NfL In CSF Research Articles

Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion.

To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion. This single-center longitudinal cohort study has followed known carriers of PRNP pathogenic variants at risk for prion disease, individuals with a close relative who died of genetic prion disease but who have not undergone predictive genetic testing, and controls. All participants were asymptomatic at first visit and returned roughly annually. We determined PRNP genotypes, measured NfL and GFAP in plasma, and RT-QuIC, total PrP, NfL, T-tau, and beta-synuclein in CSF. Among 41 carriers and 21 controls enrolled, 28 (68%) and 15 (71%) were female, and mean ages were 47.5 and 46.1. At baseline, all individuals were asymptomatic. We observed RT-QuIC seeding activity in the CSF of 3 asymptomatic E200K carriers who subsequently converted to symptomatic and died of prion disease. 1 P102L carrier remained RT-QuIC negative through symptom conversion. No other individuals developed symptoms. The prodromal window from detection of RT-QuIC positivity to disease onset was 1 year long in an E200K individual homozygous (V/V) at PRNP codon 129 and 2.5 and 3.1 years in 2 codon 129 heterozygotes (M/V). Changes in neurodegenerative and neuroinflammatory markers were variably observed prior to onset, with increases observed for plasma NfL in 4/4 converters, and plasma GFAP, CSF NfL, CSF T-tau, and CSF beta-synuclein each in 2/4 converters, although values relative to age and fold changes relative to individual baseline were not remarkable for any of these markers. CSF PrP was longitudinally stable with mean coefficient of variation 9.0% across all individuals over up to 6 years, including data from converting individuals at RT-QuIC-positive timepoints. CSF prion seeding activity may represent the earliest detectable prodromal sign in E200K carriers. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity. ClinicalTrials.gov NCT05124392 posted 2017-12-01, updated 2023-01-27.

Predictive potential of serum and cerebrospinal fluid biomarkers for disease activity in treated multiple sclerosis patients

Background: Our objective was to explore various biomarkers for predicting suboptimal responses to disease-modifying treatments (DMTs) in patients with MS (pwMS).Methods: We conducted a longitudinal, bicentric study with pwMS stratified based on their DMTs responses. Treatment failure (TF) was defined as the onset of a second relapse, presence of two or more T2 new lesions, or disability progression independent of relapse during the follow-up period. We evaluated intrathecal synthesis (ITS) of IgG and IgM using OCB, linear indices, and Reibergrams. Free kappa light chains ITS was assessed using the linear index (FKLCi). NfL and GFAP in serum and CSF, and CHI3L1 in CSF were quantified. Quantitative variables were dichotomized based on the third quartile. Predictive efficacy was assessed through bivariate and multivariate analyses, adjusting for age, sex, EDSS, acute inflammatory activity (AI) -defined as the onset of a relapse or gadolinium-enhancing lesions within a 90-day window of lumbar puncture-, treatment modality, study center, and time from disease onset to treatment initiation. In case of collinearity, multiple models were generated or confounding variables were excluded if collinearity existed between them and the biomarker. The same methodology was used to investigate the predictive potential of various combinations of two biomarkers, based on whether any of them tested positive or exceeded the third quartile.Results: A total of 137 pwMS were included. FKLCi showed no differences based on AI, no correlation with EDSS and was significantly higher in pwMS with TF (p = 0.008). FKLCi>130 was associated with TF in bivariate analysis (Log-Rank p = 0.004). Due to collinearity between age and EDSS, two different models were generated with each of them and the rest of the confounding variables, in which FKLCi>130 showed a Hazard Ratio (HR) of 2.69 (CI: 1.35–5.4) and 2.67 (CI: 1.32–5.4), respectively. The combination of either FKLC or sNfL exceeding the third quartile was also significant in bivariate (Log-Rank p = 0.04) and multivariate (HR=3.1 (CI: 1.5–6.5)) analyses. However, when analyzed independently, sNfL did not show significance, and FKLCi mirrored the pattern obtained in the previous model (HR: 3.04; CI: 1.51–6.1). Treatment with highefficacy DMTs emerged as a protective factor in all models.Discussion: Our analysis and the fact that FKLCi is independent of EDSS and AI suggest that it might be a valuable parameter for discriminating aggressive phenotypes. We propose implementing high-efficacy drugs in pwMS with elevated FKLCi.

Novel Biomarkers for Alzheimer's Disease: Plasma Neurofilament Light and Cerebrospinal Fluid.

