Anti-LINGO-1 treatment restores myelination of corticospinal tract neurons and improves functional recovery after stroke.

Demyelination of corticospinal tract neurons contributes to long-term disability after cortical stroke. Nonetheless, poststroke myelin loss has not been addressed as a therapeutic target, so far. We hypothesized that an antibody-mediated inhibition of the Nogo receptor-interacting protein (LINGO-1, leucine-rich repeat and immunoglobulin domain-containing Nogo receptor-interacting protein) may counteract myelin loss, enhance remyelination and axonal growth, and thus promote functional recovery following stroke. To verify this hypothesis, mice were subjected to photothrombotic stroke and received either an antibody against LINGO-1 (n = 19) or a control treatment (n = 18). Behavioral tests were performed to assess the effects of anti-LINGO-1 treatment on the functional recovery. Seven weeks after stroke, immunohistochemical analyses were performed to analyze the effect of anti-LINGO-1 treatment on myelination and axonal loss of corticospinal tract neurons, proliferation of oligodendrocytes and neurogenesis. Anti-LINGO-1 treatment resulted in significantly improved functional recovery (p < 0.0001, repeated measures analysis of variance), and increased neurogenesis in the hippocampus and subventricular zone of the ipsilateral hemisphere (p = 0.0094 and p = 0.032, t-test). Notably, we observed a significant increase in myelin (p = 0.0295, t-test), platelet-derived growth factor receptor α-positive oligodendrocyte precursor cells (p = 0.0356, t-test) and myelinating adenomatous polyposis coli-positive cells within the ipsilateral internal capsule of anti-LINGO-1-treated mice (p = 0.0021, t-test). In conclusion, we identified anti-LINGO-1 as the first neuroregenerative treatment that counteracts poststroke demyelination of corticospinal tract neurons, presumably by increased proliferation of myelin precursor cells, and thereby improves functional recovery. Most importantly, our study presents myelin loss as a novel therapeutic target following stroke.

Inhibition of leukocyte migration after ischemic stroke by VE-cadherin mutation in a mouse model leads to reduced infarct volumes and improved motor skills.

AIMS: To distinguish between the genuine cellular impact of the ischemic cascade by leukocytes and unspecific effects of edema and humoral components, two knock-in mouse lines were utilized. Mouse lines Y731F and Y685F possess point mutations in VE-cadherin, which lead to a selective inhibition of transendothelial leukocyte migration or impaired vascular permeability. METHODS: Ischemic stroke was induced by a model of middle cerebral artery occlusion. Analysis contained structural outcomes (infarct volume and extent of brain edema), functional outcomes (survival analysis, rotarod test, and neuroscore), and the extent and spatial distribution of leukocyte migration (heatmaps and fluorescence-activated cell sorting (FACS) analysis). RESULTS: Inhibition of transendothelial leukocyte migration as in Y731F mice leads to smaller infarct volumes (52.33 ± 4719 vs. 70.43 ± 6483 mm3 , p = .0252) and improved motor skills (rotarod test: 85.52 ± 13.24 s vs. 43.06 ± 15.32 s, p = .0285). An impaired vascular permeability as in Y685F mice showed no effect on structural or functional outcomes. Both VE-cadherin mutations did not influence the total immune cell count or spatial distribution in ischemic brain parenchyma. CONCLUSION: Selective inhibition of transendothelial leukocyte migration by VE-cadherin mutation after ischemic stroke in a mouse model leads to smaller infarct volumes and improved motor skills.

EXERTION: a pilot trial on the effect of aerobic, smartwatch-controlled exercise on stroke recovery: effects on motor function, structural repair, cognition, mental well-being, and the immune system.

