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Background: Knowledge about factors that are associated with post-stroke cognitive outcome is important to identify patients with high risk for impairment. We therefore investigated the associations of white matter integrity and functional connectivity (FC) within the brain's default-mode network (DMN) in acute stroke patients with cognitive outcome three months post-stroke., Methods: Patients aged between 18 and 85 years with an acute symptomatic MRI-proven unilateral ischemic middle cerebral artery infarction, who had received reperfusion therapy, were invited to participate in this longitudinal study. All patients underwent brain MRI within 24-72 h after symptom onset, and participated in a neuropsychological assessment three months post-stroke. We performed hierarchical regression analyses to explore the incremental value of baseline white matter integrity and FC beyond demographic, clinical, and macrostructural information for cognitive outcome., Results: The study cohort comprised 34 patients (mean age: 64 ± 12 years, 35% female). The initial median National Institutes of Health Stroke Scale (NIHSS) score was 10, and significantly improved three months post-stroke to a median NIHSS = 1 (p < .001). Nonetheless, 50% of patients showed cognitive impairment three months post-stroke. FC of the non-lesioned anterior cingulate cortex of the affected hemisphere explained 15% of incremental variance for processing speed (p = .007), and fractional anisotropy of the non-lesioned cingulum of the affected hemisphere explained 13% of incremental variance for cognitive flexibility (p = .033)., Conclusions: White matter integrity and functional MRI markers of the DMN in acute stroke explain incremental variance for post-stroke cognitive outcome beyond demographic, clinical, and macrostructural information., Competing Interests: Declaration of competing interest The authors declare no financial or other conflicts of interest that relate to the research covered in this article., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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-β 1-42 (Aβ42)-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 Aβ42 status in 11 memory clinic cohorts. Aβ42 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., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Cerebral white matter hyperintensities (WMH) have been associated with subclinical atherosclerosis including coronary artery calcification (CAC). However, previous studies on this association are limited by only cross-sectional analysis. We aimed to explore the relationship between WMH and CAC in elderly individuals both cross-sectionally and longitudinally. The study population consisted of elderly stroke- and dementia-free participants from the community-based Austrian Stroke Prevention Family Study (ASPFS). WMH volume and CAC levels (via Agatston score) were analyzed at baseline and after a 6-year follow-up period. Of 324 study participants (median age: 68 years), 115 underwent follow-up. Baseline WMH volume (median: 4.1 cm 3 ) positively correlated with baseline CAC levels in multivariable analysis correcting for common vascular risk factors (p = 0.010). While baseline CAC levels were not predictive for WMH progression (p = 0.447), baseline WMH volume was associated CAC progression (median Agatston score progression: 27) in multivariable analysis (ß = 66.3 ± 22.3 [per cm 3 ], p = 0.004). Ten of 11 participants (91%) with severe WMH (Fazekas Scale: 3) at baseline showed significant CAC progression > 100 during follow-up. In this community-based cohort of elderly individuals, WMH were associated with CAC and predictive of its progression over a 6-year follow-up. Screening for coronary artery disease might be considered in people with more severe WMH., (© 2024. The Author(s).)

