Enhancing Cognitive Performance Prediction through White Matter Hyperintensity Connectivity Assessment: A Multicenter Lesion Network Mapping Analysis of 3,485 Memory Clinic Patients.

Introduction: White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating cognitive health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. We propose that lesion network mapping (LNM), enables to infer if brain networks are connected to lesions, and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed this approach to test the following hypotheses: (1) LNM-informed markers surpass WMH volumes in predicting cognitive performance, and (2) WMH contributing to cognitive impairment map to specific brain networks. Methods & results: We analyzed cross-sectional data of 3,485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in 4 cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity across 480 atlas-based gray and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. The capacity of total and regional WMH volumes and LNM scores in predicting cognitive function was compared using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention and executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater disruptive effects of WMH on regional connectivity, in gray and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Conclusion: Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network effects, particularly in attentionrelated brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.

Low-frequency MR elastography reveals altered deep gray matter viscoelasticity in multiple sclerosis.

INTRODUCTION: Brain viscoelasticity as assessed by magnetic resonance elastography (MRE) has been discussed as a promising surrogate of microstructural alterations due to neurodegenerative processes. Existing studies indicate that multiple sclerosis (MS) is associated with a global reduction in brain stiffness. However, no study to date systematically investigated the MS-related characteristics of brain viscoelasticity separately in normal-appearing white matter (NAWM), deep gray matter (DGM) and T2-hyperintense white matter (WM) lesions. METHODS: 70 MS patients and 42 healthy volunteers underwent whole-cerebral MRE using a stimulated echo sequence (DENSE) with a low-frequency mechanical excitation at 20 Hertz. The magnitude |G∗| (Pa) and phase angle φ (rad) of the complex shear modulus G∗ were reconstructed by multifrequency dual elasto-visco (MDEV) inversion and related to structural imaging and clinical parameters. RESULTS: We observed φ in the thalamus to be higher by 4.3 % in patients relative to healthy controls (1.11 ± 0.07 vs. 1.06 ± 0.07, p < 0.0001). Higher Expanded Disability Status Scale (EDSS) scores were negatively associated with φ in the basal ganglia (p = 0.01). We measured φ to be lower in MS lesions compared to surrounding NAWM (p = 0.001), which was most prominent for lesions in the temporal lobe (1.01 ± 0.22 vs. 1.06 ± 0.19, p = 0.003). Age was associated with lower values of |G∗| (p = 0.04) and φ (p = 0.004) in the thalamus of patients. No alteration in NAWM stiffness relative to WM in healthy controls was observed. CONCLUSION: Low-frequency elastography in MS patients reveals age-independent alterations in the viscoelasticity of deep gray matter at early stages of disease.

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.

Evaluation of a self-administered iPad®-based processing speed assessment for people with multiple sclerosis in a clinical routine setting.

BACKGROUND: Limited resources often hinder regular cognitive assessment of people with multiple sclerosis (pwMS) in standard clinical care. A self-administered iPad®-based cognitive screening-tool (Processing Speed Test; PST) might mitigate this problem. OBJECTIVE: To evaluate the PST in clinical routine. METHODS: We investigated the feasibility of the PST in both a quiet and a waiting room setting. We assessed the validity of the PST in comparison with the established Symbol Digit Modalities Test (SDMT). We explored associations between processing speed assessments and the Brief International Cognitive Assessment for MS (BICAMS), magnetic resonance imaging (MRI) parameters, and psychological factors. Additionally, we explored the ability of the PST to detect impairment in processing speed compared to the SDMT. RESULTS: The PST was feasible in the waiting room setting. PST and SDMT correlated comparably with the BICAMS, MRI parameters, and psychological variables. Of 172 pwMS, 50 (30.8%) showed cognitive impairment according to the BICAMS; respective values were 47 (27.3%) for the SDMT and 9 (5.2%) for the PST. CONCLUSIONS: The PST performed in a waiting room setting correlates strongly with established cognitive tests. It thus may be used to assess processing speed in a resource-efficient manner and complement cognitive assessment in clinical routine. Despite comparable validity of the PST and SDMT, we identified more pwMS with impaired processing speed using normative data of the SDMT compared to the PST and advise caution, that the common cut-off score of - 1.5 SD from the current PST is not appropriate in Europe.

