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Acute transverse myelitis (ATM) is a disease characterized by inflammation of the spinal cord and may have various causes. In the context of this work, the distinction between isolated ATM and initial manifestation of autoimmune-mediated diseases of the central nervous system such as multiple sclerosis (MS) is crucial. Hence, the aim of this work was to identify predictive factors associated with the conversion to definite MS in a collective of individuals after their initial episode of isolated ATM (no initial identified cause). In this retrospective data analysis from the Vienna MS Database, all patients from Jan. 1, 1999, to Dec. 31, 2019, with a diagnosis of isolated ATM (according to the criteria of the Transverse Myelitis Consortium Working Group) who underwent lumbar puncture were extracted. Electronic medical records were reviewed on the availability of clinical data including therapy and follow-up, laboratory results including cerebrospinal fluid (CSF) analysis, evoked potentials (EP) as well as magnetic resonance imaging data. Among 42 patients with the diagnosis of isolated ATM, 12 (29%) were subsequently diagnosed with MS over a median follow-up period of 7.7 years. Univariately, MS converters were younger (32 years [25-39] vs. 42 years [31-50], p = 0.032), had a lower CSF/serum albumin ratio (29 [24-35] vs 37 [27-52], p = 0.037), lower CSF total protein (4.5 [2.8-4.8] vs. 5.5 [3.4-8.5], p = 0.023) and a higher proportion of CSF-specific oligoclonal bands (OCB; 83% vs. 30%, p = 0.002). In the multivariate regression analysis, the presence of CSF-specific OCB emerged as the sole predictive factor of subsequent MS diagnosis (OR: 14.42, 95% CI 1.39 to 149.48, p = 0.03). In a collective of 42 patients with isolated ATM and an MS conversion rate of nearly 30%, the only but highly predictive factor were CSF-specific OCB. This emphasizes the significance of conducting timely CSF analysis in such patients and underscores the need for tailored monitoring and follow-up strategies in this specific group., (© 2024. The Author(s).)

Background : The diagnosis and follow-up of cardiac involvement in Fabry disease constitutes an important challenge for clinicians caring for affected patients. Combining cardiac imaging with laboratory biomarkers appears most appropriate for longitudinal monitoring. Therefore, we examined the use of NT-proBNP and its association with imaging findings in patients with Fabry disease. Methods : We analysed cardiac MRI and echocardiography data, as well as laboratory results, from a single-centre prospective registry. Results : Repetitive follow-ups of 38 patients with Fabry disease, of whom 18 presented with left ventricular hypertrophy (LVH), revealed a correlation of NT-proBNP with left ventricular (LV) interventricular septal thickness, LV maximum wall thickness, LV and right ventricular (RV) mass index and trabecular mass in patients with LVH. Patients without LVH did not exhibit any tangible association between NT-proBNP and the mentioned parameters. Conversely, we could not detect an association of NT-proBNP with impairment of LV or RV ejection fraction or diastolic volume. Conclusions : NT-proBNP plays a pivotal role as a biomarker for cardiac involvement in patients with Fabry disease. Interestingly, in this specific population with mostly preserved ejection fraction, it seems to reflect ventricular hypertrophy rather than ventricular dysfunction or dilatation. While strong associations were found in hypertrophic patients, NT-proBNP's prognostic value appears limited in non- or pre-hypertrophic stages.

Fabry disease (FD) constitutes a rare, X-linked lysosomal storage disorder affecting multiple organ systems, most notably heart, kidneys, and the central nervous system. Neurofilament light chains (NfL) have emerged as a prime candidate for a body fluid biomarker reflecting neuro-axonal injury. We aimed to evaluate its addition to the diagnostic and monitoring armamentarium in FD. Serum NfL concentrations (sNfL) were measured in 50 people with FD (PwFD) and 30 healthy control subjects (HC) using the Simoa© technology, followed by calculation of Z-scores adjusted for age and body mass index. In addition, clinical disease severity in PwFD was measured using the FOS-MSSI (Fabry outcome study - Mainz severity score index), which comprises clinical and paraclinical parameters. PwFD show elevated sNfL Z-scores compared to HC (PwFD: 1.12 [SD 1.5], HC: 0.01 [SD 1.2], p < 0.001). In PwFD, males showed higher sNfL Z-scores than females (1.75 [SD 1.5] vs. 0.73 [SD 1.4]). Importantly, sNfL Z-scores were increased in PwFD with ischemic white matter lesions of the CNS (1.5, SD 2.2 vs. 0.5, SD 2.9, p = 0.03). In our small cohort, sNfL Z-scores correlated fairly with FOS-MSSI (Kendall's-Tau [τ] = 0.25, p = 0.01), and, interestingly with serum creatinine (τ = 0.28, p = 0.005) and estimated glomerular filtration rate (eGFR, τ =-0.28, p = 0.005). Based on these exploratory results, sNfL might provide value as a biomarker of neuroaxonal damage in FD, possibly reflecting cerebrovascular injury. Additionally, the correlation of sNfL with renal function warrants further investigation., (© 2024. The Author(s).)

