Influence of learned landmark correspondences on lung CT registration.

BACKGROUND: Disease or injury may cause a change in the biomechanical properties of the lungs, which can alter lung function. Image registration can be used to measure lung ventilation and quantify volume change, which can be a useful diagnostic aid. However, lung registration is a challenging problem because of the variation in deformation along the lungs, sliding motion of the lungs along the ribs, and change in density. PURPOSE: Landmark correspondences have been used to make deformable image registration robust to large displacements. METHODS: To tackle the challenging task of intra-patient lung computed tomography (CT) registration, we extend the landmark correspondence prediction model deep convolutional neural network-Match by introducing a soft mask loss term to encourage landmark correspondences in specific regions and avoid the use of a mask during inference. To produce realistic deformations to train the landmark correspondence model, we use data-driven synthetic transformations. We study the influence of these learned landmark correspondences on lung CT registration by integrating them into intensity-based registration as a distance-based penalty. RESULTS: Our results on the public thoracic CT dataset COPDgene show that using learned landmark correspondences as a soft constraint can reduce median registration error from approximately 5.46 to 4.08 mm compared to standard intensity-based registration, in the absence of lung masks. CONCLUSIONS: We show that using landmark correspondences results in minor improvements in local alignment, while significantly improving global alignment.

Bayesian modelling disentangles language versus executive control disruption in stroke.

Stroke is the leading cause of long-term disability worldwide. Incurred brain damage can disrupt cognition, often with persisting deficits in language and executive capacities. Yet, despite their clinical relevance, the commonalities and differences between language versus executive control impairments remain under-specified. To fill this gap, we tailored a Bayesian hierarchical modelling solution in a largest-of-its-kind cohort (1080 patients with stroke) to deconvolve language and executive control with respect to the stroke topology. Cognitive function was assessed with a rich neuropsychological test battery including global cognitive function (tested with the Mini-Mental State Exam), language (assessed with a picture naming task), executive speech function (tested with verbal fluency tasks), executive control functions (Trail Making Test and Digit Symbol Coding Task), visuospatial functioning (Rey Complex Figure), as well as verbal learning and memory function (Soul Verbal Learning). Bayesian modelling predicted interindividual differences in eight cognitive outcome scores three months after stroke based on specific tissue lesion topologies. A multivariate factor analysis extracted four distinct cognitive factors that distinguish left- and right-hemispheric contributions to ischaemic tissue lesions. These factors were labelled according to the neuropsychological tests that had the strongest factor loadings: One factor delineated language and general cognitive performance and was mainly associated with damage to left-hemispheric brain regions in the frontal and temporal cortex. A factor for executive control summarized mental flexibility, task switching and visual-constructional abilities. This factor was strongly related to right-hemispheric brain damage of posterior regions in the occipital cortex. The interplay of language and executive control was reflected in two distinct factors that were labelled as executive speech functions and verbal memory. Impairments on both factors were mainly linked to left-hemispheric lesions. These findings shed light onto the causal implications of hemispheric specialization for cognition; and make steps towards subgroup-specific treatment protocols after stroke.

Strategic white matter hyperintensity locations associated with post-stroke cognitive impairment: A multicenter study in 1568 stroke patients.

BACKGROUND: Post-stroke cognitive impairment (PSCI) occurs in up to 50% of stroke survivors. Presence of pre-existing vascular brain injury, in particular the extent of white matter hyperintensities (WMH), is associated with worse cognitive outcome after stroke, but the role of WMH location in this association is unclear. AIMS: We determined if WMH in strategic white matter tracts explain cognitive performance after stroke. METHODS: Individual patient data from nine ischemic stroke cohorts with magnetic resonance imaging (MRI) were harmonized through the Meta VCI Map consortium. The association between WMH volumes in strategic tracts and domain-specific cognitive functioning (attention and executive functioning, information processing speed, language and verbal memory) was assessed using linear mixed models and lasso regression. We used a hypothesis-driven design, primarily addressing four white matter tracts known to be strategic in memory clinic patients: the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus. RESULTS: The total study sample consisted of 1568 patients (39.9% female, mean age = 67.3 years). Total WMH volume was strongly related to cognitive performance on all four cognitive domains. WMH volume in the left anterior thalamic radiation was significantly associated with cognitive performance on attention and executive functioning and information processing speed and WMH volume in the forceps major with information processing speed. The multivariable lasso regression showed that these associations were independent of age, sex, education, and total infarct volume and had larger coefficients than total WMH volume. CONCLUSION: These results show tract-specific relations between WMH volume and cognitive performance after ischemic stroke, independent of total WMH volume. This implies that the concept of strategic lesions in PSCI extends beyond acute infarcts and also involves pre-existing WMH. DATA ACCESS STATEMENT: The Meta VCI Map consortium is dedicated to data sharing, following our guidelines.

Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients.

INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-ß1-42 (Aß42)-positive status. METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume. RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001). DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter. HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aß42 status in 11 memory clinic cohorts. Aß42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.

Graph convolutional networks for automated intracranial artery labeling.

Purpose: Unruptured intracranial aneurysms (UIAs) can cause aneurysmal subarachnoid hemorrhage, a severe and often lethal type of stroke. Automated labeling of intracranial arteries can facilitate the identification of risk factors associated with UIAs. This study aims to improve intracranial artery labeling using atlas-based features in graph convolutional networks. Approach: We included three-dimensional time-of-flight magnetic resonance angiography scans from 150 individuals. Two widely used graph convolutional operators, GCNConv and GraphConv, were employed in models trained to classify 12 bifurcations of interest. Cross-validation was applied to explore the effectiveness of atlas-based features in node classification. The results were tested for statistically significant differences using a Wilcoxon signed-rank test. Model repeatability and calibration were assessed on the test set for both operators. In addition, we evaluated model interpretability and node feature contribution using explainable artificial intelligence. Results: Atlas-based features led to statistically significant improvements in node classification (p<0.05). The results showed that the best discrimination and calibration performances were obtained using the GraphConv operator, which yielded a mean recall of 0.87, precision of 0.90, and expected calibration error of 0.02. Conclusions: The addition of atlas-based features improved node classification results. The GraphConv operator, which incorporates higher-order structural information during training, is recommended over the GCNConv operator based on the accuracy and calibration of predicted outcomes.

NnU-Net versus mesh growing algorithm as a tool for the robust and timely segmentation of neurosurgical 3D images in contrast-enhanced T1 MRI scans.

PURPOSE: This study evaluates the nnU-Net for segmenting brain, skin, tumors, and ventricles in contrast-enhanced T1 (T1CE) images, benchmarking it against an established mesh growing algorithm (MGA). METHODS: We used 67 retrospectively collected annotated single-center T1CE brain scans for training models for brain, skin, tumor, and ventricle segmentation. An additional 32 scans from two centers were used test performance compared to that of the MGA. The performance was measured using the Dice-Sørensen coefficient (DSC), intersection over union (IoU), 95th percentile Hausdorff distance (HD95), and average symmetric surface distance (ASSD) metrics, with time to segment also compared. RESULTS: The nnU-Net models significantly outperformed the MGA (p < 0.0125) with a median brain segmentation DSC of 0.971 [95CI: 0.945-0.979], skin: 0.997 [95CI: 0.984-0.999], tumor: 0.926 [95CI: 0.508-0.968], and ventricles: 0.910 [95CI: 0.812-0.968]. Compared to the MGA's median DSC for brain: 0.936 [95CI: 0.890, 0.958], skin: 0.991 [95CI: 0.964, 0.996], tumor: 0.723 [95CI: 0.000-0.926], and ventricles: 0.856 [95CI: 0.216-0.916]. NnU-Net performance between centers did not significantly differ except for the skin segmentations Additionally, the nnU-Net models were faster (mean: 1139 s [95CI: 685.0-1616]) than the MGA (mean: 2851 s [95CI: 1482-6246]). CONCLUSIONS: The nnU-Net is a fast, reliable tool for creating automatic deep learning-based segmentation pipelines, reducing the need for extensive manual tuning and iteration. The models are able to achieve this performance despite a modestly sized training set. The ability to create high-quality segmentations in a short timespan can prove invaluable in neurosurgical settings.

