Prognostic factors for disease activity in newly diagnosed teriflunomide-treated patients with multiple sclerosis: a nationwide Danish study.

BACKGROUND: Clinicians frequently rely on relapse counts, T2 MRI lesion load (T2L) and Expanded Disability Status Scale (EDSS) scores to guide treatment decisions for individuals diagnosed with multiple sclerosis (MS). This study evaluates how these factors, along with age and sex, influence prognosis during treatment with teriflunomide (TFL). METHODS: We conducted a nationwide cohort study using data from the Danish Multiple Sclerosis Registry.Eligible participants had relapsing-remitting MS or clinically isolated syndrome and initiated TFL as their first treatment between 2013 and 2019. The effect of age, pretreatment relapses, T2L and EDSS scores on the risk of disease activity on TFL were stratified by sex. RESULTS: In total, 784 individuals were included (57.4% females). A high number of pretreatment relapses (≥2) was associated with an increased risk of disease activity in females only (OR and (95% CI): 1.76 (1.11 to 2.81)). Age group 50+ was associated with a lower risk of disease activity in both sexes (OR females=0.28 (0.14 to 0.56); OR males=0.22 (0.09 to 0.55)), while age 35-49 showed a different impact in males and females (OR females=0.79 (0.50 to 1.23); OR males=0.42 (0.24 to 0.72)). EDSS scores and T2L did not show any consistent associations. CONCLUSION: A high number of pretreatment relapses was only associated with an increased risk of disease activity in females, while age had a differential impact on the risk of disease activity according to sex. Clinicians may consider age, sex and relapses when deciding on TFL treatment.

Extended interval dosing with ocrelizumab in multiple sclerosis.

BACKGROUND: This study investigates clinical and biomarker differences between standard interval dosing (SID) and extended interval dosing (EID) of ocrelizumab therapy in multiple sclerosis (MS). METHODS: This is a prospective, double-arm, open-label, multi-center study in Denmark. Participants diagnosed with MS on ocrelizumab therapy >12 months were included (n = 184). Clinical, radiological, and blood-based biomarker outcomes were evaluated. MRI disease activity, relapses, worsening of neurostatus, and No Evidence of Disease Activity-3 (NEDA-3) were used as a combined endpoint. RESULTS: Out of 184 participants, 107 participants received EID (58.2%), whereas 77 participants received SID (41.8%). The average extension was 9 weeks with a maximum of 78 weeks. When comparing EID to SID, we found higher levels of B-cells, lower serum concentrations of ocrelizumab, and similar levels of age-adjusted NFL and GFAP in the two groups. No difference in NEDA-3 between EID and SID was demonstrated (hazard ratio: 1.174, p = 0.69). Higher levels of NFL were identified in participants with disease activity. Body mass index correlated with levels of ocrelizumab and B-cells. CONCLUSION: Extending one treatment interval of ocrelizumab on average 9 weeks and up to 78 weeks did not result in clinical, radiological, or biomarker evidence of worsening compared with SID.

Regaining Autonomy in a Holding Environment: Patients' Perspectives on the Existential Communication with Physicians When Suffering from a Severe, Chronic Illness: A Qualitative Nordic Study.

Patients experience existential themes as pivotal in their lives, in order to be able to live with a severe, chronic illness; however, physicians report a hesitative approach to existential communication. The current study investigated Nordic patients' experiences of existential communication with their physicians related to the treatment of multiple sclerosis or chronic pain. Semi-structured interviews with 23 patients were analyzed following Interpretative Phenomenological Analysis. Physicians focusing on medical aspects at the expense of psychological and existential aspects of being ill was experienced by patients as challenging their treatment and well-being. For making a shared decision with the physician on their treatment, patients needed a transition from being dependent to being autonomous. A holding environment and existential communication about transitional objects such as relationships with something bigger than themselves, as nature or religion, supported this autonomy. The analysis showed that existential communication not only supported patients in developing and regaining autonomy but also functioned as a moderator for illness-related distress, as a prevention of withdrawal from treatment, and as significant for patients in relation to living with chronic illness. Further education in existential communication is desirable, to support physicians integrating existential dimensions in consultations and shared decision-making with patients suffering from a severe, chronic illness.

