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Barbara Landsmann,1,2 Daniela Pinter,2 Eva Pirker,1,2 Gerald Pichler,3 Walter Schippinger,3 Elisabeth M Weiss,1 Gabriel Mathie,2 Thomas Gattringer,2 Franz Fazekas,2 Christian Enzinger2,4 1Institute of Psychology, University of Graz, Graz, Austria; 2Department of Neurology, Medical University of Graz, Graz, Austria; 3Albert Schweitzer Clinic Graz, Graz, Austria; 4Division of Neuroradiology, Department of Radiology, Medical University of Graz, Graz, Austria Purpose: Previous studies demonstrated changes in sensorimotor network activation over time after stroke that have been interpreted as partly compensatory. Locomotor and balance trainings may improve both mobility and cognition even in chronic stroke and thereby impact on cerebral activation patterns. We here aimed at testing these assumptions in an exploratory study to inform subsequent larger intervention studies. Patients and methods: Eight patients (73.3±4.4 years) with a chronic lacunar stroke (mean interval 3.7 years after the acute event with a range from 2 to 4 years) and residual leg paresis leading to gait disturbance received a guided 5-week training focusing on mobility, endurance, and coordination. Before and afterward, they underwent clinical, neuropsychological, and gait assessments and brain MRI at 3 T including a functional ankle movement paradigm. Sixteen healthy controls (HCs; 68.8±5.4 years) followed the same protocol without intervention. Results: After training, patients had improved in mobility, memory, and delayed recall of memory. While cerebral activations in HC remained completely unaltered, patients showed increased activations in the right precentral gyrus, the right and left superior frontal gyri, and the right frontal lobe, with bipedal ankle movements after training. Conclusion: In this exploratory study of chronic stroke, we found not only significant effects of physical training on mobility but also distinct aspects of cognition already with a small number of highly selected patients. These improvements were paralleled by alterations in cerebral activity possibly reflecting neuronal plasticity. Larger studies including randomization are needed. Keywords: mobility, cognition, lacunar stroke, training, rehabilitation, neuronal plasticity

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. [ABSTRACT FROM AUTHOR]

Background and purpose: Guidelines on monogenic cerebral small‐vessel disease (cSVD) diagnosis and management are lacking. Endorsed by the Stroke and Neurogenetics Panels of the European Academy of Neurology, a group of experts has provided recommendations on selected monogenic cSVDs, i.e. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), autosomal dominant High Temperature Requirement A Serine Peptidase 1 (HTRA1), cathepsin‐A‐related arteriopathy with strokes and leukoencephalopathy (CARASAL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), Fabry disease, mitochondrial encephalopathy, lactic acidosis and stroke‐like episodes (MELAS) and type IV collagen (COL4)A1/2. Methods: We followed the Delphi methodology to provide recommendations on several unanswered questions related to monogenic cSVD, including genetic testing, clinical and neuroradiological diagnosis, and management. Results: We have proposed 'red‐flag' features suggestive of a monogenic disease. General principles applying to the management of all cSVDs and specific recommendations for the individual forms of monogenic cSVD were agreed by consensus. Conclusions: The results provide a framework for clinicians involved in the diagnosis and management of monogenic cSVD. Further multicentre observational and treatment studies are still needed to increase the level of evidence supporting our recommendations. [ABSTRACT FROM AUTHOR]

Background and purpose: The aim was to investigate the clinical impact of the duration of artificial ventilation in stroke patients receiving mechanical thrombectomy (MT) under general anaesthesia. Methods: All consecutive ischaemic stroke patients who had been treated at our centre with MT for anterior circulation large vessel occlusion under general anaesthesia were identified over an 8‐year period. Ventilation time was analysed as a continuous variable and patients were grouped into extubation within 6 h ('early'), 6–24 h ('delayed') and >24 h ('late'). Favourable outcome was defined as modified Rankin Scale scores of 0–2 at 3 months post‐stroke. Pneumonia rate and reasons for prolonged ventilation were also assessed. Results: Amongst 447 MT patients (mean age 69.1 ± 13.3 years, 50.1% female), the median ventilation time was 3 h. 188 (42.6%) patients had a favourable 3‐month outcome, which correlated with shorter ventilation time (Spearman's rho 0.39, P < 0.001). In patients extubated within 24 h, early compared to delayed extubation was associated with improved outcome (odds ratio 2.40, 95% confidence interval 1.53–3.76, P < 0.001). This was confirmed in multivariable analysis (P = 0.01). A longer ventilation time was associated with a higher rate of pneumonia during neurointensive care unit/stroke unit stay (early/delayed/late extubation: 9.6%/20.6%/27.7%, P < 0.01). Whilst stroke‐associated complications represented the most common reasons for late extubation (>24 h), delayed extubation (6–24 h) was associated with admission outside of core working hours (P < 0.001). Conclusions: Prolonged ventilation time after stroke thrombectomy independently predicts unfavourable outcome at 3 months and is associated with increased pneumonia rates. Therefore, extubation should be performed as early as safely possible. [ABSTRACT FROM AUTHOR]