Neurodegenerative disorders such as Alzheimer's disease (AD) represent an increasingly significant public health concern. As clinical diagnosis faces challenges, biomarkers are becoming increasingly important in research, trials, and patient assessments. While biomarkers like amyloid-β peptide, tau proteins, CSF levels (Aβ, tau, and p-tau), and neuroimaging techniques are commonly used in AD diagnosis, they are often limited and invasive in monitoring and diagnosis. For this reason, blood-based biomarkers are the optimal choice for detecting neurodegeneration in brain diseases due to their noninvasiveness, affordability, reliability, and consistency. This literature review focuses on plasma neurofilament light (NfL) and CSF NfL as blood-based biomarkers used in recent AD diagnosis. The findings revealed that the core CSF biomarkers of neurodegeneration (T-tau, P-tau, and Aβ42), CSF NFL, and plasma T-tau were strongly associated with Alzheimer's disease, and the core biomarkers were strongly associated with mild cognitive impairment due to Alzheimer's disease. Elevated levels of plasma and cerebrospinal fluid NfL were linked to decreased [18F]FDG uptake in corresponding brain areas. In participants with Aβ positivity (Aβ+), NfL correlated with reduced metabolism in regions susceptible to Alzheimer's disease. In addition, CSF NfL levels correlate with brain atrophy and predict cognitive changes, while plasma total tau does not. Plasma P-tau, especially in combination with Aβ42/Aβ40, is promising for symptomatic AD stages. Though not AD-exclusive, blood NfL holds promise for neurodegeneration detection and assessing treatment efficacy. Given the consistent levels of T-tau, P-tau, Aβ42, and NFL in CSF, their incorporation into both clinical practice and research is highly recommended.

Matching proposed clinical and MRI criteria of aggressive multiple sclerosis to serum and cerebrospinal fluid markers of neuroaxonal and glial injury

BackgroundDefinitions of aggressive MS employ clinical and MR imaging criteria to identify highly active, rapidly progressing disease courses. However, the degree of overlap between clinical and radiological parameters and biochemical markers of CNS injury is not fully understood. Aim of this cross-sectional study was to match clinical and MR imaging hallmarks of aggressive MS to serum/CSF markers of neuroaxonal and astroglial injury (neurofilament light chain (sNfL, cNfL), and glial fibrillary acidic protein (sGFAP, cGFAP)).MethodsWe recruited 77 patients with relapsing–remitting MS (RRMS) and 22 patients with clinically isolated syndrome. NfL and GFAP levels in serum and CSF were assessed using a single-molecule-array HD-1-analyzer. A general linear model with each biomarker as a dependent variable was computed. Clinical and imaging criteria of aggressive MS, as recently proposed by the ECTRIMS Consensus Group, were modeled as independent variables. Other demographic, clinical or laboratory parameters, were modeled as covariates. Analyses were repeated in a homogenous subgroup, consisting only of newly diagnosed, treatment-naïve RRMS patients presenting with an acute relapse.ResultsAfter adjusting for covariates and multiplicity of testing, sNfL and cNfL concentrations were strongly associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.00008; pcNfL = 0.004) as well as the presence of infratentorial lesions on MRI (psNfL = 0.0003; pcNfL < 0.004). No other clinical and imaging criteria of aggressive MS correlated significantly with NfL or GFAP in serum and CSF. In the more homogeneous subgroup, sNfL still was associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.001), presence of more than 20 T2-lesions (psNfL = 0.049) as well as the presence of infratentorial lesions on MRI (psNfL = 0.034), while cNfL was associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.011) and presence of more than 20 T2-lesions (psNfL = 0.029).ConclusionsAmong proposed risk factors for an aggressive disease course, MRI findings but not clinical characteristics correlated with sNfL and cNfL as a marker of neuroaxonal injury and should be given appropriate weight considering MS prognosis and therapy. No significant correlation was detected for GFAP alone.

Aging × Genetics × Environment: Characterization of Precision Disease Models for Preclinical Testing for Late‐onset Alzheimer’s disease

AbstractBackgroundThe ability to effectively translate therapeutic efficacy from the bench to clinical success for Alzheimer’s disease (AD) has been hampered in part due to limited recapitulation of the complexity of the disease in animal models. While analogous AD risk mutations have been engineered into animal models and have dominated the research field, these have primarily been familial, early onset risk alleles which do not capture the risk for AD for the majority of patients that present with sporadic late onset AD (LOAD).MethodThe IU/JAX/PITT MODEL‐AD consortium is focused on developing mouse models with genetic risk variants associated with LOAD, in combination with environmental risk factors and aging to enable improved translation. The present studies aimed to characterize mice expressing humanized Aβ in combination with multiple genetic risk factors (APOE4 and the R47H risk variant in the Trem2 gene; LOAD2) and aged in the presence of a high‐fat, high‐sugar diet (HFD).ResultLOAD2 mice exposed to HFD from adolescence (LOAD2+HFD) demonstrated aging changes relative to LOAD2 mice in the absence of HFD, including presentation of insoluble Aβ42 in brain and plasma, and increased inflammatory cytokines. 12‐month aged LOAD2+HFD mice also demonstrated increased NfL in CSF, as well as vascular and perfusion changes as measured by PET/MRI. By 18 months, LOAD2+HFD mice demonstrated reductions in hippocampal neurons as well as cognitive impairment relative to LOAD2 mice in the absence of HFD on a translational touchscreen task. Intriguingly, gene expression profiles and proteomic signatures of aged LOAD2+HFD mice aligned with ‘omics signatures of AD patients in the absence of core neuritic plaques, which were not detected up to 24 months of age.ConclusionMice with genetic risk for LOAD coupled with environmental risk factors demonstrate aging‐dependent changes in line with a spectrum and trajectory of features of clinical LOAD. From a precision medicine approach, our MODEL‐AD Preclinical Testing Core and our TREAT‐AD colleagues are prioritizing LOAD2+HFD mice as an important model system for evaluating the therapeutic potential of non‐amyloid targeting therapeutics as well as for prophylactic interventions initiated prior to significant amyloid accumulation.