Multiple sclerosis impairment scale and brain MRI in secondary progressive multiple sclerosis.

OBJECTIVE: To examine the Multiple Sclerosis Impairment Scale (MSIS) in secondary progressive MS (SPMS) in relation to the Expanded Disability Status Scale (EDSS), magnetic resonance imaging (MRI) outcomes, and mobility. METHODS: In this observational single-center study, 68 secondary progressive multiple sclerosis (SPMS) patients were examined by MSIS, EDSS, functional mobility tests of upper/lower extremities, and multimodal MRI. Participants had EDSS ≥3.5, a decline in daily activities over the last year unrelated to relapses, and/or 6-month confirmed disability progression. RESULTS: Mean disease duration was 23.1 ± 8.3 years and mean age 54.4 ± 8.1 years. MSIS, EDSS, and their corresponding motor, cerebellar, and sensory subscores correlated (p < .0001). Motor subscores of MSIS correlated stronger with Timed-25-Foot-Walk (T25FW) than pyramidal functional system score (FSS) (p = .03), but EDSS had a stronger correlation to T25FW than the total MSIS score (p = .01). MSIS cerebellar subscore correlated stronger with 9-Hole Peg Test (9-HPT) than cerebellar FSS (p = .04). The sensory MSIS subscore also showed correlation with 9-HPT in contrast to sensory FSS (p = .006). MSIS subscores had stronger correlations with MRI volumetry measures than FSS scores (lesion volume and putamen, thalamus, corpus callosum volumetry, p = .0001-0.0017). CONCLUSION: In patients with SPMS, MSIS correlated with functional motor tests. MSIS showed stronger correlations with atrophy of central nervous system areas, and may be more sensitive to scale cerebellar and sensory function than EDSS.

Investigation of oxidative stress in patients with multifocal motor neuropathy.

Background and purpose: Multifocal motor neuropathy (MMN) is a rare, immune-mediated illness attacking ex-clusively motor nerves. It is known that oxidative stress is present in peripheral neuropathies, but it has not been investigated MMN. Methods: We measured in our prospective study the L-arginine, symmetric and asymmetric dimethylarginine (SDMA, ADMA) serum concentrations of 10 patients and 10 controls before and after intravenous immunoglobulin treatment (IVIG), as markers of the L-arginine/NO pathway involved in chronic inflammation and oxidative stress. The functions of motor nerves were tested in all patients and the serum antiganglioside antibody levels were de-tec-ted, as well. Results: MMN patients showed significantly higher ADMA (p = 0.0048; 0.98 and 0.63, respectively) and SDMA le-vels (p = 0.001; 0.88 and 0.51, respectively) than healthy controls, while L-arginine was not different. Controlling for the covariant age, ADMA (B = -0.474; p = 0.041) or SDMA (B = -0.896; p < 0.0005) serum levels proved to be the significant predictors of the presence of MMN. IVIG therapy decreased significantly ADMA concentrations (p = 0.025; 0.98 and 0.84, respectively) and showed a trend to reduce SDMA levels (p = 0.1; 0.88 and 0.74, respectively). The dimethylamine levels did not correlate with the number of affected nerves, disease duration, or the presence of ganglioside antibodies. The conduction block-related peripheral motor dysfunction improved right after the IVIG treatment. Conclusion: Dimethylamine levels are elevated in the serum and are responsive to IVIG therapy in MMN. These findings support the presence of oxidative stress in MMN.

Unbiased examination of genome-wide human endogenous retrovirus transcripts in MS brain lesions.

