Elevated serum neurofilament light chain protein in patients with essential tremor.

BACKGROUND AND PURPOSE: Quantification of neurofilament light chain protein in serum (sNfL) enables the neuro-axonal damage in peripheral blood to be reliably assessed and monitored. There is a long-standing debate whether essential tremor represents a 'benign' tremor syndrome or whether it is linked to neurodegeneration. This study aims to investigate sNfL concentrations in essential tremor compared to healthy controls (cross-sectionally and longitudinally) and to assess whether sNfL is associated with motor and nonmotor markers of disease progression. METHODS: Data of patients with essential tremor from our prospective registry on movement disorders (PROMOVE) were retrospectively analysed. Age-, sex- and body-mass-index-matched healthy controls were recruited from an ongoing community-dwelling aging cohort. sNfL was quantified by an ultra-sensitive single molecule array (Simoa). All participants underwent detailed clinical examination at baseline and after approximately 5 years of follow-up. RESULTS: Thirty-seven patients with clinically diagnosed essential tremor were included and 37 controls. The essential tremor group showed significantly higher sNfL levels compared to healthy controls at baseline and follow-up. sNfL levels increased over time in both groups, and the slope of sNfL increase was similar in the essential tremor and healthy control groups. Comparing patients with a disease duration under 5 years to those with a longer disease duration, the former group had a significantly greater increase of sNfL over time, which strongly correlated to worsening of tremor and cognition. CONCLUSION: Our findings indicate that neurodegeneration, possibly happening at an early disease stage, might play a role in the pathophysiology of essential tremor.

High serum neurofilament light chain levels correlate with brain atrophy and physical disability in multiple sclerosis.

BACKGROUND AND PURPOSE: Serum neurofilament light chain (sNfL) is a promising biomarker of neuroaxonal damage in persons with multiple sclerosis (pwMS). In cross-sectional studies, sNfL has been associated with disease activity and brain magnetic resonance imaging (MRI) changes; however, it is still unclear to what extent in particular high sNfL levels impact on subsequent disease evolution. METHODS: sNfL was quantified by an ultrasensitive single molecule array (Simoa) in 199 pwMS (median age = 34.2 years, 64.3% female) and 49 controls. All pwMS underwent 3-T MRI to assess global and compartmental normalized brain volumes, T2-lesion load, and cortical mean thickness. Follow-up data and serum samples were available in 144 pwMS (median follow-up time = 3.8 years). Linear and binary logistic models were used to estimate the independent contribution of sNfL for changes in MRI and Expanded Disability Status Scale (EDSS). Age-corrected sNfL z-scores from a normative database of healthy controls were used for sensitivity analyses. RESULTS: High sNfL levels at baseline were associated with atrophy measures of the whole brain (standardized beta coefficient ßj = -0.352, p < 0.001), white matter (ßj = -0.229, p = 0.007), thalamus (ßj = -0.372, p = 0.004), and putamen (ßj = -1.687, p = 0.012). pwMS with high levels of sNfL at baseline and follow-up had a greater risk of EDSS worsening (p = 0.007). CONCLUSIONS: Already single time point elevation of sNfL has a distinct effect on brain volume changes over a short-term period, and repeated high levels of sNfL indicate accumulating physical disability. Serial assessment of sNfL may provide added value in the clinical management of pwMS.

Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis.

Importance: There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS). Objective: To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression. Design, Setting, and Participants: Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell-depleting treatment (ie, ocrelizumab or rituximab). Exposures: Patients received standard immunotherapies or were untreated. Main Outcomes and Measures: In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally. Results: This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (-1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [-0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001). Conclusions and Relevance: Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

Serum Neurofilament Light Chain as Biomarker for Cladribine-Treated Multiple Sclerosis Patients in a Real-World Setting.

