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

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.)

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 R 2  = 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 R 2  = 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 R 2  = 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., Competing Interests: Declaration of Competing Interest The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.H. has received speaking honoraria from Roche and Bristol-Myers Squibb. B.H. has received funding for travel from Janssen and speaking honoraria from Roche. I.K.P. has received honoraria for speaking at scientific meetings, serving at scientific advisory boards, and performing consulting activities, from Adamas Pharma, Almirall, Bayer Pharma, Biogen, BMS, Celgene, Desitin, Sanofi-Genzyme, Janssen, Merck, Novartis, Roche, and Teva. She received research support from the German MS Society, Celgene, Novartis, Roche, and Teva. L.P. has no disclosures. V.F. has no disclosures. B.H. has no disclosures. S.R. has no disclosures. S.W. has no disclosures. A.D. has received speaker honoraria from Sanofi-Aventis and travel funding from Novartis. S.E. has no disclosures. R.D. has no disclosures. M.K. has received funding for travel 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. D.P. has received funding for travel from merck, Genzyme/sanofi-Aventis and Biogen, as well as speaking honoraria from Biogen, Novartis and Merck. C.E. received funding for traveling and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Genzyme and Teva Pharmaceutical Industries Ltd./Sanofi-aventis, Shire; received research support from Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries Ltd./Sanofi-aventis; and serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Genzyme, Roche, and Teva Pharmaceutical Industries Ltd./Sanofi- Aventis., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency which recently has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3). Although HIES is characterized by recurrent staphylococcal infections, the microbial invasion of the central nervous system (CNS) is definitively uncommon. We here report on Staphylococcus aureus meningitis and cerebral abscesses acquired in the community in a 31-year-old female patient with a de novo heterozygous mutation of STAT3 and a Dubowitz-like syndrome characterized by growth retardation, microcephaly and eczema. The patient presented with a relative paucity of clinical symptoms despite severe cerebrospinal fluid pathology and multiple cerebral abscesses. Antimicrobial as well as treatment with intravenous immunoglobulin was well tolerated and led to a slow recovery over a 6 months period. Our observation adds community acquired S. aureus meningitis to the list of life-threatening infections in STAT3-deficient HIES and should also raise awareness for the unusual clinical presentation of severe neuroinfection in this syndrome. Whether the association of HIES with Dubowitz-like syndrome was purely coincidental, possibly supportive of the CNS infection, or suggests a genetic overlap of these syndromes, awaits clarification., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Magnetic resonance imaging (MRI) provides objective and detailed insights into morphologic changes of the central nervous system associated with multiple sclerosis (MS). Therefore, it also appears an ideal tool to investigate the possible impact of gender on MS course and severity. Only more recently some studies have specifically addressed this issue and we, therefore, reviewed the literature for investigations which analysed the impact of various factors including gender on MS-related morphologic changes and their evolution. Treatment trials were excluded and the available data refer mainly to relapsing MS with or without secondary progression. A few mostly smaller studies suggest a higher frequency of contrast-enhancing lesions in women. This was not seen in the analysis of a large and pooled dataset of untreated MS patients of the Sylvia Lawry Centre for MS Research. Other large cross-sectional and longitudinal studies found no effects of gender on T2 or T1 lesion burden or on brain atrophy. Findings between male and female MS patients also did not differ when including magnetisation transfer ratio and diffusion tensor imaging for morphologic information. Our review thus indicates no independent gender differences on brain MRI beyond demographic and clinical variables such as age, duration of disease and grade of disability.

More than half of all elderly have some degree of white matter lesions (WML) on MRI of the brain. Until recently, the rate of progression of WML was unknown. Recent work within several population based large scale studies was devoted to tackle this question, to identify factors related to WML progression and to establish a relationship with clinical variables and cognitive changes. There is converging evidence that at least a subset of WML demonstrates considerable progression over time. Increases in WML volume have been correlated with increased loss of brain volume and decline in cognitive and motor performance, indicating that progression of WML harbors clinical relevance. Correlative MRI-histopathologic studies and the clustering of vascular risk factors in subjects with progressive WML support a vascular aetiology of WML, particularly in "confluent" MRI phenotypes. Although specific rating scales have been proposed to detect WML progression, quantitative measurements appear superior given their objective and reproducible nature and regarding possibilities of statistical analyses. Measuring changes in the progression of WML may provide a valid surrogate marker in future clinical trials on cerebral small-vessel disease. Power calculations based on quantitative data of the Austrian Stroke Prevention Study (ASPS) suggest that such studies would be feasible.