Sex impacts treatment decisions in multiple sclerosis.

BACKGROUND: Individual disease-modifying treatment (DMT) decisions might differ between female and male people with MS (pwMS). OBJECTIVE: To identify sex-related differences in DMT strategies over the past decades in a real-world setting. METHODS: In this cohort study, data from the Austrian Multiple Sclerosis Treatment Registry (AMSTR), a nationwide prospectively collected registry mandatory for reimbursement, were retrospectively analyzed. Of 4840 pwMS, those with relapsing-remitting MS, aged at least 18 years, who started DMT and had at least two clinical visits, were identified. At baseline, demographics, Expanded Disability Status Scale (EDSS) score, annualized relapse rate (ARR) in the prior 12 months and MRI lesion load were assessed. At follow-up, ARR, EDSS scores, and DMT were determined. RESULTS: A total of 4224 pwMS were included into the study and had a median of 10 (IQR 5-18) clinical visits over an observation period of 3.5 (IQR 1.5-6.1) years. Multivariable Cox regression analysis revealed that the probability of DMT escalation due to relapse activity was lower in female than male pwMS (HR 4.1 vs. 8.3 per ARR). Probability of discontinuing moderate-effective DMT was higher in female pwMS when they were younger (HR 1.03 per year), and lower in male pwMS at higher age (HR 0.92). Similarly, female pwMS were more likely to stop highly effective DMT than male pwMS (HR 1.7). Among others, the most frequent reason for DMT discontinuation was family planning in female pwMS. All sex-related effects were independent of disease activity, such as MRI lesion load, baseline ARR or EDSS. CONCLUSIONS: Real-world treatment decisions are influenced by sex-related aspects. Awareness of these associations should prevent unwarranted differences in MS care.

Early intensive versus escalation treatment in patients with relapsing-remitting multiple sclerosis in Austria.

OBJECTIVES: To compare the effectiveness of early intensive treatment (EIT) versus escalation treatment (ESC) in a nationwide observational cohort of almost 1000 people with relapsing-remitting multiple sclerosis (RRMS). MATERIALS AND METHODS: The EIT cohort started with alemtuzumab (AZM), cladribine (CLAD), fingolimod (FTY), natalizumab (NTZ), ocrelizumab (OCR), or ozanimod (OZA); whereas, the ESC cohort was escalated from dimethylfumarate (DMF) or teriflunomide (TERI) to AZM, CLAD, FTY, NTZ, OCR, or OZA within the Austrian MS Treatment Registry. Patients had to stay on therapy for at least 3 months and up to 16 years. The EIT cohort included 743 and the ESC cohort 227 RRMS patients. We used multinomial propensity scores for inverse probability weighting in generalized linear (GLM) and Cox proportional hazards models to correct for the bias of this non-randomized registry study. RESULTS: Estimated mean annualized relapse rates (ARR) were 0.09 for EIT and 0.4 for ESC patients. The incidence rate ratio (IRR) in the GLM model for relapses showed a decreased relapse probability of 78% for the EIT versus ESC cohort [IRR = 0.22, 95% CI (0.16-0.30), p < 0.001]. Analyzing the time to the first relapse by Cox regression, a hazard ratio (HR) of 0.17 [95% CI (0.13-0.22), p < 0.001] revealed a decreased risk of 83% for the EIT group. Regarding sustained Expanded Disability Status Scale (EDSS) progression for 12 weeks, a HR of 0.55 [95% CI (0.40-0.76), p < 0.001] showed a decreased probability of 45% for the EIT cohort. CONCLUSIONS: ESC treatment after DMF and TERI revealed a higher relapse and EDSS progression probability compared to EIT in Austrian RRMS patients. Therefore, an early intensive treatment should be started in patients with an active or highly active disease course.