Serum neurofilament light chain (sNfL) is an intensely investigated biomarker in multiple sclerosis (MS). The aim of this study was to explore the impact of cladribine (CLAD) on sNfL and the potential of sNfL as a predictor of long-term treatment response. Data were gathered from a prospective, real-world CLAD cohort. We measured sNfL at baseline (BL-sNfL) and 12 months (12Mo-sNfL) after CLAD start by SIMOA. Clinical and radiological assessments determined fulfilment of "no evidence of disease activity" (NEDA-3). We evaluated BL-sNfL, 12M-sNfL and BL/12M sNfL ratio (sNfL-ratio) as predictors for treatment response. We followed 14 patients for a median of 41.5 months (range 24.0-50.0). NEDA-3 was fulfilled by 71%, 57% and 36% for a period of 12, 24 and 36 months, respectively. We observed clinical relapses in four (29%), MRI activity in six (43%) and EDSS progression in five (36%) patients. CLAD significantly reduced sNfL (BL-sNfL: mean 24.7 pg/mL (SD ± 23.8); 12Mo-sNfL: mean 8.8 pg/mL (SD ± 6.2); p = 0.0008). We found no correlation between BL-sNfL, 12Mo-sNfL and ratio-sNfL and the time until loss of NEDA-3, the occurrence of relapses, MRI activity, EDSS progression, treatment switch or sustained NEDA-3. We corroborate that CLAD decreases neuroaxonal damage in MS patients as determined by sNfL. However, sNfL at baseline and at 12 months failed to predict clinical and radiological treatment response in our real-world cohort. Long-term sNfL assessments in larger studies are essential to explore the predictive utility of sNfL in patients treated with immune reconstitution therapies.

Neurofilament light chain: a new marker for neuronal decay in the anterior chamber fluid of patients with glaucoma.

BACKGROUND/AIMS: Neurofilament light chain (NfL) levels in cerebrospinal fluid and serum are reliable indicators for neuroaxonal damage in a broad spectrum of neurodegenerative diseases. Herein, we investigate NfL levels in serum and anterior chamber fluid of patients with glaucoma. METHODS: Patients scheduled for routine glaucoma or cataract surgery were recruited for this study. Retinal nerve fibre layer thickness was measured by optical coherence tomography (OCT, Heidelberg Spectralis). NfL levels in serum and in anterior chamber fluid were analysed with Simoa SR-X Analyzer (Quanterix; NFLIGHT, Lexington, Massachusetts, USA). T-test was used for parametric data and Mann-Whitney-U test for nonparametric data. Spearman's rank-order correlation was used to investigate correlations. P values<0.05 were considered as statistically significant. RESULTS: Sixty patients with glaucoma and 58 controls were enrolled. Serum NfL concentration of patients with glaucoma was similar to serum NfL concentration in controls (median (IQR); 22.7 (18.9) pg/mL vs 22.5 (24.0) pg/mL; p=0.763). A positive correlation of serum NfL with age was observed in both patients with glaucoma (r=0.77; p<0.001) and in the control group (r=0.82, p<0.001). In the anterior chamber fluid, the NfL concentration was substantially increased in patients with glaucoma compared with controls (20.7 (101.3) pg/mL vs 3.1 (2.9) pg/mL; p<0.001). Furthermore, we found a positive correlation of anterior chamber fluid NfL with preoperative intraocular pressure (r=0.39, p=0.003) and with retinal nerve fibre layer thickness (r=0.58, p<0.001). CONCLUSION: NfL levels in anterior chamber fluid are elevated in patients with glaucoma and correlate with intraocular pressure and retinal nerve fibre layer thickness. The presented data strongly support anterior chamber fluid NfL as a new marker for glaucoma.

Serum glial fibrillary acidic protein is sensitive to acute but not chronic tissue damage in cerebral small vessel disease.

