Random expert sampling for deep learning segmentation of acute ischemic stroke on non-contrast CT.

BACKGROUND: Outlining acutely infarcted tissue on non-contrast CT is a challenging task for which human inter-reader agreement is limited. We explored two different methods for training a supervised deep learning algorithm: one that used a segmentation defined by majority vote among experts and another that trained randomly on separate individual expert segmentations. METHODS: The data set consisted of 260 non-contrast CT studies in 233 patients with acute ischemic stroke recruited from the multicenter DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trial. Additional external validation was performed using 33 patients with matched stroke onset times from the University Hospital Lausanne. A benchmark U-Net was trained on the reference annotations of three experienced neuroradiologists to segment ischemic brain tissue using majority vote and random expert sampling training schemes. The median of volume, overlap, and distance segmentation metrics were determined for agreement in lesion segmentations between (1) three experts, (2) the majority model and each expert, and (3) the random model and each expert. The two sided Wilcoxon signed rank test was used to compare performances (1) to 2) and (1) to (3). We further compared volumes with the 24 hour follow-up diffusion weighted imaging (DWI, final infarct core) and correlations with clinical outcome (modified Rankin Scale (mRS) at 90 days) with the Spearman method. RESULTS: The random model outperformed the inter-expert agreement ((1) to (2)) and the majority model ((1) to (3)) (dice 0.51±0.04 vs 0.36±0.05 (P<0.0001) vs 0.45±0.05 (P<0.0001)). The random model predicted volume correlated with clinical outcome (0.19, P<0.05), whereas the median expert volume and majority model volume did not. There was no significant difference when comparing the volume correlations between random model, median expert volume, and majority model to 24 hour follow-up DWI volume (P>0.05, n=51). CONCLUSION: The random model for ischemic injury delineation on non-contrast CT surpassed the inter-expert agreement ((1) to (2)) and the performance of the majority model ((1) to (3)). We showed that the random model volumetric measures of the model were consistent with 24 hour follow-up DWI.

Semiautomated Detection of Early Infarct Signs on Noncontrast CT Improves Interrater Agreement.

BACKGROUND: Acute ischemic infarct identification on noncontrast computed tomography (NCCT) is highly variable between raters. A semiautomated method for segmentation of acute ischemic lesions on NCCT may improve interrater reliability. METHODS: Patients with successful endovascular reperfusion from the DEFUSE 3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) were included. We created relative NCCT (rNCCT) color-gradient overlays by comparing the density of a voxel on NCCT to the homologous region in the contralateral hemisphere. Regions with a relative hypodensity of at least 5% were visualized. We coregistered baseline and follow-up images. Two neuroradiologists and 6 nonradiologists segmented the acute ischemic lesion on the baseline scans with 2 methods: (1) manually outlining hypodense regions on the NCCT (unassisted segmentation) and (2) manually excluding areas deemed outside of the ischemic lesion on the rNCCT color map (rNCCT-assisted segmentation). Voxelwise interrater agreement was quantified using the Dice similarity coefficient and volumetric agreement between raters with the detection index (DI), defined as the true positive volume minus the false positive volume. RESULTS: From a total of 92, we included 61 patients. Median age was 59 (64-77), and 57% were female. Stroke onset was known in 39%. Onset to NCCT was median, 8.5 hours (7-11) and median 10 hours (8.4-11.5) in patients with known and unknown onset, respectively. Compared with unassisted NCCT segmentation, rNCCT-assisted segmentation increased the Dice similarity coefficient by >50% for neuroradiologists (Dice similarity coefficient, 0.38 versus 0.83; P<0.001) and nonradiologists (Dice similarity coefficient, 0.14 versus 0.84; P<0.001), and improved the DI among nonradiologists (mean improvement, 5.8 mL [95% CI, 3.1-8.5] mL, P<0.001) but not among neuroradiologists. CONCLUSIONS: The high variability of manual segmentations of the acute ischemic lesion on NCCT is greatly reduced using semiautomated rNCCT. The rNCCT map may therefore aid acute infarct detection and provide more reliable infarct estimates for clinicians with less experience.