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., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FB is supported by the NIHR biomedical research center at UCLH. MD received honoraria for lectures from Bayer Vital and Sanofi Genzyme, Consultant for Hovid Berhad and Roche Pharma. RWP received honoraria from GE Healthcare and is co-lead of Neurofilament light consortium. CHS is supported by an Alzheimer's Society Fellowship. The remaining authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Extracellular free water (FW) increases are suggested to better provide pathophysiological information in brain aging than conventional biomarkers such as fractional anisotropy. The aim of the present study was to determine the relationship between conventional biomarkers, FW in white matter hyperintensities (WMH), FW in normal appearing white matter (NAWM) and in white matter tracts and executive functions (EF) with a speed component in elderly persons. We examined 226 healthy elderly participants (median age 69.83 years, IQR: 56.99-74.42) who underwent brain MRI and neuropsychological examination. FW in WMH and in NAWM as well as FW corrected diffusion metrics and measures derived from conventional MRI (white matter hyperintensities, brain volume, lacunes) were used in partial correlation (adjusted for age) to assess their correlation with EF with a speed component. Random forest analysis was used to assess the relative importance of these variables as determinants. Lastly, linear regression analyses of FW in white matter tracts corrected for risk factors of cognitive and white matter deterioration, were used to examine the role of specific tracts on EF with a speed component, which were then ranked with random forest regression. Partial correlation analyses revealed that almost all imaging metrics showed a significant association with EF with a speed component (r = -0.213 - 0.266). Random forest regression highlighted FW in WMH and in NAWM as most important among all diffusion and structural MRI metrics. The fornix (R 2 =0.421, p = 0.018) and the corpus callosum (genu (R 2  = 0.418, p = 0.021), prefrontal (R 2  = 0.416, p = 0.026), premotor (R 2  = 0.418, p = 0.021)) were associated with EF with a speed component in tract based regression analyses and had highest variables importance. In a normal aging population FW in WMH and NAWM is more closely related to EF with a speed component than standard DTI and brain structural measures. Higher amounts of FW in the fornix and the frontal part of the corpus callosum leads to deteriorating EF with a speed component., Competing Interests: Declarations of Competing Interest None., (Copyright © 2022. Published by Elsevier Inc.)

Objective: Recent studies suggested that CSF-mediated factors contribute to periventricular (PV) T2-hyperintense lesion formation in multiple sclerosis (MS) and this in turn correlates with cortical damage. We thus investigated if such PV-changes are observable microstructurally in early-MS and if they correlate with cortical damage., Methods: We assessed the magnetisation transfer ratio (MTR) in PV normal-appearing white matter (NAWM) and in MS lesions in 44 patients with a clinically isolated syndrome (CIS) suggestive of MS and 73 relapsing-remitting MS (RRMS) patients. Band-wise MTR values were related to cortical mean thickness (CMT) and compared with 49 healthy controls (HCs). For each band, MTR changes were assessed relative to the average MTR values of all HCs., Results: Relative to HCs, PV-MTR was significantly reduced up to 2.63% in CIS and 5.37% in RRMS (p < 0.0001). The MTR decreased towards the lateral ventricles with 0.18%/mm in CIS and 0.31%/mm in RRMS patients, relative to HCs. In RRMS, MTR-values adjacent to the ventricle and in PV-lesions correlated positively with CMT and negatively with EDSS., Conclusion: PV-MTR gradients are present from the earliest stage of MS, consistent with more pronounced microstructural WM-damage closer to the ventricles. The positive association between reduced CMT and lower MTR in PV-NAWM suggests a common pathophysiologic mechanism. Together, these findings indicate the potential use of multimodal MRI as refined marker for MS-related tissue changes., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Quantitative susceptibility mapping (QSM) has been successfully applied to study changes in deep grey matter nuclei as well as in lesional tissue, but its application to white matter has been complicated by the observed orientation dependence of gradient echo signal. The anisotropic susceptibility tensor is thought to be at the origin of this orientation dependence, and magnetic susceptibility anisotropy (MSA) derived from this tensor has been proposed as a marker of the state and integrity of the myelin sheath and may therefore be of particular interest for the study of demyelinating pathologies such as multiple sclerosis (MS). Reconstruction of the susceptibility tensor, however, requires repeated measurements with multiple head orientations, rendering the approach impractical for clinical applications. In this study, we combined single-orientation QSM with fibre orientation information to assess apparent MSA in three white matter tracts, i.e., optic radiation (OR), splenium of the corpus callosum (SCC), and superior longitudinal fascicle (SLF), in two cohorts of 64 healthy controls and 89 MS patients. The apparent MSA showed a significant decrease in optic radiation in the MS cohort compared with healthy controls. It decreased in the MS cohort with increasing lesion load in OR and with disease duration in the splenium. All of this suggests demyelination in normal appearing white matter. However, the apparent MSA observed in the SLF pointed to potential systematic issues that require further exploration to realize the full potential of the presented approach. Despite the limitations of such