BACKGROUND: Serum glial fibrillary acidic protein (sGFAP) has been proposed as a biomarker in various neurological diseases but has not yet been systematically investigated in patients with cerebral small vessel disease (CSVD). We explored whether sGFAP levels are increased in stroke patients with MRI-confirmed recent small subcortical infarcts (RSSI) and analyzed the subsequent course and determinants of sGFAP longitudinally. METHODS: In a prospectively-collected cohort of stroke patients with a single RSSI (n = 101, mean age: 61 years, 73% men), we analyzed brain MRI and sGFAP using a SIMOA assay at baseline and at 3- and 15-months post-stroke. Community-dwelling age- and sex-matched individuals (n = 51) served as controls. RESULTS: RSSI patients had higher baseline sGFAP levels compared to controls (median: 187.4 vs. 118.3 pg/ml, p < 0.001), with no influence of the time from stroke symptom onset to baseline blood sampling (median 5 days, range 1-13). At the 3- and 15-months follow-up, sGFAP returned to control levels. While baseline sGFAP correlated with larger infarct size (rs = 0.28, p = 0.01), neither baseline nor follow-up sGFAP levels were associated with chronic CSVD-related lesions (white matter hyperintensities, lacunes, microbleeds) after adjusting for age, sex and hypertension. Furthermore, sGFAP levels did not relate to the occurrence of new vascular brain lesions on follow-up MRI. CONCLUSIONS: sGFAP is increased in patients with CSVD-related stroke and correlates with the size of the RSSI. However, sGFAP levels were not related to chronic neuroimaging features or progression of CSVD, suggesting that sGFAP is sensitive to acute but not chronic cerebrovascular tissue changes in this condition.

Redox State of Human Serum Albumin in Multiple Sclerosis: A Pilot Study.

Like in many other pathologies, oxidative stress is involved in the development of neurodegenerative disorders. Human serum albumin (HSA) is the main protein in different body fluids including cerebrospinal fluid (CSF). By its redox state in terms of cysteine-34, albumin serves as marker for oxidative burden. We aimed to evaluate the redox state of HSA in patients with multiple sclerosis in serum and CSF in comparison to controls to identify possible correlations with disease activity and severity. Samples were stored at -70 °C until analysis by HPLC for the determination of albumin redox state in terms of the fractions of human mercaptalbumin (HMA), human nonmercaptalbumin1 (HNA1), and human nonmercaptalbumin2 (HNA2). Albumin in CSF showed significantly higher fractions of the reduced form HMA and decreased HNA1 and HNA2. There was no difference between albumin redox states in serum of patients and controls. In CSF of patients HNA2 showed a trend to higher fractions compared to controls. Albumin redox state in serum was associated with physical disability in remission while albumin redox state in CSF was related to disease activity. Thus, albumin redox state in serum and CSF of patients in relation to disease condition merits further investigation.

Evidence for an Intrathecal Immunoglobulin Synthesis by Kappa Free Light Chains in Neurological Patients with an Isolated Band in Isoelectric Focusing.

The gold standard for detecting intrathecal immunoglobulin synthesis is the determination of the oligoclonal band (OCB) in the cerebrospinal fluid (CSF) using isoelectric focusing (IEF). Controversy still exists regarding the significance of an isolated band in the CSF. A highly promising alternative method for the assessment of intrathecal inflammation is the quantification of kappa free light chains (k-FLC). Our aim was to evaluate the clinical significance of quantitative k-FLC in patients with an isolated band in the CSF. Using the Human Kappa Freelite Mx Kit on a turbidimetric Optilite®, we quantified the k-FLCs in paired CSF and serum samples in 47 patients with a single band in IEF. We classified patients into 27× inflammatory neurological disorders (IND), 2× peripheral inflammatory neurological disorders (PIND), 9× non-inflammatory neurological disorders (NIND) and 9× symptomatic controls (SC) based on their medical diagnosis. k-FLC were below the lower measurement limit of the analyser (LML) in all SC and PIND, as well as in 8 out of 9 NIND and 11 IND. Only 1 NIND and 16 IND were above the LML, and of these, only 14 IND were above the upper discrimination limit (Qlim). A neuroinflammatory nature of the diseases can be indicated in many cases by positive k-FLC in patients with an isolated band in IEF. The measurement of k-FLC can support the diagnosis of neurological diseases if they are included in the routine work-up.

Serum NfL in Alzheimer Dementia: Results of the Prospective Dementia Registry Austria.