USE-Evaluator: Performance metrics for medical image segmentation models supervised by uncertain, small or empty reference annotations in neuroimaging.

Performance metrics for medical image segmentation models are used to measure the agreement between the reference annotation and the predicted segmentation. Usually, overlap metrics, such as the Dice, are used as a metric to evaluate the performance of these models in order for results to be comparable. However, there is a mismatch between the distributions of cases and the difficulty level of segmentation tasks in public data sets compared to clinical practice. Common metrics used to assess performance fail to capture the impact of this mismatch, particularly when dealing with datasets in clinical settings that involve challenging segmentation tasks, pathologies with low signal, and reference annotations that are uncertain, small, or empty. Limitations of common metrics may result in ineffective machine learning research in designing and optimizing models. To effectively evaluate the clinical value of such models, it is essential to consider factors such as the uncertainty associated with reference annotations, the ability to accurately measure performance regardless of the size of the reference annotation volume, and the classification of cases where reference annotations are empty. We study how uncertain, small, and empty reference annotations influence the value of metrics on a stroke in-house data set regardless of the model. We examine metrics behavior on the predictions of a standard deep learning framework in order to identify suitable metrics in such a setting. We compare our results to the BRATS 2019 and Spinal Cord public data sets. We show how uncertain, small, or empty reference annotations require a rethinking of the evaluation. The evaluation code was released to encourage further analysis of this topic https://github.com/SophieOstmeier/UncertainSmallEmpty.git.

Non-inferiority of deep learning ischemic stroke segmentation on non-contrast CT within 16-hours compared to expert neuroradiologists.

We determined if a convolutional neural network (CNN) deep learning model can accurately segment acute ischemic changes on non-contrast CT compared to neuroradiologists. Non-contrast CT (NCCT) examinations from 232 acute ischemic stroke patients who were enrolled in the DEFUSE 3 trial were included in this study. Three experienced neuroradiologists independently segmented hypodensity that reflected the ischemic core on each scan. The neuroradiologist with the most experience (expert A) served as the ground truth for deep learning model training. Two additional neuroradiologists' (experts B and C) segmentations were used for data testing. The 232 studies were randomly split into training and test sets. The training set was further randomly divided into 5 folds with training and validation sets. A 3-dimensional CNN architecture was trained and optimized to predict the segmentations of expert A from NCCT. The performance of the model was assessed using a set of volume, overlap, and distance metrics using non-inferiority thresholds of 20%, 3 ml, and 3 mm, respectively. The optimized model trained on expert A was compared to test experts B and C. We used a one-sided Wilcoxon signed-rank test to test for the non-inferiority of the model-expert compared to the inter-expert agreement. The final model performance for the ischemic core segmentation task reached a performance of 0.46 ± 0.09 Surface Dice at Tolerance 5mm and 0.47 ± 0.13 Dice when trained on expert A. Compared to the two test neuroradiologists the model-expert agreement was non-inferior to the inter-expert agreement, [Formula: see text]. The before, CNN accurately delineates the hypodense ischemic core on NCCT in acute ischemic stroke patients with an accuracy comparable to neuroradiologists.

A Narrative Review of the Neurological Manifestations of Human Adenosine Deaminase 2 Deficiency.

