Mineralocorticoid Receptor Signaling in Peripheral Blood Cells in Patients with Multiple Sclerosis.

Multiple sclerosis (MS) is associated with alterations in neuroendocrine function, primarily the hypothalamic-pituitary-adrenal axis, including lower expression of the glucocorticoid receptor (GR) and its target genes in peripheral blood mononuclear cells (PBMC) or full blood. We previously found reduced mineralocorticoid receptor (MR) expression in MS patients' peripheral blood. MS is being treated with a widening variety of disease-modifying treatments (DMT), some of which have similar efficacy but different mechanisms of action; body-fluid biomarkers to support the choice of the optimal initial DMT and/or to indicate an unsatisfactory response before clinical activity are unavailable. Using cell culture of volunteers' PBMCs and subsequent gene expression analysis (microarray and qPCR validation), we identified the mRNA expression of OTUD1 to represent MR signaling. The MR and MR target gene expression levels were then measured in full blood samples. In 119 MS (or CIS) patients, the expression of both MR and OTUD1 was lower than in 42 controls. The expression pattern was related to treatment, with the MR expression being particularly low in patients treated with fingolimod. While MR signaling may be involved in the therapeutic effects of some disease-modifying treatments, MR and OTUD1 expression can complement the neuroendocrine assessment of MS disease course. If confirmed, such assessment may support clinical decision-making.

Motor Sequence Learning across Multiple Sessions Is Not Facilitated by Targeting Consolidation with Posttraining tDCS in Patients with Progressive Multiple Sclerosis.

Compared to relapsing-remitting multiple sclerosis (MS), progressive MS is characterized by a lack of spontaneous recovery and a poor response to pharmaceutical immunomodulatory treatment. These patients may, therefore, particularly benefit from interventions that augment training-induced plasticity of the central nervous system. In this cross-sectional double-blind cross-over pilot study, effects of transcranial direct current stimulation (tDCS) on motor sequence learning were examined across four sessions on days 1, 3, 5, and 8 in 16 patients with progressive MS. Active or sham anodal tDCS of the primary motor cortex was applied immediately after each training session. Participants took part in two experiments separated by at least four weeks, which differed with respect to the type of posttraining tDCS (active or sham). While task performance across blocks of training and across sessions improved significantly in both the active and sham tDCS experiment, neither online nor offline motor learning was modulated by the type of tDCS. Accordingly, the primary endpoint (task performance on day 8) did not differ between stimulation conditions. In sum, patients with progressive MS are able to improve performance in an ecologically valid motor sequence learning task through training. However, even multisession posttraining tDCS fails to promote motor learning in progressive MS.

Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls.

The central noradrenaline (NA) stress-response network co-mediates hypothalamic-pituitary-adrenal (HPA) axis activation and arginine-vasopressin (AVP) release. Dysregulation of these systems contributes to stress-related diseases such as human obesity, but their interrelation remains unclear. The study was aimed to test for the first time in vivo whether central noradrenergic activity quantitatively indexed by the availability of the presynaptic NA transporter (NAT) is associated with HPA axis responsiveness as measured with the combined dexamethasone suppression/corticotropin releasing hormone stimulation (dex/CRH) test and copeptin as a surrogate marker of the serum AVP tone in highly obese, otherwise, healthy individuals compared to age- and sex-matched non-obese, healthy controls. In order to assess central NAT availability, positron emission tomography (PET) was applied using the NAT-selective radiotracer S,S-[11C]O-methylreboxetine (MRB) and correlated with curve indicators derived from the dex/CRH test (maximum, MAX, and area under the curve, AUC, for cortisol and adrenocorticotropic hormone, ACTH) as well as with copeptin. In non-obese controls, positive correlations were found between the NAT distribution volume ratios (DVR) of the orbitofrontal cortex (OFC) and the amygdala with the HPA response (OFC: ACTHMAX r = 0.87, p = .001; cortisolMAX r = 0.86, p = .002; amygdala: ACTHMAX r = 0.86, p = .002; cortisolMAX r = 0.79, p = .006), while in obesity, the hypothalamic DVR correlated inversely with the HPA axis response (cortisolMAX, r = -0.66, p = .04) and with copeptin (r = -0.71, p = .02). This association of central NAT availability with HPA axis responsiveness and copeptin suggests a mechanistic interaction between noradrenergic transmission with HPA axis activity and the serum AVP system that differs between non-obese individuals with prefrontal-limbic involvement and obesity with a hypothalamic-centered relationship. Whether the latter finding contributes to obesogenic behavior needs to be further explored.