Background: Employing a rebaselining concept may reduce noise in retinal layer thinning measured by optical coherence tomography (OCT)., Methods: From an ongoing prospective observational study, we included patients with relapsing multiple sclerosis (RMS), who had OCT scans at disease-modifying treatment (DMT) start (baseline), 6-12 months after baseline (rebaseline), and ⩾12 months after rebaseline. Mean annualized percent loss (aL) rates (%/year) were calculated both from baseline and rebaseline for peripapillary-retinal-nerve-fiber-layer (aLpRNFL baseline /aLpRNFL rebaseline ) and macular-ganglion-cell-plus-inner-plexiform-layer (aLGCIPL baseline /aLGCIPL rebaseline ) by mixed-effects linear regression models., Results: We included 173 RMS patients (mean age 31.7 years (SD 8.8), 72.8% female, median disease duration 15 months (12-94) median baseline-to-last-follow-up-interval 37 months (18-71); 56.6% moderately effective DMT (M-DMT), 43.4% highly effective DMT (HE-DMT)). Both mean aLpRNFL baseline and aLGCIPL baseline significantly increased in association with relapse (0.51% and 0.26% per relapse, p < 0.001, respectively) and disability worsening (1.10% and 0.48%, p < 0.001, respectively) before baseline, but not with DMT class. Contrarily, neither aLpRNFL rebaseline nor aLGCIPL rebaseline was dependent on relapse or disability worsening before baseline, while HE-DMT significantly lowered aLpRNFL rebaseline (by 0.31%, p < 0.001) and aLGCIPL rebaseline (0.25%, p < 0.001) compared with M-DMT., Conclusions: Applying a rebaselining concept significantly improves differentiation of DMT effects on retinal layer thinning by avoiding carry-over confounding from previous disease activity., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Gabriel Bsteh has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene/BMS, Lilly, MedWhizz, Merck, Novartis, Roche, Sanofi Genzyme and Teva, and received honoraria for consulting Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. He has received unrestricted research grants from Celgene/BMS and Novartis.Harald Hegen has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Bristol Myers Squibb, Horizon, Merck, Novartis, Sanofi Genzyme, Siemens and Teva, and received honoraria for consulting Biogen, Bristol Myers Squibb, Novartis, Roche, Sanofi Genzyme, and Teva. He is associate editor of Frontiers in Neurology.Nik Krajnc has participated in meetings sponsored by, received speaker honoraria or travel funding from Alexion, BMS/Celgene, Janssen-Cilag, Merck, Novartis, Roche and Sanofi Genzyme and held a grant for a Multiple Sclerosis Clinical Training Fellowship Programme from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).Fabian Föttinger has nothing to disclose.Patrick Altmann has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Merck, Roche, Sanofi Genzyme and Teva, and received honoraria for consulting from Biogen. He received a research grant from Quanterix International and was awarded a combined sponsorship from Biogen, Merck, Sanofi Genzyme, Roche, and Teva for a clinical study.Michael Auer has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Merck, Novartis, Sanofi Genzyme and Horizon Therapeutics.Klaus Berek has participated in meetings sponsored by and received travel funding from Biogen, Roche, Sanofi Genzyme, and Teva.Barbara Kornek has received honoraria for speaking and for consulting from Biogen, BMS-Celgene, Johnson & Johnson, Merck, Novartis, Roche, Teva, and Sanofi Genzyme outside of the submitted work. No conflict of interest with respect to the present study.Fritz Leutmezer has participated in meetings sponsored by, received speaker honoraria or travel funding from Actelion, Almirall, Biogen, Celgene, Johnson & Johnson, MedDay, Merck, Novartis, Roche, Sanofi Genzyme, and Teva, and received honoraria for consulting Biogen, Celgene, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.Stefan Macher declares no conflict of interest relevant to this study.Tobias Monschein has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.Markus Ponleitner has participated in meetings sponsored by, received speaker or consulting honoraria or travel funding from Amicus, Merck, Novartis and Sanofi Genzyme.Paulus Rommer has received honoraria for consultancy/speaking from Alexion/Astra Zeneca, Allmiral, Amgen/Horizon, Amicus, Biogen, Merck, Novartis, Roche, Sandoz, Sanofi has received research grants from Amicus, Biogen, Merck, and Roche.Christiane Schmied declares no conflict of interest relevant to this study.Karin Zebenholzer received speaking honoraria or travel grants from Biogen, Celgene/BMS, Novartis, and Sanofi Genzyme.Gudrun Zulehner has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.Tobias Zrzavy has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.Florian Deisenhammer has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Almirall, Biogen, Celgene, Merck, Novartis, Roche, and Sanofi Genzyme. His institution received scientific grants from Biogen and Sanofi Genzyme.Franziska Di Pauli has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Biogen, Celgene BMS, Horizon, Johnson & Johnson, Merck, Novartis, Sanofi Genzyme, Teva, and Roche. Her institution has received research grants from Roche.Berthold Pemp has received honoraria for consulting from Novartis, has received honoraria for advisory boards/consulting from Chiesi and GenSight, and has received speaker honoraria from Novartis, Chiesi, and Santen.Thomas Berger has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for MS: Allergan, Bayer, Biogen, Bionorica, BMS/Celgene, Genesis, GSK, GW/Jazz Pharma, Horizon, Janssen-Cilag, MedDay, Merck, Novartis, Octapharma, Roche, Sandoz, Sanofi Genzyme, Teva, and UCB. His institution has received financial support in the past 12 months by unrestricted research grants (Biogen, Bayer, BMS/Celgene, Merck, Novartis, Roche, Sanofi Genzyme, Teva) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi Genzyme, and Teva.

Background: Cognitive impairment is prevalent in patients with heart failure with reduced ejection fraction (HFrEF), affecting self-care and outcomes. Novel blood-based biomarkers have emerged as potential diagnostic tools for neurodegeneration., Objectives: This study aimed to assess neurodegeneration in HFrEF by measuring neurofilament light chain (NfL), total tau (t-tau), amyloid beta 40 (Aβ40), and amyloid beta 42 (Aβ42) in a large, well-characterized cohort., Methods: The study included 470 patients with HFrEF from a biobank-linked prospective registry at the Medical University of Vienna. High-sensitivity single-molecule assays were used for measurement. Unplanned heart failure (HF) hospitalization and all-cause death were recorded as outcome parameters., Results: All markers, but not the Aβ42:Aβ40 ratio, correlated with HF severity, ie, N-terminal pro-B-type natriuretic peptide and NYHA functional class, and comorbidity burden and were significantly associated with all-cause death and HF hospitalization (crude HR: all-cause death: NfL: 4.44 [95% CI: 3.02-6.53], t-tau: 5.04 [95% CI: 2.97-8.58], Aβ40: 3.90 [95% CI: 2.27-6.72], and Aβ42: 5.14 [95% CI: 2.84-9.32]; HF hospitalization: NfL: 2.48 [95% CI: 1.60-3.85], t-tau: 3.44 [95% CI: 1.95-6.04], Aβ40: 3.13 [95% CI: 1.84-5.34], and Aβ42: 3.48 [95% CI: 1.93-6.27]; P < 0.001 for all). These associations remained statistically significant after multivariate adjustment including N-terminal pro-B-type natriuretic peptide. The discriminatory accuracy of NfL in predicting all-cause mortality was comparable to the well-established risk marker N-terminal pro-B-type natriuretic peptide (C-index: 0.70 vs 0.72; P = 0.225), whereas the C-indices of t-tau, Aβ40, Aβ42, and the Aβ42:Aβ40 ratio were significantly lower (P < 0.05 for all)., Conclusions: Neurodegeneration is directly interwoven with the progression of HF. Biomarkers of neurodegeneration, particularly NfL, may help identify patients potentially profiting from a comprehensive neurological work-up. Further research is necessary to test whether early diagnosis or optimized HFrEF treatment can preserve cognitive function., Competing Interests: Funding Support and Author Disclosures This project was funded by an unrestricted grant of the Austrian Cardiac Society (Österreichische Kardiologische Gesellschaft). The authors have reported that they have no relationships relevant to the contents of this paper to declare., (Copyright © 2024. Published by Elsevier Inc.)