Background and Objectives: The neurofilament light chain (NfL) is a biomarker for neuro-axonal injury in various acute and chronic neurological disorders, including Alzheimer's disease (AD). We here investigated the cross-sectional and longitudinal associations between baseline serum NfL (sNfL) levels and cognitive, behavioural as well as MR volumetric findings in the Prospective Dementia Registry Austria (PRODEM-Austria). Materials and Methods: All participants were clinically diagnosed with AD according to NINCDS-ADRDA criteria and underwent a detailed clinical assessment, cognitive testing (including the Mini Mental State Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD)), the neuropsychiatric inventory (NPI) and laboratory evaluation. A total of 237 patients were included in the study. Follow-up examinations were done at 6 months, 1 year and 2 years with 93.3% of patients undergoing at least one follow-up. We quantified sNfL by a single molecule array (Simoa). In a subgroup of 125 subjects, brain imaging data (1.5 or 3T MRI, with 1 mm isotropic resolution) were available. Brain volumetry was assessed using the FreeSurfer image analysis suite (v6.0). Results: Higher sNfL concentrations were associated with worse performance in cognitive tests at baseline, including CERAD (B = −10.084, SE = 2.999, p < 0.001) and MMSE (B = −3.014, SE = 1.293, p = 0.021). The sNfL levels also correlated with the presence of neuropsychiatric symptoms (NPI total score: r = 0.138, p = 0.041) and with smaller volumes of the temporal lobe (B = −0.012, SE = 0.003, p = 0.001), the hippocampus (B = −0.001, SE = 0.000201, p = 0.013), the entorhinal (B = −0.000308, SE = 0.000124, p = 0.014), and the parahippocampal cortex (B = −0.000316, SE = 0.000113, p = 0.006). The sNfL values predicted more pronounced cognitive decline over the mean follow-up period of 22 months, but there were no significant associations with respect to change in neuropsychiatric symptoms and brain volumetric measures. Conclusions: the sNfL levels relate to cognitive, behavioural, and imaging hallmarks of AD and predicts short term cognitive decline.

Intrathecal IgM Synthesis Is Associated with Spinal Cord Manifestation and Neuronal Injury in Early MS.

OBJECTIVE: Intrathecal Immunoglobulin M synthesis (IgMIntrathecal Fraction (IF) + ) and spinal MRI lesions are both strong independent predictors of higher disease activity and severity in multiple sclerosis (MS). We investigated whether IgMIF + is associated with spinal cord manifestation and higher neuroaxonal damage in early MS. METHODS: In 122 patients with a first demyelinating event associations between (1) spinal versus (vs) non-spinal clinical syndrome (2) spinal vs cerebral T2-weighted (T2w) and (3) contrast-enhancing (CE) lesion counts with IgGIF + (vs IgGIF - ) or IgMIF + (vs IgMIF - ) were investigated by logistic regression adjusted for age and sex, respectively. For serum neurofilament light chain (sNfL) analysis patients were categorized for presence or absence of oligoclonal IgG bands (OCGB), IgGIF and IgMIF (>0% vs 0%, respectively): (1) OCGB- /IgGIF - /IgMIF - ; (2) OCGB+ /IgGIF - /IgMIF - ; (3) OCGB+ /IgGIF + /IgMIF - ; and (4) OCGB+ /IgGIF + /IgMIF + . Associations between categories 2 to 4 vs category 1 with sNfL concentrations were analyzed by robust linear regression, adjusted for sex and MRI parameters. RESULTS: Patients with a spinal syndrome had a 8.36-fold higher odds of IgMIF + (95%CI 3.03-23.03; p < 0.01). Each spinal T2w lesion (odds Ratio 1.39; 1.02-1.90; p = 0.037) and CE lesion (OR 2.73; 1.22-6.09; p = 0.014) was associated with an increased risk of IgMIF + (but not of IgGIF + ); this was not the case for cerebral lesions. OCGB+ /IgGIF + /IgMIF + category patients showed highest sNfL levels (estimate:1.80; 0.55-3.06; p < 0.01). INTERPRETATION: Intrathecal IgM synthesis is strongly associated with spinal manifestation and independently more pronounced neuroaxonal injury in early MS, suggesting a distinct clinical phenotype and pathophysiology. ANN NEUROL 2022;91:814-820.

