Explore the vast range of titles available.

Background and purpose Hereditary transthyretin amyloidosis (ATTRv) is a life‐threatening disease caused by mutations in the gene encoding transthyretin (TTR). The recent therapeutic advances have underlined the importance of easily accessible, objective biomarkers of both disease onset and progression. Preliminary evidence suggests a potential role in this respect for neurofilament light chain (NfL). In this study, the aim was to determine serum NfL (sNfL) levels in a late‐onset ATTRv population and evaluate whether it might represent a reliable biomarker of disease onset (i.e., ‘conversion’ from the asymptomatic status to symptomatic disease in TTR mutation carriers). Methods In all, 111 individuals harbouring a pathogenic TTR variant (61 symptomatic ATTRv patients and 50 presymptomatic carriers) were consecutively enrolled. Fifty healthy volunteers were included as the control group. Ella™ apparatus was used to assess sNfL levels. Results Serum NfL levels were increased in ATTRv patients compared to both presymptomatic carriers and healthy controls, whilst not differing between carriers and healthy controls. An sNfL cut‐off of 37.10 pg/mL could discriminate between asymptomatic and symptomatic individuals with high diagnostic accuracy (area under the curve 0.958; p < 0.001), sensitivity (81.4%) and specificity (100%). Conclusions Serum NfL seems to be a promising biomarker of peripheral nerve involvement in ATTRv amyloidosis and might become a reliable, objective measure to detect the transition from the presymptomatic stage to the onset of symptomatic disease. Further longitudinal studies are needed to confirm such a role and determine whether it could equally represent a biomarker of disease progression and response to therapy.

Biomarkers of neurodegeneration and neuronal injury have the potential to improve diagnostic accuracy, disease monitoring, prognosis, and measure treatment efficacy. Neurofilament proteins (NfPs) are well suited as biomarkers in these contexts because they are major neuron-specific components that maintain structural integrity and are sensitive to neurodegeneration and neuronal injury across a wide range of neurologic diseases. Low levels of NfPs are constantly released from neurons into the extracellular space and ultimately reach the cerebrospinal fluid (CSF) and blood under physiological conditions throughout normal brain development, maturation, and aging. NfP levels in CSF and blood rise above normal in response to neuronal injury and neurodegeneration independently of cause. NfPs in CSF measured by lumbar puncture are about 40-fold more concentrated than in blood in healthy individuals. New ultra-sensitive methods now allow minimally invasive measurement of these low levels of NfPs in serum or plasma to track disease onset and progression in neurological disorders or nervous system injury and assess responses to therapeutic interventions. Any of the five Nf subunits – neurofilament light chain (NfL), neurofilament medium chain (NfM), neurofilament heavy chain (NfH), alpha-internexin (INA) and peripherin (PRPH) may be altered in a given neuropathological condition. In familial and sporadic Alzheimer’s disease (AD), plasma NfL levels may rise as early as 22 years before clinical onset in familial AD and 10 years before sporadic AD. The major determinants of elevated levels of NfPs and degradation fragments in CSF and blood are the magnitude of damaged or degenerating axons of fiber tracks, the affected axon caliber sizes and the rate of release of NfP and fragments at different stages of a given neurological disease or condition directly or indirectly affecting central nervous system (CNS) and/or peripheral nervous system (PNS). NfPs are rapidly emerging as transformative blood biomarkers in neurology providing novel insights into a wide range of neurological diseases and advancing clinical trials. Here we summarize the current understanding of intracellular NfP physiology, pathophysiology and extracellular kinetics of NfPs in biofluids and review the value and limitations of NfPs and degradation fragments as biomarkers of neurodegeneration and neuronal injury.

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid ( n  = 187) and serum ( n  = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer’s disease. Longitudinal, within-person analysis of serum NfL dynamics ( n  = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini–Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer’s disease, which supports its potential utility as a clinically useful biomarker. In a longitudinal cohort of familial Alzheimer’s disease patients, the rate of change of blood biomarker levels identifies disease carriers much earlier than absolute levels and predicts both neurodegeneration and cognitive decline.

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Amyloid beta (Aβ) is one of the proteins which aggregate in AD, and its key role in the disease pathogenesis is highlighted in the amyloid cascade hypothesis, which states that the deposition of Aβ in the brain parenchyma is a crucial initiating step in the future development of AD. The sensitivity of instruments used to measure proteins in blood and CSF has significantly improved, such that Aβ can now successfully be measured in plasma. However, due to the peripheral production of Aβ, there is significant overlap between diagnostic groups. The presence of pathological Aβ within the AD brain has several effects on the cells and surrounding tissue. Therefore, it is possible that using markers of tissue responses to amyloid may reveal more information about Aβ pathology and pathogenesis than looking at plasma Aβ alone. In this review paper, we will explore the concept of Aβ being the cause of AD, using the amyloid cascade hypothesis as a starting point, and delve into how the effect of Aβ on the surrounding tissue can be monitored using biomarkers. In particular, we will consider whether glial fibrillary acidic protein, triggering receptor expressed on myeloid cells 2, phosphorylated tau and neurofilament light chain could be used to phenotype and quantify the tissue response against Aβ pathology in AD.