Background: Recent studies have created awareness that facial features can be reconstructed from high-resolution MRI. Therefore, data sharing in neuroimaging requires special attention to protect participants' privacy. Facial features removal (FFR) could alleviate these concerns. We assessed the impact of three FFR methods on subsequent automated image analysis to obtain clinically relevant outcome measurements in three clinical groups.Methods: FFR was performed using QuickShear, FaceMasking, and Defacing. In 110 subjects of Alzheimer's Disease Neuroimaging Initiative, normalized brain volumes (NBV) were measured by SIENAX. In 70 multiple sclerosis patients of the MAGNIMS Study Group, lesion volumes (WMLV) were measured by lesion prediction algorithm in lesion segmentation toolbox. In 84 glioblastoma patients of the PICTURE Study Group, tumor volumes (GBV) were measured by BraTumIA. Failed analyses on FFR-processed images were recorded. Only cases in which all image analyses completed successfully were analyzed. Differences between outcomes obtained from FFR-processed and full images were assessed, by quantifying the intra-class correlation coefficient (ICC) for absolute agreement and by testing for systematic differences using paired t tests.Results: Automated analysis methods failed in 0-19% of cases in FFR-processed images versus 0-2% of cases in full images. ICC for absolute agreement ranged from 0.312 (GBV after FaceMasking) to 0.998 (WMLV after Defacing). FaceMasking yielded higher NBV (p = 0.003) and WMLV (p ≤ 0.001). GBV was lower after QuickShear and Defacing (both p < 0.001).Conclusions: All three outcome measures were affected differently by FFR, including failure of analysis methods and both "random" variation and systematic differences. Further study is warranted to ensure high-quality neuroimaging research while protecting participants' privacy.Key Points: • Protecting participants' privacy when sharing MRI data is important. • Impact of three facial features removal methods on subsequent analysis was assessed in three clinical groups. • Removing facial features degrades performance of image analysis methods. [ABSTRACT FROM AUTHOR]

Background and purpose: Information on the prevalence and course of post‐stroke cognitive impairment in young stroke patients is limited. The aim was to assess a consecutive sample of acute young ischaemic stroke patients (18–55 years) for the presence and development of neuropsychological deficits. Methods: Patients prospectively underwent a comprehensive clinical and cognitive assessment, examining general cognitive function, processing speed, attention, flexibility/executive function and word fluency within the first 3 weeks after hospital admission (median assessment at day 6) and at a 3 months' follow‐up (FU). Cognitive dysfunction was defined in comparison to age‐standardized published norms. Results: At baseline (N = 114), deficits were highly prevalent in processing speed (56.0%), flexibility/executive function (49.5%), attention (46.4%) and general cognitive function (42.1%). These frequencies were comparable for those with FU assessment (N = 87). In most domains, cognitive performance improved within 3 months, except for word fluency. However, in about one‐third of patients, cognitive deficits (as defined by 1.5 standard deviations below the standardized mean) were still present 3 months after stroke. At FU, 44.0% were impaired in the domain flexibility/executive function, 35.0% in processing speed and 30.0% in attention. Conclusions: The high prevalence of cognitive deficits in acute young patients with ischaemic stroke highlights the importance of early post‐stroke cognitive assessment to capture a patient's dysfunction in a comprehensive manner and to offer adequate rehabilitation. The role of factors which promote neuropsychological deficits needs further exploration. [ABSTRACT FROM AUTHOR]