Cerebral white matter hyperintensities indicate severity and progression of coronary artery calcification.

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 cm3) 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 cm3], 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.

Sex Differences under Vitamin D Supplementation in an Animal Model of Progressive Multiple Sclerosis.

A central role for vitamin D (VD) in immune modulation has recently been recognized linking VD insufficiency to autoimmune disorders that commonly exhibit sex-associated differences. Similar to other autoimmune diseases, there is a higher incidence of multiple sclerosis (MS) in women, but a poorer prognosis in men, often characterized by a more rapid progression. Although sex hormones are most likely involved, this phenomenon is still poorly understood. Oxidative stress, modulated by VD serum levels as well as sex hormones, may act as a contributing factor to demyelination and axonal damage in both MS and the corresponding preclinical models. In this study, we analyzed sex-associated differences and VD effects utilizing an animal model that recapitulates histopathological features of the progressive MS phase (PMS). In contrast to relapsing-remitting MS (RRMS), PMS has been poorly investigated in this context. Male (n = 50) and female (n = 46) Dark Agouti rats received either VD (400 IU per week; VD+) or standard rodent food without extra VD (VD-) from weaning onwards. Myelination, microglial activation, apoptotic cell death and neuronal viability were assessed using immunohistochemical markers in brain tissue. Additionally, we also used two different histological markers against oxidized lipids along with colorimetric methods to measure protective polyphenols (PP) and total antioxidative capacity (TAC) in serum. Neurofilament light chain serum levels (sNfL) were analyzed using single-molecule array (SIMOA) analysis. We found significant differences between female and male animals. Female rats exhibited a better TAC and higher amounts of PP. Additionally, females showed higher myelin preservation, lower microglial activation and better neuronal survival while showing more apoptotic cells than male rats. We even found a delay in reaching the peak of the disease in females. Overall, both sexes benefitted from VD supplementation, represented by significantly less cortical, neuroaxonal and oxidative damage. Unexpectedly, male rats had an even higher overall benefit, most likely due to differences in oxidative capacity and defense systems.

Time is myelin: early cortical myelin repair prevents atrophy and clinical progression in multiple sclerosis.

Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5 years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5 years and, along with 84 healthy controls, underwent a 3 T-MRI protocol including MTI at baseline and after 1 year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (ß = 0.23, P = 0.024) and lower indices of cortical remyelination (ß = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1 year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5 years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5 years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5 years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS.

Association of covert brain infarct phenotype with stroke recurrence in first-ever manifest ischemic stroke according to etiology.

INTRODUCTION: Covert brain infarcts (CBI) are frequent incidental findings on MRI and associated with future stroke risk in patients without a history of clinically evident cerebrovascular events. However, the prognostic value of CBI in first-ever ischemic stroke patients is unclear and previous studies did not report on different etiological stroke subtypes. We aimed to test CBI phenotypes and their association with stroke recurrence in first-ever ischemic stroke patients according to stroke etiology. PATIENTS AND METHODS: This study is a pooled data analysis of two prospectively collected cohorts of consecutive first-ever ischemic stroke patients admitted to the comprehensive stroke centers of Bern (Switzerland) and Graz (Austria). CBI phenotypes were identified on brain MRI within 72 h after admission. All patients underwent a routine follow-up (median: 12 months) to identify stroke recurrence. RESULTS: Of 1577 consecutive ischemic stroke patients (median age: 71 years), 691 patients showed CBI on brain MRI (44%) and 88 patients had a recurrent ischemic stroke (6%). Baseline CBI were associated with stroke recurrence in multivariable analysis (HR 1.9, 95% CI 1.1-3.3). CBI phenotypes with the highest risk for stroke recurrence were cavitatory CBI in small vessel disease (SVD)-related stroke (HR 7.1, 95% CI 1.6-12.6) and cortical CBI in patients with atrial fibrillation (HR 3.0, 95% CI 1.1-8.1). DISCUSSION AND CONCLUSION: This study reports a ≈ 2-fold increased risk for stroke recurrence in first-ever ischemic stroke patients with CBI. The risk of recurrent stroke was highest in patients with cavitatory CBI in SVD-related stroke and cortical CBI in patients with atrial fibrillation.Subject terms: Covert brain infarcts, stroke.