BackgroundNeurofilament proteins have been extensively studied in relapsing–remitting multiple sclerosis, where they are promising biomarkers of disease activity and treatment response. Their role in progressive multiple sclerosis, where there is a particularly urgent need for improved biomarkers, is less clear. The objectives of this systematic review are to summarise the literature on neurofilament light and heavy in progressive multiple sclerosis, addressing key questions.MethodsA systematic search of PubMed, Embase, Web of Science and Scopus identified 355 potential sources. 76 relevant sources were qualitatively reviewed using QUADAS-2 criteria, and 17 were identified as at low risk of bias. We summarise the findings from all relevant sources, and separately from the 17 high-quality studies.ResultsDifferences in neurofilament light between relapsing–remitting and progressive multiple sclerosis appear to be explained by differences in covariates. Neurofilament light is consistently associated with current inflammatory activity and future brain atrophy in progressive multiple sclerosis, and is consistently shown to be a marker of treatment response with immunosuppressive disease-modifying therapies. Associations with current or future disability are inconsistent, and there is no evidence of NFL being a responsive marker of purportedly neuroprotective treatments. Evidence on neurofilament heavy is more limited and inconsistent.ConclusionsNeurofilament light has shown consistent utility as a biomarker of neuroinflammation, future brain atrophy and immunosuppressive treatment response at a group level. Neither neurofilament light or heavy has shown a consistent treatment response to neuroprotective disease-modifying therapies, which will require further data from successful randomised controlled trials.

BackgroundHuntingtin (HTT)-lowering gene therapies are being evaluated in clinical trials. We have previously shown that one-time intrastriatal administration of an adeno-associated viral vector serotype 5 encoding an engineered miRNA (AAV5-miHTT) targeting human mutant huntingtin (mHTT) protein leads to sustained CSF mHTT lowering in transgenic Huntington’s disease (tgHD) minipigs up to 2 years post-injection.AimsHere, we aimed to extend the observations on long-term safety and durability in tgHD minipigs up to 4 years post-injection. Furthermore, we aimed to delineate the extent to which CSF mHTT lowering reflects mHTT lowering in deep brain regions.Methods/TechniquesrAAV5-miHTT (1.2E+13 gc/animal) was successfully administered into the striatum (bilaterally in caudate and putamen), using age-matched untreated animals as controls. CSF was collected periodically up to 48 months post-injection. In a second study, rAAV5-miHTT was administered in putamen (5.4E+12 gc/animal) or intrathecally (2.4E+14 gc/animal). CSF was collected periodically up to 12 months post-injection, when the animals were sacrificed.Results/OutcomeCSF mHTT lowering was sustained up to at least 4 years post-injection. We did not observe an increase in NfL, GFAP, Tau or UCH-L1 in CSF, supporting the safety profile of AAV5-miHTT. Intrathecal injection led to more pronounced CSF mHTT lowering compared to low dose putamen injection, while mHTT lowering in the brain was generally similar between the two groups.ConclusionsIn this study, we confirm the safety and durability profile of AAV5-miHTT in a large animal model of HD. Furthermore, our data indicate that CSF mHTT lowering likely underestimates mHTT lowering in deep brain regions.

BackgroundEstablishing fluid biomarkers enables direct assessment of relevant aspects of Huntington’s disease (HD) pathology. Therefore, monitoring blood and CSF biomarkers of neuronal impairment in HD mice enhances our understanding of disease progression and facilitates potential therapeutic development for HD.AimsTo better understand how plasma and CSF biomarker levels change with disease progression in HD mice.MethodsBlood was collected into EDTA tubes via terminal cardiac puncture from zQ175 and wild type (WT) mice at 2, 6, and 12 months of age, from R6/2:Q200 and WT at 4, 8 and 12 weeks and from R6/2:Q90 and WT at 4, 14 and 24 weeks, and plasma extracted after centrifugation. CSF was collected from terminal anaesthetised mice via the cisterna magna using a glass capillary from R6/2Q90 and WT at 16 and 24 weeks of age. Both NFL and Tau concentrations were quantified with an ultrasensitive single-molecule array method (SIMOA, Quanterix).ResultsQuantirex analysis revealed elevated levels of plasma NFL: in zQ175 at 6 and 12 months of age, in R6/2:Q200 at 8 and 12 weeks of age, in R6/2:Q90 at 4, 14 and 24 weeks of age compared to WT littermates. Plasma Tau levels were only elevated in HD mice as compared to wild type littermates at end stage. CSF NFL levels were elevated in R6/2:Q90 at 16 and 24 weeks of age compared to wild type littermates.