Background: Lipocalin 2 (LCN2) may be involved in the immunopathogenesis of multiple sclerosis (MS) and might further impact on iron homoeostasis. Brain iron accumulates in MS; however, the association to iron-related proteins is still unsolved. Objective: To investigate cerebrospinal fluid (CSF) and serum LCN2, transferrin (Trf) and ferritin in early MS in relation to disease evolution and longitudinal brain iron accumulation. Methods: We analysed CSF and serum LCN2 by enzyme-linked immunosorbent assay (ELISA) and Trf and ferritin by nephelometry in 55 patients (45 clinically isolated syndrome (CIS), 10 MS, median clinical follow-up 4.8 years) and 63 controls. In patients, we assessed sub-cortical grey matter iron by 3T magnetic resonance imaging (MRI) R2* relaxometry (median imaging follow-up 2.2 years). Results: Compared to controls serum (p < 0.01), CSF (p < 0.001) LCN2 and CSF Trf (p < 0.001) levels were reduced in the patients. CSF LCN2 correlated with CSF Trf (r = 0.5, p < 0.001). In clinically stable patients, CSF LCN2 levels correlated with basal ganglia iron accumulation (r = 0.5, p < 0.05). In CIS, higher CSF LCN2 levels were associated with conversion to clinically definite MS (p < 0.05). Conclusion: We demonstrate altered LCN2 regulation in early MS and provide first evidence for this to be possibly linked to both clinical MS activity and iron accumulation in the basal ganglia. [ABSTRACT FROM AUTHOR]

Background and purpose Acute lesions in patients with transient ischaemic attack (TIA) are important as they are associated with increased risk for recurrence. Characteristics associated with acute lesions in young TIA patients were therefore investigated. Methods The sifap1 study prospectively recruited a multinational European cohort ( n = 5023) of patients aged 18-55 years with acute cerebrovascular event. The detection of acute ischaemic lesions was based on diffusion-weighted imaging (DWI). The frequency of DWI lesions was assessed in 829 TIA patients who met the criteria of symptom duration <24 h and their association with demographic, clinical and imaging variables was analysed. Results The median age was 46 years (interquartile range 40-51 years); 45% of the patients were female. In 121 patients (15%) ≥1 acute DWI lesion was detected. In 92 patients, DWI lesions were found in the anterior circulation, mostly located in cortical-subcortical areas ( n = 63). Factors associated with DWI lesions in multiple regression analysis were left hemispheric presenting symptoms [odds ratio (OR) 1.92, 95% confidence interval (CI) 1.27−2.91], dysarthria (OR 2.17, 95% CI 1.38−3.43) and old brain infarctions on MRI (territories of the middle and posterior cerebral artery: OR 2.43, 95% CI 1.42−4.15; OR 2.41, 95% CI 1.02−5.69, respectively). Conclusions In young patients with a clinical TIA 15% demonstrated acute DWI lesions on brain MRI, with an event pattern highly suggestive of an embolic origin. Except for the association with previous infarctions there was no clear clinical predictor for acute ischaemic lesions, which indicates the need to obtain MRI in young individuals with TIA. [ABSTRACT FROM AUTHOR]

Objectives: The objectives of this paper are to compare in a multicenter setting patterns of regional cortical thickness in patients with relapsing–remitting multiple sclerosis (RRMS) and cognitive impairment (CI) and those cognitively preserved (CP), and explore the relationship between cortical thinning and cognitive performance. Methods: T1-weighted isotropic brain scans were collected at 3T from seven European centers in 60 RRMS patients and 65 healthy controls (HCs). Patients underwent clinical and neuropsychological examinations. Cortical thickness (CTh) measures were calculated using FreeSurfer (failing in four) and both lobar and vertex-based general linear model (GLM) analyses were compared between study groups. Results: Twenty (36%) MS patients were classified as CI. Mean global CTh was smaller in RRMS patients compared to HCs (left 2.43 vs. 2.53 mm, right 2.44 vs. 2.54 mm, p < 0.001). Multivariate GLM regional analysis showed significantly more temporal thinning in CI compared to CP patients. Verbal memory scores correlated to regional cortical thinning in the insula whereas visual memory scores correlated to parietal thinning. Conclusions: This multicenter study showed mild global cortical thinning in RRMS. The extent of thinning is less pronounced than previously reported. Only subtle regional differences between CI and CP patients were observed, some of which related to specific cognitive domains. [ABSTRACT FROM AUTHOR]