Subcortical vascular cognitive impairment is caused by lacunes and widespread ischemic white matter damage which closely resembles white matter abnormalities seen in multiple sclerosis. Recent evidence suggests that the progression rate of ischemic white matter lesions on MRI is very similar to that observed in multiple sclerosis. Consequently, it has been proposed to use MRI for monitoring disease activity not only in multiple sclerosis but also in vascular dementia trials. There is first evidence from magnetization transfer imaging studies that other than in MS normal appearing white matter is not affected in cerebral small vessel disease. This contrasts the hypothesis that ischemic white matter damage extends far beyond changes visible on conventional MR. The cognitive consequences of both diseases are strikingly similar which is at least partly caused by damage to frontal-subcortical circuits. Involvement of these common functional anatomical structures and their modulatory transmitter systems has now led to common interventional approaches such as the use of cholinesterase inhibitors.

Epidemiological studies provide strong evidence that susceptibility to multiple sclerosis (MS) is in part genetically determined. Likewise the heterogeneity in clinical manifestations, temporal course, severity, and in the pathological processes of MS are probably also influenced by our genes. Apolipoprotein E (apoE) polymorphism has been considered a candidate for impacting on MS because of its numerous functions related to brain tissue and evidence for an association with a variety of cerebral disorders, specifically Alzheimer's disease (AD). The apoE alleles epsilon2, epsilon3, and epsilon4 are known to impact differently on aspects such as neuronal growth and repair, neuroprotection and inflammation. After a review of the strong association of the apoE polymorphism with AD, we review the results on MS. These are far less homogenous but have gained support from morphologic and metabolic measures obtained with magnetic resonance imaging indicating a greater extent of brain destruction with the apoE epsilon4 allele. Evidence for a protective role of the epsilon2 allele in MS is weak. In view of the association with AD it is tempting to speculate that neuropsychologic functioning in MS might be even more strongly related to the apoE polymorphism and especially to the epsilon4 allele than other deficits, but few data on this issue are yet available. While part of the association of the apoE polymorphism with AD is supposed to be caused by apoE-isoform dependent effects on amyloid-beta deposition, no single pathogenetically relevant mechanism has yet been confirmed for MS. In summary we presently may assume only subtle effects of the apoE polymorphism on the course of MS. These effects are probably further modulated by other genes and need further investigation.

We performed a functional MRI (fMRI) study during the execution of the Paced Visual Serial Addition Task (PVSAT) in 9 patients with a clinically isolated syndrome suggestive of multiple sclerosis (CIS), 9 patients with clinically definite multiple sclerosis (CDMS), and 18 matched healthy control subjects. In controls, the PVSAT elicited a fronto-parietal network with cerebellar activation which we expected for this kind of working memory test and which indicates that this PVSAT version is an appropriate tool for measuring functional changes during a cognitive task. Although there were no significant differences in the actual test results of patients vs. controls, CDMS and CIS patients activated distinct cerebral networks in their attempt to solve the fMRI-PVSAT. Compared to CIS patients, CDMS patients showed increased hippocampal and parahippocampal activation, suggesting the need to additionally support their working memory. In contrast, compared to CDMS patients and healthy controls, CIS patients demonstrated stronger activation of the anterior cingulate cortex, which might indicate focused involvement of executive processes. On the PASAT (Paced Auditory Serial Addition Task) patients also performed similarly to controls but they showed decreased scores on most of the sub-tests of the Wechsler Memory Scale. Based on our observations using the fMRI-PVSAT, we hypothesize that distinct differences in cognitive processing occur with the evolution of MS and that, at these early stages of the disease, they cannot be detected with sufficient sensitivity using only the PASAT.

The rate and extent of progression of white matter hyperintensities (WMH) over time in elderly subjects is yet unclear. These abnormalities may represent an early form of subcortical vascular dementia. As to whether such changes could be used, as a surrogate marker for this subtype of vascular dementia remains to be determined. So far there exists only a very limited number of studies determining the rate, clinical predictors and cognitive consequences of WMH evolution. There is evidence that these changes do progress over time, however the results of the different studies cannot be compared due to methodological differences. The Austrian Stroke Prevention Study reported that 17.9% of normal individuals show progression over time. The only published quantitative data demonstrated an absolute increase of 1.1 cm(3) over an observational period of 4 years in healthy subjects. Diastolic blood pressure, early confluent or confluent WMH at baseline and genetic variants in the angiotensinogen gene are so far the only known predictors of WMH progression. The Austrian Stroke Prevention Study did not find an association between the evolution of WMH and cognitive functioning but the statistical power of this analysis was small and the relationship needs to be further explored.