Effect of calcineurin/NFAT inhibitors on biomarkers and cognition in a canine model of Alzheimer disease

AbstractBackgroundCalcineurin/NFAT signaling increases in Alzheimer disease (AD) and is associated with neurodegeneration, neuroinflammation, amyloid‐β (Aβ) production, and cognitive decline. Hence, calcineurin/NFAT inhibitors (e.g., tacrolimus and Q134R) are attractive potential therapeutics to improve/prevent AD‐associated cognitive impairments. In AD mouse models, both tacrolimus and Q134R improved cognition and ameliorated neuroinflammation and synapse dysfunction.We hypothesized that 1) chronic low‐dose administration of tacrolimus and Q134R will delay cognitive decline over time in middle‐aged beagles, a model of human brain aging and AD; and 2) canine plasma and CSF biomarkers will be improved with treatment.MethodsCognitive outcomes were evaluated in 37 middle‐aged beagles at baseline and during follow‐up (years 1‐3) by assessing spatial learning [landmark‐discrimination (1, 2 and 4cm)], visual discrimination learning, reversal learning (executive function), and spatial working memory (20‐, 70‐, and 110‐second delays). Dogs were ranked for cognition at baseline and randomized into treatment groups: Control (n = 12; placebo), Q134R (n = 12; 8mg/day), and tacrolimus (n = 13; 0.075mg/kg/day). Concentrations of Aβ40, Aβ42, and NfL in plasma and CSF were measured using the Quanterix SIMOA.ResultsAccuracy at all landmark‐discrimination distances declined significantly among controls 20% faster than tacrolimus, and 15% faster than Q134R dogs, at the most difficult distance of 4cm. Accuracy on spatial working memory task declined 21% faster/year among controls than tacrolimus (years 2&amp;3); and 18% faster than Q134R dogs (year 1). Performance on visual discrimination and reversal tasks declined with age but there was no treatment effect.Biomarkers in plasma tended to increase over time with no significant differences between treatment groups. In CSF, relative decreases in Aβ40 and Aβ42 in tacrolimus (2.9 and 2, respectively) and Q134R (5.4 and 3.7, respectively) were less than in control dogs. Finally, relative increases of NfL in tacrolimus and Q134R were less than in control dogs (2.3 and 3.7, respectively).ConclusionBoth tacrolimus and Q134R showed beneficial preventative effects on age‐related decline in spatial functions and memory but not on associative learning nor executive function in a canine model of AD. Finally, only CSF biomarkers tended to improve relative to treatment and are suggestive of less Aβ deposition in brain and higher clearance.

Serum neurofilament light chain (NfL)and CSF glial fibrillary acidic protein (GFAP) together improve the prediction of long-term clinical outcomes in multiple sclerosis (S9.001)

Serum neurofilament light chain (NfL)and CSF glial fibrillary acidic protein (GFAP) together improve the prediction of long-term clinical outcomes in multiple sclerosis (S9.001)

Neurofilament light chain cannot be measured in urine to distinguish frontotemporal dementia with primary psychiatric diseases