Background: The extent and clinical significance of brain volume changes in different phases of multiple sclerosis (MS) is still under discussion. Objective: To determine the rate of global and compartmental brain volume changes in patients with a clinically-isolated syndrome (CIS) compared to patients with definite MS, by long-term follow-up and as a predictor of conversion to MS in a routine clinical setting. Methods: We investigated 120 patients (63 CIS and 57 MS) at baseline and after a mean follow-up period of 43 months, including detailed clinical examination and 3-Tesla magnetic resonance imaging (MRI). Our imaging analyses comprised the normalized brain volume (NBV), cortical grey matter (cGMV) and white matter (WMV) volumes using SIENA/X, the percentage of brain volume change (PBVC) using SIENA and the change in the volume of the thalami (TV) and basal ganglia (BGV). We also determined the amount and change of T2-lesion load (T2-LL). Results: At baseline, all the brain volume metrics, except cGMV, were significantly lower; and the T2-LL was significantly higher, in patients with MS rather than CIS. During the follow-up, only the PBVC was higher in MS (p = 0.008) and this difference was driven by converters from CIS to MS. Quartiles of PBVC did not allow us to predict conversion to MS, but were associated with the degree of disability. Conclusions: PBVC is the most sensitive marker of progressing atrophy and a higher PBVC was generally associated with more active disease; however, it did not serve to predict the course of MS on an individual basis, in this study. [ABSTRACT FROM AUTHOR]

The article reports on a study which examines the difference of iron metabolism markers in cerebrospinal fluid (CSF) and serum in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS). The study used nephelometry to analyse serum ferritin, transferrin, and soluble transferrin-receptor in patients and control groups. Findings reveal that a significant decreased of CSF transferrin was observed in CIS/MS than control groups.

Objectives: Cerebral amyloid angiopathy (CAA)-associated lobar intracerebral hemorrhage (ICH) has a high risk of recurrence, but the underlying mechanisms remain uncertain. We, therefore, aimed to characterize patterns of recurrent ICH., Methods: We investigated early recurrent ICH (≥1 recurrent ICH event within 90 days of the index event) and ICH clusters (≥2 ICH events within 90 days at any time point) in 2 large cohorts of consecutive patients with first-ever ICH and available MRI., Results: In 682 included patients (median age 68 years, 40.3% female, median follow-up time 4.1 years), 18 (2.6%) had an early recurrent ICH, which was associated with higher age and CAA. In patients with probable CAA, the risk of early recurrent ICH was increased 5-fold within the first 3 months compared with during months 4-12 (hazard ratio 5.41, 95% CI 2.18-13.4) while no significant difference was observed in patients without CAA. In patients with an ICH cluster, we observed spatial clustering (recurrent ICH within close proximity of index ICH in 63.0%) and a tendency for multiple sequential hemorrhages (≥3 ICH foci within 3 months in 44.4%)., Discussion: Our data provide evidence of both temporal and spatial clustering of ICH in CAA, suggesting a transient and localized active bleeding-prone process.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an immune-mediated demyelinating disease that is challenging to differentiate from multiple sclerosis (MS), as the clinical phenotypes overlap, and people with MOGAD can fulfil the current MRI-based diagnostic criteria for MS. In addition, the MOG antibody assays that are an essential component of MOGAD diagnosis are not standardized. Accurate diagnosis of MOGAD is crucial because the treatments and long-term prognosis differ from those for MS. This Expert Recommendation summarizes the outcomes from a Magnetic Resonance Imaging in MS workshop held in Oxford, UK in May 2022, in which MS and MOGAD experts reflected on the pathology and clinical features of these disorders, the contributions of MRI to their diagnosis and the clinical use of the MOG antibody assay. We also critically reviewed the literature to assess the validity of distinctive imaging features in the current MS and MOGAD criteria. We conclude that dedicated orbital and spinal cord imaging (with axial slices) can inform MOGAD diagnosis and also illuminate differential diagnoses. We provide practical guidance to neurologists and neuroradiologists on how to navigate the current MOGAD and MS criteria. We suggest a strategy that includes useful imaging discriminators on standard clinical MRI and discuss imaging features detected by non-conventional MRI sequences that demonstrate promise in differentiating these two disorders., (© 2024. Springer Nature Limited.)