Three-Dimensional Morphological Change of Intracranial Aneurysms Before and Around Rupture.

BACKGROUND AND OBJECTIVES: Patients with an unruptured intracranial aneurysm often undergo periodic imaging to detect potential aneurysm growth, which is associated with an increased rupture risk. Because prediction of rupture based on growth is moderate, morphological changes have gained interest as a risk factor for rupture. We studied 3-dimensional-quantified morphological changes over time during radiological monitoring before rupture and around rupture. METHODS: In this retrospective observational study, we identified aneurysms that ruptured during follow-up, with imaging available for at least 2 time points before rupture and one after rupture. For each time point, we obtained 8 morphological parameters: 2-dimensional size, volume, surface area, compactness 1 and 2, sphericity, elongation, and flatness. Morphological changes before rupture and around rupture were log-transformed, scaled, and analyzed with linear mixed-effects models. RESULTS: We included 16 aneurysms in 16 patients who were imaged between 2004 and 2021. In the time period before rupture (median follow-up duration 1200 days, IQR 736-1340), 3 size-related morphological parameters increased: 2-dimensional size (estimated mean change 0.44, 95% CI 0.24-0.65), volume (estimated mean change 0.34, 95% CI 0.12-0.56), and surface area (0.33, 95% CI 0.11-0.54). In the period around rupture (median follow-up duration 407 days, IQR 148-719), these parameters further increased. In addition, 5 morphological parameters (compactness 1 and 2, sphericity, elongation, and flatness) decreased around rupture but not before rupture. CONCLUSION: Change in aneurysm volume and surface area may be novel risk factors for rupture. Because most morphological parameters changed around but not before rupture, morphological changes during these 2 periods should be regarded as different processes. This implies that postrupture morphology should not be used as a surrogate for prerupture morphology in rupture prediction models.

Where is VALDO? VAscular Lesions Detection and segmentatiOn challenge at MICCAI 2021.

Imaging markers of cerebral small vessel disease provide valuable information on brain health, but their manual assessment is time-consuming and hampered by substantial intra- and interrater variability. Automated rating may benefit biomedical research, as well as clinical assessment, but diagnostic reliability of existing algorithms is unknown. Here, we present the results of the VAscular Lesions DetectiOn and Segmentation (Where is VALDO?) challenge that was run as a satellite event at the international conference on Medical Image Computing and Computer Aided Intervention (MICCAI) 2021. This challenge aimed to promote the development of methods for automated detection and segmentation of small and sparse imaging markers of cerebral small vessel disease, namely enlarged perivascular spaces (EPVS) (Task 1), cerebral microbleeds (Task 2) and lacunes of presumed vascular origin (Task 3) while leveraging weak and noisy labels. Overall, 12 teams participated in the challenge proposing solutions for one or more tasks (4 for Task 1-EPVS, 9 for Task 2-Microbleeds and 6 for Task 3-Lacunes). Multi-cohort data was used in both training and evaluation. Results showed a large variability in performance both across teams and across tasks, with promising results notably for Task 1-EPVS and Task 2-Microbleeds and not practically useful results yet for Task 3-Lacunes. It also highlighted the performance inconsistency across cases that may deter use at an individual level, while still proving useful at a population level.

Detectability and accuracy of computational measurements of in-silico and physical representations of enlarged perivascular spaces from magnetic resonance images.