INTRODUCTION: Motor impairments are the objectively most striking sequelae after stroke, but non-motor consequences represent a high burden for stroke survivors as well. Depression is reported in one third of patients, the fatigue prevalence ranges from 23 to 75% due to heterogenous definitions and assessments. Cognitive impairment is found in one third of stroke patients 3-12 months after stroke and the risk for dementia is doubled by the event. Aerobic exercise has been shown to reduce depressive symptoms, counteract fatigue, and improve cognitive functions in non-stroke patients. Furthermore, exercise is known to strengthen the immune system. It is unknown, though, if aerobic exercise can counteract poststroke depression, fatigue, poststroke dementia and poststroke immunosuppression. Therefore, we aim to analyse the effect of aerobic exercise on functional recovery, cognition, emotional well-being, and the immune system. Reorganization of topological networks of the brain shall be visualized by diffusion MRI fibre tracking. METHODS: Adults with mild to moderate stroke impairment (initial NIHSS or NIHSS determined at the moment of maximal deterioration 1-18) are recruited within two weeks of stroke onset. Study participants must be able to walk independently without risk of falling. All patients are equipped with wearable devices (smartwatches) measuring the heart rate and daily step count. The optimal heart rate zone is determined by lactate ergometry at baseline. Patients are randomized to the control or the intervention group, the latter performing a heart rate-controlled walking training on own initiative 5 times a week for 45 min. All patients receive medical care and stroke rehabilitation to the usual standard of care. The following assessments are conducted at baseline and after 90 days: Fugl Meyer-assessment for the upper and lower extremity, 6 min-walk test, neuropsychological assessment (cognition: MoCA, SDMT; fatigue and depression: FSMC, HADS-D, participation: WHODAS 2.0 12-items), blood testing (i.e. immune profiling to obtain insights into phenotype and functional features of distinct immune-cell subsets) and cranial magnetic resonance imaging (MRI) with grid-sampled diffusion weighted imaging, white matter fibre tracking and MR spectroscopy. PERSPECTIVE: This study investigates the effect of smartwatch-controlled aerobic exercise on functional recovery, cognition, emotional well-being, the immune system, and neuronal network reorganization in stroke patients. Trial registration ClinicalTrials.gov NCT Number: NCT05690165. First posted19 January 2023. Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05690165.

Integrated single-cell transcriptomics of cerebrospinal fluid cells in treatment-naïve multiple sclerosis.

Multiple sclerosis (MS) is a chronic and often disabling autoimmune disease of the central nervous system (CNS). Cerebrospinal fluid (CSF) surrounds and protects the CNS. Analysis of CSF can aid the diagnosis of CNS diseases, help to identify the prognosis, and underlying mechanisms of diseases. Several recent studies have leveraged single-cell RNA-sequencing (scRNA-seq) to identify MS-associated changes in CSF cells that are considerably more altered than blood cells in MS. However, not all alterations were replicated across all studies. We therefore integrated multiple available scRNA-seq datasets of CSF cells from MS patients with early relapsing-remitting (RRMS) disease. We provide a searchable and interactive resource of this integrated analysis ( https://CSFinMS.bxgenomics.com ) facilitating diverse visualization and analysis methods without requiring computational skills. In the present joint analysis, we replicated the known expansion of B lineage and the recently described expansion of natural killer (NK) cells and some cytotoxic T cells and decrease of monocytes in the CSF in MS. The previous observation of the abundance of Th1-like Th17 effector memory cells in the CSF was not replicated. Expanded CSF B lineage cells resembled class-switched plasmablasts/-cells (e.g., SDC1/CD138, MZB1) as expected. Our integrative analysis thus validates increased cell type diversity and B cell maturation in the CSF in MS and improves accessibility of available data.

Deficiency of the Two-Pore Potassium Channel KCNK9 Impairs Intestinal Epithelial Cell Survival and Aggravates Dextran Sodium Sulfate-Induced Colitis.