Hippocampal atrophy (tissue loss) has become a fundamental outcome parameter in clinical trials on Alzheimer's disease. To accurately estimate hippocampus volume and track its volume loss, a robust and reliable segmentation is essential. Manual hippocampus segmentation is considered the gold standard but is extensive, time-consuming, and prone to rater bias. Therefore, it is often replaced by automated programs like FreeSurfer, one of the most commonly used tools in clinical research. Recently, deep learning-based methods have also been successfully applied to hippocampus segmentation. The basis of all approaches are clinically used T1-weighted whole-brain MR images with approximately 1 mm isotropic resolution. However, such T1 images show low contrast-to-noise ratios (CNRs), particularly for many hippocampal substructures, limiting delineation reliability. To overcome these limitations, high-resolution T2-weighted scans are suggested for better visualization and delineation, as they show higher CNRs and usually allow for higher resolutions. Unfortunately, such time-consuming T2-weighted sequences are not feasible in a clinical routine. We propose an automated hippocampus segmentation pipeline leveraging deep learning with T2-weighted MR images for enhanced hippocampus segmentation of clinical T1-weighted images based on a series of 3D convolutional neural networks and a specifically acquired multi-contrast dataset. This dataset consists of corresponding pairs of T1- and high-resolution T2-weighted images, with the T2 images only used to create more accurate manual ground truth annotations and to train the segmentation network. The T2-based ground truth labels were also used to evaluate all experiments by comparing the masks visually and by various quantitative measures. We compared our approach with four established state-of-the-art hippocampus segmentation algorithms (FreeSurfer, ASHS, HippoDeep, HippMapp3r) and demonstrated a superior segmentation performance. Moreover, we found that the automated segmentation of T1-weighted images benefits from the T2-based ground truth data. In conclusion, this work showed the beneficial use of high-resolution, T2-based ground truth data for training an automated, deep learning-based hippocampus segmentation and provides the basis for a reliable estimation of hippocampal atrophy in clinical studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: QSM provides insight into healthy brain aging and neuropathologies such as multiple sclerosis (MS), traumatic brain injuries, brain tumors, and neurodegenerative diseases. Phase data for QSM are usually acquired from 3D gradient-echo (3D GRE) scans with long acquisition times that are detrimental to patient comfort and susceptible to patient motion. This is particularly true for scans requiring whole-brain coverage and submillimeter resolutions. In this work, we use a multishot 3D echo plannar imaging (3D EPI) sequence with shot-selective 2D CAIPIRIHANA to acquire high-resolution, whole-brain data for QSM with minimal distortion and blurring., Methods: To test clinical viability, the 3D EPI sequence was used to image a cohort of MS patients at 1-mm isotropic resolution at 3 T. Additionally, 3D EPI data of healthy subjects were acquired at 1-mm, 0.78-mm, and 0.65-mm isotropic resolution with varying echo train lengths (ETLs) and compared with a reference 3D GRE acquisition., Results: The appearance of the susceptibility maps and the susceptibility values for segmented regions of interest were comparable between 3D EPI and 3D GRE acquisitions for both healthy and MS participants. Additionally, all lesions visible in the MS patients on the 3D GRE susceptibility maps were also visible on the 3D EPI susceptibility maps. The interplay among acquisition time, resolution, echo train length, and the effect of distortion on the calculated susceptibility maps was investigated., Conclusion: We demonstrate that the 3D EPI sequence is capable of rapidly acquiring submillimeter resolutions and providing high-quality, clinically relevant susceptibility maps., (© 2024 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Delirium is a common complication in acute stroke patients, occurring in 15-35% of all stroke unit admissions and is associated with prolonged hospital stay and a poor post-stroke prognosis. Managing delirium in acute stroke patients necessitates an intensive and multiprofessional therapeutic approach, placing a significant burden on healthcare staff. However, dedicated practical recommendations for delirium management developed for the population of acute stroke patients are lacking. For this purpose, the Austrian Stroke Society, in cooperation with the Austrian Society of Neurology, the Austrian Society of Neurorehabilitation, and the Austrian Society of Psychiatry, Psychotherapy, and Psychosomatics has formulated an evidence-based position paper addressing the management of delirium in acute stroke patients. The paper outlines practical recommendations on the three pillars of care in stroke patients with delirium: (a) Key aspects of delirium prevention including stroke-specific delirium risk factors and delirium prediction scores are described. Moreover, a non-pharmacological delirium prevention bundle is presented. (b) The paper provides recommendations on timing and frequency of delirium screening to ensure early diagnosis of delirium in acute stroke patients. Moreover, it reports on the use of different delirium screening tools in stroke populations. (c) An overview of non-pharmacological and pharmacological treatment strategies in patients with delirium and acute stroke is presented and summarized as key recommendation statements., (© The Author(s), 2024.)