Diagnostic Performance of Cortical Lesions and the Central Vein Sign in Multiple Sclerosis.

Importance: Multiple sclerosis (MS) misdiagnosis remains an important issue in clinical practice. Objective: To quantify the performance of cortical lesions (CLs) and central vein sign (CVS) in distinguishing MS from other conditions showing brain lesions on magnetic resonance imaging (MRI). Design, Setting, and Participants: This was a retrospective, cross-sectional multicenter study, with clinical and MRI data acquired between January 2010 and May 2020. Centralized MRI analysis was conducted between July 2020 and December 2022 by 2 raters blinded to participants' diagnosis. Participants were recruited from 14 European centers and from a multicenter pan-European cohort. Eligible participants had a diagnosis of MS, clinically isolated syndrome (CIS), or non-MS conditions; availability of a brain 3-T MRI scan with at least 1 sequence suitable for CL and CVS assessment; presence of T2-hyperintense white matter lesions (WMLs). A total of 1051 individuals were included with either MS/CIS (n = 599; 386 [64.4%] female; mean [SD] age, 41.5 [12.3] years) or non-MS conditions (including other neuroinflammatory disorders, cerebrovascular disease, migraine, and incidental WMLs in healthy control individuals; n = 452; 302 [66.8%] female; mean [SD] age, 49.2 [14.5] years). Five individuals were excluded due to missing clinical or demographic information (n = 3) or unclear diagnosis (n = 2). Exposures: MS/CIS vs non-MS conditions. Main Outcomes and Measures: Area under the receiver operating characteristic curves (AUCs) were used to explore the diagnostic performance of CLs and the CVS in isolation and in combination; sensitivity, specificity, and accuracy were calculated for various cutoffs. The diagnostic importance of CLs and CVS compared to conventional MRI features (ie, presence of infratentorial, periventricular, and juxtacortical WMLs) was ranked with a random forest model. Results: The presence of CLs and the previously proposed 40% CVS rule had a sensitivity, specificity, and accuracy for MS of 59.0% (95% CI, 55.1-62.8), 93.6% (95% CI, 91.4-95.6), and 73.9% (95% CI, 71.6-76.3) and 78.7% (95% CI, 75.5-82.0), 86.0% (95% CI, 82.1-89.5), and 81.5% (95% CI, 78.9-83.7), respectively. The diagnostic performance of the CVS (AUC, 0.89 [95% CI, 0.86-0.91]) was superior to that of CLs (AUC, 0.77 [95% CI, 0.75-0.80]; P < .001), and was increased when combining the 2 imaging markers (AUC, 0.92 [95% CI, 0.90-0.94]; P = .04); in the random forest model, both CVS and CLs outperformed the presence of infratentorial, periventricular, and juxtacortical WMLs in supporting MS differential diagnosis. Conclusions and Relevance: The findings in this study suggest that CVS and CLs may be valuable tools to increase the accuracy of MS diagnosis.

Assessing treatment response to oral drugs for multiple sclerosis in real-world setting: a MAGNIMS Study.