BACKGROUND: Human endogenous retrovirus (HERV) expression in multiple sclerosis (MS) brain lesions may contribute to chronic inflammation, but expression of genome-wide HERVs in different MS lesions is unknown. OBJECTIVE: We examined the HERV expression landscape in different MS lesions compared to control brains. METHODS: Transcripts from 71 MS brain samples and 25 control WM were obtained by next-generation RNA sequencing and mapped against HERV transcripts across the human genome. Differential expression of mapped HERV-W and HERV-H reads between MS lesion types and controls was analysed. RESULTS: Out of 6.38 billion high-quality paired end reads, 174 million reads (2.73%) mapped to HERV transcripts. There was no difference in HERVs expression level between MS and control brains, but HERV-W transcripts were significantly reduced in chronic active lesions. Of the four HERV-W transcripts exclusively present in MS, ERV3633503 located on chromosome 7q21.13 close to the MS genetic risk locus had the highest number of reads. In the HERV-H family, 75% of transcripts located to nearby 7q21-22 were overrepresented in MS, and ERV3643914 was expressed more than 16 times in MS compared to control brains. CONCLUSION: Novel HERV-W and HERV-H transcripts located at chromosome 7 regions were uniquely expressed in MS lesions, indicating their potential role in brain lesion evolution.

Alemtuzumab treatment in Denmark: A national study based on the Danish Multiple Sclerosis Registry.

OBJECTIVE: To investigate clinical outcomes in a real-world setting in the complete population-based cohort of alemtuzumab-treated MS patients in Denmark. METHODS: Data were retrieved from The Danish Multiple Sclerosis Registry between 2009 and 2019. Demographic and disease-specific patient parameters related to treatment history, efficacy, and safety outcomes were assessed at baseline and during follow-up visits. RESULTS: A total of 209 patients (78% female) started treatment with alemtuzumab during the study period with 3.1 ± 1.4 years follow-up. After 2 years, 75% of patients were relapse-free compared to 48% the year before alemtuzumab (p < 0.001). The annual number of relapses was reduced by 69% in year 4 compared with the year prior alemtuzumab. More active disease before alemtuzumab increased the annual hazard rate for relapse (HR: 2.88, p < 0.001). The Expanded Disability Status Scale (EDSS) score remained stable or improved in 81% of patients after 2 years. The need for an additional treatment course was associated with higher number of relapses in the year before alemtuzumab (odds ratio (OR) = 1.95, p = 0.001). CONCLUSION: In a country with primarily escalation strategy, relapse rate reduction was maintained for 5 years, and EDSS stabilized/improved in majority of patients. Higher relapse rate 1 year before alemtuzumab increased the odds for additional courses. Novel serious AEs were not observed.

Detection of silent cerebral microcirculatory abnormalities in patients with manifest ischemic coronary disease: a perfusion brain MRI study combined with dipyridamole stress.

OBJECTIVES: Intravenous dipyridamole (DP) can induce transient perfusion abnormalities in the heart but also the brain indicated by brain SPECT. L-arginine can regulate the vascular tone via nitric oxide (NO). Therefore, we examined cerebral blood volume (CBV) by perfusion MRI and L-arginine level before and after DP stress in patients, who developed transient neurological signs, and compared these to unaffected patients. DESIGN: A total of nine patients with ischemic coronary disease after myocardial perfusion scintigraphy were selected for this prospective pilot study. Four had DP-induced transient mild neurologic signs during myocardial perfusion scintigraphy, while five had no neurological signs. By using perfusion MRI in both groups in a second stage, we examined CBV in identical areas of the two hemispheres before and during DP stress. Besides, pre-and post-stress L-arginine serum levels were also analyzed by high-performance liquid chromatography. Trial registration: NCT03688815. RESULTS: CBV in the sensory-motor area at baseline was significantly higher in patients with DP-induced transient neurological signs compared to patients without signs (p = 0.028). Intravenous DP normalized the higher perfusion by decreasing CBV, and also increased serum L-arginine level (p = 0.001). CONCLUSIONS: Intravenous DP changed the CBV accompanied by a systemic elevation of L-arginine: this indicates a direct vasorelaxing effect on brain vessels, and an indirect vasodilator effect through L-arginine release presumably via NO. In areas with decreased CBV before DP, such double effects caused transient neurological symptoms presumably due to steal phenomenon. Therefore, intravenous DP may have a potential to identify patients with high risk for cerebral ischemia.

[Treatment and new evidences in neuromyelitis optica spectrum disorder]. / Terápiás megközelítés és új evidenciák a neuromyelitis optica spektrum kezelésében.