AbstractBackgroundClinical overlap of the behavioral variant of FTD and primary psychiatric diseases (PPD) hampers diagnostic distinction, leading to frequent misdiagnosis and diagnostic delay. NfL in CSF and blood has shown great potential to accurately distinguish bvFTD from PPD and controls. Measurement of NfL in urine would be a minimal invasive, patient‐friendly biomarker assessment and thereby beneficial for future clinical implementation. We aimed to evaluate the diagnostic value of urine NfL concentration to distinguish bvFTD from PPD and controls and to assess if urine and serum NfL levels correlate.Method55 subjects (n = 19 FTD, n = 19 psychiatric patients: functional neurologic disorder n =2; obsessive compulsive disorder n= 1; unspecified mental disorder n =1; bipolar disorder, depressive phase n =1; depression, n = 6; adjustment disorder n = 3; anxiety disorder n = 1; autism spectrum disorder n =1; personality disorder n =2; somatic symptom disorder n = 2, and n = 17 controls) were included with available paired urine and serum samples. All subjects underwent standardized extensive diagnostic assessment. Samples were analyzed with the ultrasensitive SIMOA NfL assay. NfL group comparisons were performed adjusted for age and sex.ResultsIn the majority of the cohort NfL concentrations were not detectable in urine (n = 6 samples above lower limit of detection (0.038 pg/ml): n = 5 FTD, n =1 PPD). The frequency of a detectable NfL level in urine in the FTD (5/19) group did not differ from PPD (1/19); Fisher Exact‐test p = 0.180). In the individuals with detectable urine NfL values there was no correlation between the urine and serum NfL levels. As expected, serum NfL levels were higher in bvFTD compared to psychiatric patients and controls (p &lt; 0.000), adjusted for age and sex.ConclusionOur results implicate that using urine as matrix for NfL analysis is not suitable.

A mink (Neovison vison) model of self-injury: Effects of CBP-CREB axis on neuronal damage and behavior.

Self-injurious behavior (SIB) is a clinically challenging problem in the general population and several clinical disorders. However, the precise molecular mechanism of SIB is still not clear. In this paper, the systematic investigation of the genesis and development of SIB is conducted based on behavioral and pathophysiology studies in mink (Neovison vison) models. The night-vision video was used to observe the mink behavior, and the duration was a month. HE stain was performed to characterize the pathology change in the brain of a mink. IHC assay was performed to conduct the protein level detection of Iba-1, p-CREB, CBP, and p300 in the brain tissues. Elisa assay was used to examine the levels of NfL and NfH in serum and CSF of mink. The qRT-PCR assay was used to detect the expression of Bcl-2, NOR1, FoxO4, c-FOS, CBP, and p300 in brain tissues. Western blot was used to detect the protein levels of p-CREB, CBP, and p300 in brain tissues. We also used Evans Blue as a tracer to detect whether the blood-brain barrier was impaired in the brain of mink. The behavioral test, histopathological and molecular biology experiments were combined in this paper, and the results showed that CBP was related to SIB. Mechanism analysis showed that the dysregulation of CBP in brain-activated CREB signaling will result in nerve damage of the brain and SIB symptoms in minks. More importantly, the CBP-CREB interaction inhibitor might help relieve SIB and nerve damage in brain tissues. Our results illustrate that the induction of CBP and the activation of CREB are novel mechanisms in the genesis of SIB. This finding indicates that the CBP-CREB axis is critical for SIB and demonstrates the efficacy of the CBP-CREB interaction inhibitor in treating these behaviors.

P02-04 Performance of NF-L, GFAP, NSE and TAU in Rat Plasma and CSF as Translational Biomarkers of Nervous System Toxicity

P02-04 Performance of NF-L, GFAP, NSE and TAU in Rat Plasma and CSF as Translational Biomarkers of Nervous System Toxicity

The prodromal phase of hereditary spastic paraplegia type 4: the preSPG4 cohort study.

This cohort study aimed to characterize the prodromal phase of hereditary spastic paraplegia type 4 (SPG4) using biomarkers and clinical signs and symptoms that develop before manifest gait abnormalities. Fifty-six first-degree relatives at risk of developing SPG4 underwent blinded genotyping and standardized phenotyping, including the Spastic Paraplegia Rating Scale (SPRS), complicating symptoms, non-motor affection, Three-Minute Walk, and neurophysiological assessment. Automated MR image analysis was used to compare volumetric properties. CSF of 33 probands was analysed for neurofilament light chain (NfL), tau, and amyloid-β (Aβ). Thirty participants turned out to be SPAST mutation carriers, whereas 26 did not inherit a SPAST mutation. Increased reflexes, ankle clonus, and hip abduction weakness were more frequent in prodromal mutation carriers but were also observed in non-mutation carriers. Only Babinski's sign differentiated reliably between the two groups. Timed walk and non-motor symptoms did not differ between groups. Whereas most mutation carriers had total SPRS scores of 2 points or more, only two non-mutation carriers reached more than 1 point. Motor evoked potentials revealed no differences between mutation and non-mutation carriers. We found NfL but not tau or Aβ to rise in CSF of mutation carriers when approaching the time point of predicted disease manifestation. Serum NfL did not differ between groups. Volumetric MRI analyses did not reveal group differences apart from a smaller cingulate gyrus in mutation carriers. This study depicts subtle clinical signs which develop before gait abnormalities in SPG4. Long-term follow-up is needed to study the evolution of SPG4 in the prodromal stage and conversion into manifest disease. NfL in CSF is a promising fluid biomarker that may indicate disease activity in prodromal SPG4 but needs further evaluation in longitudinal studies.

