Neurofilament Light Chain Concentrations Research Articles

Associations Between Blood-Based Biomarkers and Cognitive and Functional Trajectories Among Participants of the MEMENTO Cohort.

Elevated levels of Alzheimer disease (AD) blood-based biomarkers are associated with accelerated cognitive decline. However, their distinct relationships with specific cognitive and functional domains require further investigation. We aimed at estimating the associations between AD blood-based biomarkers and the trajectories of distinct cognitive and functional domains over a 5-year follow-up period. We conducted a clinic-based prospective study using data from the MEMENTO study, a nationwide French cohort. We selected dementia-free individuals at baseline aged 60 years or older. Baseline measurements of β-amyloid (Aβ) 40 and 42, phosphorylated tau (p-tau181), and neurofilament light chain (NfL) concentrations were obtained using the Simoa HD-X analyzer. Mini-Mental State Examination (MMSE), Free and Cued Selective Reminding Test (FCSRT), animal fluency, Trail Making Tests A and B, Short Physical Performance Battery (SPPB), and Instrumental Activities of Daily Living were administered annually for up to 5 years. We used linear mixed models, adjusted for potential confounders, to model AD biomarkers' relation with cognitive and functional decline. A total of 1,938 participants were included in this study, with a mean (SD) baseline age of 72.8 (6.6) years, and 62% were women. Higher baseline p-tau181 and NfL were associated with significantly faster decline in most cognitive, physical, and functional outcomes (+1 SD p-tau181: βMMSE = -0.055, 95% CI -0.067 to -0.043, βFCSRT = -0.034, 95% CI -0.043 to -0.025, βfluency = -0.029, 95% CI -0.038 to -0.020, βSPPB = -0.040, 95% CI -0.057 to -0.022, and β4IADL = -0.115, 95% CI 0.091-0.140. +1 SD NfL: βMMSE = -0.039, 95% CI -0.053 to -0.025, βFCSRT = -0.022, 95% CI -0.032 to -0.012, βfluency = -0.014, 95% CI -0.024 to -0.004, and β4IADL = 0.077, 95% CI 0.048-0.105). A multiplicative association of p-tau181 and NfL with worsening cognitive and functional trajectories was evidenced. Lower Aβ42/40 ratio was only associated with slightly faster cognitive decline in FCSRT and semantic fluency (+1 SD: β = 0.011, 95% CI 0.002-0.020, and β = 0.011, 95% CI 0.003-0.020, respectively). These associations were not modified by APOE ε4, sex, nor education level. In a memory clinic sample, p-tau181 and NfL, both independently and jointly, are linked to more pronounced cognitive, physical and functional declines. Blood-based biomarker measurement in AD research may provide useful insights regarding biological processes underlying cognitive, physical, and functional declines in at-risk individuals.

Pumping up the Fight against Multiple Sclerosis: The Effects of High-Intensity Resistance Training on Functional Capacity, Muscle Mass, and Axonal Damage.

Resistance training (RT) has been recognized as a beneficial non-pharmacological intervention for multiple sclerosis (MS) patients, but its impact on neurodegeneration is not fully understood. This study aimed to investigate the effects of high-intensity RT on muscle mass, strength, functional capacity, and axonal damage in MS patients. Eleven relapsing-remitting MS patients volunteered in this within-subject counterbalanced intervention study. Serum neurofilament light-chain (NfL) concentration, vastus lateralis thickness (VL), timed up-and-go test (TUG), sit-to-stand test (60STS), and maximal voluntary isometric contraction (MVIC) were measured before and after intervention. Participants performed 18 sessions of high-intensity RT (70-80% 1-RM) over 6 weeks. Significant (p < 0.05) differences were observed post-intervention for VL (ES = 2.15), TUG (ES = 1.98), 60STS (ES = 1.70), MVIC (ES = 1.78), and NfL (ES = 1.43). Although moderate correlations between changes in VL (R = 0.434), TUG (R = -0.536), and MVIC (R = 0.477) and changes in NfL were observed, only the correlation between VL and MVIC changes was significant (R = 0.684, p = 0.029). A 6-week RT program significantly increased muscle mass, functional capacity, and neuromuscular function while also decreasing serum NfL in MS patients. These results suggest the effectiveness of RT as a non-pharmacological approach to mitigate neurodegeneration while improving functional capacity in MS patients.

Neurofilament Light Chain Concentration in Cerebrospinal Fluid in Children with Acute Nontraumatic Neurological Disorders.