Outcome of MS relapses in the era of disease-modifying therapy.

BACKGROUND: In multiple sclerosis (MS), neurological disability results from incomplete remission of relapses and from relapse-independent progression. Intravenous high dose methylprednisolone (IVMP) is the established standard treatment to accelerate clinical relapse remission, although some patients do not respond. Most studies of relapse treatment have been performed when few patients received disease-modifying treatment and may no longer apply today. METHODS: We prospectively assessed, over one year, the course of patients who presented with a clinically isolated syndrome (CIS) or MS relapse, documenting demographic, clinical, treatment and outcome data. A standardized follow-up examination was performed 10-14 days after end of relapse treatment. RESULTS: We documented 119 relapses in 108 patients (31 CIS, 77 MS). 114 relapses were treated with IVMP resulting in full remission (29.2%), partial remission (38.7%), no change (18.2%) or worsening (4.4%). In 27 relapses (22.7%), escalating relapse treatment was indicated, and performed in 24, using double-dose IVMP (n = 18), plasmapheresis (n = 2) or immunoadsorption (n = 4). CONCLUSIONS: Standardised follow-up visits and outcome documentation in treated relapses led to escalating relapse treatment in every fifth relapse. We recommend incorporating scheduled follow-up visits into routine relapse management. Our data facilitate the design of prospective trials addressing methods and timelines of relapse treatment.

Anti-CD20 therapies and pregnancy in neuroimmunologic disorders: A cohort study from Germany.

OBJECTIVE: To report pregnancy outcomes and disease activity (DA) in women with MS, neuromyelitis optica spectrum disorders (NMOSDs), and other neuroimmunologic diseases (ONID) after treatment with rituximab (RTX)/ocrelizumab (OCR) 12 months before or during pregnancy. METHODS: Data were collected in the German MS and pregnancy registry and centers from the Neuromyelitis Optica Study Group. Sixty-eight known outcomes of 88 pregnancies from 81 women (64 MS, 10 NMOSD, and 7 ONID) were included and stratified in 3 exposure groups: >6M-group = RTX/OCR >6 but ≤12 months before the last menstrual period (LMP) (n = 8); <6M group = RTX/OCR <6 months before the LMP (n = 47); preg group = RTX/OCR after the LMP (n = 13). RESULTS: Pregnancy outcomes were similar between groups, but significantly more preterm births (9.8% vs 45%) occurred after exposure during pregnancy. Overall, 2 major congenital abnormalities (3.3%), both in the preg group, were observed. Three women had severe infections during pregnancy. All women with MS (35) and 12/13 women with NMOSD, RTX/OCR exposure before the LMP and known pregnancy outcomes after gestational week 22 were relapse free during pregnancy. Five of 29 (17.2%) women with relapsing-remitting MS (RRMS) and 1 of 12 (8.3%) with NMOSD and at least 6 months postpartum follow-up experienced a relapse postpartum. Duration of RTX/OCR and early retreatment but not detection of B-cells were possible predictors for postpartum relapses in patients with RRMS/NMOSD. CONCLUSIONS: Although RTX/OCR might be an interesting option for women with RRMS/NMOSD who plan to become pregnant to control DA, more data on pregnancy outcomes and rare risks are needed.

Changes of central noradrenaline transporter availability in immunotherapy-naïve multiple sclerosis patients.

