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. AIM: We determined if WMH in strategic white matter tracts explain cognitive performance after stroke. METHODS: Individual patient data from 9 ischemic stroke cohorts with 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. CONCLUSIONS: 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 AVAILABILITY: The Meta VCI Map consortium is dedicated to data sharing, following our guidelines.

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.

Assessment of aortic and cerebral haemodynamics and vascular brain injury with 3 and 7†T magnetic resonance imaging in patients with aortic coarctation.

Aims: Coarctation of the aorta (CoA) is characterized by a central arteriopathy resulting in increased arterial stiffness. The condition is associated with an increased risk of stroke. We aimed to assess the aortic and cerebral haemodynamics and the presence of vascular brain injury in patients with previous surgical CoA repair. Methods and results: Twenty-seven patients with CoA (median age 22 years, range 12-72) and 25 age- and sex-matched controls (median age 24 years, range 12-64) underwent 3 T (heart, aorta, and brain) and 7 T (brain) magnetic resonance imaging scans. Haemodynamic parameters were measured using two-dimensional phase-contrast images of the ascending and descending aorta, internal carotid artery (ICA), basilar artery (BA), middle cerebral artery (MCA), and perforating arteries. Vascular brain injury was assessed by rating white matter hyperintensities, cortical microinfarcts, lacunes, and microbleeds. Pulse wave velocities in the aortic arch and descending aorta were increased and ascending aortic distensibility was decreased in patients with CoA vs. controls. Patients with CoA showed a higher mean flow velocity in the right ICA, left ICA, and BA and a reduced distensibility in the right ICA, BA, and left MCA. Haemodynamic parameters in the perforating arteries, total cerebral blood flow, intracranial volumes, and vascular brain injury were similar between the groups. Conclusion: Patients with CoA show an increased flow velocity and reduced distensibility in the aorta and proximal cerebral arteries, which suggests the presence of a generalized arteriopathy that extends into the cerebral arterial tree. No substantial vascular brain injury was observed in this relatively young CoA population, although the study was inadequately powered regarding this endpoint.

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.

Network impact score is an independent predictor of post-stroke cognitive impairment: A multicenter cohort study in 2341 patients with acute ischemic stroke.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a common consequence of stroke. Accurate prediction of PSCI risk is challenging. The recently developed network impact score, which integrates information on infarct location and size with brain network topology, may improve PSCI risk prediction. AIMS: To determine if the network impact score is an independent predictor of PSCI, and of cognitive recovery or decline. METHODS: We pooled data from patients with acute ischemic stroke from 12 cohorts through the Meta VCI Map consortium. PSCI was defined as impairment in ≥ 1 cognitive domain on neuropsychological examination, or abnormal Montreal Cognitive Assessment. Cognitive recovery was defined as conversion from PSCI < 3 months post-stroke to no PSCI at follow-up, and cognitive decline as conversion from no PSCI to PSCI. The network impact score was related to serial measures of PSCI using Generalized Estimating Equations (GEE) models, and to PSCI stratified according to post-stroke interval (<3, 3-12, 12-24, >24 months) and cognitive recovery or decline using logistic regression. Models were adjusted for age, sex, education, prior stroke, infarct volume, and study site. RESULTS: We included 2341 patients with 4657 cognitive assessments. PSCI was present in 398/844 patients (47%) <3 months, 709/1640 (43%) at 3-12 months, 243/853 (28%) at 12-24 months, and 208/522 (40%) >24 months. Cognitive recovery occurred in 64/181 (35%) patients and cognitive decline in 26/287 (9%). The network impact score predicted PSCI in the univariable (OR 1.50, 95%CI 1.34-1.68) and multivariable (OR 1.27, 95%CI 1.10-1.46) GEE model, with similar ORs in the logistic regression models for specified post-stroke intervals. The network impact score was not associated with cognitive recovery or decline. CONCLUSIONS: The network impact score is an independent predictor of PSCI. As such, the network impact score may contribute to a more precise and individualized cognitive prognostication in patients with ischemic stroke. Future studies should address if multimodal prediction models, combining the network impact score with demographics, clinical characteristics and other advanced brain imaging biomarkers, will provide accurate individualized prediction of PSCI. A tool for calculating the network impact score is freely available at https://metavcimap.org/features/software-tools/lsm-viewer/.