(1) Introduction: This pilot study aimed to analyze neurofilament light chain levels in cerebrospinal fluid (cNfL) in a cohort of children with different acute nontraumatic neurological conditions. (2) Methods: This prospective observational cohort study consisted of 35 children aged 3 months to 17 years and was performed from November 2017 to December 2019. Patients' clinical data were reviewed, and patients were assigned to the following groups: n = 10 (28.6%) meningitis, 5 (14.3%) Bell's palsy, 7 (20.0%) febrile non-CNS infection, 3 (8.6%) complex febrile seizure, 4 (11.4%) idiopathic intracranial hypertension, and 6 (17.1%) others. cNfL levels were measured using a sensitive single-molecule array assay. (3) Results: The cNfL levels [median (range)] in children with meningitis were 120.5 pg/mL (58.1-205.4), in Bell's palsy 88.6 pg/mL (48.8-144.5), in febrile non-CNS infection 103.9 pg/mL (60.1-210.8), in complex febrile seizure 56 pg/mL (53.2-58.3), and in idiopathic intracranial hypertension 97.1 pg/mL (60.1-124.6). Within the meningitis group, children with Lyme neuroborreliosis (LNB) had significantly higher cNfL concentrations (median 147.9 pg/mL; range 87.8-205.4 pg/mL) than children with enterovirus meningitis (72.5 pg/mL; 58.1-95.6 pg/mL; p = 0.048) and non-significantly higher cNfL levels when compared to Bell's palsy (88.6 pg/mL; 48.8-144.5 pg/mL; p = 0.082). There was no correlation between cNfL levels and age. (4) Conclusions: Although the number of patients in this pilot study cohort is limited, higher cNfL levels in children with LNB compared to those with viral meningitis (significant) and Bell's palsy (trend) may indicate the potential of cNfL as a biomarker in the differential diagnosis of pediatric meningitis and facial palsy.

Neurofilament light-chain (NfL) and 18 kDa translocator protein in early psychosis and its putative high-risk

Evidence of elevated peripheral Neurofilament light-chain (NfL) as a biomarker of neuronal injury can be utilized to reveal nonspecific axonal damage, which could reflect altered neuroimmune function. To date, only a few studies have investigated NfL as a fluid biomarker in schizophrenia primarily, though none in its putative prodrome (Clinical High-Risk, CHR) or in untreated first-episode psychosis (FEP). Further, it is unknown whether peripheral NfL is associated with 18 kDa translocator protein (TSPO), a validated neuroimmune marker. In this secondary study, we investigated for the first time (1) serum NfL in early stages of psychosis including CHR and FEP as compared to healthy controls, and (2) examined its association with brain TSPO, using [18F]FEPPA positron emission tomography (PET). Further, in the exploratory analyses, we aimed to assess associations between serum NfL and symptom severity in patient group and cognitive impairment in the combined cohort. A large cohort of 84 participants including 27 FEP (24 antipsychotic-naive), 41 CHR (34 antipsychotic-naive) and 16 healthy controls underwent structural brain MRI and [18F]FEPPA PET scan and their blood samples were obtained and assessed for serum NfL concentrations. We found no significant differences in serum NfL levels across clinical groups, controlling for age. We also found no significant association between NfL levels and brain TSPO in the entire cohort. We observed a negative association between serum NfL and negative symptom severity in CHR. Our findings suggest that neither active neuroaxonal deterioration as measured with NfL nor associated neuroimmune activation (TSPO) is clearly identifiable in an early mostly untreated psychosis sample including its putative high-risk.

Neurofilament light chain concentration does not correlate with disease status in Labrador Retrievers affected with idiopathic laryngeal paralysis.

The aim of this study was to investigate whether plasma neurofilament light chain (pNfL) concentration was altered in Labrador Retrievers with idiopathic laryngeal paralysis (ILP) compared to a control population. A secondary aim was to investigate relationships between age, height, weight, and body mass index in the populations studied. 123 dogs: 62 purebred Labrador Retrievers with ILP (ILP Cases) and 61 age-matched healthy medium- to large-breed dogs (Controls). Dogs, recruited from August 1, 2016, to March 1, 2022, were categorized as case or control based on a combination of physical exam, neurologic exam, and history. Blood plasma was collected, and pNfL concentration was measured. pNfL concentrations were compared between ILP Cases and Controls. Covariables including age, height, and weight were collected. Relationships between pNfL and covariables were analyzed within and between groups. In dogs where 2 plasma samples were available from differing time points, pNfL concentrations were measured to evaluate alterations over time. No significant difference in pNfL concentration was found between ILP Cases and Control (P = .36). pNfL concentrations had moderate negative correlations with weight and height in the Control group; other variables did not correlate with pNfL concentrations in ILP Case or Control groups. pNfL concentrations do not correlate with ILP disease status or duration in Labrador Retrievers. There is no evidence that pNfL levels are altered due to ILP disease duration or progression when compared with healthy controls. When evaluating pNfL concentrations in the dog, weight and height should be considered.