Treatment and new evidences in neuromyelitis optica spectrum disorder Illés Zs, MD, PhD Ideggyogy Sz 2021;74(9-10):309-321. Neuromyelitis optica spectrum disorder (NMOSD) is associated with antibodies against AQP4 in about 80% of the cases. In about one-fourth of seronegative cases, antibodies against the MOG protein are present in the serum (MOG-antibody associated disease, MOGAD). This article discusses off-label azathioprine and mycophenolate mofetil in the treatment of NMOSD and reviews the evidence-based clinical aspects of B/plasma cell depletion, antagonization of IL-6 signaling and blocking the complement pathway. The review also summarizes basic aspects of NMOSD pregnancy focusing on treatment, and the different therapeutic approach in MOGAD. In the recent two years, phase 3 clinical trials provided class I evidence for the efficacy and safety of rituximab (anti-CD20), inebilizumab (anti-CD19), tocilizumab (anti-IL6R), satralizumab (anti-IL6R), and eculizumab (anti-C5) in combination with other immunosuppressants or in monotherapy. The treatment approach in MOGAD is complicated by the monophasic course in about half of the cases and by the potential disappearance of MOG antibody. The necessity of maintenance treatment in MOGAD should be decided after tapered oral steroid. Immunosuppression is recommended in NMOSD during pregnancy and lactation, and this should be considered for optimal selection of treatment in fertile female patients. The new monoclonal antibodies broadened treatment options NMOSD, and the treatment strategy of MOGAD has become more straightforward.

Clinically stable disease is associated with a lower risk of both income loss and disability pension for patients with multiple sclerosis.

OBJECTIVE: To assess the risk of losing income from salaries and risk disability pension for multiple sclerosis patients with a clinically stable disease course 3 years after the start of disease-modifying therapy (DMT). METHODS: Data from the Danish Multiple Sclerosis Registry were linked to other Danish nationwide population-based databases. We included patients who started treatment with a DMT between 2001 and 2014. Patients were categorised into a clinically stable group (No Evidence of Disease Activity (NEDA-2)) and a clinically active group (relapse activity or 6-month confirmed Expanded Disability Status Scale worsening). Outcomes were: (1) loss of regular income from salaries and (2) a transfer payment labelled as disability pension. We used a Cox proportional hazards model to estimate confounder-adjusted HRs, and absolute risks were plotted using cumulative incidence curves accounting for competing risks. RESULTS: We included 2406 patients for the income analyses and 3123 patients for the disability pension analysis. Median follow-up from index date was ~5 years in both analyses. The NEDA-2 group had a 26% reduced rate of losing income (HR 0.74; 95% CI 0.60 to 0.92). HRs were calculated for 5-year intervals in the disability pension analysis: year 0-5: a 57% reduced rate of disability pension for the NEDA-2 group (HR 0.43; 95% CI 0.33 to 0.55) and year 5-10: a 36% reduced rate (HR 0.64; 95% CI 0.40 to 1.01). CONCLUSION: Clinically stable disease course (NEDA-2) is associated with a reduced risk of losing income from salaries and a reduced risk of disability pension.

Associations between serum L-arginine and ficolins in the early phase of acute ischemic stroke - A pilot study.

INTRODUCTION: Activation of both the L-arginine and the lectin pathway contributes to the pathophysiology and the outcome of acute ischemic stroke (AIS). However, the interplay between the two systems has not yet been examined. METHODS: A total of 44 patients with AIS were recruited into this study. Serial measurement of serum L-arginine, asymmetric and symmetric dimethylarginine (ADMA, SDMA), and hsCRP, ficolin-2, ficolin-3, MAP-1, MASP-3 and mannose-binding lectin (MBL) were analyzed within 6 h after onset of stroke and 72 h later. Outcomes were assessed as National Institutes of Health Stroke Scale (NIHSS) worsening by 24 h, poststroke infection, and death by 1 month. RESULTS: In the hyperacute stage of AIS, ficolin-3, MAP-1 and MBL were positively correlated with L-arginine within 6 h after onset of symptoms (p<0.05 respectively). Significantly lower ficolin-3 and MASP-3 levels were found at 72 h in patients, who developed post-stroke infection after day 4, when compared to patients without post-stroke infections (p=0.03 and p=0.009). At 72 hours, ficolin-3 levels negatively correlated with S100B (p=0.01). Ficolin-3 at 72 post-stroke hours remained an independent predictor of post-stroke infection, while only hsCRP was an independent predictor of 30-day mortality. CONCLUSION: Early consumption of ficolin-3 is associated with complications such as post-stroke infections. In the hyperacute phase of AIS, the positive correlation between ficolins and the NO donor L-arginine may reflect the protective role of L-arginine presumably by improving the cerebral microcirculation in a prothrombotic environment induced by complement activation.

