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.

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.

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.

Efficacy assessment of an active tau immunotherapy in Alzheimer's disease patients with amyloid and tau pathology: a post hoc analysis of the "ADAMANT" randomised, placebo-controlled, double-blind, multi-centre, phase 2 clinical trial.

BACKGROUND: Tau pathology correlates with and predicts clinical decline in Alzheimer's disease. Approved tau-targeted therapies are not available. METHODS: ADAMANT, a 24-month randomised, placebo-controlled, parallel-group, double-blinded, multicenter, Phase 2 clinical trial (EudraCT2015-000630-30, NCT02579252) enrolled 196 participants with Alzheimer's disease; 119 are included in this post-hoc subgroup analysis. AADvac1, active immunotherapy against pathological tau protein. A machine learning model predicted likely Amyloid+Tau+ participants from baseline MRI. STATISTICAL METHODS: MMRM for change from baseline in cognition, function, and neurodegeneration; linear regression for associations between antibody response and endpoints. RESULTS: The prediction model achieved PPV of 97.7% for amyloid, 96.2% for tau. 119 participants in the full analysis set (70 treatment and 49 placebo) were classified as A+T+. A trend for CDR-SB 104-week change (estimated marginal means [emm] = -0.99 points, 95% CI [-2.13, 0.13], p = 0.0825]) and ADCS-MCI-ADL (emm = 3.82 points, CI [-0.29, 7.92], p = 0.0679) in favour of the treatment group was seen. Reduction was seen in plasma NF-L (emm = -0.15 log pg/mL, CI [-0.27, -0.03], p = 0.0139). Higher antibody response to AADvac1 was related to slowing of decline on CDR-SB (rho = -0.10, CI [-0.21, 0.01], p = 0.0376) and ADL (rho = 0.15, CI [0.03, 0.27], p = 0.0201), and related to slower brain atrophy (rho = 0.18-0.35, p < 0.05 for temporal volume, whole cortex, and right and left hippocampus). CONCLUSIONS: In the subgroup of ML imputed or CSF identified A+T+, AADvac1 slowed AD-related decline in an antibody-dependent manner. Larger anti-tau trials are warranted. FUNDING: AXON Neuroscience SE.

Multimodal analytical tools for the molecular and elemental characterisation of lesions in brain tissue of multiple sclerosis patients.

Multiple sclerosis (MS) is a prevalent immune-mediated inflammatory disease of the central nervous system inducing a widespread degradation of myelin and resulting in neurological deficits. Recent advances in molecular and atomic imaging provide the means to probe the microenvironment in affected brain tissues at an unprecedented level of detail and may provide new insights. This study showcases state-of-the-art spectroscopic and mass spectrometric techniques to compare distributions of molecular and atomic entities in MS lesions and surrounding brain tissues. MS brains underwent post-mortem magnetic resonance imaging (MRI) to locate and subsequently dissect MS lesions and surrounding white matter. Digests of lesions and unaffected white matter were analysed via ICP-MS/MS revealing significant differences in concentrations of Li, Mg, P, K, Mn, V, Rb, Ag, Gd and Bi. Micro x-ray fluorescence spectroscopy (µXRF) and laser ablation - inductively coupled plasma - time of flight - mass spectrometry (LA-ICP-ToF-MS) were used as micro-analytical imaging techniques to study distributions of both endogenous and xenobiotic elements. The essential trace elements Fe, Cu and Zn were subsequently calibrated using in-house manufactured gelatine standards. Lipid distributions were studied using IR-micro spectroscopy and matrix assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI). MALDI-MSI was complemented with high-resolution tandem mass spectrometry and trapped ion mobility spectroscopy for the annotation of specified phospho- and sphingolipids, revealing specific lipid species decreased in MS lesions compared to surrounding white matter. This explorative study demonstrated that modern molecular and atomic mapping techniques provide high-resolution imaging for relevant bio-indicative entities which may complement our current understanding of the underlying pathophysiological processes.

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.

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.

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.

Long-term risk of recurrent vascular events and mortality in young stroke patients: Insights from a multicenter study.

BACKGROUND: Although the incidence of stroke in the young is rising, data on long-term outcomes in these patients are scarce. We thus aimed to investigate the long-term risk of recurrent vascular events and mortality in a multicenter study. METHODS: We followed 396 consecutive patients aged 18-55 years with ischemic stroke (IS) or transient ischemic attack (TIA) enrolled in three European centers during the period 2007-2010. A detailed outpatient clinical follow-up assessment was performed between 2018 and 2020. When an in-person follow-up visit was not possible, outcome events were assessed using electronic records and registry data. RESULTS: During a median follow-up of 11.8 (IQR 10.4-12.7) years, 89 (22.5%) patients experienced any recurrent vascular event, 62 (15.7%) had any cerebrovascular event, 34 (8.6%) had other vascular events, and 27 (6.8%) patients died. Cumulative 10-year incidence rate per 1000 person-years was 21.6 (95% CI 17.1-26.9) for any recurrent vascular event and 14.9 (95% CI 11.3-19.3) for any cerebrovascular event. The prevalence of cardiovascular risk factors increased over time, and 22 (13.5%) patients lacked any secondary preventive medication at the in-person follow-up. After adjustment for demographics and comorbidities, atrial fibrillation at baseline was found to be significantly associated with recurrent vascular events. CONCLUSIONS: This multicenter study shows a considerable risk of recurrent vascular events in young IS and TIA patients. Further studies should investigate whether detailed individual risk assessment, modern secondary preventive strategies, and better patient adherence may reduce recurrence risk.