Temporal serum neurofilament light chain concentrations in sheep inoculated with the agent of classical scrapie.

Neurofilament light chain (Nf-L) has been used to detect neuroaxonal damage in the brain caused by physical injury or disease. The purpose of this study was to determine if serum Nf-L could be used as a biomarker for pre-symptomatic detection of scrapie in sheep. Four sheep with prion protein genotype AVQQ were intranasally inoculated with the classical scrapie strain x124. Blood was collected every 4 weeks until 44 weeks post-inoculation, at which point weekly collection commenced. Serum was analyzed using single molecule array (Quanterix SR-X) to evaluate Nf-L concentrations. Scrapie was confirmed in each sheep by testing homogenized brainstem at the level of the obex with a commercially available enzyme immunoassay. Increased serum Nf-L concentrations were identified above the determined cutoff during the last tenth of the respective incubation period for each sheep. Throughout the time course study, PrPSc accumulation was not detected antemortem by immunohistochemistry in rectal tissue at any timepoint for any sheep. RT-QuIC results were inconsistently positive throughout the timepoints tested for each sheep; however, each sheep had at least one timepoint detected positive. When assessing serum Nf-L utility using receiver operator characteristic curves against different clinical parameters, such as asymptomatic and symptomatic (pruritus or neurologic signs), results showed that Nf-L was most useful at being an indicator of disease only late in disease progression when neurologic signs were present. Serum Nf-L concentrations in the cohort of sheep increased as disease progressed; however, serum Nf-L did not increase during the presymptomatic window. The levels increased substantially throughout the final 10% of the animals' scrapie incubation period when other clinical signs were present. Serum Nf-L is not a reliable biomarker for pre-clinical detection of scrapie.

Comparing the effects of augmented virtual reality treadmill training versus conventional treadmill training in patients with stage II-III Parkinson's disease: the VIRTREAD-PD randomized controlled trial protocol.

Intensive treadmill training (TT) has been documented to improve gait parameters and functional independence in Parkinson's Disease (PD), but the optimal intervention protocol and the criteria for tailoring the intervention to patients' performances are lacking. TT may be integrated with augmented virtual reality (AVR), however, evidence of the effectiveness of this combined treatment is still limited. Moreover, prognostic biomarkers of rehabilitation, potentially useful to customize the treatment, are currently missing. The primary aim of this study is to compare the effects on gait performances of TT + AVR versus TT alone in II-III stage PD patients with gait disturbance. Secondary aims are to assess the effects on balance, gait parameters and other motor and non-motor symptoms, and patient's satisfaction and adherence to the treatment. As an exploratory aim, the study attempts to identify biomarkers of neuroplasticity detecting changes in Neurofilament Light Chain concentration T0-T1 and to identify prognostic biomarkers associated to blood-derived Extracellular Vesicles. Single-center, randomized controlled single-blind trial comparing TT + AVR vs. TT in II-III stage PD patients with gait disturbances. Assessment will be performed at baseline (T0), end of training (T1), 3 (T2) and 6 months (T3, phone interview) from T1. The primary outcome is difference in gait performance assessed with the Tinetti Performance-Oriented Mobility Assessment gait scale at T1. Secondary outcomes are differences in gait performance at T2, in balance and spatial-temporal gait parameters at T1 and T2, patients' satisfaction and adherence. Changes in falls, functional mobility, functional autonomy, cognition, mood, and quality of life will be also assessed at different timepoints. The G*Power software was used to estimate a sample size of 20 subjects per group (power 0.95, α < 0.05), raised to 24 per group to compensate for potential drop-outs. Both interventions will be customized and progressive, based on the participant's performance, according to a predefined protocol. This study will provide data on the possible superiority of AVR-associated TT over conventional TT in improving gait and other motor and non-motor symptoms in persons with PD and gait disturbances. Results of the exploratory analysis could add information in the field of biomarker research in PD rehabilitation.

Neurofilament light chain concentration mediates the association between regional medial temporal lobe structure and memory in adults with Down syndrome.

Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimer's disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS. T1-weighted structural magnetic resonance imaging (MRI) data were collected from 101 participants with DS. Hippocampus and EC volume, as well as EC subregional cortical thickness, were derived. In a subset of participants, plasma NfL concentrations and modified Cued Recall Test scores were obtained. Partial correlation and mediation were used to test relationships between medial temporal lobe (MTL) atrophy, plasma NfL, and episodic memory. Hippocampus volume, left anterolateral EC (alEC) thickness, and plasma NfL were correlated with each other and were associated with memory. Plasma NfL mediated the relationship between left alEC thickness and memory as well as hippocampus volume and memory. The relationship between MTL gray matter and memory is mediated by plasma NfL levels, suggesting a link between neurodegenerative processes underlying axonal injury and frank gray matter loss in key structures supporting episodic memory in people with DS.