single-orientation ROI-specific estimation, we believe that our clinically feasible approach to study degenerative changes in WM is worthy of further investigation., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Cognitive impairment is a common sequel of recent small subcortical infarction (RSSI) and might be negatively affected by preexisting cerebral small vessel disease (SVD). We investigated whether the course of cognitive function in patients with RSSI is influenced by the severity of white matter hyperintensities (WMH), an important imaging feature of SVD., Methods: Patients with magnetic resonance imaging (MRI)-proven single RSSI were tested neuropsychologically concerning global cognition, processing speed, attention, and set-shifting. Deep and periventricular WMH severity was assessed using the Fazekas scale, and total WMH lesion volume was calculated from T1-weighted MRI images. We compared baseline function and course of cognition 15 months after the acute event in patients with absent, mild, and moderate-to-severe WMH., Results: The study cohort comprised 82 RSSI patients (mean age: 61 ± 10 years, 23% female). At baseline, 40% had cognitive impairment (1.5 standard deviations below standardized mean), and deficits persisted in one-third of the sample after 15 months. After age correction, there were no significant differences in set-shifting between WMH groups at baseline. However, although patients without WMH (deep: p < 0.001, periventricular: p = 0.067) or only mild WMH (deep: p = 0.098, periventricular: p = 0.001) improved in set-shifting after 15 months, there was no improvement in patients with moderate-to-severe WMH (deep: p = 0.980, periventricular: p = 0.816). Baseline total WMH volume (p = 0.002) was the only significant predictor for attention 15 months poststroke., Conclusions: This longitudinal study demonstrates that preexisting moderate-to-severe WMH negatively affect the restoration of cognitive function after RSSI, suggesting limited functional reserve in patients with preexisting SVD., (© 2020 The Authors. European Journal of Neurology Published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Information on microstructural white matter integrity has been shown to explain post-stroke recovery beyond clinical measures and focal brain damage. Especially, knowledge about early white matter changes might improve prediction of outcome. We investigated 42 acute reperfused ischemic stroke patients (mean age 66.5 years, 40% female, median admission NIHSS 9.5) with a symptomatic MRI-confirmed unilateral middle cerebral artery territory infarction 24-72 h post-stroke and after 3 months. All patients underwent neurological examination and brain MRI. Fifteen older healthy controls (mean age 57.3 years) were also scanned twice. We assessed fractional anisotropy (FA), mean diffusivity (MD), axial (AD), and radial diffusivity (RD). Patients showed significantly decreased white matter integrity in the hemisphere affected by the acute infarction 24-72 h post-stroke, which further decreased over 3 months compared with controls. Less decrease in FA of remote white matter tracts was associated with better stroke recovery even after correcting for infarct location and extent. A regression model including baseline information showed that the modified Rankin Scale and mean FA of the genu of the corpus callosum explained 53.5% of the variance of stroke recovery, without contribution of infarct volume. Furthermore, early dynamic FA changes of the corpus callosum within the first 3 months post-stroke independently predicted stroke recovery. Information from advanced MRI measures on white matter integrity at the acute stage, as well as early dynamic white matter degeneration beyond infarct location and extent, improve our understanding of post-stroke reorganization in the affected hemisphere and contribute to an improved prediction of recovery.

Background and Purpose: Previous studies suggested an association between increased intracranial arterial pulsatility and the severity of microangiopathic white matter hyperintensities (WMH). However, possible confounders such as age and hypertension were seldomly considered and longitudinal data are lacking. We here aimed to explore whether increased middle cerebral artery pulsatility is associated with baseline severity and progression of cerebral small vessel disease-related WMH in elderly individuals., Methods: The study population consisted of elderly participants from the community-based ASPS (Austrian Stroke Prevention Study). Baseline and follow-up assessment comprised transcranial Doppler sonography, brain magnetic resonance imaging, and clinical/laboratory examination of vascular risk factors. Pulsatility index on transcranial Doppler sonography was averaged from baseline indices of both middle cerebral arteries and was correlated with baseline WMH severity and WMH progression over a median follow-up period of 5 years in uni- and multivariable analyses. WMH severity was graded according to the Fazekas scale, and WMH load was quantified by semiautomated volumetric assessment., Results: The study cohort comprised 491 participants (mean age: 60.7±6.9 years; female: 48.5%). Pulsatility index was increased in participants with more severe WMH at baseline ( P <0.001) but was not associated with WMH progression during follow-up (r s : 0.097, P =0.099). In multivariable analyses, only arterial hypertension remained significantly associated with baseline severity ( P =0.04) and progression ( P =0.008) of WMH, although transcranial Doppler sonography pulsatility index was not predictive ( P >0.1, respectively)., Conclusions: This community-based cohort study of elderly individuals does not support the pulsatility index of the middle cerebral artery on transcranial Doppler sonography as an independent marker of microangiopathic WMH severity and progression over time.