The neurotransmitter noradrenaline (NA) mediates arousal, attention and mood, and exerts anti-inflammatory and neuroprotective effects. Alterations of monoamine signalling were reported in multiple sclerosis (MS) and psychiatric illness and may account for the high prevalence of comorbid depression and fatigue in MS patients. We assessed central noradrenaline transporter (NAT) availability using positron emission tomography (PET) and the NAT selective radiotracer S,S-[11C]O-methylreboxetine in immunotherapy-naïve patients with relapsing-remitting MS (RRMS; n = 11) compared to healthy controls (HC; n = 12), and its association to lesion load, time since manifestation, the expanded disability status scale (EDSS), the fatigue scale Würzburger Erschöpfungsinventar bei MS (WEIMuS) and Beck Depression Inventory (BDI). We found NAT availability to be increased in the thalamus, amygdala, putamen and pons/midbrain of MS patients. No relation to clinical or psychometric variables was found. These first data indicate higher NAT availability in subcortical brain regions of immunotherapy-naïve RRMS patients. If these changes of noradrenergic neurotransmission predispose to psychiatric symptoms or associate with disease activity needs to be investigated in longitudinal studies or a larger sample which allows subgroup analyses.

Hyperstable arousal regulation in multiple sclerosis.

BACKGROUND: Fatigue is common in multiple sclerosis (MS) patients. Exhaustion of physiological reserves and mental stress are postulated causes, the latter supported by more pronounced hypothalamic-pituitary-adrenal (HPA) axis activation in fatigued patients. Divergent dysregulation of arousal appears to play important roles in depression- (hyperstable arousal) and in cancer-related (unstable arousal) fatigue, where HPA axis is hyperactive or hypoactive, respectively. OBJECTIVE: This study assessed arousal regulation in multiple sclerosis patients, explored if fatigue can be physiologically described by altered arousal regulation, and if HPA axis activity corresponds to the type(s) of arousal regulation. METHODS: 51 mildly-affected patients with relapsing-remitting MS (86% on disease-modifying treatment) and 20 healthy controls were analysed via Vigilance Algorithm Leipzig and combined dexamethasone/corticotropin releasing hormone test. RESULTS: Hyperstable arousal pattern was significantly more frequent in patients than in controls (62.7% vs. 45.0%, p = 0.011). Patients scored higher on all fatigue, but not on sleepiness scales. All patients combined showed mild activation of the hypothalamic-pituitary-adrenal axis (p < 0.05 for post-CRH ACTH and AUC ACTH; cortisol n.s.). While fatigue was numerically more pronounced in both hyperstable and unstable arousal, HPA axis activity was highest in hyperstable and lowest in unstable arousal (p = 0.013 for post-CRH ACTH; p = 0.087 for AUC ACTH; cortisol n.s.). CONCLUSION: Frequency of arousal patterns are altered in MS. An association with HPA axis activity was weak, possibly because the present sample was stable on immunotherapy.

Compromised tDCS-induced facilitation of motor consolidation in patients with multiple sclerosis.

OBJECTIVE: To investigate whether consolidation after motor learning can be facilitated by offline (post-training) transcranial direct current stimulation (tDCS) in patients with multiple sclerosis (MS). METHODS: In this cross-sectional double-blind interventional study, effects of tDCS on motor consolidation were examined in 14 patients with relapsing remitting MS [median Expanded Disability Status Scale score 2.0 (range 1-4)] and 14 age- and sex-matched healthy controls. tDCS with the anode placed over the left primary motor cortex and the cathode placed over the right supraorbital region was applied immediately after a training session of an explicit sequential finger-tapping task that was performed with the right (dominant) hand. Task performance was retested after an interval of 8 h to assess consolidation. Participants took part in two experimental sessions separated by at least 7 days which differed with respect to type of post-training tDCS, i.e., sham and verum stimulation. RESULTS: Patients with MS performed worse than controls in functional motor tests and the motor sequence task. However, learning speed and magnitude of online performance increments during the training session were comparable to controls. While post-training tDCS facilitated motor consolidation in controls, patients with MS did not benefit from this type of intervention. CONCLUSION: Absence of post-training tDCS-induced facilitation of consolidation in patients with MS suggests that the interaction of tDCS with the motor consolidation network is inefficient. Identification of the underlying disease-related mechanisms will have important implications for the design of studies aiming to promote motor recovery in MS by non-invasive brain stimulation.