Significant dose‐dependent reduction in neurofilament light chain concentration in plasma with oral tau aggregation inhibitor hydromethylthionine mesylate

AbstractBackgroundHydromethylthionine mesylate (HMTM) is a potent oral tau aggregation inhibitor. Recent results from Study TRx‐237‐039 (LUCIDITY) suggest strong effects on cognitive and functional decline and progression of brain atrophy. We investigated the effect of HMTM on change in the plasma biomarker neurofilament light chain (NfL) in LUCIDITY. NfL is a clinically accessible and established biomarker for neurodegeneration that is known to be correlated with measures of clinical decline and brain atrophy in AD and MCI due to AD (MCI‐AD).MethodLUCIDITY is a double‐blind randomised controlled Phase 3 clinical trial comparing change over 12 months in cognitive, functional and brain atrophy outcomes at HMTM doses of 16 mg/day, 8 mg/day and methylthioninium chloride (MTC) at a dose of 4 mg twice weekly as a control in a 4:1:4 randomisation, with a subsequent 12 month blinded open‐label extension phase in which all participants received 16 mg/day.ResultBaseline and 12‐month NfL plasma levels were available as randomised in 161/185 participants receiving HMTM 16 mg/day, 38/48 receiving HMTM 8 mg/day and 136/185 receiving MTC 8 mg/week. The corresponding prespecified analysis model showed a 93% reduction in the change in NfL levels relative to control for HMTM 16 mg/day overall (p = 0.0278). Reduction in NfL change in the MCI‐AD subgroup was significant also at HMTM 8 mg/day (p = 0.0242). In the AD subgroup, there were directional dose‐dependent trends that did not reach statistical significance. Change in NfL level at 12 months was significantly correlated with change in ADAS‐cog11 (p = 0.0038) and whole brain volume (p = 0.0359) over 24 months.ConclusionThese results demonstrate that the orally administered tau aggregation‐inhibitor, HMTM, is able to produce a significant dose‐dependent reduction in neurodegeneration in AD as measured by change in plasma NfL levels.

Plasma biomarkers in relation to spatial distribution of Alzheimer’s disease neuropathology

AbstractBackgroundThe clinical utility of plasma biomarkers will in part be based on the information they convey regarding the distribution of neuropathology, especially beyond the information provided by demographics. We examined the associations of plasma biomarkers with cerebral amyloid and tau pathology determined by positron emission tomography (PET).MethodIn the Baltimore Longitudinal Study of Aging, plasma Aß42/Aß40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) concentrations were measured using Quanterix Simoa assays. Plasma concentrations of phosphorylated tau at threonine 181 (p‐tau181) and at 231 (p‐tau231) were measured using in‐house Simoa assays at University of Gothenburg. Using voxelwise linear regression models, we investigated cross‐sectional associations of plasma biomarkers with brain fibrillar amyloid and phosphorylated tau pathology as measured by PET with 11C‐Pittsburgh compound B (PiB) conducted on a GE Advance scanner (N = 189) and 18F‐flortaucipir (FTP) conducted on a Siemens High Resolution Research Tomograph (N = 107), respectively. In addition to unadjusted analyses, we conducted analyses adjusting for age, sex, and race. Results were corrected for multiple comparisons using permutation test‐based threshold‐free cluster enhancement (TFCE).ResultLower plasma Aß42/Aß40 was associated with higher PiB distribution volume ratio (DVR) in the unadjusted model, but not in the adjusted model (Figure 1). The remaining plasma biomarkers exhibited statistically significant positive associations with PiB DVR in both unadjusted and adjusted models. The plasma biomarker with the strongest and most widespread association with PiB DVR was p‐tau231 (Figure 2). Both p‐tau biomarkers exhibited statistically significant associations with FTP standardized uptake value ratio (SUVR) in both unadjusted and adjusted models. Aß42/Aß40, GFAP, and NfL did not exhibit statistically significant associations with FTP SUVR. Associations of p‐tau biomarkers with PiB DVR were stronger and more widespread than with FTP SUVR. We did not find any statistically significant associations when we repeated the analyses separately by binary PiB group.ConclusionPlasma biomarkers convey information beyond age, sex, and race in relation to the cerebral distribution of amyloid, and to a lesser extent, tau. The smaller sample size of our FTP PET study might in part explain the weaker associations we observed with FTP SUVR compared to PiB DVR.