Background: Pregnancy and delivery outcomes in women with Fabry disease are not well described., Methods: Retrospective cohort-study of women with Fabry disease in Austria using a specific questionnaire and the Austrian Mother-Child Health Passport., Results: Out of a total of 44 enrolled women (median age at study entry 44 years, p25: 30, p75: 51), 86.4% showed signs and symptoms of Fabry disease with an increase in pain burden during pregnancy, primarily in women with moderate pain before pregnancy. Thirty-two of 44 women with Fabry disease reported a total of 70 pregnancies (median age at first pregnancy 24 years, p25: 21, p75: 31), 61 (87.1%) of which resulted in 64 live births including 3 sets of twins, six miscarriages (8.6%) in five women, and three induced abortions (4.3%) in two women. Risk factors for poor maternal and foetal outcomes during pregnancy, overrepresented in our cohort as compared to the general population, were hypertension (n = 10, 16.4%), proteinuria (n = 17, 27.9%) and smoking (n = 24, 39.3%). Preeclampsia was reported in 7 pregnancies (11.5%). Fifty-one (79.7%) children were born at term and 13 (20.3%) were preterm (including one neonatal death), with a median gestational age of 39 weeks (p25: 38, p75: 40) and delivery by C-section in 15 pregnancies (24.6%). Thirteen (20.3%) children presented with low birth weight and 18 (28.1%) were small for their gestational age. In comparison to global and national data-sets, preeclampsia, prematurity, low birth weight, being small for their gestational age as well as inpatient stay were significantly more common in patients with Fabry disease., Conclusions: Our cohort-study in women with Fabry disease shows an increase of pain burden during pregnancies and clearly points to an increased risk for preeclampsia, prematurity, and neonates small for gestational age. With a substantial number of high-risk pregnancies, neonatal outcomes are somewhat worse in Fabry disease than in the general public. Thus, we provide valuable data enabling informed decision-making in pregnancy counselling for Fabry disease., (© 2024. The Author(s).)

Neuromyelitis optica spectrum disorder (NMOSD) represents a rare neuroimmunological disease causing recurrent attacks and accumulation of permanent disability in affected patients. The discovery of the pathogenic IgG‑1 antibody targeting a water channel expressed in astrocytes, aquaporin 4, constitutes a milestone achievement. Subsequently, multiple pathophysiological aspects of this distinct disease entity have been investigated. Demyelinating lesions and axonal damage ensue from autoantibodies targeting an astroglial epitope. This conundrum has been addressed in the current disease model, where activation of the complement system as well as B cells and interleukin 6 (IL-6) emerged as key contributors. It is the aim of this review to address these factors in light of novel treatment compounds which reflect these pathophysiological concepts in aiming for attack prevention, thus reducing disease burden in patients with NMOSD., (© 2022. The Author(s).)

Background: Critical illness polyneuropathy (CIP) commonly occurs in critical care unit (CCU) patients, but timely diagnosis can be challenging. Therefore, new biomarkers, such as serum neurofilament light chain (sNfL), could help to improve early identification of patients with this condition., Methods: CIP was diagnosed or excluded with neurological assessment and nerve conduction measurement in a prospective study of CCU patients. sNfL and secondary predictors for neuropathy (neuron-specific enolase (NSE), S100, folic acid, and vitamin B12) were measured at admission. Cases and controls were compared regarding the predictors., Results: Nineteen patients met the inclusion criteria. CIP was considered definitely or most likely present in seven (37%, cases) and definitely or most likely absent in 12 individuals (63%, controls). At admission, sNfL levels were significantly higher in the cases than in the controls: 405 (IQR 77 to 835) vs. 27 (IQR 12 to 90) pg/mL; difference of medians 375, 95% confidence interval [14, 736], pg/mL; P=0.04. We found no significant differences regarding the secondary predictors at baseline. Cases had longer durations of CCU stay (median 19 (IQR 11 to 44) vs. 8 (IQR five to ten) and increased mortality (57% vs. 33% deceased) compared to controls., Conclusions: Levels of serum neurofilament light chain are higher in patients who develop CIP soon after CCU admission and might be helpful in identifying those individuals early.

Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation.