BACKGROUND: Magnetic Resonance Imaging (MRI) visible perivascular spaces (PVS) have been associated with age, decline in cognitive abilities, interrupted sleep, and markers of small vessel disease. But the limits of validity of their quantification have not been established. NEW METHOD: We use a purpose-built digital reference object to construct an in-silico phantom for addressing this need, and validate it using a physical phantom. We use cylinders of different sizes as models for PVS. We also evaluate the influence of 'PVS' orientation, and different sets of parameters of the two vesselness filters that have been used for enhancing tubular structures, namely Frangi and RORPO filters, in the measurements' accuracy. RESULTS: PVS measurements in MRI are only a proxy of their true dimensions, as the boundaries of their representation are consistently overestimated. The success in the use of the Frangi filter relies on a careful tuning of several parameters. Alpha= 0.5, beta= 0.5 and c= 500 yielded the best results. RORPO does not have these requirements and allows detecting smaller cylinders in their entirety more consistently in the absence of noise and confounding artefacts. The Frangi filter seems to be best suited for voxel sizes equal or larger than 0.4 mm-isotropic and cylinders larger than 1 mm diameter and 2 mm length. 'PVS' orientation did not affect measurements in data with isotropic voxels. COMPARISON WITH EXISTENT METHODS: Does not apply. CONCLUSIONS: The in-silico and physical phantoms presented are useful for establishing the validity of quantification methods of tubular small structures.

Spatial distributions of white matter hyperintensities on brain MRI: A pooled analysis of individual participant data from 11 memory clinic cohorts.

INTRODUCTION: The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns. METHODS: Individual participant data (N = 3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented. RESULTS: WMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected. DISCUSSION: Aggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered.

White Matter Hyperintensity Volume and Poststroke Cognition: An Individual Patient Data Pooled Analysis of 9 Ischemic Stroke Cohort Studies.

BACKGROUND: White matter hyperintensities (WMH) are associated with cognitive dysfunction after ischemic stroke. Yet, uncertainty remains about affected domains, the role of other preexisting brain injury, and infarct types in the relation between WMH burden and poststroke cognition. We aimed to disentangle these factors in a large sample of patients with ischemic stroke from different cohorts. METHODS: We pooled and harmonized individual patient data (n=1568) from 9 cohorts, through the Meta VCI Map consortium (www.metavcimap.org). Included cohorts comprised patients with available magnetic resonance imaging and multidomain cognitive assessment <15 months poststroke. In this individual patient data meta-analysis, linear mixed models were used to determine the association between WMH volume and domain-specific cognitive functioning (Z scores; attention and executive functioning, processing speed, language and verbal memory) for the total sample and stratified by infarct type. Preexisting brain injury was accounted for in the multivariable models and all analyses were corrected for the study site as a random effect. RESULTS: In the total sample (67 years [SD, 11.5], 40% female), we found a dose-dependent inverse relationship between WMH volume and poststroke cognitive functioning across all 4 cognitive domains (coefficients ranging from -0.09 [SE, 0.04, P=0.01] for verbal memory to -0.19 [SE, 0.03, P<0.001] for attention and executive functioning). This relation was independent of acute infarct volume and the presence of lacunes and old infarcts. In stratified analyses, the relation between WMH volume and domain-specific functioning was also largely independent of infarct type. CONCLUSIONS: In patients with ischemic stroke, increasing WMH volume is independently associated with worse cognitive functioning across all major domains, regardless of old ischemic lesions and infarct type.

Bayesian modeling disentangles language versus executive control disruption in stroke.

Stroke is the leading cause of long-term disability worldwide. Incurred brain damage disrupts cognition, often with persisting deficits in language and executive capacities. Despite their clinical relevance, the commonalities, and differences of language versus executive control impairments remain under-specified. We tailored a Bayesian hierarchical modeling solution in a largest-of-its-kind cohort (1080 stroke patients) to deconvolve language and executive control in the brain substrates of stroke insults. Four cognitive factors distinguished left- and right-hemispheric contributions to ischemic tissue lesion. One factor delineated language and general cognitive performance and was mainly associated with damage to left-hemispheric brain regions in the frontal and temporal cortex. A factor for executive control summarized control and visual-constructional abilities. This factor was strongly related to right-hemispheric brain damage of posterior regions in the occipital cortex. The interplay of language and executive control was reflected in two factors: executive speech functions and verbal memory. Impairments on both were mainly linked to left-hemispheric lesions. These findings shed light onto the causal implications of hemispheric specialization for cognition; and make steps towards subgroup-specific treatment protocols after stroke.