Anatomy of phonemic and semantic fluency: A lesion and disconnectome study in 1231 stroke patients.

Disturbances of semantic and phonemic fluency are common after brain damage, as a manifestation of language, executive, or memory dysfunction. Lesion-symptom mapping (LSM) studies can provide fundamental insights in shared and distinct anatomical correlates of these cognitive functions and help to understand which patients suffer from these deficits. We performed a multivariate support vector regression-based lesion-symptom mapping and structural disconnection study on semantic and phonemic fluency in 1231 patients with acute ischemic stroke. With the largest-ever LSM study on verbal fluency we achieved almost complete brain lesion coverage. Lower performance on both fluency types was related to left hemispheric frontotemporal and parietal cortical regions, and subcortical regions centering on the left thalamus. Distinct correlates for phonemic fluency were the anterior divisions of middle and inferior frontal gyri. Distinct correlates for semantic fluency were the posterior regions of the middle and inferior temporal gyri, parahippocampal and fusiform gyri and triangular part of the inferior frontal gyrus. The disconnectome-based analyses additionally revealed phonemic fluency was associated with a more extensive frontoparietal white matter network, whereas semantic fluency was associated with disconnection of the fornix, mesiotemporal white matter, splenium of the corpus callosum. These results provide the most detailed outline of the anatomical correlates of phonemic and semantic fluency to date, stress the crucial role of subcortical regions and reveal a novel dissociation in the left temporal lobe.

Generative lesion pattern decomposition of cognitive impairment after stroke.

Cognitive impairment is a frequent and disabling sequela of stroke. There is however incomplete understanding of how lesion topographies in the left and right cerebral hemisphere brain interact to cause distinct cognitive deficits. We integrated machine learning and Bayesian hierarchical modelling to enable a hemisphere-aware analysis of 1080 acute ischaemic stroke patients with deep profiling ∼3 months after stroke. We show the relevance of the left hemisphere in the prediction of language and memory assessments and relevance of the right hemisphere in the prediction of visuospatial functioning. Global cognitive impairments were equally well predicted by lesion topographies from both sides. Damage to the hippocampal and occipital regions on the left was particularly informative about lost naming and memory functions, while damage to these regions on the right was linked to lost visuospatial functioning. Global cognitive impairment was predominantly linked to lesioned tissue in the supramarginal and angular gyrus, the post-central gyrus as well as the lateral occipital and opercular cortices of the left hemisphere. Hence, our analysis strategy uncovered that lesion patterns with unique hemispheric distributions are characteristic of how cognitive capacity is lost due to ischaemic brain tissue damage.

Strategic infarct locations for post-stroke cognitive impairment: a pooled analysis of individual patient data from 12 acute ischaemic stroke cohorts.