Plasma amyloid‐β, total tau, and neurofilament light chain across the Alzheimer clinical spectrum: a population‐based study

AbstractBackgroundPlasma biomarkers have emerged as a promising approach for defining mild cognitive impairment (MCI) and Alzheimer’s disease (AD). We aimed to characterize Alzheimer’s plasma biomarkers across the clinical continuum of AD, and to assess their ability to differentiate between MCI, AD, and normal cognition.MethodThis population‐based study engaged 1446 rural‐dwelling older adults (age≥60 years, 61.0% women) derived from Multimodal Interventions to Delay Dementia and Disability in Rural China study; of these, 902 were defined with normal cognition, 402 with MCI, and 142 with AD according to the international criteria. Plasma amyloid‐beta (Aβ), total‐tau (t‐tau), and neurofilament light chain (NfL) concentrations were analysed using Simoa platform. Data were analysed using the logistic and general linear models, and receiver operating characteristic (ROC) analysis.ResultPlasma concentrations of Aβ40, Aβ42, t‐tau, and NfL were significantly increased with age (P&lt;0.01). Women had higher plasma Aβ2 (age‐adjusted β = 0.62; 95%CI = 0.30‐0.94), Aβ42/Aβ40 ratio (0.19; 0.01‐0.36) and lower NfL concentrations (‐0.11; ‐0.16‐ ‐0.06). Plasma Aβ42 (age‐ and sex‐adjusted β = ‐0.73; ‐1.15‐ ‐0.31) and Aβ42/Aβ40 ratio (‐0.51; ‐0.74‐ ‐0.29) were lower in APOE ε4 carriers than that in non‐carriers. Plasma Aβ40 and Aβ42/Aβ40 ratio showed an increased and decreased trend, respectively, across AD clinical spectrum. Plasma t‐tau and t‐tau/Aβ42 ratio were higher in people with AD than those with MCI or normal cognition. Plasma NfL was increased across the AD clinical continuum and outperformed other Alzheimer’s biomarkers in differentiating AD from normal cognition (area under the ROC curve [AUC] = 0.75). However, all of these plasma biomarkers performed poorly to distinguish MCI from normal cognition (AUC&lt;0.60). When adding plasma NfL to the basic model that included age, sex, education, and APOE genotype, the AUC was 0.87 for differentiating between AD and normal cognition, 0.79 between AD and MCI, and 0.64 between MCI and normal cognition.ConclusionAge, sex, and APOE genotype should be considered in clinical interpretation of Alzheimer’s plasma biomarkers. Plasma Aβ, t‐tau, and NfL concentrations differ across the cognitive continuum, but plasma NfL, which starts to elevate in the early stages of AD development, appears to be superior than plasma Aβ and t‐tau for defining cognitive continuum in old age.

Associations between blood‐based biomarkers and cognitive decline among participants at risk of Alzheimer’s disease: the Memento cohort

AbstractBackgroundBlood‐based biomarkers for Alzheimer’s disease (AD) pathology and neurodegeneration are promising biomarkers due to their lower cost, accessibility, and minimally invasive nature. Higher levels of AD blood‐based biomarkers have been shown to be associated with the risk of AD and cognitive decline. Yet, the specific cognitive domains involved need to be further investigated. We thus aimed at estimating the association between levels of baseline AD blood‐based biomarkers with cognitive trajectories over 5 years of follow‐up across different domains in a large clinical based cohort.MethodWe selected the 2060 dementia‐free individuals aged 60 years and older included in the Memento study, a French nationwide cohort, following patients from 28 memory clinics with either isolated cognitive complaints or mild cognitive impairment. Amyloid‐β 40 and 42, P‐tau181, and Neurofilament Light Chain (NfL) concentrations were measured at baseline using Simoa HD‐X analyzer. Global cognition, episodic memory, semantic memory, and executive functioning were assessed every year up to 5 years using the Mini Mental State Examination, the Free and Cued Reminding test, the Animal fluency test, and the Trail Making Test B respectively. Linear mixed models adjusted for sex, education level, APOE‐ε4 status, and practice effect, with age as time scale and quadratic slopes were performed to examine how AD blood‐based biomarkers relate to longitudinal cognitive trajectories by domain.ResultMean age was 72.8 years, 62% were women, 28% were APOE‐ε4 carriers, and 58% had a Clinical Dementia Rating score of 0.5. Higher baseline plasma P‐tau181 was associated with significantly faster nonlinear cognitive decline in all four cognitive domains (p&lt;0.001). On the opposite, baseline plasma Aβ42/40 ratio and NfL were not associated with cognitive decline whatever the domain. Associations between AD blood‐based biomarkers and faster cognitive decline were not modified by APOE‐ε4, sex, nor education level (p value for interaction &gt; 0.05).ConclusionIn a memory clinic population, plasma P‐tau181 is a marker of future cognitive decline. This marker is a good candidate for additional studies assessing biomarkers relevant for the identification of individuals who may benefit from treatment early in the disease course.