Objective: To determine if vascular risk factor (VRF), that is, smoking, arterial hypertension (HT), dyslipidaemia and diabetes, have an effect on multiple sclerosis (MS) pathology as measured by MS typical brain lesions, we have compared brain MRIs from patients with MS with and without VRF age-matched and sex-matched., Methods: Brain MRIs from five centres were scored for the presence of Dawson's fingers (DF) and juxtacortical lesions (JCL). A regression model was built to predict the effect of each individual VRF on DF and JCL, considering age and disease duration., Results: 92 MS cases without VRF and 106 MS with one or more VRF (80 ever-smokers, 43 hypertensives, 25 dyslipidaemics and 10 diabetics) were included. Ever-smoking associated with a higher burden of DF (Exp(B)=1.29, 95% CI 1.10 to 1.51, p<0.01) and JCL (Exp(B)=1.38, 95% CI 1.21 to 1.57, p<0.01). No other VRF had an impact on DF. Dyslipidaemia associated with increased JCL (Exp(B)=1.30, 95% CI 1.10 to 1.56, p<0.01) but HT did not associate with any of the outcomes., Conclusions: Individual VRF appear to affect MS-specific lesions differently. An increase in MS lesions was mainly seen in smokers; however, this VRF is most likely to be present from onset of MS, and other VRF effects may be partly mitigated by treatment. Our findings support that treating VRF and cessation of smoking may be important in the management of MS., Competing Interests: Competing interests: RG has received support for scientific meetings and courses or honoraria for advisory work from Wolfson College, by the EAN, Bayer, Biogen, Merck and Novartis. GdP has received scholarships from the ECTRIMS, the World Federation of Neurology and Novartis; funding for research from Biogen, Novartis and Roche; travel grants from Roche, Sanofi-Genzyme and Teva and fees for editorial content from Bayer, Merck Serono and Roche. KC has received honoraria for speaking at meetings, advisory work or support to attend meetings from Teva, Biogen Idec and Roche. JS-G reports in the last 36 months grants and personal fees from Genzyme, personal fees from: Biogen, Bayer, Merck, Almirall, Bial, Novartis, Roche, TEVA, Celgene; he is Director of Revista de Neurologia, for which he does not receive any compensation, and serves of Editorial Board of Multiple Sclerosis Journal, for which he receives a compensation. CE has received funding for travel and speaker honoraria from Biogen, Bayer, Genzyme, Merck, Novartis, Shire and Teva, research support from Biogen, Merck and Teva, and has served on scientific advisory boards for Bayer, Biogen, Merck, Novartis, Roche and Teva. DTC has received, in the last 3 years, honoraria (paid to his employer) from Excemed for faculty-led education work; had meeting expenses funded by EAN, ECTRIMS, Novartis and Société des Neurosciences. He has received research funding from the International Progressive MS Alliance, the MS society of Great Britain and Northern Ireland and the Institute for Health Research (NIHR), University College London Hospitals (UCLH) Biomedical Research Centre. GCD is supported by the NIHR Biomedical Research Centre (BRC), Oxford and has research funding from the Oxford BRC, MRC (UK) and Merck-Serono. He has received travel expenses from Bayer Schering, Biogen Idec, Genzyme, Merck Serono and Novartis and honoraria as an invited speaker for Bayer Schering and Novartis. JP is partly funded by highly specialised services to run a national congenital myasthenia service and a neuromyelitis service. She has received support for scientific meetings and honorariums for advisory work from Merck Serono, Biogen Idec, Novartis, Teva, Chugai Pharma and Bayer Schering, Alexion, Roche, Genzyme, MedImmune, EuroImmune, MedDay, Abide and ARGENX, and grants from Merck Serono, Novartis, Biogen Idec, Teva, Abide and Bayer Schering. She has received grants from the MS society and Guthie Jackson Foundation for research studies. FB serves as a consultant for Biogen, Bayer, Genzyme, Jansen Research, Merck, Novartis, Roche, Synthon BV and Teva. CG has received compensation for consulting from Bayer and Biogen and speaker's fees for lectures from Biogen, Bayer, Genzyme, Merck, Novartis