The optic nerve is frequently involved in multiple sclerosis (MS). However, MRI of the optic nerve is considered optional in the differential diagnosis of optic neuropathy symptoms either at presentation or in established MS. In addition, unlike spinal cord imaging in comparable scenarios, no role is currently recommended for optic nerve MRI in patients presenting with optic neuritis for its confirmation, to plan therapeutic strategy, within the MS diagnostic framework, nor for the detection of subclinical activity in established MS. In this article, evidence related to these 3 aspects will be summarized and gaps in knowledge will be highlighted, including (1) the acquisition challenges and novel sequences that assess pathologic changes within the anterior visual pathways; (2) the clinical implications of quantitative magnetic resonance studies of the optic nerve, focusing on atrophy measures, magnetization transfer, and diffusion tensor imaging; and (3) the relevant clinical studies performed to date. Finally, an algorithm for the application of optic nerve MRI will be proposed to guide future studies aimed at addressing our knowledge gaps.

Background: Actual and imagined cued gait trainings have not been compared in people with multiple sclerosis (MS)., Objective: To analyze the effects of cued motor imagery (CMI), cued gait training (CGT), and combined CMI and cued gait training (CMI-CGT) on motor, cognitive, and emotional functioning, and health-related quality of life in people with MS., Methods: In this double-blind randomized parallel-group multicenter trial, people with MS were randomized (1:1:1) to CMI, CMI-CGT, or CGT for 30 minutes, 4×/week for 4 weeks. Patients practiced at home, using recorded instructions, and supported by ≥6 phone calls. Data were collected at weeks 0, 4, and 13. Co-primary outcomes were walking speed and distance, analyzed by intention-to-treat. Secondary outcomes were global cognitive impairment, anxiety, depression, suicidality, fatigue, HRQoL, motor imagery ability, music-induced motivation, pleasure and arousal, self-efficacy, and cognitive function. Adverse events and falls were continuously monitored., Results: Of 1559 screened patients, 132 were randomized: 44 to CMI, 44 to CMI-CGT, and 44 to CGT. None of the interventions demonstrated superiority in influencing walking speed or distance, with negligible effects on walking speed (η 2  = 0.019) and distance (η 2  = 0.005) observed in the between-group comparison. Improvements in walking speed and walking distance over time corresponded to large effects for CMI, CMI-CGT, and CGT (η 2  = 0.348 and η 2  = 0.454 respectively). No severe study-related adverse events were reported., Conclusions: CMI-GT did not lead to improved walking speed and distance compared with CMI and CGT alone in people with MS. Lack of a true control group represents a study limitation., Trial Registration: German Clinical Trials Register, DRKS00023978., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Recent small subcortical infarcts (RSSI) are the neuroimaging hallmark feature of small vessel disease (SVD)-related acute lacunar stroke. Long-term data on recurrent cerebrovascular events including their aetiology after RSSI are scarce., Patients and Methods: This retrospective study included all consecutive ischaemic stroke patients with an MRI-confirmed RSSI (in the supply area of a small single brain artery) at University Hospital Graz between 2008 and 2013. We investigated associations between clinical and SVD features on MRI (STRIVE criteria) and recurrent cerebrovascular events, using multivariable Cox regression adjusted for age, sex, vascular risk factors and MRI parameters., Results: We analysed 332 consecutive patients (mean age 68 years, 36% women; median follow-up time 12 years). A recurrent ischaemic cerebrovascular event occurred in 70 patients (21.1%; 54 ischaemic strokes, 22 transient ischaemic attacks) and was mainly attributed to SVD (68%). 26 patients (7.8%) developed intracranial haemorrhage. In multivariable analysis, diabetes (HR 2.43, 95% CI 1.44-3.88), severe white matter hyperintensities (HR 1.97, 95% CI 1.14-3.41), and cerebral microbleeds (HR 1.89, 95% CI 1.32-3.14) on baseline MRI were related to recurrent ischaemic stroke/TIA, while presence of cerebral microbleeds increased the risk for intracranial haemorrhage (HR 3.25, 95% CI 1.39-7.59). A widely used SVD summary score indicated high risks of recurrent ischaemic (HR 1.22, 95% CI 1.01-1.49) and haemorrhagic cerebrovascular events (HR 1.57, 95% CI 1.11-2.22)., Conclusion: Patients with RSSI have a substantial risk for recurrent cerebrovascular events-particularly those with coexisting chronic SVD features. Recurrent events are mainly related to SVD again., (© 2024. The Author(s).)

