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-
CO-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: ACTH
r = 0.87, p = .001; cortisol
r = 0.86, p = .002; amygdala: ACTH
r = 0.86, p = .002; cortisol
r = 0.79, p = .006), while in obesity, the hypothalamic DVR correlated inversely with the HPA axis response (cortisol
, 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.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Objective
To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein‐antibody‐associated disease (MOGAD) in a changing ...treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age.
Methods
We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS).
Results
We included 483 patients: 298 AQP4‐IgG+ NMOSD, 52 AQP4‐IgG−/MOG‐IgG− NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4‐IgG+ NMOSD 7.7 (95% CI 6.6–9.6) years, AQP4‐IgG−/MOG‐IgG− NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4–27.6) years; EDSS 4: 11.9 (95% CI 9.7–14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5–32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4‐IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time.
Interpretation
AQP4‐IgG+ NMOSD, AQP4‐IgG−/MOG‐IgG− NMOSD, and MOGAD patients show distinctive relapse‐associated disability progression, with MOGAD having a less severe disease course. Investigator‐initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024;95:720–732
Cognitive impairment (CI) affects 40–65% of multiple sclerosis (MS) patients. This study attempted evaluating the effects of fingolimod and interferon beta-1b (IFN β-1b) on CI progression, magnetic ...resonance imaging (MRI) and clinical outcomes in relapsing–remitting MS (RRMS) patients over 18 months. The GOLDEN study was a pilot study including RRMS patients with CI randomised (2:1) to fingolimod (0.5 mg daily)/IFN β-1b (250 µg every other day). CI was assessed via Rao’s Brief Repeatable Battery and Delis–Kaplan Executive Function System test. MRI parameters, Expanded Disability Status Scale scores and relapses were measured. Overall, 157 patients were randomised, of whom 30 discontinued the study (fingolimod, 8.49%; IFN β-1b, 41.18%;
p
≤ 0.0001). Patients randomised to fingolimod had more severe clinical and MRI disease characteristics at baseline compared with IFN β-1b. At Month (M) 18, both treatment groups showed improvements in all cognitive parameters. At M18, relapse rate, total number and volume of T2/T1 gadolinium-enhancing lesions were higher with IFN β-1b, as well as the percentage brain volume change during the study. Safety and tolerability of both treatments were similar to previous studies. Both treatments showed improvements in cognitive parameters. Fingolimod demonstrated significantly better effects on MRI parameters and relapse rate. Imbalance in baseline characteristics and the drop-out pattern may have favoured IFN β-1b. A longer duration trial may be needed to observe the complete expression of differential effects on CI scales reflecting the between-groups differences on MRI. Although limited in size, the GOLDEN study confirms the favourable benefit–risk profile of fingolimod reported in previous studies.
OBJECTIVETo assess clinical characteristics, distribution of disease-modifying treatments (DMTs), and neuropsychological symptoms in a large cohort of patients with early-stage MS.
METHODSThe 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.
RESULTSOf 1,124 patients, with a 2.2:1 female-to-male ratio and median age at onset of 31.71 years (interquartile range IQR26.06–40.33), 44.6% and 55.3% had CIS and RRMS, respectively. The median Expanded Disability Status Scale (EDSS) score at baseline was 1.5 (IQR1.0–2.0). 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.
CONCLUSIONBaseline 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.
To evaluate the effects of the coronavirus disease 2019 (COVID-19) pandemic on the life of patients with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein ...antibody-associated diseases (MOGAD).
This multicenter, cross-sectional study included data of 187 patients recruited from 19 different German and Austrian Neuromyelitis Optica Study Group (NEMOS) centers between July 2021 and March 2022. The effects of the pandemic on immunotherapeutic treatment and access to care, the possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of vaccination against SARS-CoV-2 on disease incidence and relapse risk were assessed using a patient questionnaire. Health-related quality of life (HRQoL) was measured with the EuroQoL Group 5-Dimension 5-Level Scale (EQ-5D-5L). Demographic and clinical characteristics were retrieved from the NEMOS database.
One hundred eighty-seven patients (75% women; median age 47 range 21-86 years; median disease duration 5.5 range 0-67 years; median Expanded Disability Status Scale 2.0 range 0-8.0; 51% aquaporin-4 immunoglobulin G (AQP4-IgG)-positive, 36% myelin oligodendrocyte glycoprotein (MOG)-IgG-positive 13% double-seronegative) were analyzed. Most patients maintained excellent access to healthcare services throughout the pandemic. Immunotherapy was not changed in 88% of patients. Ninety-one percent of all patients were satisfied with medical care during the pandemic. Nearly two-thirds (64%) of patients rated their risk of infection with SARS-CoV-2 as low or moderate. Among this study sample, 23 patients (12%) knowingly acquired an infection with SARS-CoV-2 and predominantly had a nonsevere course of illness (n = 22/23, 96%). The SARS-CoV-2 vaccination rate was 89%, with 4 cases of confirmed attack or first manifestation of NMOSD/MOGAD occurring in temporal association with the vaccination (range 2-9 days). The reported HRQoL did not decline compared with a prepandemic assessment (mean EQ-5D-5L index value 0.76, 95% bootstrap confidence interval CI 0.72-0.80; mean EQ-VAS 66.5, 95% bootstrap CI 63.5-69.3).