and Teva. AR serves on scientific advisory boards for Novartis, Sanofi-Genzyme, Icometrix, SyntheticMR, Bayer, Biogen and OLEA Medical and has received speaker honoraria from Bayer, Sanofi-Genzyme, Bracco, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche and Biogen., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Machine learning classification is an attractive approach to automatically differentiate patients from healthy subjects, and to predict future disease outcomes. A clinically isolated syndrome (CIS) is often the first presentation of multiple sclerosis (MS), but it is difficult at onset to predict who will have a second relapse and hence convert to clinically definite MS. In this study, we thus aimed to distinguish CIS converters from non-converters at onset of a CIS, using recursive feature elimination and weight averaging with support vector machines. We also sought to assess the influence of cohort size and cross-validation methods on the accuracy estimate of the classification. We retrospectively collected 400 patients with CIS from six European MAGNIMS MS centres. Patients underwent brain MRI at onset of a CIS according to local standard-of-care protocols. The diagnosis of clinically definite MS at one-year follow-up was the standard against which the accuracy of the model was tested. For each patient, we derived MRI-based features, such as grey matter probability, white matter lesion load, cortical thickness, and volume of specific cortical and white matter regions. Features with little contribution to the classification model were removed iteratively through an interleaved sample bootstrapping and feature averaging approach. Classification of CIS outcome at one-year follow-up was performed with 2-fold, 5-fold, 10-fold and leave-one-out cross-validation for each centre cohort independently and in all patients together. The estimated classification accuracy across centres ranged from 64.9% to 88.1% using 2-fold cross-validation and from 73% to 92.9% using leave-one-out cross-validation. The classification accuracy estimate was higher in single-centre, smaller data sets than in combinations of data sets, being the lowest when all patients were merged together. Regional MRI features such as WM lesions, grey matter probability in the thalamus and the precuneus or cortical thickness in the cuneus and inferior temporal gyrus predicted the occurrence of a second relapse in patients at onset of a CIS using support vector machines. The increased accuracy estimate of the classification achieved with smaller and single-centre samples may indicate a model bias (overfitting) when data points were limited, but also more homogeneous. We provide an overview of classifier performance from a range of cross-validation schemes to give insight into the variability across schemes. The proposed recursive feature elimination approach with weight averaging can be used both in single- and multi-centre data sets in order to bridge the gap between group-level comparisons and making predictions for individual patients., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

We aimed to assess whether and how changes in brain volume and increases in white matter hyperintensity (WMH) volume over three years predict gait speed and its change independently of demographics, vascular risk factors and physical status. We analyzed 443 individuals from the Lothian Birth Cohort 1936, at mean age 73 and 76 years. Gait speed at age 76 was predicted by age, grip strength and body mass index at mean age 73, three-year brain volume decrease and WMH volume increase, explaining 26.1% of variance. Decline in gait speed to age 76 was predicted by the same five variables explaining 40.9% of variance. In both analyses, grip strength and body mass index explained the most variance. A clinically significant decline in gait speed (≥ 0.1 m/s per year) occurred in 24.4%. These individuals had more structural brain changes. Brain volume and WMH changes were independent predictors of gait dysfunction and its three-year change, but the impact of malleable physical factors such as grip strength or body mass index was greater.