Background and Objectives: Chronic kidney disease (CKD) may be associated with the pathogenesis and phenotype of cerebral small vessel disease (SVD), which is the commonest cause of intracerebral hemorrhage (ICH). The purpose of this study was to investigate the associations of CKD with ICH neuroimaging phenotype, volume, and location, total burden of small vessel disease, and its individual components., Methods: In 2 cohorts of consecutive patients with ICH evaluated with MRI, we investigated the frequency and severity of CKD based on established Kidney Disease Improving Global Outcomes criteria, requiring estimated glomerular filtration rate (eGFR) measurements <60 mL/min/1.73 2 ≥ 3 months apart to define CKD. MRI scans were rated for ICH neuroimaging phenotype (arteriolosclerosis, cerebral amyloid angiopathy, mixed location SVD, or cryptogenic ICH) and the presence of markers of SVD (white matter hyperintensities [WMHs], cerebral microbleeds [CMBs], lacunes, and enlarged perivascular spaces, defined according to the STandards for ReportIng Vascular changes on nEuroimaging criteria). We used multinomial, binomial logistic, and ordinal logistic regression models adjusted for age, sex, hypertension, and diabetes to account for possible confounding caused by shared risk factors of CKD and SVD., Results: Of 875 patients (mean age 66 years, 42% female), 146 (16.7%) had CKD. After adjusting for age, sex, and comorbidities, patients with CKD had higher rates of mixed SVD than those with eGFR >60 (relative risk ratio 2.39, 95% CI 1.16-4.94, p = 0.019). Severe WMHs, deep microbleeds, and lacunes were more frequent in patients with CKD, as was a higher overall SVD burden score (odds ratio 1.83 for each point on the ordinal scale, 95% CI 1.31-2.56, p < 0.001). Patients with eGFR ≤30 had more CMBs (median 7 [interquartile range 1-23] vs 2 [0-8] for those with eGFR >30, p = 0.007)., Discussion: In patients with ICH, CKD was associated with SVD burden, a mixed SVD phenotype, and markers of arteriolosclerosis. Our findings indicate that CKD might independently contribute to the pathogenesis of arteriolosclerosis and mixed SVD, although we could not definitively account for the severity of shared risk factors. Longitudinal and experimental studies are, therefore, needed to investigate causal associations. Nevertheless, stroke clinicians should be aware of CKD as a potentially independent and modifiable risk factor of SVD.

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.)