Life threatening rare lymphomas presenting as longitudinally extensive transverse myelitis: a diagnostic challenge.

Background and aims - Description of two cases of rare intravascular large B-cell lymphoma and secondary T-cell lymphoma diagnosed postmortem, that manifested clinically as longitudinally extensive transverse myelitis (LETM). We discuss causes of diagnostic difficulties, deceptive radiological and histological investigations, and outline diagnostic procedures based on our and previously reported cases. Case reports - Our first case, a 48-year-old female was admitted to the neurological department due to paraparesis. MRI suggested LETM, but the treatments were ineffective. She died after four weeks because of pneumonia and untreatable polyserositis. Pathological examination revealed intravascular large B-cell lymphoma (IVL). Our second case, a 61-year-old man presented with headache and paraparesis. MRI showed small bitemporal lesions and lesions suggesting LETM. Diagnostic investigations were unsuccessful, including tests for possible lymphoma (CSF flow cytometry and muscle biopsy for suspected IVL). Chest CT showed focal inflammation in a small area of the lung, and adrenal adenoma. Brain biopsy sample from the affected temporal area suggested T-cell mediated lymphocytic (paraneoplastic or viral) meningoencephalitis and excluded diffuse large B-cell lymphoma. The symptoms worsened, and the patient died in the sixth week of disease. The pathological examination of the presumed adenoma in the adrenal gland, the pancreatic tail and the lung lesions revealed peripheral T-cell lymphoma, as did the brain and spinal cord lesions. Even at histological examination, the T-cell lymphoma had the misleading appearance of inflammatory condition as did the MRI. Conclusion - Lymphoma can manifest as LETM. In cases of etiologically unclear atypical LETM in patients older than 40 years, a random skin biopsy (with subcutaneous adipose tissue) from the thigh and from the abdomen is strongly recommended as soon as possible. This may detect IVL and provide the possibility of prompt chemotherapy. In case of suspicion of lymphoma, parallel examination of the CSF by flow cytometry is also recommended. If skin biopsy is negative but lymphoma suspicion remains high, biopsy from other sites (bone marrow, lymph nodes or adrenal gland lesion) or from a simultaneously existing cerebral lesion is suggested, to exclude or prove diffuse large B-cell lymphoma, IVL, or a rare T-cell lymphoma.

Dimethyl fumarate decreases neurofilament light chain in CSF and blood of treatment naïve relapsing MS patients.

OBJECTIVES: In a prospective phase IV trial of the first-line oral treatment dimethyl fumarate (DMF), we examined dynamics of neurofilament light (NFL) chain in serum, plasma and cerebrospinal fluid (CSF) samples collected over 12 months from relapsing-remitting multiple sclerosis (RRMS) patients. NFL changes were related to disease activity. METHODS: We examined NFL levels by single-molecule array in 88 CSF, 348 plasma and 131 sera from treatment-naïve RRMS patients (n=52), healthy controls (n=23) and a placebo group matched by age, sex and NFL (n=52). Plasma/sera were collected at baseline, and 1, 3, 6 and 12 months after DMF. CSF samples were collected at baseline and 12 months after DMF. RESULTS: NFL concentration in CSF, plasma and serum correlated highly (p<0.0001 for all), but plasma levels were only 76.9% of paired serum concentration. After 12 months of DMF treatment, NFL concentration decreased by 73%, 69% and 55% in the CSF, serum and plasma (p<0.0001, respectively). Significant reduction in blood was observed after 6 and 12 months treatment compared with baseline (p<0.01 and p<0.0001, respectively) and to placebo (p<0.0001). Patients with NFL above the 807.5 pg/mL cut-off in CSF had 5.0-times relative risk of disease activity (p<0.001). CONCLUSIONS: This study provides Class II evidence that first-line DMF reduces NFL in both blood and CSF after 6 months and normalises CSF levels in 73% of patients. High NFL concentration in CSF after a year reflected disease activity. NFL levels were higher in serum than in plasma, which should be considered when NFL is used as a biomarker.