Sex Differences in Poststroke Cognitive Impairment: A Multicenter Study in 2343 Patients With Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment (PSCI) occurs in about half of stroke survivors. Cumulative evidence indicates that functional outcomes of stroke are worse in women than men. Yet it is unknown whether the occurrence and characteristics of PSCI differ between men and women. METHODS: Individual patient data from 9 cohorts of patients with ischemic stroke were harmonized and pooled through the Meta-VCI-Map consortium (n=2343, 38% women). We included patients with visible symptomatic infarcts on computed tomography/magnetic resonance imaging and cognitive assessment within 15 months after stroke. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment. Logistic regression analyses were performed to compare men to women, adjusted for study cohort, to obtain odds ratios for PSCI and individual cognitive domains. We also explored sensitivity and specificity of cognitive screening tools for detecting PSCI, according to sex (Mini-Mental State Examination, 4 cohorts, n=1814; Montreal Cognitive Assessment, 3 cohorts, n=278). RESULTS: PSCI was found in 51% of both women and men. Men had a lower risk of impairment of attention and executive functioning (men: odds ratio, 0.76 [95% CI, 0.61-0.96]), and language (men: odds ratio, 0.67 [95% CI, 0.45-0.85]), but a higher risk of verbal memory impairment (men: odds ratio, 1.43 [95% CI, 1.17-1.75]). The sensitivity of Mini-Mental State Examination (<25) for PSCI was higher for women (0.53) than for men (0.27; P=0.02), with a lower specificity for women (0.80) than men (0.96; P=0.01). Sensitivity and specificity of Montreal Cognitive Assessment (<26.) for PSCI was comparable between women and men (0.91 versus 0.86; P=0.62 and 0.29 versus 0.28; P=0.86, respectively). CONCLUSIONS: Sex was not associated with PSCI occurrence but affected domains differed between men and women. The latter may explain why sensitivity of the Mini-Mental State Examination for detecting PSCI was higher in women with a lower specificity compared with men. These sex differences need to be considered when screening for and diagnosing PSCI in clinical practice.

Geometric Deep Learning Using Vascular Surface Meshes for Modality-Independent Unruptured Intracranial Aneurysm Detection.

Early detection of unruptured intracranial aneurysms (UIAs) enables better rupture risk and preventative treatment assessment. UIAs are usually diagnosed on Time-of-Flight Magnetic Resonance Angiographs (TOF-MRA) or contrast-enhanced Computed Tomography Angiographs (CTA). Various automatic voxel-based deep learning UIA detection methods have been developed, but these are limited to a single modality. We propose a modality-independent UIA detection method using a geometric deep learning model with high resolution surface meshes of brain vessels. A mesh convolutional neural network with ResU-Net style architecture was used. UIA detection performance was investigated with different input and pooling mesh resolutions, and including additional edge input features (shape index and curvedness). Both a higher resolution mesh (15,000 edges) and additional curvature edge features improved performance (average sensitivity: 65.6%, false positive count/image (FPC/image): 1.61). UIAs were detected in an independent TOF-MRA test set and a CTA test set with average sensitivity of 52.0% and 48.3% and average FPC/image of 1.04 and 1.05 respectively. We provide modality-independent UIA detection using a deep-learning vascular surface mesh model with comparable performance to state-of-the-art UIA detection methods.

Implications of quantitative susceptibility mapping at 7 Tesla MRI for microbleeds detection in cerebral small vessel disease.

Background: Cerebral microbleeds (MBs) are a hallmark of cerebral small vessel disease (CSVD) and can be found on T2*-weighted sequences on MRI. Quantitative susceptibility mapping (QSM) is a postprocessing method that also enables MBs identification and furthermore allows to differentiate them from calcifications. Aims: We explored the implications of using QSM at submillimeter resolution for MBs detection in CSVD. Methods: Both 3 and 7 Tesla (T) MRI were performed in elderly participants without MBs and patients with CSVD. MBs were quantified on T2*-weighted imaging and QSM. Differences in the number of MBs were assessed, and subjects were classified in CSVD subgroups or controls both on 3T T2*-weighted imaging and 7T QSM. Results: 48 participants [mean age (SD) 70.9 (8.8) years, 48% females] were included: 31 were healthy controls, 6 probable cerebral amyloid angiopathy (CAA), 9 mixed CSVD, and 2 were hypertensive arteriopathy [HA] patients. After accounting for the higher number of MBs detected at 7T QSM (Median = Mdn; Mdn7T-QSM = 2.5; Mdn3T-T2 = 0; z = 4.90; p < 0.001) and false positive MBs (6.1% calcifications), most healthy controls (80.6%) demonstrated at least one MB and more MBs were discovered in the CSVD group. Conclusions: Our observations suggest that QSM at submillimeter resolution improves the detection of MBs in the elderly human brain. A higher prevalence of MBs than so far known in healthy elderly was revealed.