Autolysis Affects the Iron Cargo of Ferritins in Neurons and Glial Cells at Different Rates in the Human Brain.

Iron is known to accumulate in neurological disorders, so a careful balance of the iron concentration is essential for healthy brain functioning. An imbalance in iron homeostasis could arise due to the dysfunction of proteins involved in iron homeostasis. Here, we focus on ferritin-the primary iron storage protein of the brain. In this study, we aimed to improve a method to measure ferritin-bound iron in the human post-mortem brain, and to discern its distribution in particular cell types and brain regions. Though it is known that glial cells and neurons differ in their ferritin concentration, the change in the number and distribution of iron-filled ferritin cores between different cell types during autolysis has not been revealed yet. Here, we show the cellular and region-wide distribution of ferritin in the human brain using state-of-the-art analytical electron microscopy. We validated the concentration of iron-filled ferritin cores to the absolute iron concentration measured by quantitative MRI and inductively coupled plasma mass spectrometry. We show that ferritins lose iron from their cores with the progression of autolysis whereas the overall iron concentrations were unaffected. Although the highest concentration of ferritin was found in glial cells, as the total ferritin concentration increased in a patient, ferritin accumulated more in neurons than in glial cells. Summed up, our findings point out the unique behaviour of neurons in storing iron during autolysis and explain the differences between the absolute iron concentrations and iron-filled ferritin in a cell-type-dependent manner in the human brain. The rate of loss of the iron-filled ferritin cores during autolysis is higher in neurons than in glial cells.

High serum neurofilament light chain levels correlate with brain atrophy and physical disability in multiple sclerosis.

BACKGROUND AND PURPOSE: Serum neurofilament light chain (sNfL) is a promising biomarker of neuroaxonal damage in persons with multiple sclerosis (pwMS). In cross-sectional studies, sNfL has been associated with disease activity and brain magnetic resonance imaging (MRI) changes; however, it is still unclear to what extent in particular high sNfL levels impact on subsequent disease evolution. METHODS: sNfL was quantified by an ultrasensitive single molecule array (Simoa) in 199 pwMS (median age = 34.2 years, 64.3% female) and 49 controls. All pwMS underwent 3-T MRI to assess global and compartmental normalized brain volumes, T2-lesion load, and cortical mean thickness. Follow-up data and serum samples were available in 144 pwMS (median follow-up time = 3.8 years). Linear and binary logistic models were used to estimate the independent contribution of sNfL for changes in MRI and Expanded Disability Status Scale (EDSS). Age-corrected sNfL z-scores from a normative database of healthy controls were used for sensitivity analyses. RESULTS: High sNfL levels at baseline were associated with atrophy measures of the whole brain (standardized beta coefficient ßj = -0.352, p < 0.001), white matter (ßj = -0.229, p = 0.007), thalamus (ßj = -0.372, p = 0.004), and putamen (ßj = -1.687, p = 0.012). pwMS with high levels of sNfL at baseline and follow-up had a greater risk of EDSS worsening (p = 0.007). CONCLUSIONS: Already single time point elevation of sNfL has a distinct effect on brain volume changes over a short-term period, and repeated high levels of sNfL indicate accumulating physical disability. Serial assessment of sNfL may provide added value in the clinical management of pwMS.

The relevance of rich club regions for functional outcome post-stroke is enhanced in women.

This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.

Radiomics-Derived Brain Age Predicts Functional Outcome After Acute Ischemic Stroke.

BACKGROUND AND OBJECTIVES: While chronological age is one of the most influential determinants of poststroke outcomes, little is known of the impact of neuroimaging-derived biological "brain age." We hypothesized that radiomics analyses of T2-FLAIR images texture would provide brain age estimates and that advanced brain age of patients with stroke will be associated with cardiovascular risk factors and worse functional outcomes. METHODS: We extracted radiomics from T2-FLAIR images acquired during acute stroke clinical evaluation. Brain age was determined from brain parenchyma radiomics using an ElasticNet linear regression model. Subsequently, relative brain age (RBA), which expresses brain age in comparison with chronological age-matched peers, was estimated. Finally, we built a linear regression model of RBA using clinical cardiovascular characteristics as inputs and a logistic regression model of favorable functional outcomes taking RBA as input. RESULTS: We reviewed 4,163 patients from a large multisite ischemic stroke cohort (mean age = 62.8 years, 42.0% female patients). T2-FLAIR radiomics predicted chronological ages (mean absolute error = 6.9 years, r = 0.81). After adjustment for covariates, RBA was higher and therefore described older-appearing brains in patients with hypertension, diabetes mellitus, a history of smoking, and a history of a prior stroke. In multivariate analyses, age, RBA, NIHSS, and a history of prior stroke were all significantly associated with functional outcome (respective adjusted odds ratios: 0.58, 0.76, 0.48, 0.55; all p-values < 0.001). Moreover, the negative effect of RBA on outcome was especially pronounced in minor strokes. DISCUSSION: T2-FLAIR radiomics can be used to predict brain age and derive RBA. Older-appearing brains, characterized by a higher RBA, reflect cardiovascular risk factor accumulation and are linked to worse outcomes after stroke.