Background: Walking impairment is one of the most prevalent symptoms in people with multiple sclerosis (pwMS). In this study, we aimed to explore the usefulness of a simple walking test, the Timed 25 Foot Walk (T25FW), in detecting subtle differences in "fully ambulatory" pwMS compared to HC., Methods: We therefore investigated retrospective data from a clinical real-life cohort of 650 pwMS. We first analyzed the amount of patients showing clinically relevant impairment in the T25FW (T25FW > 6 s) within different levels of disability according to the Expanded Disability Status Scale (EDSS). For detailed analysis in "fully ambulatory" pwMS, we formed four groups according to the respective levels of disability (EDSS 0, EDSS 1, EDSS 1.5-2, EDSS 2.5-3), and compared their walking speed to age- and sex-matched healthy controls (HC)., Results: In our cohort, the number of patients showing clinically relevant slowing in the T25FW ranged from 15% in "fully ambulatory" patients (EDSS 0-3) to 69% in patients with moderate (EDSS 3.5-5.5) and 100% in patients with severe impairment (EDSS ≥6). Further analyses in "fully ambulatory" patients revealed that all EDSS-subgroups showed significant slowing compared to HC. The mean difference to walking speed of HC became gradually more pronounced from 0.15 m/s in asymptomatic patients (EDSS 0) to 0.5 m/s in patients with EDSS 2.5-3., Conclusion: These findings underline the ability of the T25FW to detect slowing even in patients with minimal disability. While the difference to HC was slightly below clinical relevance in asymptomatic patients (EDSS 0), slowing gradually worsened from EDSS 1 onwards and exceeded published thresholds for clinical meaningfulness., Competing Interests: Declaration of competing interest Bi.H. received speaker honoraria from Roche and Bristol-Myers Squibb, and travel funding from Janssen. D.P. received travel funding from Merck, Genzyme/Sanofi-Aventis and Biogen and speaker honoraria from Biogen, Novartis and Merck. S.H. received speaker honoraria from Roche and Bristol-Myers Squibb. G.B. has nothing to disclose. M.K. received travel funding and speaker honoraria from Bayer Schering Pharma, Novartis, Genzyme, Merck Serono, Biogen Idec and Teva Pharmaceutical Industries Ltd., and a research grant from Teva Pharmaceutical Industries Ltd. Be.H. received travel funding or speaker honoraria from Bayer Schering Pharma, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. A.D. received speaker honoraria from Sanofi-Aventis and travel funding from Novartis. A.P. has nothing to disclose. C.E. received travel funding and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Genzyme and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis, Shire and Janssen; has received research support from Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis; and served on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Genzyme, Roche, and Teva Pharmaceutical Industries Ltd./Sanofi- Aventis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To explore the experiences and acceptability of music-cued motor imagery (MCMI), music-cued gait training (MCGT), and combined MCMI and MCGT (MCMI-MCGT) in people with multiple sclerosis (pwMS). We also aimed to explore participants' self-rated health status postintervention and gather recommendations for further programme development., Design: Qualitative study alongside the double-blind randomised controlled real and imagined gait training with music-cueing (RIGMUC) multicentre trial of MCMI, MCGT and MCMI-MCGT., Setting: PwMS recruited for the RIGMUC trial from Departments of Neurology at Medical Universities of Innsbruck and Graz and Clinic for Rehabilitation Muenster, Austria., Participants: All 132 pwMS with mild to moderate disability randomised into the trial were included in the analysis., Methods: Participants practised home-based MCMI, MCGT or MCMI-MCGT for 30 min, 4×/week, for 4 weeks. Three trained researchers conducted weekly semistructured telephone interviews during the intervention period, supporting adherence, addressing problems, sharing experiences and assessing intervention acceptability. Follow-up interviews at 4-week postintervention aimed to understand participants' self-rated changes in walking, fatigue and overall health compared with their prestudy condition. Investigator triangulation was employed among the researchers to enhance trustworthiness and credibility., Results: Using thematic analysis, we identified five themes: (1) empowerment, (2) remaining in sync, (3) interconnection between imagined and actual walking, (4) sustaining focus and (5) real-world transfer. Participants appreciated and found the imagined and actual MCGT innovative. Problems included concentration issues, early fatigue in advanced disability and difficulty synchronising with music cues. Positive changes in walking, fatigue and overall health postinterventions were reported offering valuable insights for programme development., Conclusions: A participatory study to codevelop a music-cued exercise programme for pwMS seems appropriate as participants appreciated the innovation and effectiveness of both imagined and actual MCGT. Future studies should also investigate pwMS' potential and limitations in enhancing their MCMI abilities with intensive therapist-supported practice., Trial Registration Number: DRKS00023978., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)