BACKGROUND: The assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored whether a scoring system developed within the MAGNIMS (MRI in Multiple Sclerosis) network to evaluate treatment response to injectable drugs can be adopted also to oral DMTs. METHODS: A multicentre dataset of 1200 patients who started three oral DMTs (fingolimod, teriflunomide and dimethyl fumarate) was collected within the MAGNIMS network. Disease activity after the first year was classified by the 'MAGNIMS' score based on the combination of relapses (0-≥2) and/or new T2 lesions (<3 or ≥3) on brain MRI. We explored the association of this score with the following 3-year outcomes: (1) confirmed disability worsening (CDW); (2) treatment failure (TFL); (3) relapse count between years 1 and 3. The additional value of contrast-enhancing lesions (CELs) and lesion location was explored. RESULTS: At 3 years, 160 patients experienced CDW: 12% of them scored '0' (reference), 18% scored '1' (HR=1.82, 95% CI 1.20 to 2.76, p=0.005) and 37% scored '2' (HR=2.74, 95% CI 1.41 to 5.36, p=0.003) at 1 year. The analysis of other outcomes provided similar findings. Considering the location of new T2 lesions (supratentorial vs infratentorial/spinal cord) and the presence of CELs improved the prediction of CDW and TFL, respectively, in patients with minimal MRI activity alone (one or two new T2 lesions). CONCLUSIONS: Early relapses and substantial MRI activity in the first year of treatment are associated with worse short-term outcomes in patients treated with some of the oral DMTs.

Long-term outcome of natalizumab-associated progressive multifocal leukoencephalopathy in Austria: a nationwide retrospective study.

BACKGROUND/OBJECTIVE: The use of natalizumab (NAT) in multiple sclerosis (MS) may be complicated by progressive multifocal leukoencephalopathy (PML), a rare and life-threatening opportunistic brain infection. We aimed to analyze the course of MS after PML recovery together with the long-term outcome of NAT-associated PML (NAT-PML) in Austria. METHODS: Retrospective study based on identification of cases in the nationwide Austrian MS treatment registry (AMSTR) and MS centers with review of patient records. The expanded disability status scale (EDSS) was used to measure neurological disability and outcome. RESULTS: As of December 2022, we identified 15 NAT-PML cases in Austria; only 20% occurred after 2016, when increased vigilance commenced. Two patients did not survive acute PML, and an additional patient died five years later, yielding a mortality rate of 20%. Seizures occurred exclusively in patients with pronounced EDSS increase. Gadolinium (Gd)-enhancement on brain magnetic resonance imaging (MRI) on PML suspicion was associated with minor changes of post-PML neurological disability. Long-term follow-up of up to 132 months (median 76 months) was available in 11/15. The overall median EDSS increased from 3.5 at pre-PML to 6.5 at the last assessment. Regarding inflammatory MS-related disease activity during the observation period, one single individual experienced an MS relapse and another patient had two Gd-enhancing brain lesions. Three patients converted to progressive MS within three years from PML and the EDSS further increased in 6/11. CONCLUSIONS: The number of NAT-PML cases is decreasing over time. While many patients accumulated severe persistent neurological deficits compared to pre-PML, inflammatory MS-related disease activity after PML recovery was rare.

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.

Psychological factors and brain magnetic resonance imaging metrics associated with fatigue in persons with multiple sclerosis.

BACKGROUND: Besides demographics and clinical factors, psychological variables and brain-tissue changes have been associated with fatigue in persons with multiple sclerosis (pwMS). Identifying predictors of fatigue could help to improve therapeutic approaches for pwMS. Therefore, we investigated predictors of fatigue using a multifactorial approach. METHODS: 136 pwMS and 49 normal controls (NC) underwent clinical, neuropsychological, and magnetic resonance imaging examinations. We assessed fatigue using the "Fatigue Scale for Motor and Cognitive Functions", yielding a total, motor, and cognitive fatigue score. We further analyzed global and subcortical brain volumes, white matter lesions and microstructural changes (examining fractional anisotropy; FA) along the cortico striatal thalamo cortical (CSTC) loop. Potential demographic, clinical, psychological, and magnetic resonance imaging predictors of total, motor, and cognitive fatigue were explored using multifactorial linear regression models. RESULTS: 53% of pwMS and 20% of NC demonstrated fatigue. Besides demographics and clinical data, total fatigue in pwMS was predicted by higher levels of depression and reduced microstructural tissue integrity in the CSTC loop (adjusted R2 = 0.52, p < 0.001). More specifically, motor fatigue was predicted by lower education, female sex, higher physical disability, higher levels of depression, and self-efficacy (adjusted R2 = 0.54, p < 0.001). Cognitive fatigue was also predicted by higher levels of depression and lower self-efficacy, but in addition by FA reductions in the CSTC loop (adjusted R2 = 0.45, p < 0.001). CONCLUSIONS: Our results indicate that depression and self-efficacy strongly predict fatigue in MS. Incremental variance in total and cognitive fatigue was explained by microstructural changes along the CSTC loop, beyond demographics, clinical, and psychological variables.