BackgroundPridopidine is a S1R agonist in clinical development for HD and ALS. S1R activation by pridopidine enhances neuroprotective pathways. Increased levels of neurofilament light (NfL) protein indicate neuronal injury, serving as a biomarker that correlates with longitudinal disease progression. In other neurodegenerative diseases (e.g. MS), NfL reduction is associated with clinical efficacy. To date, no treatment has shown stabilization of NfL levels in HD. PRIDE-HD (Ph2) assessed pridopidine for the treatment of HD for 1 year. Post-hoc analysis of early HD patients with available plasma samples (placebo, n=34; pridopidine 45 mg bid, n=31) at baseline and Wk52 examined the effect of pridopidine on NfL levels (Simoa). The association between NfL and TFC (placebo n=41, pridopidine n=37) was modelled by a linear mixed model.ResultsThere were similar demographics, CAG repeat length, baseline TFC and NfL levels in placebo and pridopidine groups. Pridopidine shows TFC maintenance at 52 weeks ΔTFC +0.09 vs -1.0 in placebo (p=0.0006). Placebo shows the expected annual increase in NfL (ΔNfL+0.05 log2 pg/ml, similar to TRACK-HD (ΔNfL+0.037 log2 pg/ml). However, pridopidine group shows no annual increase in plasma NfL (ΔNfL -0.06 log2 pg/ml).In placebo, increased NfL is associated with decreased TFC (p=0.008). In the pridopidine group, NfL stabilization is associated with TFC maintenance, significantly different from placebo (p=0.02). Significance is maintained after corrections for age (p=0.03), CAG length (p=0.02), BMI (p=0.03) and their combination (p=0.02).ConclusionsPridopidine 45 mg bid stabilizes plasma NfL levels in association with TFC maintenance in early HD patients.

Purpose Neurofilament light (NfL) is a biomarker reflecting neurodegeneration and acute neuronal injury, and an increase is found following hypoxic brain damage. We assessed the ability of plasma NfL to predict outcome in comatose patients after out-of-hospital cardiac arrest (OHCA). We also compared plasma NfL concentrations between patients treated with two different targets of arterial carbon dioxide tension (PaCO 2 ), arterial oxygen tension (PaO 2 ), and mean arterial pressure (MAP). Methods We measured NfL concentrations in plasma obtained at intensive care unit admission and at 24, 48, and 72 h after OHCA. We assessed neurological outcome at 6 months and defined a good outcome as Cerebral Performance Category (CPC) 1–2 and poor outcome as CPC 3–5. Results Six-month outcome was good in 73/112 (65%) patients. Forty-eight hours after OHCA, the median NfL concentration was 19 (interquartile range [IQR] 11–31) pg/ml in patients with good outcome and 2343 (587–5829) pg/ml in those with poor outcome, p  < 0.001. NfL predicted poor outcome with an area under the receiver operating characteristic curve (AUROC) of 0.98 (95% confidence interval [CI] 0.97–1.00) at 24 h, 0.98 (0.97–1.00) at 48 h, and 0.98 (0.95–1.00) at 72 h. NfL concentrations were lower in the higher MAP (80–100 mmHg) group than in the lower MAP (65–75 mmHg) group at 48 h (median, 23 vs. 43 pg/ml, p  = 0.04). PaCO 2 and PaO 2 targets did not associate with NfL levels. Conclusions NfL demonstrated excellent prognostic accuracy after OHCA. Higher MAP was associated with lower NfL concentrations.

Background For clinical implementation of Alzheimer’s disease (AD) blood-based biomarkers (BBMs), knowledge of short-term variability, is crucial to ensure safe and correct biomarker interpretation, i.e., to capture changes or treatment effects that lie beyond that of expected short-term variability and considered clinically relevant. In this study we investigated short-term intra- and inter-individual variability of AD biomarkers in the intended use population, memory clinic patients. Methods In a consecutive sample of memory clinic patients (AD n  = 27, non-AD n  = 20), blood samples were collected on three separate days within a period of 36 days and analysed for plasma Aβ40, Aβ42, p-tau181, p-tau217, p-tau231, T-tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). We measured intra- and inter-individual variability and explored if the variability could be affected by confounding factors. Secondly, we established the minimum change required to detect a difference between two given blood samples that exceeds intra-individual variability and analytical variation (reference change value, RCV). Finally, we tested if classification accuracy varied across the three visits. Results Intra-individual variability ranged from ~ 3% (Aβ42/40) to ~ 12% (T-tau). Inter-individual variability ranged from ~ 7% (Aβ40) to ~ 39% (NfL). Adjusting the models for time, eGFR, Hba1c, and BMI did not affect the variation. RCV was lowest for Aβ42/Aβ40 (- ~ 15%/ + ~ 17%) and highest in p-tau181 (- ~ 30/ + ~ 42%). No variation in classification accuracies was found across visits. Conclusion We found low intra-individual variability, robust to various factors, appropriate to capture individual changes in AD BBMs, while moderate inter-individual variability may give rise to caution in diagnostic contexts. High RCVs may pose challenges for AD BBMs with low fold changes and consequently, short-term variability is important to take into consideration when, e.g., estimating intervention effect and longitudinal changes of AD BBM levels. Trial registration Clinicaltrials.gov (NCT05175664), date of registration 2021–12-01.