OBJECTIVE Cerebral damage in frontal, parietal, and temporal brain areas and, probably more importantly, their interconnections can lead to deficits in language. However, neural plasticity and repair allow the brain to partly compensate for neural injury, mediated by both functional and structural changes. In this study, the authors sought to systematically investigate the relationship between language performance in brain tumor patients and structural perisylvian pathways (i.e., the arcuate fasciculus [AF]) using probabilistic fiber tracking on diffusion tensor imaging. The authors used a previously proposed model in which the AF is divided into anterior, long, and posterior segments. The authors hypothesized that right-handed patients with gliomas in the language-dominant (left) hemisphere would benefit from a more symmetrical or right-lateralized language pathway in terms of better preservation of language abilities. Furthermore, they investigated to what extent specific tumor characteristics, including proximity to the AF, affect language outcome in such patients. METHODS Twenty-seven right-handed patients (12 males and 15 females; mean age 52 ± 16 years) with 11 low-grade and 16 high-grade gliomas of the left hemisphere underwent 3-T diffusion-weighted MRI (30 directions) and language assessment as part of presurgical planning. For a systematic quantitative evaluation of the AF, probabilistic fiber tracking with a 2 regions of interest approach was carried out. Volumes of the 3 segments of both hemispheric AFs were evaluated by quantifying normalized and thresholded pathways. Resulting values served to generate the laterality index of the AFs. RESULTS Patients without language deficits tended to have an AF that was symmetric or lateralized to the right, whereas patients with deficits in language significantly more often demonstrated a left-lateralized posterior segment of the AF. Patients with high-grade gliomas had more severe language deficits than those with low-grade gliomas. Backward logistic regression revealed the laterality index of the posterior AF segment and tumor grade as the only independent statistically significant predictors for language deficits in this cohort. CONCLUSIONS In addition to the well-known fact that tumor entity influences behavioral outcome, the authors' findings suggest that the right homologs of structural language-associated pathways could be supportive for language function and facilitate compensation mechanisms after brain damage in functionally eloquent areas. This further indicates that knowledge about preoperative functional redistribution (identified by neurofunctional imaging) increases the chance for total or near-total resections of tumors in eloquent areas. In the future, longitudinal studies with larger groups are mandatory to overcome the methodological limitations of this cross-sectional study and to map neuroplastic changes associated with language performance and rehabilitation in brain tumor patients.

Background and Purpose: In vivoidentification of white matter lesions plays a key-role in evaluation of patients with multiple sclerosis (MS). Automated lesion segmentation methods have been developed to substitute manual outlining, but evidence of their performance in multi-center investigations is lacking. In this work, five research-domain automated segmentation methods were evaluated using a multi-center MS dataset., Methods: 70 MS patients (median EDSS of 2.0 [range 0.0-6.5]) were included from a six-center dataset of the MAGNIMS Study Group (www.magnims.eu) which included 2D FLAIR and 3D T1 images with manual lesion segmentation as a reference. Automated lesion segmentations were produced using five algorithms: Cascade; Lesion Segmentation Toolbox (LST) with both the Lesion growth algorithm (LGA) and the Lesion prediction algorithm (LPA); Lesion-Topology preserving Anatomical Segmentation (Lesion-TOADS); and k-Nearest Neighbor with Tissue Type Priors (kNN-TTP). Main software parameters were optimized using a training set (N = 18), and formal testing was performed on the remaining patients (N = 52). To evaluate volumetric agreement with the reference segmentations, intraclass correlation coefficient (ICC) as well as mean difference in lesion volumes between the automated and reference segmentations were calculated. The Similarity Index (SI), False Positive (FP) volumes and False Negative (FN) volumes were used to examine spatial agreement. All analyses were repeated using a leave-one-center-out design to exclude the center of interest from the training phase to evaluate the performance of the method on 'unseen' center., Results: Compared to the reference mean lesion volume (4.85 ± 7.29 mL), the methods displayed a mean difference of 1.60 ± 4.83 (Cascade), 2.31 ± 7.66 (LGA), 0.44 ± 4.68 (LPA), 1.76 ± 4.17 (Lesion-TOADS) and -1.39 ± 4.10 mL (kNN-TTP). The ICCs were 0.755, 0.713, 0.851, 0.806 and 0.723, respectively. Spatial agreement with reference segmentations was higher for LPA (SI = 0.37 ± 0.23), Lesion-TOADS (SI = 0.35 ± 0.18) and kNN-TTP (SI = 0.44 ± 0.14) than for Cascade (SI = 0.26 ± 0.17) or LGA (SI = 0.31 ± 0.23). All methods showed highly similar results when used on data from a center not used in software parameter optimization., Conclusion: The performance of the methods in this multi-center MS dataset was moderate, but appeared to be robust even with new datasets from centers not included in training the automated methods., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Several quantitative magnetic resonance imaging (MRI) techniques have been proposed to investigate microstructural tissue changes in amyotrophic lateral sclerosis (ALS) including diffusion tensor imaging (DTI), magnetization transfer imaging, and R2* mapping. Here, in this study, we compared these techniques with regard to their capability for detecting ALS related white matter (WM) changes in the brain and their association with clinical findings. We examined 27 ALS patients and 35 age-matched healthy controls. MRI was performed at 3T, after which we analyzed the diffusion properties, the magnetization transfer ratio (MTR), and the effective transversal relaxation rate R2* in 18 WM tracts that were obtained by a fully automated segmentation technique. ALS patients, especially with a bulbar onset, showed a bilateral increase in radial and mean diffusivity, as well as a reduction in fractional anisotropy of the corticospinal tract (CST), and diffusion changes in the parietal and temporal superior longitudinal fasciculus. A reduction of the MTR was found in both CSTs and an R2* reduction was seen only in the left CST. Tract-specific diffusion properties were not related to clinical status in a cross-sectional manner but demonstrated some association with disease progression over three subsequent months. DTI reveals more widespread WM tissue changes than MTR and R2*. These changes are not restricted to the CST, but affect also other WM tracts (especially in patients with bulbar onset), and are associated with the short term course of the disease.

Besides specific iron accumulation in some neurodegenerative disorders, increased iron deposition in cerebral deep gray matter (DGM) is found in multiple sclerosis. As this is considered largely a white matter (WM) disease, we speculated that patients with more severe ischemic WM hyperintensities (WMH) might also have an increased iron concentration in DGM structures and tested this assumption by using magnetic resonance imaging-based quantitative R2* relaxometry. WMH severity was measured in 61 patients with acute transient neurological symptoms (mean age: 71.5 ± 8.3 years) undergoing 3-Tesla magnetic resonance imaging. Despite a 6-year higher age of patients with more severe (i.e., early confluent or confluent) WMH, their DGM R2* rates did not differ from patients with punctate or no WMH. In the globus pallidum, R2* rates were even lower in patients with severe WMH. WMH volume was not correlated with R2* levels in any of the analyzed DGM structures. These findings argue against WM damage per se causing increased DGM iron deposition in multiple sclerosis and suggest no role of iron accumulation in ischemic small vessel disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: It has been suggested recently that cortical pathology in multiple sclerosis (MS) may, at least partly, be caused by factors in cerebrospinal fluid (CSF). We thus hypothesized that MS-related tissue changes in compartments close to the CSF, such as periventricular lesions, might correlate with cortical pathology., Methods: We investigated a cohort of 160 patients, comprising 91 with a clinically isolated syndrome (CIS) and 69 with relapsing-remitting MS (RRMS; mean age: CIS: 31.4 ± 9.0; RRMS: 33.0 ± 8.7 years; mean disease duration: CIS: 7.2 ± 15 months; RRMS: 8.0 ± 6.5 years, Expanded Disability Status Scale (median, min-max): CIS: 1, 0-3.5; RRMS: 1.25, 0-4) with 3.0T magnetic resonance imaging. MS lesions were segmented semiautomatically on fluid-attenuated inversion recovery images. To quantify periventricular lesion load (PV-LL), we generated ventricle masks and dilated them by a voxel factor of 3. Lesions within the dilated ventricle margin were classified as periventricular. Cortical thinning was assessed by cortical mean thickness (CMT) and compared to data from 58 healthy controls (HCs; mean age: 29.1 ± 7.4 years)., Results: Compared to HC, CIS and (even more so) RRMS patients demonstrated significantly reduced CMT. Even after controlling for ventricular volume and total lesion load, increased periventricular lesion occupancy (percentage of PV-LL) significantly correlated with decreased CMT in RRMS (r = -0.295; p = 0.015), but not in CIS (r = 0.032; p = 0.768) patients., Interpretation: The correlation between increased periventricular lesion burden and decreased CMT indicative of subpial cortical pathology supports the concept that common CSF-mediated factors might play a role in the accumulation of damage to gray and white matter in MS., (© 2015 American Neurological Association.)