Renal function, Alzheimer’s plasma biomarker, and cognitive phenotypes among rural older adults in China: a population‐based study

AbstractBackgroundEmerging evidence has linked impaired renal function with dementia, but the neuropathological mechanisms underlying the association remains poorly understood. We sought to examine the relationships of renal function, Alzheimer’s plasma biomarker, and cognitive phenotypes among rural Chinese older adults.MethodThis population‐based cross‐sectional study included 5715 participants (age ≥60 years; 57.15% women; 40.49% illiteracy) in the Multimodal Interventions to Delay Dementia and Disability in Rural China (MIND‐China). We calculated the estimate glomerular filtration rate (eGFR) using serum creatinine and the simplified modification of diet in renal disease equation specifically for individuals from China, and impaired renal function was defined as eGFR &lt;60 mL/min/1.73 m2. Dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) were diagnosed following the international criteria. Plasma amyloid‐β (Aβ) 40, Aβ42, total tau, and neurofilament light chain (NfL) concentrations were measured using the SIMOA platform in a subsample (n = 1446). Data were analyzed using logistic, the general linear regression, and mediation models.ResultOf the 5715 participants, 283 (4.95%) were detected with renal function impairment, and 326 (5.70%) were diagnosed with dementia (195 with AD and 10 with VaD). The multivariable‐adjusted odds ratios of eGFR &lt;60 mL/min/1.73 m2 (vs. &gt;90mL/min/1.73 m2) were 2.43 (95% confidence interval [CI] 1.56‐3.72) for all‐cause dementia, 2.74 (1.64‐4.49) for AD, and 1.30 (0.50‐2.98) for VaD. In the plasma biomarkers subsample, controlling for demographic factors, impaired renal function was significantly associated with higher levels of plasma Aβ40 (demographic‐adjusted β‐coefficient = 59.06; 95%CI 46.93‐71.19), Aβ42 (3.41; 2.62‐4.20), NfL (14.57; 9.08‐20.05), and total tau (0.74; 0.48‐1.01), and the observed associations remained significant even in the multivariable‐adjusted model (P&lt;0.001). The mediation analysis showed that total tau mediated 12.77% of the association between impaired renal function and AD.ConclusionImpaired renal function is associated with an increased risk of dementia and AD. Plasma total tau may partly underlie the association of renal function with Alzheimer’s dementia.

Plasma Amyloid-β, Total Tau, and Neurofilament Light Chain Across the Alzheimer's Disease Clinical Spectrum: A Population-Based Study.

Plasma biomarkers have emerged as a promising approach for characterizing pathophysiology in mild cognitive impairment (MCI) and Alzheimer's disease (AD). We aimed to characterize plasma biomarkers for AD and neurodegeneration across the AD clinical continuum, and to assess their ability to differentiate between AD, MCI, and normal cognition. This population-based study engaged 1,446 rural-dwelling older adults (age ≥60 years, 61.0% women) derived from MIND-China; of these, 402 were defined with MCI and 142 with AD. Plasma amyloid-β (Aβ), total tau (t-tau), and neurofilament light chain (NfL) concentrations were analyzed using the Simoa platform. Data were analyzed using linear and logistic regression models, and receiver operating characteristic (ROC) analysis. Across the AD clinical spectrum, plasma Aβ40 and NfL increased, whereas Aβ42/Aβ40 ratio decreased. Plasma t-tau was higher in people with AD dementia than those with MCI or normal cognition. Plasma NfL outperformed other biomarkers in differentiating AD from normal cognition (area under the ROC curve [AUC] = 0.75), but all plasma biomarkers performed poorly to distinguish MCI from normal cognition (AUC <0.60). Plasma NfL in combination with age, sex, education, and APOE genotype yielded the AUC of 0.87 for differentiating between AD and normal cognition, 0.79 between AD and MCI, and 0.64 between MCI and normal cognition. In this Chinese population, AD plasma biomarkers vary by age, sex, and APOE genotype. Plasma Aβ, t-tau, and NfL differ across the AD clinical spectrum, and plasma NfL appears to be superior to plasma Aβ and t-tau for defining the clinical spectrum.