Super-resolution QSM in little or no additional time for imaging (NATIve) using 2D EPI imaging in 3 orthogonal planes.

Quantitative Susceptibility Mapping has the potential to provide additional insights into neurological diseases but is typically based on a quite long (5-10 min) 3D gradient-echo scan which is highly sensitive to motion. We propose an ultra-fast acquisition based on three orthogonal (sagittal, coronal and axial) 2D simultaneous multi-slice EPI scans with 1 mm in-plane resolution and 3 mm thick slices. Images in each orientation are corrected for susceptibility-related distortions and co-registered with an iterative non-linear Minimum Deformation Averaging (Volgenmodel) approach to generate a high SNR, super-resolution data set with an isotropic resolution of close to 1 mm. The net acquisition time is 3 times the volume acquisition time of EPI or about 12 s, but the three volumes could also replace "dummy scans" in fMRI, making it feasible to acquire QSM in little or No Additional Time for Imaging (NATIve). NATIve QSM values agreed well with reference 3D GRE QSM in the basal ganglia in healthy subjects. In patients with multiple sclerosis, there was also a good agreement between the susceptibility values within lesions and control ROIs and all lesions which could be seen on 3D GRE QSMs could also be visualized on NATIve QSMs. The approach is faster than conventional 3D GRE by a factor of 25-50 and faster than 3D EPI by a factor of 3-5. As a 2D technique, NATIve QSM was shown to be much more robust to motion than the 3D GRE and 3D EPI, opening up the possibility of studying neurological diseases involving iron accumulation and demyelination in patients who find it difficult to lie still for long enough to acquire QSM data with conventional methods.

Long-term risk of recurrent cerebrovascular events after patent foramen ovale closure: Results from a real-world stroke cohort.

INTRODUCTION: Patent foramen ovale (PFO)-closure is recommended for stroke prevention in selected patients with suspected PFO-associated stroke. However, studies on cerebrovascular event recurrence after PFO-closure are limited by relatively short follow-up periods and information on the underlying aetiology of recurrent events is scarce. PATIENTS AND METHODS: All consecutive patients with a cerebral ischaemic event and PFO-closure at the University Hospital Graz were prospectively identified from 2004 to 2021. Indication for PFO-closure was based on a neurological-cardiological PFO board decision. Patients underwent standardized clinical and echocardiographic follow-up 6 months after PFO-closure. Recurrent cerebrovascular events were assessed via electronical health records. RESULTS: PFO-closure was performed in 515 patients (median age: 49 years; Amplatzer PFO occluder: 42%). Over a median follow-up of 11 years (range: 2-18 years, 5141 total patient-years), recurrent ischaemic cerebrovascular events were observed in 34 patients (ischaemic stroke: n = 22, TIA: n = 12) and associated with age, hyperlipidaemia and smoking in multivariable analysis (p < 0.05 each). Large artery atherosclerosis and small vessel disease were the most frequent aetiologies of recurrent stroke/TIA (27% and 24% respectively), and only two events were related to atrial fibrillation (AF). Recurrent ischaemic cerebrovascular event rates and incident AF were comparable in patients treated with different PFO occluders (p > 0.1). DISCUSSION AND CONCLUSION: In this long-term follow-up-study of patients with a cerebral ischaemic event who had received PFO-closure with different devices, rates of recurrent stroke/TIA were low and largely related to large artery atherosclerosis and small vessel disease. Thorough vascular risk factor control seems crucial for secondary stroke prevention in patients treated for PFO-related stroke.