BACKGROUND: Post-stroke cognitive impairment (PSCI) occurs in approximately half of people in the first year after stroke. Infarct location is a potential determinant of PSCI, but a comprehensive map of strategic infarct locations predictive of PSCI is unavailable. We aimed to identify infarct locations most strongly predictive of PSCI after acute ischaemic stroke and use this information to develop a prediction model. METHODS: In this large-scale multicohort lesion-symptom mapping study, we pooled and harmonised individual patient data from 12 cohorts through the Meta-analyses on Strategic Lesion Locations for Vascular Cognitive Impairment using Lesion-Symptom Mapping (Meta VCI Map) consortium. The identified cohorts (as of Jan 1, 2019) comprised patients with acute symptomatic infarcts on CT or MRI (with available infarct segmentations) and a cognitive assessment up to 15 months after acute ischaemic stroke onset. PSCI was defined as performance lower than the fifth percentile of local normative data, on at least one cognitive domain on a multidomain neuropsychological assessment or on the Montreal Cognitive Assessment. Voxel-based lesion-symptom mapping (VLSM) was used to calculate voxel-wise odds ratios (ORs) for PSCI that were mapped onto a three-dimensional brain template to visualise PSCI risk per location. For the prediction model of PSCI risk, a location impact score on a 5-point scale was derived from the VLSM results on the basis of the mean voxel-wise coefficient (ln[OR]) within each patient's infarct. We did combined internal-external validation by leave-one-cohort-out cross-validation for all 12 cohorts using logistic regression. Predictive performance of a univariable model with only the location impact score was compared with a multivariable model with addition of other clinical PSCI predictors (age, sex, education, time interval between stroke onset and cognitive assessment, history of stroke, and total infarct volume). Testing of visual ratings was done by three clinicians, and accuracy, inter-rater reliability, and intra-rater reliability were assessed with Cohen's weighted kappa. FINDINGS: In our sample of 2950 patients (mean age 66·8 years [SD 11·6]; 1157 [39·2%] women), 1286 (43·6%) had PSCI. We achieved high lesion coverage of the brain in our analyses (86·9%). Infarcts in the left frontotemporal lobes, left thalamus, and right parietal lobe were strongly associated with PSCI (after false discovery rate correction, q<0·01; voxel-wise ORs >20). On cross-validation, the location impact score showed good correspondence, based on visual assessment of goodness of fit, between predicted and observed risk of PSCI across cohorts after adjusting for cohort-specific PSCI occurrence. Cross-validations showed that the location impact score by itself had similar performance to the combined model with other PSCI predictors, while allowing for easy visual assessment. Therefore the univariable model with only the location impact score was selected as the final model. Correspondence between visual ratings and actual location impact score (Cohen's weighted kappa: range 0·88-0·92), inter-rater agreement (0·85-0·87), and intra-rater agreement (for a single rater, 0·95) were all high. INTERPRETATION: To the best of our knowledge, this study provides the first comprehensive map of strategic infarct locations associated with risk of PSCI. A location impact score was derived from this map that robustly predicted PSCI across cohorts. Furthermore, we developed a quick and reliable visual rating scale that might in the future be applied by clinicians to identify individual patients at risk of PSCI. FUNDING: The Netherlands Organisation for Health Research and Development.

Post-stroke cognitive impairment on the Mini-Mental State Examination primarily relates to left middle cerebral artery infarcts.

BACKGROUND: Post-stroke cognitive impairment can occur after damage to various brain regions, and cognitive deficits depend on infarct location. The Mini-Mental State Examination (MMSE) is still widely used to assess post-stroke cognition, but it has been criticized for capturing only certain cognitive deficits. Along these lines, it might be hypothesized that cognitive deficits as measured with the MMSE primarily involve certain infarct locations. AIMS: This comprehensive lesion-symptom mapping study aimed to determine which acute infarct locations are associated with post-stroke cognitive impairment on the MMSE. METHODS: We examined associations between impairment on the MMSE (<5th percentile; normative data) and infarct location in 1198 patients (age 67 ± 12 years, 43% female) with acute ischemic stroke using voxel-based lesion-symptom mapping. As a frame of reference, infarct patterns associated with impairments in individual cognitive domains were determined, based on a more detailed neuropsychological assessment. RESULTS: Impairment on the MMSE was present in 420 patients (35%). Large voxel clusters in the left middle cerebral artery territory and thalamus were significantly (p < 0.01) associated with cognitive impairment on the MMSE, with highest odds ratios (>15) in the thalamus and superior temporal gyrus. In comparison, domain-specific impairments were related to various infarct patterns across both hemispheres including the left medial temporal lobe (verbal memory) and right parietal lobe (visuospatial functioning). CONCLUSIONS: Our findings indicate that post-stroke cognitive impairment on the MMSE primarily relates to infarct locations in the left middle cerebral artery territory. The MMSE is apparently less sensitive to cognitive deficits that specifically relate to other locations.

Patient-specific fine-tuning of convolutional neural networks for follow-up lesion quantification.