Subacute Elevation of Plasma Level of Caspase-Cleaved Cytokeratin-18 is Associated with Hemorrhagic Transformation and Functional Outcome in Ischemic Stroke.

BACKGROUND: Caspase-cleaved cytokeratin-18 (CCCK-18) is an apoptosis marker. Here, we analyzed the relationship between plasma level of CCCK-18 in the acute and subacute stage of ischemic stroke and early and late functional outcome. Besides, correlation among CCCK-18 and complications, such as hemorrhagic transformation (HT) were also explored. METHODS: Plasma concentration of CCCK-18 was investigated in 54 patients at admission and poststroke 72 hours. HT was evaluated by CT scans on 24 poststroke hours. Outcome measures were assessed by modified Rankin scale at hospital discharge and 6-month later. Receiver operating characteristics (ROC) analysis was used to determine the best cut-off values of CCCK-18 as a predictor of unfavorable functional outcome. RESULTS: Significantly elevated CCCK-18 level was observed at 72 hours after onset of stroke, in nonsurviving compared to surviving patients (331 ± 191 ng/L versus 251 ± 164 ng/L, P = .01). Based on ROC analysis, the cut-off value of plasma CCCK-18 levels >223 ng/L at 72 poststroke hours predicted 6-month unfavorable stroke outcome with a sensitivity of 84.4% and a specificity of 77.3% (area under the curve: .851, 95% confidence interval = .745-.955, P < .001). The rate of complications such as HT and in-hospital infection was significantly higher in patients presented with a plasma CCCK-18 level above the cut-off value. CONCLUSIONS: The association between high serum CCCK-18 levels and unfavorable early and late stroke outcome in an unselected study population was first described here. Besides, the apoptosis marker CCCK-18 might be a predictor of further complication such as HT and in-hospital infection.

L-arginine pathway metabolites can discriminate paroxysmal from permanent atrial fibrillation in acute ischemic stroke.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is the most common arrhythmia diagnosed in clinical practice. We aimed to measure the L-arginine pathway metabolites as well as their ratios in patients with different types of AF or sinus rhythm and to explore the relationship among the markers and clinical variables in the subacute phase of acute ischemic stroke (AIS). METHODS: A total of 46 patients with AIS were prospectively enrolled. The patients were divided into three groups based on diagnosis of either sinus rhythm, paroxysmal or permanent AF. Plasma concentration of the L-arginine pathway metabolites were analyzed at post-stroke 24 hours in the three rhythm groups. Besides, clinical variables and laboratory data were recorded. RESULTS: Asymmetric dimetylarginine (ADMA) was significantly higher in patients with permanent AF compared to sinus rhythm (p<0.001). Both ADMA (p<0.001) and symmetric dimethylarginine (SDMA) (p<0.002) at 24 hours were significantly higher among patients with permanent AF compared to those with paroxysmal AF. The L-arginine/SDMA (p<0.031) ratios at 24 hours were significantly higher among patients with sinus rhythm compared to those with permanent AF. ROC analysis also revealed that plasma SDMA cut-off level over 0.639 µmol/L discriminated permanent AF from paroxysmal AF or sinus rhythm with a 90.9% sensitivity and 77.1% specificity. Neutrophil-lymphocyte ratio also showed significantly higher value in individuals with both paroxysmal and permanent AF (p=0.029). CONCLUSION: Plasma level of SDMA could discriminate permanent from paroxysmal AF in the subacute phase of ischemic stroke. In addition, an increased neutrophil-lymphocyte ratio may suggest inflammatory process in the evolution of atrial fibrillation.

Changes to the septo-fornical area might play a role in the pathogenesis of anxiety in multiple sclerosis.