The myth of brain damage: no change of neurofilament light chain during transient cognitive side-effects of ECT

Electroconvulsive therapy (ECT) is an effective, safe, and mostly well-tolerated treatment for patients with severe or difficult to treat depression or psychotic disorders. However, a relevant number of patients experience subjective and/or objective cognitive side-effects. The mechanism of these transient deficits is not yet clear. Thus, our study prospectively investigated neurofilament light chain (NfL) concentrations as a highly sensitive biomarker for neuroaxonal damage along with cognitive performance during a course of ECT. Serum NfL concentrations from 15 patients with major depressive disorder receiving ECT were analyzed (1) 24 h before the first ECT, (2) 24 h and (3) 7 days after the last ECT (45 measurements in total). Neuropsychological testing including memory, executive functions and attention was performed at each time-point. NfL concentrations did not change between the three time-points, while a temporary cognitive impairment was found. Even in the subset of patients with the strongest impairment, NfL concentrations remained unchanged. Neuropsychological testing revealed the common pattern of transient cognitive side-effects with reduced performance 24 h post-ECT (global cognition score: p < 0.001; memory: p = 0.043; executive functions: p = 0.002) and return to baseline after 7 days (all p < 0.001). Our study adds to the evidence that neither ECT per se nor the transient cognitive side-effects seem to be associated with an increase of NfL as a marker of neuroaxonal damage. In contrast, we discuss cognitive side effects to be potentially interpreted as a byproduct of ECT’s neuroplastic effects.

A randomized, double-blind, placebo-controlled, phase 2 study to assess safety, tolerability and efficacy of RT001 in patients with amyotrophic lateral sclerosis.

RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). We conducted a randomized, multicenter, placebo-controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24 weeks. After the double-blind period, all patients received RT001 during an open-label phase for 24 weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS functional rating scale (ALSFRS-R), %predicted slow vital capacity, and plasma neurofilament light chain concentration. In total, 43 patients (RT001=21; placebo=22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more adverse events in the RT001 group compared to the placebo group (71% versus 55%, p = 0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo, p = 0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least-squares mean difference in ALSFRS-R total score at week 24 of treatment was 1.90 (95% CI: -1.39, 5.19) in favor of RT001, p = 0.25. The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed. Initial data indicate that RT001 is safe and well-tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.

C-NODDI: a constrained NODDI model for axonal density and orientation determinations in cerebral white matter.

Neurite orientation dispersion and density imaging (NODDI) provides measures of neurite density and dispersion through computation of the neurite density index (NDI) and the orientation dispersion index (ODI). However, NODDI overestimates the cerebrospinal fluid water fraction in white matter (WM) and provides physiologically unrealistic high NDI values. Furthermore, derived NDI values are echo-time (TE)-dependent. In this work, we propose a modification of NODDI, named constrained NODDI (C-NODDI), for NDI and ODI mapping in WM. Using NODDI and C-NODDI, we investigated age-related alterations in WM in a cohort of 58 cognitively unimpaired adults. Further, NDI values derived using NODDI or C-NODDI were correlated with the neurofilament light chain (NfL) concentration levels, a plasma biomarker of axonal degeneration. Finally, we investigated the TE dependence of NODDI or C-NODDI derived NDI and ODI. ODI derived values using both approaches were virtually identical, exhibiting constant trends with age. Further, our results indicated a quadratic relationship between NDI and age suggesting that axonal maturation continues until middle age followed by a decrease. This quadratic association was notably significant in several WM regions using C-NODDI, while limited to a few regions using NODDI. Further, C-NODDI-NDI values exhibited a stronger correlation with NfL concentration levels as compared to NODDI-NDI, with lower NDI values corresponding to higher levels of NfL. Finally, we confirmed the previous finding that NDI estimation using NODDI was dependent on TE, while NDI derived values using C-NODDI exhibited lower sensitivity to TE in WM. C-NODDI provides a complementary method to NODDI for determination of NDI in white matter.

Serum neurofilament light chain reference database for individual application in paediatric care: a retrospective modelling and validation study

