta-analysis of published reports. <b><i>Methods:</i></b> We searched PubMed, Embase and the Cochrane library using the terms ‘perfusion computed tomography', ‘ischemic stroke' and synonyms. We included studies that: (1) reported original data, (2) studied the diagnostic value of CTP for detecting ischemic stroke, (3) used MRI-DWI, follow-up MRI or follow-up CT as the reference standard, (4) included at least 10 patients who were suspected of ischemic stroke, and (5) reported the number of true positives, true negatives, false positives and false negatives for the diagnosis of ischemic stroke. <b><i>Results:</i></b> Fifteen studies were finally included in the current review with a total of 1,107 patients. A pooled analysis resulted in a sensitivity of 80% (95% confidence interval, CI: 72-86%) and a specificity of 95% (95% CI: 86-98%). Almost two thirds of the false negatives were due to small lacunar infarcts; the remaining false negatives were mostly due to limited coverage. <b><i>Conclusions:</i></b> The current systematic review shows that CTP has a high sensitivity and a very high specificity for detecting infarcts

Supplementary Material for: The relation between vascular risk factors and flow in cerebral perforating arteries. A 7 Tesla MRI study.

Introduction: Cerebral perforating arteries provide blood supply to the deep regions of the brain. Recently, it became possible to measure blood flow velocity and pulsatility in these small arteries. It is unknown if vascular risk factors are related to these measures. Methods: We measured perforating artery flow with 2D phase contrast 7 Tesla MRI at the level of the centrum semiovale (CSO) and the basal ganglia (BG) in seventy participants from the Heart Brain Connection study with carotid occlusive disease (COD), vascular cognitive impairment (VCI), or no actual cerebrovascular disease. Vascular risk factors included hypertension, diabetes, hyperlipidemia and smoking. Results: No consistent relations were found between any of the vascular risk factors and either flow velocity or flow pulsatility, although there was a relation between lower diastolic blood pressure and higher pulse pressure and higher cerebral perforator pulsatility (p=0,045 and p=0,044, respectively) at the BG level. Results were similar in stratified analyses for patients with and without a history of cardiovascular disease, or only COD or VCI. Conclusion: We conclude that, cross-sectionally, cerebral perforating artery flow velocity and pulsatility are largely independent of the presence of common vascular risk factors in a population with a mixed vascular burden

Supplementary Material for: Microstructure of Strategic White Matter Tracts and Cognition in Memory Clinic Patients with Vascular Brain Injury

<b><i>Background:</i></b> White matter injury is an important factor for cognitive impairment in memory clinic patients. We determined the added value of diffusion tensor imaging (DTI) of strategic white matter tracts in explaining variance in cognition in memory clinic patients with vascular brain injury. <b><i>Methods:</i></b> We included 159 patients. Conventional MRI markers (white matter hyperintensity volume, lacunes, nonlacunar infarcts, brain atrophy, and microbleeds), and fractional anisotropy and mean diffusivity (MD) of the whole brain white matter and of 18 white matter tracts were related to cognition using linear regression and Bayesian network analysis. <b><i>Results:</i></b> On top of all conventional MRI markers combined, MD of the whole brain white matter explained an additional 3.4% (<i>p</i> = 0.014), 7.8% (<i>p</i> < 0.001), and 1.2% (<i>p</i> = 0.119) variance in executive functioning, speed, and memory, respectively. The Bayesian analyses of regional DTI measures identified strategic tracts for executive functioning (right superior longitudinal fasciculus), speed (left corticospinal tract), and memory (left uncinate fasciculus). MD within these tracts explained an additional 3.4% (<i>p</i> = 0.012), 3.8% (<i>p</i> = 0.007), and 2.1% (<i>p</i> = 0.041) variance in executive functioning, speed, and memory, respectively, on top of all conventional MRI and global DTI markers combined. <b><i>Conclusion:</i></b> In memory clinic patients with vascular brain injury, DTI of strategic white matter tracts has a significant added value in explaining variance in cognitive functioning

Supplementary Material for: The Missing Link in the Pathophysiology of Vascular Cognitive Impairment: Design of the Heart-Brain Study