Factors influencing serum neurofilament light chain levels in normal aging.

OBJECTIVE: Serum neurofilament light (sNfL) is a promising marker for neuro-axonal damage and it is now well known that its levels also increase with higher age. However, the effect of other determinants besides age is still poorly investigated. We therefore aimed to identify factors influencing the sNfL concentration by analysing a large set of demographical, life-style and clinical variables in a normal aging cohort. METHODS: sNfL was quantified by single molecule array (Simoa) assay in 327 neurologically inconspicuous individuals (median age 67.8±10.7 years, 192 female) who participated in the Austrian Stroke Prevention Family Study (ASPS-Fam). Random forest regression analysis was used to rank the association of included variables with sNfL in the entire cohort and in age-stratified subgroups. Linear regression then served to identify factors independently influencing sNfL concentration. RESULTS: Age (ß=0.513, p<0.001) was by far the most important factor influencing sNfL, which was mainly driven by individuals ≥60 years. In age stratified sub-groups, body mass index (BMI) (ß=-0.298, p<0.001) independently predicted sNfL in individuals aged 38-60 years. In individuals ≥60 years, age (ß=0.394, p<0.001), renal function (ß=0.376, p<0.001), blood volume (ß=-0.198, p=0.008) and high density lipoprotein (HDL) (ß=0.149, p=0.013) were associated with sNfL levels. CONCLUSIONS: Age is the most important factor influencing sNfL concentrations, getting increasingly relevant in elderly people. BMI further influences sNfL levels, especially at younger age, whereas renal function gets increasingly relevant in the elderly.

Tetravalent Influenza Vaccine Is Not Associated With Neuroaxonal Damage in Multiple Sclerosis Patients.

Background: Efficacy of vaccines and disease activity linked to immunization are major concerns among people with multiple sclerosis (pwMS). Objective: To assess antibody responses to seasonal influenza antigens and vaccine-associated neuroaxonal damage utilizing serum neurofilament light chain (sNfL) in pwMS receiving dimethyl fumarate (DMF). Methods: In this prospective study, the 2020/2021 seasonal tetravalent influenza vaccine was administered to 20 pwMS treated with DMF and 15 healthy controls (HCs). The primary endpoints were responder rate of strain-specific antibody production (seroconversion or significant (4-fold) increase in influenza-antibody titers for ≥2/4 strains) at 30 days post-vaccination and changes in sNfL levels. Results: All patients treated with DMF fulfilled the responder criteria for immunization compared with 53% of the controls. However, higher proportions of HCs already had influenza-antibody titers ≥1:40 at baseline (53% vs. 41%, p = 0.174). sNfL levels were comparable among both groups at baseline and did not increase 34 days after vaccination. In addition, no clinical or radiological disease reactivation was found. Conclusion: DMF-treated patients mount an adequate humoral immune response to influenza vaccines. Within the limits of the small cohort investigated, our data suggest that influenza immunization is not associated with clinical or subclinical disease reactivation.

Serum neurofilament level increases after ascent to 4559 m but is not related to acute mountain sickness.