Background: X-linked adrenoleukodystrophy (X-ALD) is highly variable, ranging from slowly progressive adrenomyeloneuropathy to severe brain demyelination and inflammation (cerebral ALD, CALD) affecting males with childhood peak onset. Risk models integrating blood-based biomarkers to indicate CALD onset, enabling timely interventions, are lacking. Therefore, we evaluated the prognostic value of blood biomarkers in addition to current neuroimaging predictors for early detection of CALD., Methods: We measured blood biomarkers in a retrospective, male CALD risk-assessment cohort consisting of 134 X-ALD patients and 66 controls and in a phenotype-blinded validation set (25 X-ALD boys, 4-13 years) using Simoa®and Luminex® technologies., Findings: Among 25 biomarkers indicating axonal damage, astrocye/microglia activation, or immune-cell recruitment, neurofilament light chain (NfL) had the highest prognostic value for early indication of childhood/adolescent CALD. A plasma NfL cut-off level of 8.33 pg/mL, determined in the assessment cohort, correctly discriminated CALD with an accuracy of 96% [95% CI: 80-100] in the validation group. Multivariable logistic regression models revealed that combining NfL with GFAP or cytokines/chemokines (IL-15, IL-12p40, CXCL8, CCL11, CCL22, and IL-4) that were significantly elevated in CALD vs healthy controls had no additional benefit for detecting neuroinflammation. Some cytokines/chemokines were elevated only in childhood/adolescent CALD and already upregulated in asymptomatic X-ALD children (IL-15, IL-12p40, and CCL7). In adults, NfL levels distinguished CALD but were lower than in childhood/adolescent CALD patients with similar (MRI) lesion severity. Blood GFAP did not differentiate CALD from non-inflammatory X-ALD., Interpretation: Biomarker-based risk prediction with a plasma NfL cut-off value of 8.33 pg/mL, determined by ROC analysis, indicates CALD onset with high sensitivity and specificity in childhood X-ALD patients. A specific pro-inflammatory cytokine/chemokine profile in asymptomatic X-ALD boys may indicate a primed, immanent inflammatory state aligning with peak onset of CALD. Age-related differences in biomarker levels in adult vs childhood CALD patients warrants caution in predicting onset and progression of CALD in adults. Further evaluations are needed to assess clinical utility of the NfL cut-off for risk prognosis of CALD onset., Funding: Austrian Science Fund, European Leukodystrophy Association., Competing Interests: Declaration of interests MP received support from Amicus, Merck, Novartis and Sanofi-Genzyme; BZ received support from ACTRIMS 2022 and 2023 endMS SPRINT; JG received support from Quanterix; HAY was supported by an emerging investigator grant from ALD connect; CGB received grants from the German Research Foundation and the Ministry for Science and Culture of Lower Saxony; ME received support from Minoryx and is member of the advisory board of Minoryx, Poxel and SwanBio Therapeutics; FE is holding a license for “Intrathecal delivery of nucleic acid sequences encoding ABCD1 for treatment of Adrenomyeloneuropathy” (NO. 29539-021PCT), received consulting fees from SwanBio Therapeutics and UpToDate, is founder of SwanBio Therapeutics, ALD Connect and organizer of trial sites for ASPA, Bluebird Bio Therapeutics, Ionis Pharmaceuticals and Sanofi; AP received consulting fees from Swanbio Therapeutics and Sanofi and is member of the Advisory Board of Bluebird Bio Therapeutics and MedDay Therapeutics. JSK is member of the advisory board for Krabbe Disease of PassageBio. MCR received a grant from Novartis. EM has received funding from the National Institutes of Health (K23NS118044). All remaining authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: With the approval of natalizumab in Europe in 2006, the Austrian Multiple Sclerosis Therapy Registry (AMSTR) was established. Here, we present data from this registry about effectiveness and safety of natalizumab in patients treated up to 14 years., Patients/methods: Data retrieved from the AMSTR contained baseline characteristics and biannual documentation of annualised relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score as well as adverse events and reasons for discontinuation on follow-up visits., Results: A total of 1596 natalizumab patients (71% women, n = 1133) were included in the analysis and the observed treatment duration ranged from 0 to 164 months (13.6 years). The mean ARR was 2.0 (SD = 1.13) at baseline, decreasing to 0.16 after 1 year and 0.01 after 10 years. A total of 325 patients (21.6%) converted to secondary progressive multiple sclerosis (SPMS) during the observational period. Of 1502 patients, 1297 (86.4%) reported no adverse events (AE) during follow-up visits. The most common reported AEs were infections and infusion-related reactions. John Cunningham virus (JCV) seropositivity was the most common specified reason for treatment discontinuation (53.7%, n = 607). There were five confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) with 1 death., Conclusion: The effectiveness of natalizumab in patients with active relapsing-remitting multiple sclerosis (RRMS) could be confirmed in our real-world cohort even after follow-up of up to 14 years, though after year 10, there were less than 100 remaining patients. A low number of AE were reported in this nationwide registry study, establishing Natalizumab's favourable safety profile during long-term use., (© 2023. The Author(s).)

Background: Fabry cardiomyopathy is characterized by left ventricular hypertrophy, myocardial fibrosis, arrhythmia, and premature death. Treatment with migalastat, an oral pharmacological chaperone, was associated with a stabilization of cardiac biomarkers and a reduction in left ventricular mass index, as measured by echocardiography. A recent study, using cardiac magnetic resonance (CMR) as the gold standard, found a stable course of myocardial involvement after 18 months of treatment with migalastat. Our study aimed to provide long-term CMR data for the treatment with migalastat. Methods: A total of 11 females and four males with pathogenic amenable GLA mutations were treated with migalastat and underwent 1.5T CMR imaging for routine treatment effect monitoring. The main outcome was a long-term myocardial structural change, reflected by CMR. Results: After migalastat treatment initiation, left ventricular mass index, end diastolic volume, interventricular septal thickness, posterior wall thickness, estimated glomerular filtration rate, and plasma lyso-Gb3 remained stable during the median follow-up time of 34 months (min.: 25; max.: 47). The T1 relaxation times, reflecting glycosphingolipid accumulation and subsequent processes up to fibrosis, fluctuated over the time without a clear trend. No new onset of late gadolinium enhancement (LGE) areas, reflecting local fibrosis or scar formation of the myocardium, could be detected. However, patients with initially present LGE showed an increase in LGE as a percentage of left ventricular mass. The median α-galactosidase A enzymatic activity increased from 37.3% (IQR 5.88-89.3) to 105% (IQR 37.2-177) of the lower limit of the respective reference level ( p = 0.005). Conclusion: Our study confirms an overall stable course of LVMi in patients with FD, treated with migalastat. However, individual patients may experience disease progression, especially those who present with fibrosis of the myocardium already at the time of therapy initiation. Thus, a regular treatment re-evaluation including CMR is needed to provide the optimal management for each patient.