Purpose: Convolutional neural network (CNN) methods have been proposed to quantify lesions in medical imaging. Commonly, more than one imaging examination is available for a patient, but the serial information in these images often remains unused. CNN-based methods have the potential to extract valuable information from previously acquired imaging to better quantify lesions on current imaging of the same patient. Approach: A pretrained CNN can be updated with a patient's previously acquired imaging: patient-specific fine-tuning (FT). In this work, we studied the improvement in performance of lesion quantification methods on magnetic resonance images after FT compared to a pretrained base CNN. We applied the method to two different approaches: the detection of liver metastases and the segmentation of brain white matter hyperintensities (WMH). Results: The patient-specific fine-tuned CNN has a better performance than the base CNN. For the liver metastases, the median true positive rate increases from 0.67 to 0.85. For the WMH segmentation, the mean Dice similarity coefficient increases from 0.82 to 0.87. Conclusions: We showed that patient-specific FT has the potential to improve the lesion quantification performance of general CNNs by exploiting a patient's previously acquired imaging.

A Case of Sporadic Cerebral Small Vessel Disease in an Identical Twin.

Sporadic cerebral small vessel disease (cSVD) is primarily attributed to heritability and vascular risk factors. Still, our understanding of the causative factors in cSVD lesion burden in the brain is far from complete. This is exemplified by this case of identical twins with remarkably similar vascular risk profiles, where one twin had developed severe cSVD on neuroimaging with cognitive deficits, while the other twin had no cSVD. This case highlights the need to search for further causes of cSVD, also beyond genetic and conventional vascular risk factors. Identification of other potential risk factors or disease mechanisms should be a priority for cSVD research to improve our understanding, prevention and treatment of this common cause of vascular brain injury with major clinical consequences.

Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients.

INTRODUCTION: Microstructural alterations as assessed by diffusion tensor imaging (DTI) are key findings in both Alzheimer's disease (AD) and small vessel disease (SVD). We determined the contribution of each of these conditions to diffusion alterations. METHODS: We studied six samples (N = 365 participants) covering the spectrum of AD and SVD, including genetically defined samples. We calculated diffusion measures from DTI and free water imaging. Simple linear, multivariable random forest, and voxel-based regressions were used to evaluate associations between AD biomarkers (amyloid beta, tau), SVD imaging markers, and diffusion measures. RESULTS: SVD markers were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analysis across all memory clinic samples. Voxel-wise analyses between tau and diffusion measures were not significant. DISCUSSION: In memory clinic patients, the effect of SVD on diffusion alterations largely exceeds the effect of AD, supporting the value of diffusion measures as markers of SVD.

Extent to Which Network Hubs Are Affected by Ischemic Stroke Predicts Cognitive Recovery.

Background and Purpose- It is uncertain what determines the potential for cognitive recovery after ischemic stroke. The extent to which strategic areas of the brain network, so-called hubs, are affected by the infarct could be a key factor. We developed a lesion impact score, which estimates the damage to network hubs by integrating information on infarct size with healthy brain network topology. We verified whether the lesion impact score indeed reflects global network disturbances in patients and assessed if it could predict cognitive recovery. Methods- Seventy-five ischemic stroke patients without signs of a prestroke cognitive disorder were included, all with evidence of a cognitive disorder during hospitalization. A brain magnetic resonance imaging and neuropsychological assessment were performed 5 weeks (±1 week) after stroke. Neuropsychological testing was repeated after 1 year to assess cognitive recovery. Brain networks were reconstructed from diffusion-weighted data and consisted of 90 gray matter regions (ie, network nodes). A standard brain network map, indicating the hub-score of each node, was obtained from network data of 44 cognitively healthy adults. For each patient, we calculated the lesion impact score by multiplying the percentage of node volume affected by the infarct with the node's corresponding hub-score. The patients' maximum lesion impact score was used as outcome predictor. Results- A higher lesion impact score in patients, indicating an increasing infarct size in nodes with a higher hub-score, was related to lower global brain network efficiency (ß=-0.528 [-0.776 to -0.277]; P<0.001), independent of age, brain volume, infarct volume, and white matter hyperintensity severity. A lower lesion impact score, however, was an independent predictor of cognitive recovery 1 year after stroke (odds ratio=0.434 [0.193-0.978]; P=0.044). Conclusions- We introduced a lesion impact score that combines information on infarct size and network topology to predict long-term recovery after stroke. This score can potentially be used in a clinical setting, also without availability of high-resolution diffusion-weighted magnetic resonance imaging.