BACKGROUND AND PURPOSE: At high altitude the brain is exposed to hypoxic stress, which may result in neurological conditions, with acute mountain sickness (AMS) being the most common. We aimed to test the hypothesis that rapid ascent to high altitude alters neuro-axonal integrity, which can be detected by increased concentration of serum neurofilament light (sNfL) in the blood and may even be exaggerated in people with AMS. METHODS: Serum neurofilament light was measured using a single-molecule array (Simoa, Quanterix, Lexington, MA, USA) assay at low altitude (423 m) in 47 healthy study participants and 44 h after rapid and active ascent to high altitude (4559 m). Peripheral oxygen saturation (SpO2 ) and partial pressures of oxygen (pO2 ) were obtained at low and high altitude. The Acute Mountain Sickness-Cerebral (AMS-C) scoring system was used to assess AMS incidence and AMS severity. RESULTS: There was an increase in sNfL from its baseline value compared with its value at high altitude (6.34 ± 1.96 vs. 7.19 ± 3.14 pg/ml; p = 0.014), but sNfL level did not correlate with SpO2 (r = -0.19; p = 0.066) or pO2 (r = -0.19; p = 0.068). The incidence of AMS at high altitude was 62%. Neither at low altitude (p = 0.706) nor at high altitude (p = 0.985) was there a difference in sNfL between participants with and without AMS as measured 3 days after rapid ascent and 44 h of high-altitude exposure. Altitude sNfL did not correlate with AMS-C, either overall or with single-item scores such as headache severity. CONCLUSIONS: Rapid ascent of healthy people to high altitude provokes an increase in sNfL 44 h after arrival at 4559 m, which is not related to the magnitude of hypoxemia or AMS incidence and severity, suggesting that neuro-axonal injury does not directly contribute to AMS.

Serum neurofilament levels correlate with retinal nerve fiber layer thinning in multiple sclerosis.

BACKGROUND: Serum neurofilament light chain (sNfL) levels and peripapillary retinal nerve fiber layer (pRNFL) are both emerging biomarkers of neuro-axonal damage in multiple sclerosis (MS). However, data on the relation between sNfL and pRNFL are scarce. OBJECTIVE: We aimed to determine the relation of sNfL levels with pRNFL thinning in a large cohort of relapsing-remitting (RR) MS patients. METHODS: We identified 80 patients from a prospective, 3-year observational study on retinal changes in RRMS with annual blood samples available. sNfL levels were measured using single-molecule array (SimoaTM) assay. Annualized loss of pRNFL (aLpRNFL) was determined by individual linear regression models. Correlations between single and repeated sNfL levels and aLpRNFL were analyzed using multivariate linear regression and mixed-effect models. RESULTS: After correction for sex, age, and baseline sNfL, an sNfL increase of 10 pg/mL was associated with an aLpRNFL of -0.7 µm (95% confidence interval (CI): (-1.3, -0.2), p < 0.001). Patients with ⩾2 sNfL measurements >75th percentile displayed higher aLpRNFL (2.2 µm, standard deviation (SD) 0.6) compared to patients with no sNfL measure >75th percentile (0.4 µm, SD 0.2, p < 0.001). Between 15% and 20% of the aLpRNFL variance could be predicted from sNfL levels. CONCLUSION: sNfL levels contribute to the prediction of retinal thinning in patients with RRMS, strengthening its value as a biomarker of neuro-axonal damage.

Serum neurofilament light levels correlate with change of olfactory function in multiple sclerosis.

BACKGROUND: Serum neurofilament light chain levels (sNfL) and impairment of olfactory function emerge as biomarkers in multiple sclerosis (MS). However, the relation between sNfL and olfactory function in MS has not been investigated yet. OBJECTIVE: We aimed to determine whether sNfL levels correlate with olfactory function in relapsing-remitting (RR) MS. METHODS: We annually measured sNfL and olfactory function (Sniffin' Sticks test: Threshold (T) and combined discrimination-identification (DI) score) in 80 RRMS patients and compared sNfL to T and DI scores. RESULTS: T scores significantly correlated with sNfL levels at simultaneous measurement (-1.5 points, 95% CI: -2.6-0.5 per 10 pg/ml sNfL increase; p < 0.001 per 10 pg/ml sNfL increase), but not at temporally distant measurement. Patients with ≥2 sNfL measures above the 75th percentile displayed significantly larger DI decrease (median 3.0 points, IQR 2.0-4.5) compared to patients with no or only one sNfL measure above the 75th percentile (0.0, IQR -0.5-0.5, p < 0.001 and 1.0, IQR 0.0-3.30, p = 0.008, respectively). 13-18% of the variance in T and 22% in DI decrease could be predicted from sNfL levels. CONCLUSIONS: sNfL correlates with different qualities of olfactory function in patients with RRMS further strengthening the value of olfactory function as a biomarker of inflammation and axonal damage in MS.