<p><b><i>Background:</i></b> Hemodynamic balance in the heart-brain axis is increasingly recognized as a crucial factor in maintaining functional and structural integrity of the brain and thereby cognitive functioning. Patients with heart failure (HF), carotid occlusive disease (COD), and vascular cognitive impairment (VCI) present themselves with complaints attributed to specific parts of the heart-brain axis, but hemodynamic changes often go beyond the part of the axis for which they primarily seek medical advice. The Heart-Brain Study hypothesizes that the hemodynamic status of the heart and the brain is an important but underestimated cause of VCI. We investigate this by studying to what extent hemodynamic changes contribute to VCI and what the mechanisms involved are. Here, we provide an overview of the design and protocol. <b><i>Methods:</i></b> The Heart-Brain Study is a multicenter cohort study with a follow-up measurement after 2 years among 645 participants (175 VCI, 175 COD, 175 HF, and 120 controls). Enrollment criteria are the following: 1 of the 3 diseases diagnosed according to current guidelines, age ≥50 years, no magnetic resonance contraindications, ability to undergo cognitive testing, and independence in daily life. A core clinical dataset is collected including sociodemographic factors, cardiovascular risk factors, detailed neurologic, cardiac, and medical history, medication, and a physical examination. In addition, we perform standardized neuropsychological testing, cardiac, vascular and brain MRI, and blood sampling. In subsets of participants we assess Alz­heimer biomarkers in cerebrospinal fluid, and assess echocardiography and 24-hour blood pressure monitoring. Follow-up measurements after 2 years include neuropsychological testing, brain MRI, and blood samples for all participants. We use centralized state-of-the-art storage platforms for clinical and imaging data. Imaging data are processed centrally with automated standardized pipelines. <b><i>Results and Conclusions:</i></b> The Heart-Brain Study investigates relationships between (cardio-)vascular factors, the hemodynamic status of the heart and the brain, and cognitive impairment. By studying the complete heart-brain axis in patient groups that represent components of this axis, we have the opportunity to assess a combination of clinical and subclinical manifestations of disorders of the heart, vascular system and brain, with hemodynamic status as a possible binding factor.</p

Supplementary Material for: The Prognostic Value of CT Angiography and CT Perfusion in Acute Ischemic Stroke

<br><strong><em>Background:</em></strong> CT angiography (CTA) and CT perfusion (CTP) are important diagnostic tools in acute ischemic stroke. We investigated the prognostic value of CTA and CTP for clinical outcome and determined whether they have additional prognostic value over patient characteristics and non-contrast CT (NCCT). <b><i>Methods:</i></b> We included 1,374 patients with suspected acute ischemic stroke in the prospective multicenter Dutch acute stroke study. Sixty percent of the cohort was used for deriving the predictors and the remaining 40% for validating them. We calculated the predictive values of CTA and CTP predictors for poor clinical outcome (modified Rankin Scale score 3-6). Associations between CTA and CTP predictors and poor clinical outcome were assessed with odds ratios (OR). Multivariable logistic regression models were developed based on patient characteristics and NCCT predictors, and subsequently CTA and CTP predictors were added. The increase in area under the curve (AUC) value was determined to assess the additional prognostic value of CTA and CTP. Model validation was performed by assessing discrimination and calibration. <b><i>Results:</i></b> Poor outcome occurred in 501 patients (36.5%). Each of the evaluated CTA measures strongly predicted outcome in univariable analyses: the positive predictive value (PPV) was 59% for Alberta Stroke Program Early CT Score (ASPECTS) ≤7 on CTA source images (OR 3.3; 95% CI 2.3-4.8), 63% for presence of a proximal intracranial occlusion (OR 5.1; 95% CI 3.7-7.1), 66% for poor leptomeningeal collaterals (OR 4.3; 95% CI 2.8-6.6), and 58% for a >70% carotid or vertebrobasilar stenosis/occlusion (OR 3.2; 95% CI 2.2-4.6). The same applied to the CTP measures, as the PPVs were 65% for ASPECTS ≤7 on cerebral blood volume maps (OR 5.1; 95% CI 3.7-7.2) and 53% for ASPECTS ≤7 on mean transit time maps (OR 3.9; 95% CI 2.9-5.3). The prognostic model based on patient characteristics and NCCT measures was highly predictive for poor clinical outcome (AUC 0.84; 95% CI 0.81-0.86). Adding CTA and CTP predictors to this model did not improve the predictive value (AUC 0.85; 95% CI 0.83-0.88). In the validation cohort, the AUC values were 0.78 (95% CI 0.73-0.82) and 0.79 (95% CI 0.75-0.83), respectively. Calibration of the models was satisfactory. <b><i>Conclusions:</i></b> In patients with suspected acute ischemic stroke, admission CTA and CTP parameters are strong predictors of poor outcome and can be used to predict long-term clinical outcome. In multivariable prediction models, however, their additional prognostic value over patient characteristics and NCCT is limited in an unselected stroke population