BACKGROUND: Reports on the relationships between white matter lesion load (WMLL) and fatigue and anxiety in multiple sclerosis (MS) are inconsistent. OBJECTIVE: To investigate the association of total and tract-specific WMLL with fatigue and anxiety. METHODS: Total and regional T2 WMLL was assessed for 19 tracts in 48 MS patients (30 females). ICBM-DTI-81 Atlas-based parcellation was combined with WMLL segmentation of T2-weighted magnetic resonance imaging (MRI). Fatigue, anxiety, and depression were assessed using Fatigue Impact Scale, State Trait Anxiety Inventory, and Beck Depression Inventory, respectively. RESULTS: Fatigue, anxiety, and depression showed significant inter-correlation. We found no association between fatigue and total or regional WMLLs, whereas anxiety was associated with total and regional WMLLs in nine tracts. After adjusting for total WMLL, age, and depression, only the column and body of the fornix (CBF) remained significantly associated with anxiety. Post hoc analyses showed no CBF lesions on T1-weighted MRI and suggested, but could not confirm, that the septum pellucidum might play a role in the pathogenesis of anxiety. CONCLUSION: Our results suggest that anxiety in MS patients may have a neuropathological substrate in the septo-fornical area, which requires further validation using larger sample size and ultra-high-field MRI in targeted prospective studies.

Macrophage migration inhibitory factor (MIF) modulates trophic signaling through interaction with serine protease HTRA1.

Macrophage migration inhibitory factor (MIF), a small conserved protein, is abundant in the immune- and central nervous system (CNS). MIF has several receptors and binding partners that can modulate its action on a cellular level. It is upregulated in neurodegenerative diseases and cancer although its function is far from clear. Here, we report the finding of a new binding partner to MIF, the serine protease HTRA1. This enzyme cleaves several growth factors, extracellular matrix molecules and is implicated in some of the same diseases as MIF. We show that the function of the binding between MIF and HTRA1 is to inhibit the proteolytic activity of HTRA1, modulating the availability of molecules that can change cell growth and differentiation. MIF is therefore the first endogenous inhibitor ever found for HTRA1. It was found that both molecules were present in astrocytes and that the functional binding has the ability to modulate astrocytic activities important in development and disease of the CNS.

Relationship between Cardiac Troponin and Thrombo-Inflammatory Molecules in Prediction of Outcome after Acute Ischemic Stroke.

BACKGROUND: In patients with acute ischemic stroke (AIS) without cardiovascular complications, we investigated the association of serum concentration of cardiac troponin (high-sensitivity cardiac troponin T [hs-cTnT]) with thrombo-inflammatory markers. METHODS: Thirty-five patients with first-ever AIS were prospectively examined. Serum hs-cTnT was measured 6 and 24 hours after stroke, whereas S100B, high-sensitivity C-reactive protein (hsCRP), soluble CD40 ligand, tissue plasminogen activator (tPA), monocyte chemoattractant protein-1 (MCP-1), and P-selectin were measured 6 and 72 hours after stroke. Severity of stroke was assessed by the National Institutes of Health Stroke Scale (NIHSS) on admission, 24 hours later, and at discharge. RESULTS: Concentration of MCP-1 at 6 hours was higher in the serum of patients with worsened NIHSS by 24 hours (P = .009). Concentration of hs-cTnT at both 6 and 24 hours was higher, if NIHSS worsened by discharge (P = .026 and P = .001). A cutoff value for hs-cTnT measured at T24 greater than or equal to 9.4 predicted worsened NIHSS on discharge with a sensitivity of 81% and a specificity of 74% (area: .808, P = .002). Concentration of hs-cTnT at both 6 and 24 hours was also higher in nonsurvivors compared with survivors (P = .03, respectively), and correlated with (1) tPA levels at 6 hours (P = .001 and P = .002, respectively); (2) MCP-1 concentration at 6 hours (P = .01 and P = .015, respectively); and increased hsCRP levels at 72 hours (P = .01, respectively). Concentration of hs-cTnT at 24 hours was an independent predictor of worsened NIHSS at discharge (odds ratio: 1.58, 95% confidence interval: 1.063-2.370, P = .024). CONCLUSIONS: Elevated concentration of hs-cTnT measured 24 hours after AIS is an independent predictor of progressing neurologic deficit in patients without apparent myocardial damage, and also correlates with acute elevation of tPA and MCP-1.