Treatment choices and neuropsychological symptoms of a large cohort of early MS.

OBJECTIVE: To assess clinical characteristics, distribution of disease-modifying treatments (DMTs), and neuropsychological symptoms in a large cohort of patients with early-stage MS. METHODS: The German National MS Cohort is a multicenter prospective longitudinal cohort study that has recruited DMT-naive patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) since 2010. We evaluated their baseline characteristics and the prevalence of neuropsychological symptoms. RESULTS: Of 1,124 patients, with a 2.2:1 female-to-male ratio and median age at onset of 31.71 years (interquartile range [IQR]: 26.06-40.33), 44.6% and 55.3% had CIS and RRMS, respectively. The median Expanded Disability Status Scale (EDSS) score at baseline was 1.5 (IQR: 1.0-2.0). A proportion of 67.8% of patients started DMT after a median time of 167.0 days (IQR 90.0-377.5) since the first manifestation. A total of 64.7% and 70.4% of the 762 patients receiving early DMT were classified as CIS and RRMS, respectively. Fatigue, depressive symptoms, and cognitive dysfunction were detected in 36.5%, 33.5%, and 14.7% of patients, respectively. CONCLUSION: Baseline characteristics of this large cohort of patients with early, untreated MS corroborated with other cohorts. Most patients received early DMT within the first year after disease onset, irrespective of a CIS or RRMS diagnosis. Despite the low EDSS score, neuropsychological symptoms affected a relevant proportion of patients.

Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity.

CONTEXT: Increased activities of the arginine-vasopressin (AVP) system and the hypothalamic-pituitary-adrenal (HPA) axis were shown to be associated with human obesity, but relationships between these systems in obesity remain unclear. OBJECTIVES: To assess HPA axis responsiveness and its relation to serum concentrations of the AVP-surrogate copeptin in subjects with obesity (OB) in comparison to non-obesity controls (NOC). METHODS: In a cross-sectional monocentric study, thirty-nine OB (f/m 25/14; age 36.5±10.0years; body mass index, BMI, 41.5±4.7kg/m2) were compared to twenty-two NOC (f/m 12/10; age 35.3±8.5years; BMI 23.1±2.4kg/m2), matched for age and sex. All individuals underwent the combined dexamethasone/CRH test. MAIN OUTCOME MEASURES: Plasma ACTH and cortisol curve indicators derived from the dex/CRH test (post-CRH concentrations 30min after 100µg CRH; maximum concentration, MAX; area-under-the-curve, AUC; ACTH/cortisol ratios). Copeptin was assessed in 1500h samples of the dex/CRH test (after 1.5mg of oral dexamethasone, prior to CRH administration). RESULTS: Copeptin serum concentrations were higher in OB (median [IQR]: OB 4.62 [2.60-5.88] vs. NOC 3.04 [2.52-4.29] pmol/l, P=0.04). Correspondingly, OB showed higher post-CRH cortisol concentrations (OB: 51.5 [25.9-159.3] vs. NOC: 28.6 [20.0-41.6] nmol/l, P=0.01) and a lower post-CRH ACTH/cortisol ratio (OB: 0.028 [0.016-0.053] vs. NOC: 0.048 [0.034-0.070] pmol/nmol, P<0.01). Serum copeptin was significantly associated with HPA responsiveness in OB (post-CRH ACTH: R=0.42, P<0.01), driven by OB men (post-CRH ACTH: R=0.76, P<0.01, post-CRH cortisol: R=0.64, P=0.02). All associations withstand adjustments for BMI and age. CONCLUSIONS: The association between increased copeptin with ACTH and cortisol release suggests a potential mechanistic interaction of the AVP system with HPA activation in human obesity. The relation of copeptin and HPA responsiveness should be further validated in situations with pronounced HPA activation, such as depression or multiple sclerosis.