Background: Inter-individual courses of multiple sclerosis (MS) are extremely variable. The objective of this study was to investigate whether κ-free light chain (κ-FLC) index and serum neurofilament light (sNfL) have an additive predictive value for MS disease activity., Methods: Patients with early MS who had cerebrospinal fluid (CSF) and serum sampling at disease onset were followed for four years. At baseline, age, sex, disease duration, number of T2-hyperintense (T2L), and contrast-enhancing T1 lesions (CEL) on MRI were determined. During follow-up, the occurrence of a second clinical attack and start of disease-modifying treatment (DMT) were registered. κ-FLC was measured by nephelometry, and κ-FLC index calculated as [CSF κ-FLC/serum κ-FLC]/albumin quotient. sNfL was determined by single-molecule array, and age- and body-mass-index adjusted Z scores were calculated., Findings: A total of 86 patients at a mean age of 33 ± 10 years and with a female predominance of 67% were included; 36 (42%) patients experienced a second clinical attack during follow-up. Cox regression analysis adjusted for age, sex, T2L, CEL, disease and follow-up duration, and DMT use during follow-up revealed that both κ-FLC index as well as sNfL Z score independently predict time to second clinical attack. The chance for freedom of relapse within 12 months was 2% in patients with high levels of κ-FLC index (>100) and high sNfL Z score (>3), 30% in patients with high κ-FLC index (>100) and lower sNfL Z score (≤3), 70% in patients with lower κ-FLC index (≤100) but high sNfL Z score (>3), and 90% in patients with lower levels of κ-FLC index (≤100) and sNfL Z score (≤3)., Interpretation: κ-FLC index and sNfL Z score have an additive predictive value for early MS disease activity that is independent of known predictors., Funding: This study was funded by a grant of the charitable foundation of the Austrian Multiple Sclerosis Society., Competing Interests: Declaration of interests HH has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Siemens, Teva, and received honoraria for acting as consultant for Biogen, Celgene, Novartis and Teva. He is associate editor of Frontiers in Neurology. KB has participated in meetings sponsored by and received travel funding or speaker honoraria from Roche, Teva, Merck, Biogen, Sanofi. GB has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene, Lilly, Merck, Novartis, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Celgene, Merck, Novartis, Roche and Teva. MA received speaker honoraria and/or travel grants from Biogen, Novartis, Merck and Sanofi. PA has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Merck, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting from Biogen. He received a research grant from Quanterix International and was awarded a combined sponsorship from Biogen, Merck, Sanofi-Genzyme, Roche, and Teva for a clinical study. FDP has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Roche and Teva. AG has nothing to disclose. DM has participated in meetings sponsored by Siemens. MP has participated in meetings sponsored by, received speaker or consulting honoraria or travel funding from Amicus, Merck, Novartis and Sanofi-Genzyme. PP has nothing to disclose. CS has participated in meetings sponsored by Siemens. SW has participated in meetings sponsored by, received honoraria or travel funding from Allergan, Biogen, Ipsen Pharma, Merck, Novartis, Roche, Sanofi Genzyme, Teva and Bristol Myers Squibb. AZ has participated in meetings sponsored by, received speaking honoraria or travel funding from Biogen, Merck, Novartis, Sanofi-Genzyme and Teva. TB has participated in the last 2 years in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for multiple sclerosis: Almirall, Biogen, Bionorica, BMS/Celgene, Eisai, Horizon, Jazz Pharmaceuticals, Janssen-Cilag, MedDay, Merck, Novartis, Roche, Sanofi Aventis/Genzyme, Sandoz, TG Therapeutics, TEVA and UCB. His institution has received financial support in the last 2 years by unrestricted research grants (Biogen, BMS/Celgene, Novartis, Sanofi Aventis/Genzyme, Roche, TEVA) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, BMS/Celegen, Merck, Novartis, Roche, Sanofi Aventis/Genzyme, TEVA. JW has nothing to disclose. FD has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Almirall, Biogen, Celgene-BMS, Genzyme-Sanofi, Horizon, Merck, Novartis Pharma, Roche, and Teva. His institution has received research grants from Biogen and Genzyme Sanofi. He is section editor of the MSARD Journal (Multiple Sclerosis and Related Disorders) and review editor of Frontiers Neurology., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Many patients with neuromyelitis optica spectrum disorders (NMOSD) suffer from cognitive impairment affecting memory, processing speed and attention and suffer from depressive symptoms. Because some of these manifestations could trace back to the hippocampus, several magnetic resonance imaging (MRI) studies have been performed in the past, with a number of groups describing volume loss of the hippocampus in NMOSD patients, whereas others did not observe such changes. Here, we addressed these discrepancies., Methods: We performed pathological and MRI studies on the hippocampi of NMOSD patients, combined with detailed immunohistochemical analysis of hippocampi from experimental models of NMOSD., Results: We identified different pathological scenarios for hippocampal damage in NMOSD and its experimental models. In the first case, the hippocampus was compromised by the initiation of astrocyte injury in this brain region and subsequent local effects of microglial activation and neuronal damage. In the second case, loss of hippocampal volume was seen by MRI in patients with large tissue-destructive lesions in the optic nerves or the spinal cord, and the pathological work-up of tissue derived from a patient with such lesions revealed subsequent retrograde neuronal degeneration affecting different axonal tracts and neuronal networks. It remains to be seen whether remote lesions and associated retrograde neuronal degeneration on their own are sufficient to cause extensive volume loss of the hippocampus, or whether they act in concert with small astrocyte-destructive, microglia-activating lesions in the hippocampus that escape detection by MRI, either due to their small size or due to the chosen time window for examination., Conclusions: Different pathological scenarios can culminate in hippocampal volume loss in NMOSD patients., (© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