In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica-related pathology.

OBJECTIVE: Neuromyelitis optica (NMO) is an autoimmune disease of the central nervous system, which resembles multiple sclerosis (MS). NMO differs from MS, however, in the distribution and histology of neuroinflammatory lesions and shows a more aggressive clinical course. Moreover, the majority of NMO patients carry immunoglobulin G autoantibodies against aquaporin-4 (AQP4), an astrocytic water channel. Antibodies against AQP4 can damage astrocytes by complement, but NMO histopathology also shows demyelination, and - importantly-axon injury, which may determine permanent deficits following NMO relapses. The dynamics of astrocyte injury in NMO and the mechanisms by which toxicity spreads to axons are not understood. METHODS: Here, we establish in vivo imaging of the spinal cord, one of the main sites of NMO pathology, as a powerful tool to study the formation of experimental NMO-related lesions caused by human AQP4 antibodies in mice. RESULTS: We found that human AQP4 antibodies caused acute astrocyte depletion with initial oligodendrocyte survival. Within 2 hours of antibody application, we observed secondary axon injury in the form of progressive swellings. Astrocyte toxicity and axon damage were dependent on AQP4 antibody titer and complement, specifically C1q. INTERPRETATION: In vivo imaging of the spinal cord reveals the swift development of NMO-related acute axon injury after AQP4 antibody-mediated astrocyte depletion. This approach will be useful in studying the mechanisms underlying the spread of NMO pathology beyond astrocytes, as well as in evaluating potential neuroprotective interventions. Ann Neurol 2016;79:794-805.

Serum L-arginine and dimethylarginine levels in migraine patients with brain white matter lesions.

Background/Aim Migraine is a risk factor for the formation of silent brain white matter lesions (WMLs) that are possibly ischemic in nature. Although dysfunction of the L-arginine/nitric oxide (NO) pathway has been associated with oxidative stress and endothelial dysfunction in migraine, its role in WML development has not been specifically investigated. Thus, this prospective study aimed to measure the serum concentrations of the NO substrate L-arginine, the NO synthase inhibitor asymmetric dimethylarginine (ADMA), and the L-arginine transport regulator symmetric dimethylarginine (SDMA) in migraine patients in a headache-free period. Methods All participants underwent MR imaging to assess for the presence of WMLs on fluid-attenuated inversion recovery imaging. Altogether 109 migraine patients (43 with lesions, 66 without lesions) and 46 control individuals were studied. High-performance liquid chromatography was used to quantify L-arginine, ADMA and SDMA serum concentrations. Migraine characteristics were investigated, and participants were screened for risk factors that can lead to elevated serum ADMA levels independent of migraine. Results Migraine patients and controls did not differ in regard to vascular risk factors. Migraineurs with WMLs had a longer disease duration ( p < 0.001) and a higher number of lifetime headache attacks ( p = 0.005) than lesion-free patients. Higher L-arginine serum levels were found in both migraine subgroups compared to controls ( p < 0.001). Migraine patients with WMLs showed higher ADMA concentrations than lesion-free patients and controls ( p < 0.001, for both). In migraineurs, the presence of WMLs, aura and increasing age proved to be significant predictors of increased ADMA levels ( p = 0.008, 0.047 and 0.012, respectively). SDMA serum levels of lesional migraineurs were higher than in nonlesional patients ( p < 0.001). The presence of lesions and increasing age indicated an increased SDMA level ( p = 0.017 and 0.001, respectively). Binary logistic regression analysis showed that ADMA level ( p = 0.006), increasing age ( p = 0.017) and the total number of lifetime migraine attacks ( p = 0.026) were associated with an increased likelihood of exhibiting WMLs. There was no significant effect of age on ADMA and SDMA concentrations in controls. Conclusions Elevated ADMA levels may impact the pathogenesis of migraine-related WMLs by influencing cerebrovascular autoregulation and vasomotor reactivity. Higher SDMA concentrations may indirectly influence NO synthesis by reducing substrate availability. Elevated L-arginine serum levels might reflect an increased demand for NO synthesis.