BACKGROUND & AIMS: The 2-pore potassium channel subfamily K member 9 (KCNK9) regulates intracellular calcium concentration and thus modulates cell survival and inflammatory signaling pathways. It also was recognized as a risk allele for inflammatory bowel disease. However, it remains unclear whether KCNK9 modulates inflammatory bowel disease via its impact on immune cell function or whether its influence on calcium homeostasis also is relevant in intestinal epithelial cells. METHODS: Kcnk9-/- mice were challenged with 3% dextran sulfate sodium (DSS) to induce experimental acute colitis. Primary cultures of intestinal epithelial cells were generated, and expression of potassium channels as well as cytosolic calcium levels and susceptibility to apoptosis were evaluated. Furthermore, we evaluated whether KCNK9 deficiency was compensated by the closely related 2-pore potassium channel KCNK3 in vivo or in vitro. RESULTS: Compared with controls, KCNK9 deficiency or its pharmacologic blockade were associated with aggravated DSS-induced colitis compared with wild-type animals. In the absence of KCNK9, intestinal epithelial cells showed increased intracellular calcium levels and were more prone to mitochondrial damage and caspase-9-dependent apoptosis. We found that expression of KCNK3 was increased in Kcnk9-/- mice but did not prevent apoptosis after DSS exposure. Conversely, increased levels of KCNK9 in Kcnk3-/- mice were associated with an ameliorated course of DSS-induced colitis. CONCLUSIONS: KCNK9 enhances mitochondrial stability, reduces apoptosis, und thus supports epithelial cell survival after DSS exposure in vivo and in vitro. Conversely, its increased expression in Kcnk3-/- resulted in less mitochondrial damage and apoptosis and was associated with beneficial outcomes in DSS-induced colitis.

Cytotoxic corpus callosum lesion and mild CSF pleocytosis during hantavirus infection: a case report.

A middle-aged, previously healthy male patient presented with high fever, headache, and aching limbs for 3 days. Laboratory results showed signs of acute kidney injury, elevated procalcitonin, and mild thrombocytopenia. On neurological examination, he had no focal neurological deficits, especially no meningism or visual disturbances. Cerebrospinal fluid (CSF) examination showed mild lymphocytic pleocytosis, and magnetic resonance imaging (MRI) revealed a lesion of the splenium corporis callosum. The patient received anti-infective treatment with acyclovir and ceftriaxone until laboratory results returned positive hantavirus IgM and IgG antibodies in the serum indicating an active hantavirus infection. The renal retention parameters and thrombocytopenia receded following treatment with intravenous fluids, analgesic, and antipyretic agents. MRI follow-up 10 days later showed a residual small FLAIR-positive lesion without any persistent callosal diffusion abnormality. The patient was discharged symptom-free after 8 days and had recovered fully 2 months later. The source of infection in this patient remained unclear. Cytotoxic lesions of the corpus callosum (CLCC) are secondary lesions usually with a good prognosis but require further investigation regarding their underlying etiology and should not be confounded with primary callosal lesions, such as ischemia or lymphoma.

Efficacy and safety of alemtuzumab versus fingolimod in RRMS after natalizumab cessation.

BACKGROUND: Natalizumab (NTZ) was the first approved monoclonal antibody for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite proven and sustained efficacy, its use is limited by the risk of progressive multifocal leukoencephalopathy (PML). Moreover, some patients show ongoing disease activity under NTZ, requiring a switch to another disease-modifying treatment (DMT). However, evidence regarding the optimal DMT for treatment of active RRMS after NTZ-cessation is still scarce. OBJECTIVE: To evaluate efficacy and safety outcomes of ALEM vs FTY treatment after cessation of NTZ. METHODS: We retrospectively identified patients at 12 German neurology centers and analyzed risks for disease activity, adverse events, disability progression, and treatment discontinuation. RESULTS: 195 patients were identified and 144 underwent final analysis (FTY: 101; ALEM: 42). The hazard ratio for clinical relapses was 2.24 favoring ALEM (95% CI 1.12-4.50; p = 0.015). The hazard ratio for adverse events was 7.78 (95% CI 1.04-57.95; p = 0.006) and 2.41 for MRI progression (95% CI 1.26-4.60; p = 0.004). The odds ratio for disability progression after 12 months was 4.84 (95% CI 1.74-13.47, p = 0.003). Differences remained after adjusting for possible confounders (e.g., age, sex, baseline disability, NTZ treatment duration, washout time). CONCLUSION: Our findings indicated particular advantages of ALEM compared to FTY in patients stopping NTZ.