We report the case of a 22-year-old woman presenting with an acute onset of dizziness, gait dysbalance and blurred vision. Magnetic resonance imaging included 3 Tesla and 7 Tesla imaging and revealed a T2-hyperintense, T1-hypointense, non-contrast-enhancing lesion strictly confined to the white matter affecting the right optic radiation. An extensive ophthalmologic examination yielded mild quadrantanopia but no signs of optic neuropathy. The lesion was biopsied. The neuropathological evaluation revealed a demyelinating lesion with marked tissue vacuolization and granular myelin disintegration accompanied by mild T cell infiltration and a notable absence of myelin uptake by macrophages. Oligodendrocytes were strikingly enlarged, displaying oncocytic characteristics and showed cytoplasmic accumulation of mitochondria, which had mildly abnormal morphology on electron microscopy. The diagnosis of multiple sclerosis was excluded. Harding's disease, a variant of Leber's hereditary optic neuropathy, was then suspected. However, neither PCR for relevant mutations nor whole exome sequencing yielded known pathogenetic mutations in the patient's genome. We present a pattern of demyelinating tissue injury of unknown etiology with an oncocytic change of oligodendrocytes and a lack of adequate phagocytic response by macrophages, which to the best of our knowledge, has not been described before., (© 2022. The Author(s).)

Background: Monitoring of patient outcomes in multiple sclerosis (MS) is fundamental for individualized treatment decisions. So far, these decisions have been motivated by conventional outcomes, i.e., relapses or clinical disability supported by radiological disease activity. Complementing this concept, patient reported outcomes (PROs) assess individual health-related quality of life, among other constructs. Their inclusion in clinical routine, however, has been challenging as assessing them requires resources of time and personnel., Objective: This interventional feasibility study investigated the haMSter app, a mobile health solution for remote and longitudinal monitoring of PROs in a sample of people with MS (pwMS)., Methods: The core feature of haMSter is the provision of three PRO questionnaires relevant to MS (anxiety/depression, MS-related quality of life, and fatigue) that patients can fill out once a month. For this feasibility trial, we offered 50 volunteers to use the haMSter app over six months and to take part in a haMSter study visit. This consultation concluded the study and participants had the opportunity to discuss their graphically plotted PRO results with their treating physician., Results: The main outcome was overall patient adherence to monthly completion of the PRO questionnaires, which remained high up to 4 months (98%) and dropped over time (months 5: 83% and 6: 66%). Exploratory outcomes included patient satisfaction as estimated on the Telemedicine Perception Questionnaire (TMPQ, 17-85 points). The mean TMPQ score was 64 (95%CI: 62-66) points, indicating a high degree of approval. Ancillary tests included subgroup analyses of participants with particularly high or low satisfaction and upper extremity disability as a potential obstacle to utility or acceptance. We found no distinct characteristics separating participants with high or low satisfaction., Conclusions: In this first feasibility trial, the haMSter app for longitudinal PRO monitoring was well received in terms of adherence and satisfaction. ClinicalTrials.gov identifier: NCT04555863., Competing Interests: The ethics review board at the Medical University of Vienna approved this study (EK1798/2019)., (© The Author(s) 2022.)

Introduction: Continuous monitoring is the hallmark of managing chronic disease. Multiple sclerosis (MS), in particular, requires patients to visit their treating neurologists typically twice a year, at least. In that respect, the COVID-19 pandemic made us rethink our communication strategies. This study determined satisfaction with remote visits for people with MS (pwMS) by comparing non-inferiority to conventional visits., Methods: TELE MS was a randomized controlled trial that was open to any person with MS. We randomized a volunteer sample of 45 patients. We compared satisfaction with remote visits (via phone or via videochat) with conventional outpatient visits. The primary endpoint was patient satisfaction determined by the Telemedicine Perception Questionnaire (TMPQ, min: 17 and max: 85 points) with the hypothesis of non-inferiority of televisits to conventional visits. Physician satisfaction measured on the PPSM score (Patient and Physician Satisfaction with Monitoring, min: 5 and max: 25 points) was the secondary endpoint., Results: The trial met both endpoints. Mean (SD) TMPQ scores in the individual groups were 58 (6.7) points for conventional visits, 65 (7.5) points for phone visits, and 62 (5.5) points for video visits. Physician satisfaction over the whole cohort was similarly high. Median (range) PPSM scores were 23 (16-25) for the whole cohort, 19 (16-25) for conventional visits, 25 (17-25) for phone visits, and 25 (16-25) for video visits., Conclusions: Televisits in multiple sclerosis yield a high level of satisfaction for both patients and treating physicians. This concept for remote patient monitoring adopted during the current pandemic may be communicable to other chronic diseases as well. ClinicalTrials.gov identifier: NCT04838990., Competing Interests: Conflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Continuous advances in resuscitation care have increased survival, but the rate of favorable neurological outcome remains low. We have shown the usefulness of proteomics in identifying novel biomarkers to predict neurological outcome. Neurofilament light chain (NfL), a marker of axonal damage, has since emerged as a promising single marker. The aim of this study was to assess the predictive value of NfL in comparison with and in addition to our established model., Methods: NfL was measured in plasma samples drawn at 48 h after cardiac arrest using single-molecule assays. Neurological function was recorded on the cerebral performance category (CPC) scale at discharge from the intensive care unit and after 6 months. The ability to predict a dichotomized outcome (CPC 1-2 vs. 3-5) was assessed with receiver operating characteristic (ROC) curves., Results: Seventy patients were included in this analysis, of whom 21 (30%) showed a favorable outcome (CPC 1-2), compared with 49 (70%) with an unfavorable outcome (CPC 3-5) at discharge. NfL increased from CPC 1 to 5 (16.5 pg/ml to 641 pg/ml, p < 0.001). The addition of NfL to the existing model improved it significantly (Wald test, p < 0.001), and the combination of NfL with a multimarker model showed high areas under the ROC curve (89.7% [95% confidence interval 81.7-97.7] at discharge and 93.7% [88.2-99.2] at 6 months) that were significantly greater than each model alone., Conclusions: The combination of NfL with other plasma and clinical markers is superior to that of either model alone and achieves high areas under the ROC curve in this relatively small sample., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Folding-deficient mutants of solute carrier 6 (SLC6) family members have been linked to human diseases. The serotonin transporter [(SERT)/SLC6A4] is an important drug target in the treatment of depression, anxiety, and obsessive-compulsive disorders and-with structural information in several conformational states-one of the best understood transporters. Here, we surmised that thermal unfolding offered a glimpse on the folding energy landscape of SLC6 transporters. We carried out molecular dynamic (MD) simulations to understand the mechanistic basis for enhanced and reduced stability, respectively, of the thermostabilized variant SERT-Y110A/I291A/T439S, which had previously been used for crystallization of human SERT in the outward-facing state, and of the folding-deficient SERT-P601A/G602A. We also examined the hydrophobic mismatch caused by the absence of cholesterol to explore the contribution of cholesterol to protein stability. When compared with wild type SERT, the thermodynamic and kinetic stability of SERT-Y110A/I291A/T439S was enhanced. In the other instances, changes in these two components were not correlated: the mutations in SERT-P601A/G602A led to a drop in thermodynamic but an increase in kinetic stability. The divergence was even more pronounced after cholesterol depletion, which reduced thermodynamic stability but increased the kinetic stability of wild type SERT to a level comparable to that of SERT-Y110A/I291A/T439S. We conclude that the low cholesterol content of the endoplasmic reticulum facilitates progression of the folding trajectory by reducing the energy difference between folding intermediates and the native state. SIGNIFICANCE STATEMENT: Point mutations in solute carrier 6 (SLC6) family members cause folding diseases. The serotonin transporter [(SERT)/SLC6A4] is a target for antidepressants and the best understood SLC6. This study produced molecular dynamics simulations and examined thermal unfolding of wild type and mutant SERT variants to understand their folding energy landscape. In the folding-deficient SERT-P012A/G602A, changes in kinetic and thermodynamic stability were not correlated. Similarly, cholesterol depletion lowered thermodynamic but enhanced kinetic stability. These observations allow for rationalizing the action of pharmacochaperones., (Copyright © 2022 by The Author(s).)