CSF Biomarkers in COVID-19 Associated Encephalopathy and Encephalitis Predict Long-Term Outcome.

Patients with coronavirus disease 2019 (COVID-19) frequently develop acute encephalopathy and encephalitis, but whether these complications are the result from viral-induced cytokine storm syndrome or anti-neural autoimmunity is still unclear. In this study, we aimed to evaluate the diagnostic and prognostic role of CSF and serum biomarkers of inflammation (a wide array of cytokines, antibodies against neural antigens, and IgG oligoclonal bands), and neuroaxonal damage (14-3-3 protein and neurofilament light [NfL]) in patients with acute COVID-19 and associated neurologic manifestations (neuro-COVID). We prospectively included 60 hospitalized neuro-COVID patients, 25 (42%) of them with encephalopathy and 14 (23%) with encephalitis, and followed them for 18 months. We found that, compared to healthy controls (HC), neuro-COVID patients presented elevated levels of IL-18, IL-6, and IL-8 in both serum and CSF. MCP1 was elevated only in CSF, while IL-10, IL-1RA, IP-10, MIG and NfL were increased only in serum. Patients with COVID-associated encephalitis or encephalopathy had distinct serum and CSF cytokine profiles compared with HC, but no differences were found when both clinical groups were compared to each other. Antibodies against neural antigens were negative in both groups. While the levels of neuroaxonal damage markers, 14-3-3 and NfL, and the proinflammatory cytokines IL-18, IL-1RA and IL-8 significantly associated with acute COVID-19 severity, only the levels of 14-3-3 and NfL in CSF significantly correlated with the degree of neurologic disability in the daily activities at 18 months follow-up. Thus, the inflammatory process promoted by SARS-CoV-2 infection might include blood-brain barrier disruption in patients with neurological involvement. In conclusion, the fact that the levels of pro-inflammatory cytokines do not predict the long-term functional outcome suggests that the prognosis is more related to neuronal damage than to the acute neuroinflammatory process.

CSF Neurofilament Light Chain Concentrations Predict Outcome in Bacterial Meningitis.

Background and ObjectivesNeurofilament light chain (NfL) is a biomarker for neuroaxonal damage and has been found to be elevated proportionally to the degree of neuronal damage in neurologic diseases. The objective of this study was to determine the prognostic accuracy of NfL concentrations on unfavorable outcome in adults with community-acquired bacterial meningitis.MethodsWe measured NfL concentration CSF samples from a prospective cohort study of adults with community-acquired bacterial meningitis in The Netherlands and determined associations between NfL CSF concentrations, clinical characteristics, and outcome in multivariate analyses. We identified independent predictors of an unfavorable outcome (Glasgow Outcome Scale scores 1–4) by logistic regression.ResultsCSF NfL concentrations were evaluated in 429 episodes of 425 patients with community-acquired bacterial meningitis. The median age of 429 episodes was 62 years (interquartile range, 50–69 years). Of note, 290 of 422 (68%) episodes presented with an altered mental status (Glasgow Coma Scale score < 14). Most common causative pathogens were Streptococcus pneumoniae (73%), Neisseria meningitidis (7%), and Listeria monocytogenes (5%). The overall case fatality rate was 62 of 429 (15%), and unfavorable outcome occurred in 57 (37%) of 429 episodes. In multivariate analysis, predictors of unfavorable outcome were older age (OR 1.03, 95% CI 1.01–1.05), cranial nerve palsy (OR 4, 95% CI 1.6–10.3), high serum C-reactive protein concentration (OR 1.3, 95% CI 1.01–1.05), and high CSF NfL concentration (OR 1.5, 95% CI 1.07–2.00). CSF NfL concentrations were higher in patients presenting with focal cerebral deficits (717 pg/mL [416–1,401] vs 412 pg/mL [278–731]; p < 0.001). The area under the curve (AUC) for predicting unfavorable outcome in bacterial meningitis of CSF NfL concentration was 0.69 (95% CI, 0.64–0.74).DiscussionCSF NfL concentration is independently associated with unfavorable outcome in adults with community-acquired bacterial meningitis, suggesting that CSF NfL concentration may be a useful biomarker for prognostic assessment in bacterial meningitis.Classification of EvidenceCan the level of NfL in CSF (the index test) predict unfavorable outcome in patients with bacterial meningitis, in a cohort of bacterial meningitis patients with a favorable and unfavorable outcome? This study provides Class II evidence that NfL level in CSF is a moderate predictor, with the AUC for predicting unfavorable outcome in bacterial meningitis being 0.69 (95% CI, 0.64–0.74).