Brain Infarct Segmentation and Registration on MRI or CT for Lesion-symptom Mapping.

In lesion-symptom mapping (LSM), brain function is inferred by relating the location of acquired brain lesions to behavioral or cognitive symptoms in a group of patients. With recent advances in brain imaging and image processing, LSM has become a popular tool in cognitive neuroscience. LSM can provide fundamental insights into the functional architecture of the human brain for a variety of cognitive and non-cognitive functions. A crucial step in performing LSM studies is the segmentation of lesions on brains scans of a large group of patients and registration of each scan to a common stereotaxic space (also called standard space or a standardized brain template). Described here is an open-access, standardized method for infarct segmentation and registration for the purpose of LSM, as well as a detailed and hands-on walkthrough based on exemplary cases. A comprehensive tutorial for the manual segmentation of brain infarcts on CT scans and DWI or FLAIR MRI sequences is provided, including criteria for infarct identification and pitfalls for different scan types. The registration software provides multiple registration schemes that can be used for processing of CT and MRI data with heterogeneous acquisition parameters. A tutorial on using this registration software and performing visual quality checks and manual corrections (which are needed in some cases) is provided. This approach provides researchers with a framework for the entire process of brain image processing required to perform an LSM study, from gathering of the data to final quality checks of the results.

Cerebral amyloid burden is associated with white matter hyperintensity location in specific posterior white matter regions.

White matter hyperintensities (WMHs) are a common manifestation of cerebral small vessel disease. WMHs are also frequently observed in patients with familial and sporadic Alzheimer's disease, often with a particular posterior predominance. Whether amyloid and tau pathologies are linked to WMH occurrence is still debated. We examined whether cerebral amyloid and tau burden, reflected in cerebrospinal fluid amyloid-beta 1-42 (Aß-42) and phosphorylated tau (p-tau), are related to WMH location in a cohort of 517 memory clinic patients. Two lesion mapping techniques were performed: voxel-based analyses and region of interest-based linear regression. Voxelwise associations were found between lower Aß-42 and parieto-occipital periventricular WMHs. Regression analyses demonstrated that lower Aß-42 correlated with larger WMH volumes in the splenium of the corpus callosum and posterior thalamic radiation, also after controlling for markers of vascular disease. P-tau was not consistently related to WMH occurrence. Our findings indicate that cerebral amyloid burden is associated with WMHs located in specific posterior white matter regions, possibly reflecting region-specific effects of amyloid pathology on the white matter.

Trans-saccadic memory after right parietal brain damage.

INTRODUCTION: Spatial remapping, the process of updating information across eye movements, is an important mechanism for trans-saccadic perception. The right posterior parietal cortex (PPC) is a region that has been associated most strongly with spatial remapping. The aim of the project was to investigate the effect of damage to the right PPC on direction specific trans-saccadic memory. We compared trans-saccadic memory performance for central items that had to be remembered while making a left- versus rightward eye movement, or for items that were remapped within the left versus right visual field. METHODS: We included 9 stroke patients with unilateral right PPC lesions and 31 healthy control subjects. Participants memorized the location of a briefly presented item, had to make one saccade (either towards the left or right, or upward or downward), and subsequently had to decide in what direction the probe had shifted. We used a staircase to adjust task difficulty (i.e., the distance between the memory item and probe). Bayesian repeated measures ANOVAs were used to compare left versus right eye movements and items in the left versus right visual field. RESULTS: In both conditions, patients with right PPC damage showed worse trans-saccadic memory performance compared to healthy control subjects (for the condition with left- and rightward gaze shifts, BF10 = 3.79; and when items were presented left or right, BF10 = 6.77), regardless of the direction of the gaze or the initial location of the memory item. At the individual level, none of the patients showed a direction specific deficit after leftward versus rightward saccades, whereas two patients showed worse performance for items in the left versus right visual field. CONCLUSION: Damage in the right PPC did not lead to gaze direction specific impairments in trans-saccadic memory, but instead caused more general spatial memory impairments.