Telehealth is a growing domain with particular relevance for remote patient monitoring. With respect to the biopsychosocial model of health, it is important to evaluate perception and satisfaction with new methods in telehealth as part of an integrative approach. The Telemedicine Perception Questionnaire (TMPQ) is a 17-item questionnaire measuring patients' perception of and satisfaction with telecare. We translated this survey into German and determined its validity and reliability in 32 adolescents and adults. Furthermore, we derived a short version of the TMPQ, named Patient and Physician Satisfaction with Monitoring (PPSM), which is a 5-item questionnaire that can be administered to both patients and physicians. Validity and reliability were tested in 32 patients and 32 physicians. Crohnbach's α for the translated TMPQ was 0.76, and the German version yielded high validity (intraclass correlation coefficient (ICC) 0.995). We tested the PPSM in both patients and physicians and found acceptable values for Crohnbach's α (0.72 and 0.78) with excellent validity (ICC 0.965). We therefore concluded from this small study that both German versions of the TMPQ and PPSM can be used to investigate the acceptance of telehealth applications.

Neurofilament light chain (NfL) has emerged as a biomarker of neuroaxonal damage in several neurologic conditions. With increasing availability of fourth-generation immunoassays detecting NfL in blood, aspects of pre-analytical stability of this biomarker remain unanswered. This study investigated NfL concentrations in serum and plasma samples of 32 patients with neurological diagnoses using state of the art Simoa technology. We tested the effect of delayed freezing of up to 7 days and statistically determined stability and validity of measured concentrations. We found concentrations of NfL in serum and plasma to remain stable at room temperature when processing of samples is delayed up to 7 days (serum: mean absolute difference 0.9 pg/mL, intraindividual variation 1.2%; plasma: mean absolute difference 0.5 pg/mL, intraindividual variation 1.3%). Consistency of these results was nearly perfect for serum and excellent for plasma (intraclass correlation coefficients 0.99 and 0.94, respectively). In conclusion, the soluble serum and plasma NfL concentration remains stable when unprocessed blood samples are stored up to 7 days at room temperature. This information is essential for ensuring reliable study protocols, for example, when shipment of fresh samples is needed.

Background: Treatment and monitoring decisions in people with multiple sclerosis (MS) are based commonly on clinician-reported outcomes. These reflect physical and radiological disease activity and are the most relevant endpoints in clinical trials. Over the past few years, the number of studies evaluating so-called patient-reported outcomes (PROs) has been increasing. PROs are reports from patients concerning their own health perception. They are typically obtained by means of questionnaires and aim to quantify symptoms such as fatigue, depression, and sexual dysfunction. The emergence of PROs has made a tremendous contribution to understanding the individual impact of disease in people with MS and their health-related quality of life. However, the assessment of PROs consumes resources, including time and personnel. Thus, useful ways to conveniently introduce PROs into clinical practice are needed., Objective: We aim to provide a rationale and pilot study protocol for a mobile health (mHealth) solution named "haMSter" that allows for remote monitoring of PROs in people with MS., Methods: The core function of haMSter is to provide three scientifically validated PRO questionnaires relevant to MS for patients to fill out at home once a month. Thereby, longitudinal and remote documentation of PROs is enabled. A scoring algorithm graphically plots PRO scores over time and makes them available at the next visit., Results: The pilot study is currently ongoing and will evaluate adherence to this mHealth solution in 50 patients over a period of 6 months. Results from the haMSter pilot study are expected in 2021., Conclusions: haMSter is a novel mHealth-based solution for modern PRO research, which may constitute the first step in achieving the ability to integrate PROs in clinical practice. This allows for a more problem-oriented approach in monitoring visits, which addresses patient needs and ultimately saves time., Trial Registration: ClinicalTrials.gov NCT04555863; https://clinicaltrials.gov/ct2/show/NCT04555863., International Registered Report Identifier (irrid): DERR1-10.2196/25011., (©Patrick Altmann, Werner Hinterberger, Fritz Leutmezer, Markus Ponleitner, Tobias Monschein, Tobias Zrzavy, Gudrun Zulehner, Barbara Kornek, Rupert Lanzenberger, Klaus Berek, Paulus Stefan Rommer, Thomas Berger, Gabriel Bsteh. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 07.05.2021.)