Microstructural and functional brain abnormalities in multiple sclerosis predicted by osteopontin and neurofilament light

BackgroundOsteopontin (OPN) is a proinflammatory biomarker, and neurofilament light chain (NFL) levels reflect axonal damage. Resting-state functional MRI (rs-fMRI) defines brain networks during wakeful rest. ObjectiveTo examine, if levels of OPN and NFL are associated on the long term with (i) lesion evolution, (ii) changes in normal-appearing white matter (NAWM) microstructure and (iii) functional connectivity in multiple sclerosis (MS). MethodsConcentration of NFL and OPN in the blood and CSF were related to MRI findings 10.3 ± 2.8 years later in 53 patients with MS. NFL was examined by Simoa method, OPN by ELISA. Lesion volume in the brain and cervical spinal cord was examined by 3D FLAIR images. Voxel-wise images of fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) were examined by tract-based spatial statistics corrected for gender, age and lesion volume. Metabolites were examined by single-voxel MR-spectroscopy in the NAWM. Fifty-five default mode network connections were examined by rs-fMRI corrected for gender, age, MS subtype and current therapy as covariates. ResultsWhile NFL in paired serum and CSF positively correlated (p = 0.019), there was no correlation between serum and CSF OPN. Higher OPN levels in the CSF but not in the serum showed association with increased brain WM lesion volume (p = 0.009) in 10.3 ± 2.8 years. Higher OPN in the CSF was associated with reduced FA, increased MD, and reduced RD in different NAWM areas 10.3 ± 2.8 years later. Higher OPN in the serum and CSF were associated with increased connectivity strength between the medial prefrontal cortex (MPFC) and other regions except with inferior parietal lobule. NFL in the CSF and in the serum was associated with decreased connectivity strength except for ventral MPFC-hippocampal formation. Neither serum OPN nor NFL at the time of the MRI were associated with functional connectivity changes. ConclusionWhile serum NFL levels reflects CNS production, OPN in serum and CSF may have different cellular sources. OPN within the CSF but not in the serum may forecast development of lesions and microstructural abnormalities in 10 years, indicating the detrimental role of CNS inflammation on the long-term. Although both OPN and NFL in the CSF were associated with functional connectivity changes in 10 years, NFL was associated with decreased strength possibly indicating general axonal loss. In contrast, the positive association of OPN levels in the CSF with increased connectivity strength in 10 years may point to adaptive re-organization due to inflammatory WM lesions and microstructural changes.

Chitinase 3-like 1 and neurofilament light chain in CSF and CNS atrophy in MS.

ObjectiveTo investigate cross-sectional associations of CSF levels of neurofilament light chain (NfL) and of the newly emerging marker chitinase 3–like protein 1 (CHI3L1) with brain and spinal cord atrophy, which are established MRI markers of disease activity in MS, to study CHI3L1 and NfL in relapsing (RMS) and progressive MS (PMS), and to assess the expression of CHI3L1 in different cell types.MethodsIn a single-center study, 131 patients with MS (42 RMS and 89 PMS) were assessed for NfL and CHI3L1 concentrations in CSF, MRI-based spinal cord and brain volumetry, MS subtype, age, disease duration, and disability. We included 42 matched healthy controls receiving MRI. CHI3L1 expression of human brain cell types was examined in 2 published single-cell RNA sequencing data sets.ResultsCHI3L1 was associated with spinal cord volume (B = −1.07, 95% CI −2.04 to −0.11, p = 0.029) but not with brain volumes. NfL was associated with brain gray matter (B = −7.3, 95% CI −12.0 to −2.7, p = 0.003) but not with spinal cord volume. CHI3L1 was suitable to differentiate between progressive or relapsing MS (p = 0.015, OR 1.0103, CI for OR 1.002–1.0187), and its gene expression was found in MS-associated microglia and macrophages and in astrocytes of MS brains.ConclusionsNfL and CHI3L1 in CSF were differentially related to brain and spinal cord atrophy. CSF CHI3L1 was associated with spinal cord volume loss and was less affected than NfL by disease duration and age, whereas CSF NfL was associated with brain gray matter atrophy. CSF NfL and CHI3L1 measurement provides complementary information regarding brain and spinal cord volumes.Classification of evidenceThis study provides Class II evidence that CSF CHI3L1 is associated with spinal cord volume loss and that CSF NfL is associated with gray matter atrophy.

SMA: REGISTRIES, BIOMARKERS & OUTCOME MEASURES: P.178 Development of motor function and changes in NFL in CSF in children with SMA treated with nusinersen

Recently, the anti-sense oligonucleotide drug nusinersen was approved for spinal muscular atrophy (SMA). Our aim was to evaluate the development in motor function of the patients receiving treatment and to investigate response markers in CSF for this treatment. All patients with SMA started on treatment with nusinersen during the period of November 2016 – June 2020 at Queen Silvia Children's Hospital were included in the study. Clinical data were obtained from the patients’ medical records. Motor function was assessed by standardized motor function scales validated for patients with SMA.