Disentangling poststroke cognitive deficits and their neuroanatomical correlates through combined multivariable and multioutcome lesion-symptom mapping.

Studies in patients with brain lesions play a fundamental role in unraveling the brain's functional anatomy. Lesion-symptom mapping (LSM) techniques can relate lesion location to cognitive performance. However, a limitation of current LSM approaches is that they can only evaluate one cognitive outcome at a time, without considering interdependencies between different cognitive tests. To overcome this challenge, we implemented canonical correlation analysis (CCA) as combined multivariable and multioutcome LSM approach. We performed a proof-of-concept study on 1075 patients with acute ischemic stroke to explore whether addition of CCA to a multivariable single-outcome LSM approach (support vector regression) could identify infarct locations associated with deficits in three well-defined verbal memory functions (encoding, consolidation, retrieval) based on four verbal memory subscores derived from the Seoul Verbal Learning Test (immediate recall, delayed recall, recognition, learning ability). We evaluated whether CCA could extract cognitive score patterns that matched prior knowledge of these verbal memory functions, and if these patterns could be linked to more specific infarct locations than through single-outcome LSM alone. Two of the canonical modes identified with CCA showed distinct cognitive patterns that matched prior knowledge on encoding and consolidation. In addition, CCA revealed that each canonical mode was linked to a distinct infarct pattern, while with multivariable single-outcome LSM individual verbal memory subscores were associated with largely overlapping patterns. In conclusion, our findings demonstrate that CCA can complement single-outcome LSM techniques to help disentangle cognitive functions and their neuroanatomical correlates.

Strategic Infarct Locations for Poststroke Depressive Symptoms: A Lesion- and Disconnection-Symptom Mapping Study.

BACKGROUND: Depression is the most common neuropsychiatric complication after stroke. Infarct location is associated with poststroke depressive symptoms (PSDS), but it remains debated which brain structures are critically involved. We performed a large-scale lesion-symptom mapping study to identify infarct locations and white matter disconnections associated with PSDS. METHODS: We included 553 patients (mean [SD] age = 69 [11] years, 42% female) with acute ischemic stroke. PSDS were measured using the 30-item Geriatric Depression Scale. Multivariable support vector regression (SVR)-based analyses were performed both at the level of individual voxels (voxel-based lesion-symptom mapping) and at predefined regions of interest to relate infarct location to PSDS. We externally validated our findings in an independent stroke cohort (N = 459). Finally, disconnectome-based analyses were performed using SVR voxel-based lesion-symptom mapping, in which white matter fibers disconnected by the infarct were analyzed instead of the infarct itself. RESULTS: Infarcts in the right amygdala, right hippocampus, and right pallidum were consistently associated with PSDS (permutation-based p < .05) in SVR voxel-based lesion-symptom mapping and SVR region-of-interest analyses. External validation confirmed the association between infarcts in the right amygdala and pallidum, but not the right hippocampus, and PSDS. Disconnectome-based analyses revealed that disconnections in the right parahippocampal white matter, right thalamus and pallidum, and right anterior thalamic radiation were significantly associated (permutation-based p < .05) with PSDS. CONCLUSIONS: Infarcts in the right amygdala and pallidum and disconnections of right limbic and frontal cortico-basal ganglia-thalamic circuits are associated with PSDS. Our findings provide a comprehensive and integrative picture of strategic infarct locations for PSDS and shed new light on pathophysiological mechanisms of depression after stroke.

Strategic white matter hyperintensity locations for cognitive impairment: A multicenter lesion-symptom mapping study in 3525 memory clinic patients.