Background: Cerebral white matter lesions (WML) have been found in normal aging, vascular disease and several neuropsychiatric conditions. Correlations of WML with clinical parameters in BD have been described, but not with the number of affective episodes, illness duration, age of onset and Body Mass Index in a well characterized group of euthymic bipolar adults. Herein, we aimed to evaluate the associations between bipolar course of illness parameters and WML measured with volumetric analysis., Methods: In a cross-sectional study 100 euthymic individuals with BD as well as 54 healthy controls (HC) were enrolled to undergo brain magnetic resonance imaging using 3T including a FLAIR sequence for volumetric assessment of WML-load using FSL-software. Additionally, clinical characteristics and psychometric measures including Structured Clinical Interview according to DSM-IV, Hamilton-Depression, Young Mania Rating Scale and Beck's Depression Inventory were evaluated., Results: Individuals with BD had significantly more (F = 3.968, p < .05) WML (Mdn = 3710 mm3; IQR = 2961 mm3) than HC (Mdn = 2185 mm3; IQR = 1665 mm3). BD men (Mdn = 4095 mm3; IQR = 3295 mm3) and BD women (Mdn = 3032 mm3; IQR = 2816 mm3) did not significantly differ as to the WML-load or the number and type of risk factors for WML. However, in men only, the number of manic/hypomanic episodes (r = 0.72; p < .001) as well as depressive episodes (r = 0.51; p < .001) correlated positively with WML-load., Conclusions: WML-load strongly correlated with the number of manic episodes in male BD patients, suggesting that men might be more vulnerable to mania in the context of cerebral white matter changes.

Background: Leber's hereditary optic neuropathy (LHON) and a multiple sclerosis (MS)-like illness appear to coexist 50 times more frequently than would be expected by chance. This association of LHON and MS (LMS) raises an important question about whether there could be a common pathophysiological mechanism involving mitochondrial dysfunction., Objective: The primary aim was to define MRI features of LMS and LHON, and to assess the proportions of individuals displaying features typical of MS. Secondarily, we investigated the effect of gender on the risk of developing white matter lesions in the context of LHON., Methods: A blinded standardised review of conventional brain MRIs of 30 patients with MS, 31 patients with LHON and 11 patients with LMS was conducted by three independent experts in the field. MS-like MRI features were assessed., Results: All patients with LMS and 26% of patients with LHON had white matter lesions. Of these, all patients with LMS and 25% with LHON were found to have an MRI appearance typical of MS. Female patients with LHON had a significantly greater risk of having white matter lesions consistent with MS compared with male patients (relative risk 8.3)., Conclusions: A blinded review of conventional brain MRIs shows that patients with LMS have a scan appearance indistinguishable from MS. Mitochondrial dysfunction could be a common pathophysiological pathway in the formation of white matter lesions. There appears to be a strong female influence on the radiological appearance as well as clinical development of MS in patients with LHON., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose: The R2* relaxation rate constant has been suggested as a sensitive measure for iron accumulation. The aim of this multi-center study was to assess the inter-scanner and inter-subject variability of R2* mapping and to investigate the relationship between brain volume and R2* in specific structures., Methods: R2* mapping was performed in 81 healthy subjects in seven centers using different 3 T systems. R2* was calculated from a dual-echo gradient echo sequence and was assessed in several deep gray matter structures. The inter-scanner and inter-subject variability of R2* was calculated by means of the coefficient of variation before and after correcting for age., Results: Significant center effects were seen in some regions which get lost after age correction. The coefficient of variation for the inter-center variability was much lower (<5.6%) than for the intra-subject variability (6.7%-11.7%). R2* in the putamen and red nucleus scaled with cortical volume while R2* in the globus pallidus and the substantia nigra was negatively associated with white matter volume., Conclusion: R2* is a robust and reproducible measure in a multicenter setting provided that a standardized MRI protocol is used. The relationship between iron concentration in deep gray matter and volume of specific brain compartments needs further investigation., (Copyright © 2013 Wiley Periodicals, Inc.)