Neurofilament light protein in CSF and blood is associated with neurodegeneration and disease severity in Huntington\u2019s disease R6/2 mice

There is an unmet need to reliably and non-invasively monitor disease progression in preclinical Huntington’s disease (HD) models. As a marker of axonal damage, neurofilament light chain (NfL) has been suggested a marker for neurodegeneration. NfL concentrations in blood and CSF were recently shown to have prognostic value for clinical HD progression and brain atrophy. We therefore hypothesized that CSF and blood NfL concentrations could be useful preclinical HD markers, reflecting underlying pathology. To test our hypothesis we utilized the R6/2 mouse model of HD and measured NfL concentrations in CSF and serum using the ultrasensitive Single molecule array (Simoa) platform. In addition, we assessed HD mouse disease characteristics. We found robust increases of NfL in CSF and serum in R6/2 mice compared to wild-type littermates. CSF and serum concentrations of NfL were significantly correlated, suggesting similar marker potential of serum NfL. CSF and serum concentrations of NfL correlated with disease severity, as assessed by striatal volume and body weight loss. We here provide evidence that CSF and blood NfL concentrations can be used as accessible and reliable pre-clinical HD markers. This will be of potential use for monitoring HD mouse model disease progression and evaluating preclinical disease-modifying treatment response.

CSF sAPPβ, YKL-40, and neurofilament light in frontotemporal lobar degeneration.

To analyze the clinical utility of 3 CSF biomarkers and their structural imaging correlates in a large cohort of patients with different dementia and parkinsonian syndromes within the spectrum of frontotemporal lobar degeneration (FTLD). We analyzed 3 CSF biomarkers (YKL-40, soluble β fragment of amyloid precursor protein [sAPPβ], neurofilament light [NfL]) and core Alzheimer disease (AD) biomarkers (β-amyloid1-42, total tau, phosphorylated tau) in patients with FTLD-related clinical syndromes (n = 159): behavioral variant of frontotemporal dementia (n = 68), nonfluent (n = 23) and semantic (n = 19) variants of primary progressive aphasia, progressive supranuclear palsy (n = 28), and corticobasal syndrome (n = 21). We also included patients with AD (n = 72) and cognitively normal controls (CN; n = 76). We compared cross-sectional biomarker levels between groups, studied their correlation with cortical thickness, and evaluated their potential diagnostic utility. Patients with FTLD-related syndromes had lower levels of sAPPβ than CN and patients with AD. The levels of sAPPβ showed a strong correlation with cortical structural changes in frontal and cingulate areas. NfL and YKL-40 levels were high in both the FTLD and AD groups compared to controls. In the receiver operating characteristic analysis, the sAPPβ/YKL-40 and NfL/sAPPβ ratios had areas under the curve of 0.91 and 0.96, respectively, distinguishing patients with FTLD from CN, and of 0.84 and 0.85, distinguishing patients with FTLD from patients with AD. The combination of sAPPβ with YKL-40 and with NfL in CSF could be useful to increase the certainty of the diagnosis of FTLD-related syndromes in clinical practice. This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to identify patients with FTLD-related syndromes.

Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis

SummaryBackgroundBlood biomarkers of neuronal damage could facilitate clinical management of and therapeutic development for Huntington's disease. We investigated whether neurofilament light protein NfL (also known as NF-L) in blood is a potential prognostic marker of neurodegeneration in patients with Huntington's disease.MethodsWe did a retrospective analysis of healthy controls and carriers of CAG expansion mutations in HTT participating in the 3-year international TRACK-HD study. We studied associations between NfL concentrations in plasma and clinical and MRI neuroimaging findings, namely cognitive function, motor function, and brain volume (global and regional). We used random effects models to analyse cross-sectional associations at each study visit and to assess changes from baseline, with and without adjustment for age and CAG repeat count. In an independent London-based cohort of 37 participants (23 HTT mutation carriers and 14 controls), we further assessed whether concentrations of NfL in plasma correlated with those in CSF.FindingsBaseline and follow-up plasma samples were available from 97 controls and 201 individuals carrying HTT mutations. Mean concentrations of NfL in plasma at baseline were significantly higher in HTT mutation carriers than in controls (3·63 [SD 0·54] log pg/mL vs 2·68 [0·52] log pg/mL, p<0·0001) and the difference increased from one disease stage to the next. At any given timepoint, NfL concentrations in plasma correlated with clinical and MRI findings. In longitudinal analyses, baseline NfL concentration in plasma also correlated significantly with subsequent decline in cognition (symbol-digit modality test r=–0·374, p<0·0001; Stroop word reading r=–0·248, p=0·0033), total functional capacity (r=–0·289, p=0·0264), and brain atrophy (caudate r=0·178, p=0·0087; whole-brain r=0·602, p<0·0001; grey matter r=0·518, p<0·0001; white matter r=0·588, p<0·0001; and ventricular expansion r=–0·589, p<0·0001). All changes except Stroop word reading and total functional capacity remained significant after adjustment for age and CAG repeat count. In 104 individuals with premanifest Huntington's disease, NfL concentration in plasma at baseline was associated with subsequent clinical onset during the 3-year follow-up period (hazard ratio 3·29 per log pg/mL, 95% CI 1·48–7·34, p=0·0036). Concentrations of NfL in CSF and plasma were correlated in mutation carriers (r=0·868, p<0·0001).InterpretationNfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington's disease.FundingMedical Research Council, GlaxoSmithKline, CHDI Foundation, Swedish Research Council, European Research Council, Wallenberg Foundation, and Wolfson Foundation.

CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis

Alzheimer's disease biomarkers are important for early diagnosis in routine clinical practice and research. Three core CSF biomarkers for the diagnosis of Alzheimer's disease (Aβ42, T-tau, and P-tau) have been assessed in numerous studies, and several other Alzheimer's disease markers are emerging in the literature. However, there have been no comprehensive meta-analyses of their diagnostic performance. We systematically reviewed the literature for 15 biomarkers in both CSF and blood to assess which of these were most altered in Alzheimer's disease. In this systematic review and meta-analysis, we screened PubMed and Web of Science for articles published between July 1, 1984, and June 30, 2014, about CSF and blood biomarkers reflecting neurodegeneration (T-tau, NFL, NSE, VLP-1, and HFABP), APP metabolism (Aβ42, Aβ40, Aβ38, sAPPα, and sAPPβ), tangle pathology (P-tau), blood-brain-barrier function (albumin ratio), and glial activation (YKL-40, MCP-1, and GFAP). Data were taken from cross-sectional cohort studies as well as from baseline measurements in longitudinal studies with clinical follow-up. Articles were excluded if they did not contain a cohort with Alzheimer's disease and a control cohort, or a cohort with mild cognitive impairment due to Alzheimer's disease and a stable mild cognitive impairment cohort. Data were extracted by ten authors and checked by two for accuracy. For quality assessment, modified QUADAS criteria were used. Biomarker performance was rated by random-effects meta-analysis based on the ratio between biomarker concentration in patients with Alzheimer's disease and controls (fold change) or the ratio between biomarker concentration in those with mild cognitive impariment due to Alzheimer's disease and those with stable mild cognitive impairment who had a follow-up time of at least 2 years and no further cognitive decline. Of 4521 records identified from PubMed and 624 from Web of Science, 231 articles comprising 15 699 patients with Alzheimer's disease and 13 018 controls were included in this analysis. The core biomarkers differentiated Alzheimer's disease from controls with good performance: CSF T-tau (average ratio 2·54, 95% CI 2·44-2·64, p<0·0001), P-tau (1·88, 1·79-1·97, p<0·0001), and Aβ42 (0·56, 0·55-0·58, p<0·0001). Differentiation between cohorts with mild cognitive impairment due to Alzheimer's disease and those with stable mild cognitive impairment was also strong (average ratio 0·67 for CSF Aβ42, 1·72 for P-tau, and 1·76 for T-tau). Furthermore, CSF NFL (2·35, 1·90-2·91, p<0·0001) and plasma T-tau (1·95, 1·12-3·38, p=0·02) had large effect sizes when differentiating between controls and patients with Alzheimer's disease, whereas those of CSF NSE, VLP-1, HFABP, and YKL-40 were moderate (average ratios 1·28-1·47). Other assessed biomarkers had only marginal effect sizes or did not differentiate between control and patient samples. The core CSF biomarkers of neurodegeneration (T-tau, P-tau, and Aβ42), CSF NFL, and plasma T-tau were strongly associated with Alzheimer's disease and the core biomarkers were strongly associated with mild cognitive impairment due to Alzheimer's disease. Emerging CSF biomarkers NSE, VLP-1, HFABP, and YKL-40 were moderately associated with Alzheimer's disease, whereas plasma Aβ42 and Aβ40 were not. Due to their consistency, T-tau, P-tau, Aβ42, and NFL in CSF should be used in clinical practice and clinical research. Swedish Research Council, Swedish State Support for Clinical Research, Alzheimer's Association, Knut and Alice Wallenberg Foundation, Torsten Söderberg Foundation, Alzheimer Foundation (Sweden), European Research Council, and Biomedical Research Forum.