INTRODUCTION: Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study. METHODS: Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel-based and region of interest tract-based analyses. RESULTS: WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus were significantly related to domain-specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains. DISCUSSION: The data show that the impact of WMH on cognition is location-dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment. HIGHLIGHTS: We analyzed white matter hyperintensities (WMH) in 3525 memory clinic patients from 11 cohorts The impact of WMH on cognition depends on location We identified four strategic white matter tracts A single strategic WMH score was derived from these four strategic tracts The strategic WMH score was an independent determinant of four cognitive domains.

Carotid Artery Stenosis and Progression of Hemispheric Brain Atrophy: The SMART-MR Study.

INTRODUCTION: It has been hypothesized that carotid artery stenosis (CAS) may lead to greater atrophy of subserved brain regions; however, prospective studies on the impact of CAS on progression of hemispheric brain atrophy are lacking. We examined the association between CAS and progression of hemispheric brain atrophy. METHODS: We included 654 patients (57 ± 9 years) of the SMART-MR study, a prospective cohort study of patients with manifest arterial disease. Patients had baseline CAS duplex measurements and a 1.5T brain MRI at baseline and after 4 years of follow-up. Mean change in hemispheric brain volumes (% of intracranial volume [ICV]) was estimated between baseline and follow-up for left-sided and right-sided CAS across three degrees of stenosis (mild [≤29%], moderate [30-69%], and severe [≥70%]), adjusting for demographics, cerebrovascular risk factors, and brain infarcts. RESULTS: Mean decrease in left and right hemispheric brain volumes was 1.15% ICV and 0.82% ICV, respectively, over 4 years of follow-up. Severe right-sided CAS, compared to mild CAS, was associated with a greater decrease in volume of the left hemisphere (B = -0.49% ICV, 95% CI: -0.86 to -0.13) and more profoundly of the right hemisphere (B = -0.90% ICV, 95% CI: -1.27 to -0.54). This pattern was independent of cerebrovascular risk factors, brain infarcts, and white matter hyperintensities on MRI, and was also observed when accounting for the presence of severe bilateral CAS. Increasing degrees of left-sided CAS, however, was not associated with greater volume loss of the left or right hemisphere. CONCLUSIONS: Our data indicate that severe (≥70%) CAS could represent a risk factor for greater ipsilateral brain volume loss, independent of cerebrovascular risk factors, brain infarcts, or white matter hyperintensities on MRI. Further longitudinal studies in other cohorts are warranted to confirm this novel finding.

Brain Deep Medullary Veins on 7T MRI in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND: Deep medullary vein (DMV) changes occur in cerebral small vessel diseases (SVD) and in Alzheimer's disease. Cerebral amyloid angiopathy (CAA) is a common SVD that has a high co-morbidity with Alzheimer's disease. So far, DMVs have not been evaluated in CAA. OBJECTIVE: To evaluate DMVs in Dutch-type hereditary CAA (D-CAA) mutation carriers and controls, in relation to MRI markers associated with D-CAA. METHODS: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density were quantified on 7 Tesla 3D susceptibility weighted MRI in pre-symptomatic D-CAA mutation carriers (n = 8), symptomatic D-CAA mutation carriers (n = 8), and controls (n = 25). Hemorrhagic MRI markers (cerebral microbleeds, intracerebral hemorrhages, cortical superficial siderosis, convexity subarachnoid hemorrhage), non-hemorrhagic MRI markers (white matter hyperintensities, enlarged perivascular spaces, lacunar infarcts, cortical microinfarcts), cortical grey matter perfusion, and diffusion tensor imaging parameters were assessed in D-CAA mutation carriers. Univariate general linear analysis was used to determine associations between DMV parameters and MRI markers. RESULTS: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density did not differ between pre-symptomatic D-CAA mutation carriers, symptomatic D-CAA mutation carriers, and controls. No associations were found between DMV parameters and MRI markers associated with D-CAA. CONCLUSION: This study indicates that vascular amyloid-ß deposition does not affect DMV parameters. In patients with CAA, DMVs do not seem to play a role in the pathogenesis of MRI markers associated with CAA.