Neurological conditions represent an important driver of paediatric disability burden worldwide. Measurement of serum neurofilament light chain (sNfL) concentrations, a specific marker of neuroaxonal injury, has the potential to contribute to the management of children with such conditions. In this context, the European Medicines Agency recently declared age-adjusted reference values for sNfL a top research priority. We aimed to establish an age-adjusted sNfL reference range database in a population of healthy children and adolescents, and to validate this database in paediatric patients with neurological conditions to affirm its clinical applicability. To generate a paediatric sNfL reference dataset, sNfL values were measured in a population of healthy children and adolescents (aged 0-22 years) from two large cohorts in Europe (the Coronavirus Antibodies in Kids from Bavaria study, Germany) and North America (a US Network of Paediatric Multiple Sclerosis Centers paediatric case-control cohort). Children with active or previous COVID-19 infection or SARS-CoV-2 antibody positivity at the time of sampling, or a history of primary systemic or neurological conditions were excluded. Linear models were used to restrospectively study the effect of age and weight on sNfL concentrations. We modelled the distribution of sNfL concentrations as a function of age-related physiological changes to derive reference percentile and Z score values via a generalised additive model for location, scale, and shape. The clinical utility of the new reference dataset was assessed in children and adolescents (aged 1-19 years) with neurological diseases (epilepsy, traumatic brain injury, bacterial CNS infections, paediatric-onset multiple sclerosis, and myelin oligodendrocyte glycoprotein antibody-associated disease) from the paediatric neuroimmunology clinic at the University of California San Francisco (San Francisco, CA, USA) and the Children's Hospital of the University of Regensburg (Regensburg, Germany). Samples from 2667 healthy children and adolescents (1336 [50·1%] girls and 1331 [49·9%] boys; median age 8·0 years [IQR 4·0-12·0]) were used to generate the reference database covering neonatal age to adolescence (target age range 0-20 years). In the healthy population, sNfL concentrations decreased with age by an estimated 6·8% per year until age 10·3 years (estimated multiplicative effect per 1 year increase 0·93 [95% CI 0·93-0·94], p<0·0001) and was mostly stable thereafter up to age 22 years (1·00 [0·52-1·94], p>0·99). Independent of age, the magnitude of the effect of weight on sNfL concentrations was marginal. Samples from 220 children with neurological conditions (134 [60·9%] girls and 86 [39·1%] boys; median age 14·7 years [IQR 10·8-16·5]) were used to validate the clinical utility of the reference Z scores. In this population, age-adjusted sNfL Z scores were higher than in the reference population of healthy children and adolescents (p<0·0001) with higher effect size metrics (Cohen's d=1·56) compared with the application of raw sNfL concentrations (d=1·28). The established normative sNfL values in children and adolescents provide a foundation for the clinical application of sNfL in the paediatric population. Compared with absolute sNfL values, the use of sNfL Z score was associated with higher effect size metrics and allowed for more accurate estimation of the extent of ongoing neuroaxonal damage in individual patients. Swiss National Science Foundation, US National Institutes of Health, and the National Multiple Sclerosis Society.

Serum Neurofilaments in Motor Neuron Disease and Their Utility in Differentiating ALS, PMA and PLS.

Neurofilament levels are elevated in many neurodegenerative diseases and have shown promise as diagnostic and prognostic biomarkers in Amyotrophic Lateral Sclerosis (ALS), the most common form of Motor Neuron Disease (MND). This study assesses serum neurofilament light (NFL) and neurofilament heavy (NFH) chain concentrations in patients with ALS, other variants of motor neuron disease such as Progressive Muscular Atrophy (PMA) and Primary Lateral Sclerosis (PLS), and a range of other neurological diseases. It aims to evaluate the use of NFL and NFH to differentiate these conditions and for the prognosis of MND disease progression. NFL and NFH levels were quantified using electrochemiluminescence immunoassays (ECLIA). Both were elevated in 47 patients with MND compared to 34 patients with other neurological diseases and 33 healthy controls. NFL was able to differentiate patients with MND from the other groups with a Receiver Operating Characteristic (ROC) curve area under the curve (AUC) of 0.90 (p < 0.001). NFL correlated with the rate of disease progression in MND (rho 0.758, p < 0.001) and with the ALS Functional Rating Scale (rho -0.335, p = 0.021). NFL levels were higher in patients with ALS compared to both PMA (p = 0.032) and PLS (p = 0.012) and were able to distinguish ALS from both PMA and PLS with a ROC curve AUC of 0.767 (p = 0.005). These findings support the use of serum NFL to help diagnose and differentiate types of MND, in addition to providing prognostic information to patients and their families.

Association between neurofilament light chain concentration and lesion size in dogs with meningoencephalitis of unknown origin.

Neurofilament light chain (NfL) is an axonal cytoplasmic protein in neurons. Recently, NfL has shown potential as a diagnostic biomarker in dogs with meningoencephalitis of unknown origin (MUO). However, there have been no studies on the biomarkers of lesion progression and resolution in MUO. To identify the potential of NfL as a biomarker for predicting changes in lesions. Seven dogs with MUO who had undergone two magnetic resonance imaging (MRI) scans were included. The serum NfL levels were measured using a single-molecule array. The relationship between the rate of change in lesion size and the rate of change in serum NfL level was analysed using simple linear regression. To investigate the effect of changes in lesion size on NfL levels, the dogs were divided into two groups depending on the change in lesion size: decreased lesion size group (n = 5) and increased lesion size group (n = 2). Trends in lesion size change were identified in the second MRI compared with the first MRI. A significant positive relationship between the rate of lesion size change and the rate of NfL level change was identified (R2 = 0.9239, p = 0.0006). In the decreased lesion size group (n = 5), all NfL levels in each dog decreased, and in the increased lesion size group (n = 2), all NfL levels in each dog increased. This preliminary study showed a positive relationship between the rate of change in lesion size and rate of change in serum NfL levels. Therefore, the serum NfL level may be a promising biomarker of lesion progression and resolution in MUO.