Frequency and predictors of poststroke epilepsy after mechanical thrombectomy for large vessel occlusion stroke: results from a multicenter cohort study.

BACKGROUND: Poststroke epilepsy (PSE) represents an important complication of stroke. Data regarding the frequency and predictors of PSE in patients with large-vessel occlusion stroke receiving mechanical thrombectomy (MT) are scarce. Furthermore, information on acute and preexisting lesion characteristics on brain MRI has not yet been systematically considered in risk prediction of PSE. This study thus aims to assess PSE risk after acute ischemic stroke treated with MT, based on clinical and MRI features. METHODS: In this multicenter study from two tertiary stroke centers, we included consecutive acute ischemic stroke patients who had received MT for acute intracranial large vessel occlusion (LVO) between 2011 and 2017, in whom post-interventional brain MRI and long term-follow-up data were available. Infarct size, affected cerebrovascular territory, hemorrhagic complications and chronic cerebrovascular disease features were assessed on MRI (blinded to clinical information). The primary outcome was the occurrence of PSE (> 7 days after stroke onset) assessed by systematic follow-up via phone interview or electronic records. RESULTS: Our final study cohort comprised 348 thrombectomy patients (median age: 67 years, 45% women) with a median long-term follow-up of 78 months (range 0-125). 32 patients (9%) developed PSE after a median of 477 days (range 9-2577 days). In univariable analyses, larger postinterventional infarct size, infarct location in the parietal, frontal or temporal lobes and cerebral microbleeds were associated with PSE. Multivariable Cox regression analysis confirmed larger infarct size (HR 3.49; 95% CI 1.67-7.30) and presence of cerebral microbleeds (HR 2.56; 95% CI 1.18-5.56) as independent predictors of PSE. CONCLUSION: In our study, patients with large vessel occlusion stroke receiving MT had a 9% prevalence of PSE over a median follow-up period of 6.5 years. Besides larger infarct size, presence of cerebral microbleeds on brain MRI predicted PSE occurrence.

Improved dynamic distortion correction for fMRI using single-echo EPI and a readout-reversed first image (REFILL).

The boundaries between tissues with different magnetic susceptibilities generate inhomogeneities in the main magnetic field which change over time due to motion, respiration and system instabilities. The dynamically changing field can be measured from the phase of the fMRI data and corrected. However, methods for doing so need multi-echo data, time-consuming reference scans and/or involve error-prone processing steps, such as phase unwrapping, which are difficult to implement robustly on the MRI host. The improved dynamic distortion correction method we propose is based on the phase of the single-echo EPI data acquired for fMRI, phase offsets calculated from a triple-echo, bipolar reference scan of circa 3-10 s duration using a method which avoids the need for phase unwrapping and an additional correction derived from one EPI volume in which the readout direction is reversed. This Reverse-Encoded First Image and Low resoLution reference scan (REFILL) approach is shown to accurately measure B0 as it changes due to shim, motion and respiration, even with large dynamic changes to the field at 7 T, where it led to a > 20% increase in time-series signal to noise ratio compared to data corrected with the classic static approach. fMRI results from REFILL-corrected data were free of stimulus-correlated distortion artefacts seen when data were corrected with static field mapping. The method is insensitive to shim changes and eddy current differences between the reference scan and the fMRI time series, and employs calculation steps that are simple and robust, allowing most data processing to be performed in real time on the scanner image reconstruction computer. These improvements make it feasible to routinely perform dynamic distortion correction in fMRI.