Deficiency of human adenosine deaminase type 2 (DADA2) is a complex systemic autoinflammatory disorder characterized by vasculopathy, immune dysregulation, and hematologic abnormalities. The most notable neurological manifestations of DADA2 are strokes that can manifest with various neurological symptoms and are potentially fatal. However, neurological presentations can be diverse. We here present a review of the neurological manifestations of DADA2 to increase clinical awareness of DADA2 as the underlying diagnosis. We reviewed all published cases of DADA2 from 1 January 2014 until 19 July 2022 found via PubMed. A total of 129 articles describing the clinical features of DADA2 were included in the analysis. Six hundred twenty-eight patients diagnosed with DADA2 were included in the review. 50.3% of patients had at least signs of one reported neurological event, which was the initial or sole manifestation in 5.7% and 0.6%, respectively. 77.5% of patients with neurological manifestations had at least signs of one cerebrovascular accident, with lacunar strokes being the most common and 35.9% of them having multiple stroke episodes. There is a remarkable predilection for the brain stem and deep gray matter, with 37.3% and 41.6% of ischemic strokes, respectively. Other neurological involvement included neuropathies, focal neurological deficits, ophthalmological findings, convulsions, and headaches. In summary, neurological manifestations affect a significant proportion of patients with DADA2, and the phenotype is broad. Neurological manifestations can be the first and single manifestation of DADA2. Therefore, stroke, encephalitis, posterior reversible encephalopathy syndrome, mononeuropathy and polyneuropathy, and Behçet's disease-like presentations should prompt the neurologist to exclude DADA2, especially but not only in childhood.

Microhemorrhages in MELAS Lesions: A Case Report.

Introduction: Microhemorrhages have not been described in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome (MELAS) on magnetic resonance imaging (MRI). Main symptoms and/or important findings: A MELAS-patient had a rapid succession of 3 stroke-like episodes with dysphasia, visual field deficits and paresis of the right arm. MRI showed a lesion with corticosubcortical vasogenic edema without reduced diffusion, conforming to a stroke-like MELAS-lesion. Microhemorrhages within MELAS-lesions were detected on MRI. The main diagnoses, therapeutic interventions, and outcomes: Microhemorrhages are an atypical imaging finding in MELAS. The patient was treated with L-arginine. Conclusion: Microhemorrhages can present on MRI in (sub)acute MELAS lesions and may reflect mitochondrial microangiopathy.

Child Neurology: Familial Hemophagocytic Lymphohistiocytosis Underlying Isolated CNS Inflammation.

Encephalitis and encephalopathy in children represent a diagnostic challenge. We describe a patient with relapsing encephalitis in whom the differential diagnosis included acute disseminated encephalomyelitis, human herpesvirus 6 encephalitis, and hemophagocytic lymphohistiocytosis (HLH). Because of its rarity, HLH is often overlooked as a differential diagnosis in encephalitis, especially in the isolated CNS forms. As this case illustrates, inborn errors of immunity can underlie isolated encephalitis and should be included in the differential diagnosis of these presentations.

Evaluation of Sarcopenia in Older Patients Undergoing Head and Neck Cancer Surgery.

OBJECTIVES/HYPOTHESIS: Sarcopenia is a hallmark of aging and its identification may help predict adverse postoperative events in patients undergoing head and neck surgery. The study objective was to assess the relationship between sarcopenia and postoperative complications and length of stay in patients undergoing major head and neck cancer surgery. STUDY DESIGN: Prospective cohort study. METHODS: A prospective cohort study was performed of patients 50 years and older undergoing major head and neck surgery. Sarcopenia was defined as low muscle mass (determined by neck muscle cross-sectional imaging) with either low muscle strength (grip strength) or low muscle performance (timed walk test). Logistic regression was applied on binary outcomes, and linear regression was used for log-transformed length of hospital stay (LOS). Univariate and multivariate analyses were performed. RESULTS: Of the 251 patients enrolled, pre-sarcopenia was present in 34.9% (n = 87) and sarcopenia in 15.6% (n = 39) of patients. Patients with sarcopenia were more likely to be older (P = .001), female (P = .001), have a lower body mass index (P = .001), and lower preoperative hemoglobin (P < .001). On univariate analysis, the presence and severity of sarcopenia was associated with the development of medical complications (P = .029), higher grade of complications (P = .032), LOS (P = .015), and overall survival (P = .001). On multivariate analysis, sarcopenia was associated with a longer LOS (ß = 0.32 [95% CI: 0.19-0.45], P < .001) and worse overall survival (HR = 2.21 [95% CI: 1.01-4.23], P = .017). CONCLUSIONS: Sarcopenia may aid in the prediction of prolonged hospital stay and death in patients who are candidates for major head and neck surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:356-363, 2022.

Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats.

Dementia is a major social and economic problem for our aging population. One of the most common of dementia in the elderly is cerebral small vessel disease (SVD). Magnetic resonance scans of SVD patients typically show white matter abnormalities, but we do not understand the mechanistic pathological link between blood vessels and white matter myelin damage. Hypertension is suggested as the cause of sporadic SVD, but a recent alternative hypothesis invokes dysfunction of the blood-brain barrier as the primary cause. In a rat model of SVD, we show that endothelial cell (EC) dysfunction is the first change in development of the disease. Dysfunctional ECs secrete heat shock protein 90α, which blocks oligodendroglial differentiation, contributing to impaired myelination. Treatment with EC-stabilizing drugs reversed these EC and oligodendroglial pathologies in the rat model. EC and oligodendroglial dysfunction were also observed in humans with early, asymptomatic SVD pathology. We identified a loss-of-function mutation in ATPase11B, which caused the EC dysfunction in the rat SVD model, and a single-nucleotide polymorphism in ATPase11B that was associated with white matter abnormalities in humans with SVD. We show that EC dysfunction is a cause of SVD white matter vulnerability and provide a therapeutic strategy to treat and reverse SVD in the rat model, which may also be of relevance to human SVD.

Markers of cerebral small vessel disease and severity of depression in the general population.

The vascular depression hypothesis postulates that cerebral small vessel disease can cause or exacerbate depression in elderly persons. Numerous studies explored the association of imaging markers of cerebral small vessel disease including white matter lesions (WMLs) and lacunar infarcts with depressive symptoms or disorders. However, cerebral microbleeds have not been tested in depression. In the current study, we aimed to explore the association of WMLs, lacunar infarcts and cerebral microbleeds with depression continuum in a large population-based sample, the Rotterdam Study. Study population consisted of 3799 participants (aged 45 or over) free of dementia. WML volumes, lacunar infarcts and cerebral microbleeds were measured with brain magnetic resonance imaging. Depressive symptoms, depressive disorders and co-morbid anxiety disorders were assessed with validated questionnaires and clinical interview. WML volumes and lacunar infarcts were associated with depressive symptoms and disorders. Cerebral microbleeds, especially in deep or infratentorial brain regions, were related to depressive disorders only. Our results indicate that WMLs and lacunar infarcts might be non-specific vascular lesions seen in depressive symptoms and disorders. Association of cerebral microbleeds with more severe forms of depression may indicate impaired brain iron homeostasis or minor episodes of cerebrovascular extraversion, which may play a role in depression etiology.

Prevalence, Clinical Management, and Natural Course of Incidental Findings on Brain MR Images: The Population-based Rotterdam Scan Study.

Purpose To present an updated prevalence estimate for incidental findings on brain magnetic resonance (MR) images and provide information on clinical relevance, including natural course, over a period of up to 9 years. Materials and Methods This study was approved by the institutional review board and all participants gave informed consent. In a prospective population-based setting, structural brain MR imaging was performed in 5800 participants (mean age, 64.9 years; 3194 women [55.1%]). Trained reviewers recorded abnormalities, which were subsequently evaluated by neuroradiologists. The prevalence with 95% confidence interval (CI) of incidental findings was determined, and clinical management of findings that required the attention of a medical specialist was followed. Follow-up imaging in the study context provided information on the natural course of findings that were not referred. Results In 549 of 5800 participants (9.5% [95% CI: 8.7%, 10.3%]), incidental findings were found, of which meningiomas (143 of 5800; 2.5% [95% CI: 2.1%, 2.9%]) and cerebral aneurysms (134 of 5800; 2.3% [95% CI: 2.0%, 2.7%]) were most common. A total of 188 participants were referred to medical specialists for incidental findings (3.2% [95% CI: 2.8%, 3.7%]). Of these, 144 (76.6% [95% CI: 70.1%, 82.1%]) either underwent a wait-and-see policy or were discharged after the initial clinical visit. The majority of meningiomas and virtually all aneurysms not referred or referred but untreated remained stable in size during follow-up. Conclusion Incidental findings at brain MR imaging that necessitate further diagnostic evaluation occur in over 3% of the general middle-aged and elderly population, but are mostly without direct clinical consequences. © RSNA, 2016.