Interpretable brain disease classification and relevance-guided deep learning.

Deep neural networks are increasingly used for neurological disease classification by MRI, but the networks' decisions are not easily interpretable by humans. Heat mapping by deep Taylor decomposition revealed that (potentially misleading) image features even outside of the brain tissue are crucial for the classifier's decision. We propose a regularization technique to train convolutional neural network (CNN) classifiers utilizing relevance-guided heat maps calculated online during training. The method was applied using T1-weighted MR images from 128 subjects with Alzheimer's disease (mean age = 71.9 ± 8.5 years) and 290 control subjects (mean age = 71.3 ± 6.4 years). The developed relevance-guided framework achieves higher classification accuracies than conventional CNNs but more importantly, it relies on less but more relevant and physiological plausible voxels within brain tissue. Additionally, preprocessing effects from skull stripping and registration are mitigated. With the interpretability of the decision mechanisms underlying CNNs, these results challenge the notion that unprocessed T1-weighted brain MR images in standard CNNs yield higher classification accuracy in Alzheimer's disease than solely atrophy.

Deep profiling of multiple ischemic lesions in a large, multi-center cohort: Frequency, spatial distribution, and associations to clinical characteristics.

Background purpose: A substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort. Materials and methods: Analyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome. Results: We analyzed 2,466 patients (age = 63.4 ± 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio ∼1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, p FDR < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, p FDR = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only among those with MAL. Conclusion: Multiple lesions, especially those within one vascular territory, occurred more frequently than previously reported. Overall, multiple lesions were distinctly linked to a higher acute stroke severity, a higher total DWI lesion volume and a lower WMH lesion volume. In posterior circulation stroke, lesion volume was linked to a higher stroke severity in multiple lesions only.

Association of Stroke Lesion Pattern and White Matter Hyperintensity Burden With Stroke Severity and Outcome.

BACKGROUND AND OBJECTIVES: To examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways. METHODS: MR neuroimaging and NIH Stroke Scale data at index stroke and the modified Rankin Scale (mRS) score at 3-6 months after stroke were obtained from the MRI-Genetics Interface Exploration study of patients with acute ischemic stroke (AIS). Individual WMH volume was automatically derived from fluid-attenuated inversion recovery images. Stroke lesions were automatically segmented from diffusion-weighted imaging (DWI) images, parcellated into atlas-defined brain regions and further condensed to 10 lesion patterns via machine learning-based dimensionality reduction. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS score >2) were modeled within purpose-built Bayesian linear and logistic regression frameworks. Interaction effects between stroke lesions and a high vs low WMH burden were integrated via hierarchical model structures. Models were adjusted for age, age2, sex, total DWI lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts. RESULTS: A total of 928 patients with AIS contributed to acute stroke severity analyses (age: 64.8 [14.5] years, 40% women) and 698 patients to long-term functional outcome analyses (age: 65.9 [14.7] years, 41% women). Stroke severity was mainly explained by lesions focused on bilateral subcortical and left hemispherically pronounced cortical regions across patients with both a high and low WMH burden. Lesions centered on left-hemispheric insular, opercular, and inferior frontal regions and lesions affecting right-hemispheric temporoparietal regions had more pronounced effects on stroke severity in case of high compared with low WMH burden. Unfavorable outcomes were predominantly explained by lesions in bilateral subcortical regions. In difference to the lesion location-specific WMH effects on stroke severity, higher WMH burden increased the odds of unfavorable outcomes independent of lesion location. DISCUSSION: Higher WMH burden may be associated with an increased stroke severity in case of stroke lesions involving left-hemispheric insular, opercular, and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporoparietal regions (potentially linked to attention). Our findings suggest that patients with specific constellations of WMH burden and lesion locations may have greater benefits from acute recanalization treatments. Future clinical studies are warranted to systematically assess this assumption and guide more tailored treatment decisions.

Magnetic susceptibility anisotropy in normal appearing white matter in multiple sclerosis from single-orientation acquisition.

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.

Free water diffusion MRI and executive function with a speed component in healthy aging.

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 (R2=0.421, p = 0.018) and the corpus callosum (genu (R2 = 0.418, p = 0.021), prefrontal (R2 = 0.416, p = 0.026), premotor (R2 = 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.

Periventricular magnetisation transfer abnormalities in early multiple sclerosis.

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.

Sex-specific lesion pattern of functional outcomes after stroke.

Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men - women) = -0.295 (90% highest posterior density interval = -0.556 to -0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.