Background: Little is known on how to address sexuality in clinical care for patients with multiple sclerosis (pwMS)., Aim: To describe and contrast the perception of sexuality and associated aspects of communication in pwMS and their treating neurologists ("MSologists") and provide a standard of care., Methods: Patients were surveyed using a 13-item questionnaire investigating perception on their own sexuality and opinions on communication about sexuality in context with MS. Certified MSologists in Austria received an 18-item survey regarding their approach to taking a sexual history of their patients., Outcomes: We report the frequency of answers given in this survey and propose a possible standard of care how sexuality could be addressed in clinical routine., Results: Ninety-three pwMS (mean age 39 ± 11 years, 57% female) and 75 MSologists (mean age 43 ± 9 years, 63% male) completed this survey. Seventy-six percent of patients report their own sexuality as being (very) important to them and 95% think that sexual dysfunction would influence their quality of life. 84% would like to be asked about their sexuality by their MSologist. In contrast, only 15% of MSologists reported discussing sexuality with every patient. The most common reason for not doing so was a fear of crossing personal borders (34%). There is a strong desire for further medical education on this subject (76%)., Clinical Implications: Discussing sexuality is important to pwMS and MSologists should consider their patients' wishes and needs to talk about it., Strengths & Limitations: This is the largest survey contrasting the views of patients and their treating physicians on the topic of communication about sexuality. The use of an empirical unvalidated questionnaire may have introduced bias. Moreover, patients that are open to talk about their sexuality may be potentially overrepresented in this study., Conclusion: MSologists should offer their patients an open opportunity and appropriate framework to discuss their sexuality during a consultation. Altmann P, Leithner K, Leutmezer F, et al. Sexuality and Multiple Sclerosis: Patient and Doctor Perspectives. J Sex Med 2021;18:743-749., (Copyright © 2021 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Sexual dysfunction (SD) in people with multiple sclerosis (pwMS) has a detrimental impact on individual health-related quality of life (HRQoL). It is not clear whether SD in multiple sclerosis (MS) is an independent symptom or merely a byproduct of other symptoms such as depression or anxiety. This cross-sectional study of 93 pwMS determines risk factors for SD in MS based on prevalence, HRQoL, and associated disease outcomes. Diagnosis of SD was determined based on the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19) and correlated with physical disability (measured by Expanded Disability Status scale, EDSS), depression and anxiety [Hospital Anxiety and Depression Scale (HADS)], and HRQoL [Multiple Sclerosis Quality of Life-54 (MSQoL-54)]. Multivariate regression models were performed to determine independent risk factors for SD in pwMS. Almost half of the participants in this study (46%) reported SD. HRQoL was significantly poorer in patients with MS suffering from SD (median [IQR] MSQoL-54 scores: physical subscale 52 [41-68] vs. 81 [69-89], p < 0.001; mental subscale 50 [38-82] vs. 86 [70-89], p < 0.001). In the multivariate model, EDSS was the only independent risk factor for SD (OR 18.1 for EDSS ≥4 [95% CI 3.3-31.4, p < 0.001]), while depression and anxiety were not. We conclude that the risk for SD is growing with increasing EDSS and is independent of depression or anxiety. Screening for SD becomes particularly relevant in patients with growing disability., Competing Interests: PA has participated in meetings sponsored by and received speaker honoraria or travel funding from Biogen, Merck, Roche, Sanofi-Genzyme, and Teva and received honoraria for consulting from Biogen. He received a research grant from Quanterix International and was awarded a combined sponsorship from Biogen, Merck, Roche, Sanofi-Genzyme, and Teva for a clinical study. FL has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Bayer, Biogen, Celgene, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. TM has participated in meetings sponsored by or received travel funding from Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. PR has received honoraria for consultancy/speaking from AbbVie, Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sandoz, and Sanofi-Genzyme and has received research grants from Amicus, Biogen, Merck, and Roche. TZ has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. KB has participated in meetings sponsored by and received travel funding from Roche. TB has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for MS: Allergan, Almirall, Bayer, Biogen, Biologix, Bionorica, Celgene, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva, and TG Pharmaceuticals. His institution has received financial support in the past 12 months by unrestricted research grants (Biogen, Merck, Novartis, Sanofi-Genzyme, and Teva and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, and Teva. GB has participated in meetings sponsored by and received speaker honoraria or travel funding from Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, and Teva and received honoraria for consulting Biogen, Roche, and Teva. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Altmann, Leutmezer, Leithner, Monschein, Ponleitner, Stattmann, Rommer, Zrzavy, Zulehner, Berek, Berger and Bsteh.)

Serum neurofilament light chain (sNfL) and its ability to expose axonal damage in neurologic disorders have solicited a considerable amount of attention in blood biomarker research. Hence, with the proliferation of high-throughput assay technology, there is an imminent need to study the pre-analytical stability of this biomarker. We recruited 20 patients with common neurological diagnoses and 10 controls (i.e. patients without structural neurological disease). We investigated whether a variation in pre-analytical variables (delayed freezing up to 24 h and repeated thawing/freezing for up to three cycles) affects the measured sNfL concentrations using state of the art Simoa technology. Advanced statistical methods were applied to expose any relevant changes in sNfL concentration due to different storing and processing conditions. We found that sNfL concentrations remained stable when samples were frozen within 24 h (mean absolute difference 0.2 pg/ml; intraindividual variation below 0.1%). Repeated thawing and re-freezing up to three times did not change measured sNfL concentration significantly, either (mean absolute difference 0.7 pg/ml; intraindividual variation below 0.2%). We conclude that the soluble sNfL concentration is unaffected at 4-8 °C when samples are frozen within 24 h and single aliquots can be used up to three times. These observations should be considered for planning future studies.