White Matter Lesion Progression: Genome-Wide Search for Genetic Influences.

BACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden. CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

Small cortical infarcts: prevalence, determinants, and cognitive correlates in the general population.

BACKGROUND: Cortical brain infarcts are defined as infarcts involving cortical gray matter, but may differ considerably in size. It is unknown whether small cortical infarcts have a similar clinical phenotype as larger counterparts. We investigated prevalence, determinants, and cognitive correlates of small cortical infarcts in the general population and compared these with large cortical infarcts and lacunar infarcts. METHODS: Four thousand nine hundred five nondemented individuals (age 63·95 ± 10·99) from a population-based study were included. Infarcts were rated on magnetic resonance imaging and participants were classified according to mean infarct diameter into small (≤15 mm in largest diameter) or large (>15 mm) cortical infarcts, lacunar infarcts, or a combination of subtypes. Spatial distribution maps were created for manually labeled small and large infarcts. Participants underwent cognitive testing. Analyses were performed using multinomial regression and analysis of covariance. RESULTS: Three hundred eighty-one (7·8%) persons had any infarct on magnetic resonance imaging, among whom 54 with small (1·1%) and 77 (1·6%) with large cortical infarcts. Small cortical infarcts were mainly localized in external watershed areas, whereas large cortical infarcts were localized primarily in large arterial territories. Age (odds ratio = 1·06; 95% confidence interval = 1·02, 1·09), male gender (1·98; 1·01, 3·92), and smoking (2·55; 1·06, 6·14) were determinants of small cortical infarcts. Participants with these infarcts had worse scores in delayed memory, processing speed, and attention tests than persons without infarcts, even after adjustment for cardiovascular risk factors. CONCLUSIONS: In the elderly, small cortical infarcts appear as frequent as large infarcts but in different localization. Our results suggest that small cortical infarcts share cardiovascular risk factors and cognitive correlates with large cortical, but also with lacunar infarcts.

Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.

BACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium.

BACKGROUND: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk. METHODS AND RESULTS: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026). CONCLUSION: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.

TMEM106B influences volume of left-sided temporal lobe and interhemispheric structures in the general population.

BACKGROUND: Frontotemporal lobar degeneration is a neurodegenerative disease characterized by brain atrophy of the frontal and anterior temporal lobes. The associated frontotemporal dementia syndromes are clinically heterogeneous, and the pattern of affected cortical regions varies among subtypes. The TMEM106B rs1990622 polymorphism is associated with frontotemporal lobar degeneration, but little is known about how it affects the brain. METHODS: We investigated the rs1990622 polymorphism in relation to regional brain volumes to identify potential structures through which TMEM106B confers risk for frontotemporal lobar degeneration. In 4413 nondemented and stroke-free participants from the population-based Rotterdam Study, 150 cortical brain structures and 6 commissural regions were segmented from magnetic resonance imaging. RESULTS: A distinct pattern of association was found between rs1990622 and gray matter volume of left-sided temporal brain regions important for language processing, including the superior temporal gyrus (ß=-88.8 µL per risk allele, p=7.64×10(-5)), which contains Wernicke's area. The risk allele was also associated with a smaller anterior commissure cross-sectional area (ß=-.167 mm2 per risk allele, p=4.90×10(-5)) and posterior part of the corpus callosum (ß=-15.3 µL per risk allele, p=1.23×10(-5)), both of which contain temporal lobe commissural tracts. CONCLUSIONS: The asymmetric, predominantly left-sided involvement suggests an effect of TMEM106B on functions lateralized to the dominant hemisphere, such as language. These results show that, in nondemented persons, TMEM106B influences the volume of temporal brain regions that are important for language processing.

Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies.

BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts. METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification. CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.

Rating method for dilated Virchow-Robin spaces on magnetic resonance imaging.

BACKGROUND AND PURPOSE: Dilated Virchow-Robin spaces are an emerging neuroimaging biomarker, but their assessment on MRI needs standardization. METHODS: We developed a rating method for dilated Virchow-Robin spaces in 4 brain regions (centrum semiovale, basal ganglia, hippocampus, and mesencephalon) and tested its reliability in a total of 125 MRI scans from 2 population-based studies. Six investigators with varying levels of experience performed the ratings. Intraclass correlation coefficients were calculated to determine intra- and interrater reliability. RESULTS: Intrarater reliability was excellent for all 4 regions (intraclass correlation coefficient, >0.8). Interrater reliability was excellent for the centrum semiovale and hippocampus (intraclass correlation coefficient, >0.8) and good for the basal ganglia and mesencephalon (intraclass correlation coefficient, 0.6-0.8). This did not differ between the cohorts or experience levels. CONCLUSIONS: We describe a reliable rating method that can facilitate pathogenic and prognostic research on dilated Virchow-Robin spaces using MRI.

The relation of uric acid to brain atrophy and cognition: the Rotterdam Scan Study.

BACKGROUND: Uric acid has been associated with focal vascular brain disease. However, it is unknown whether uric acid also relates to global brain changes such as brain atrophy. We therefore studied the relation of uric acid to brain atrophy and whether this is accompanied by worse cognitive function. METHODS: In 814 persons of the population-based Rotterdam Study (mean age 62.0 years), we studied the relation of uric acid levels to brain tissue atrophy and cognition using linear regression models adjusted for age, sex and putative confounders. Brain atrophy was assessed using automated processing of magnetic resonance imaging. Cognition was assessed using a validated neuropsychological test battery and we computed compound scores of cognitive domains. RESULTS: Higher uric acid levels were associated with white matter atrophy [difference in Z-score of white matter volume per standard deviation increase in uric acid: -0.07 (95% CI: -0.12; -0.01)], but not with gray matter atrophy. This was particularly marked when comparing hyperuricemic to normouricemic persons [Z-score difference: -0.27 (-0.43; -0.11)]. Worse cognition was primarily found in persons with hyperuricemia [-0.28 (-0.48; -0.08)]. CONCLUSIONS: Hyperuricemia is related to white matter atrophy and worse cognition.

High blood pressure and cerebral white matter lesion progression in the general population.

High blood pressure is considered an important risk factor for cerebral white matter lesions (WMLs) in the aging population. In a longitudinal population-based study of 665 nondemented persons, we investigated the longitudinal relationship of systolic blood pressure, diastolic blood pressure, and pulse pressure with annual progression of WMLs. Means of blood pressure were calculated over a 5-year period before longitudinal MRI scanning. WML progression was subsequently measured on 2 scans 3.5 years apart. We performed analyses with linear regression models and evaluated adjustments for age, sex, cardiovascular risk factors, and baseline WML volume. In addition, we evaluated whether treatment of hypertension is related to less WML progression. Both systolic and diastolic blood pressures were significantly associated with annual WML progression (regression coefficient [95% confidence interval], 0.08 [0.03; 0.14] mL/y and 0.09 [0.03; 0.15] mL/y per SD increase in systolic and diastolic blood pressure, respectively). Pulse pressure was also significantly associated with WML progression, but not independent from hypertension. After adjustment for baseline WML volume, only systolic blood pressure remained significantly associated: 0.05 (0.00; 0.09) mL/y per SD increase. People with uncontrolled untreated hypertension had significantly more WML progression than people with uncontrolled treated hypertension (difference [95% confidence interval], 0.12 [0.00; 0.23] mL/y). The present study further establishes high blood pressure to precede WMLs and implies that hypertension treatment could reduce WML progression in the general population.