This study demonstrates that, overall, patients with NMOSD/MOGAD affiliated with specialized centers received ongoing medical care during the pandemic. Patients' satisfaction with medical care and HRQoL did not decrease.
Background
Cognitive impairment (CI) affects approximately one-third of the patients with early multiple sclerosis (MS) and clinically isolated syndrome (CIS). Little is known about factors ...predicting CI and progression after initial diagnosis.
Methods
Neuropsychological screening data from baseline and 1-year follow-up of a prospective multicenter cohort study (NationMS) involving 1123 patients with newly diagnosed MS or CIS were analyzed. Employing linear multilevel models, we investigated whether demographic, clinical and conventional MRI markers at baseline were predictive for CI and longitudinal cognitive changes.
Results
At baseline, 22% of patients had CI (impairment in ≥2 cognitive domains) with highest frequencies and severity in processing speed and executive functions. Demographics (fewer years of academic education, higher age, male sex), clinical (EDSS, depressive symptoms) but no conventional MRI characteristics were linked to baseline CI. At follow-up, only 14% of patients showed CI suggesting effects of retesting. Neither baseline characteristics nor initiation of treatment between baseline and follow-up was able to predict cognitive changes within the follow-up period of 1 year.
Conclusions
Identification of risk factors for short-term cognitive change in newly diagnosed MS or CIS is insufficient using only demographic, clinical and conventional MRI data. Change-sensitive, re-test reliable cognitive tests and more sophisticated predictors need to be employed in future clinical trials and cohort studies of early-stage MS to improve prediction.
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.
OBJECTIVETo assess the impact of APOE polymorphisms on cognitive performance in patients newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS).
METHODSThis ...multicenter cohort study included 552 untreated patients recently diagnosed with CIS or RRMS according to the 2005 revised McDonald criteria. The single nucleotide polymorphisms rs429358 (ε4) and rs7412 (ε2) of the APOE haplotype were assessed by allelic discrimination assays. Cognitive performance was evaluated using the 3-second paced auditory serial addition test and the Multiple Sclerosis Inventory Cognition (MUSIC). Sum scores were calculated to approximate the overall cognitive performance and memory-centered cognitive functions. The impact of the APOE carrier status on cognitive performance was assessed using multiple linear regression models, also including demographic, clinical, MRI, and lifestyle factors.
RESULTSAPOE ε4 homozygosity was associated with lower overall cognitive performance, whereas no relevant association was observed for APOE ε4 heterozygosity or APOE ε2 carrier status. Furthermore, higher disability levels, MRI lesion load, and depressive symptoms were associated with lower cognitive performance. Patients consuming alcohol had higher test scores than patients not consuming alcohol. Female sex, lower disability, and alcohol consumption were associated with better performance in the memory-centered subtests of MUSIC, whereas no relevant association was observed for APOE carrier status.
CONCLUSIONAlong with parameters of a higher disease burden, APOE ε4 homozygosity was identified as a potential predictor of cognitive performance in this large cohort of patients with CIS and early RRMS.
Pain of various causes is a common phenomenon in patients with Multiple Sclerosis (MS). A biopsychosocial perspective has proven a useful theoretical construct in other chronic pain conditions and ...was also started in MS. To support such an approach, we aimed to investigate pain in MS with special emphasis on separating quantitative and qualitative aspects, and its interrelation to behavioral and physical aspects.
Pain intensity (NRS) and quality (SES) were measured in 38 consecutive outpatients with MS (mean age, 42.0 ± 11.5 years, 82% women). Pain-related behavior (FSR), health care utilization, bodily complaints (GBB-24) and fatigue (WEIMuS) were assessed by questionnaires, and MS-related neurological impairment by a standardized neurological examination (EDSS).
Mean pain intensity was 4.0 (range, 0-10) and mean EDSS 3.7 (range, 0-8) in the overall sample. Currently present pain was reported by 81.6% of all patients. Disease duration and EDSS did not differ between patients with and without pain and were not correlated to quality or intensity of pain. Patients with pain had significantly higher scores of musculoskeletal complaints, but equal scores of exhaustion, gastrointestinal and cardiovascular complaints. Pain intensity correlated only with physical aspects, whereas quality of pain was additionally associated with increased avoidance, resignation and cognitive fatigue.
As in other conditions, pain in MS must be assessed in a multidimensional way. Further research should be devoted to adapt existing models to a MS-specific model of pain.
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