Alzheimer's disease

The Lancet, Journal Year: 2021, Volume and Issue: 397(10284), P. 1577 - 1590

Published: March 2, 2021

Language: Английский

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Neurofilaments as biomarkers in neurological disorders

Nature Reviews Neurology, Journal Year: 2018, Volume and Issue: 14(10), P. 577 - 589

Published: Aug. 31, 2018

Language: Английский

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Neurofilament light chain as a biomarker in neurological disorders

Journal of Neurology Neurosurgery & Psychiatry, Journal Year: 2019, Volume and Issue: 90(8), P. 870 - 881

Published: April 9, 2019

In the management of neurological diseases, identification and quantification axonal damage could allow for improvement diagnostic accuracy prognostic assessment. Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase cerebrospinal fluid (CSF) blood proportionally to degree variety disorders, including inflammatory, neurodegenerative, traumatic cerebrovascular diseases. New immunoassays able detect biomarkers at ultralow have allowed measurement NfL blood, thus making it possible easily repeatedly measure monitoring diseases’ courses. Evidence that both CSF may serve as diagnostic, diseases progressively increasing, one most promising be used clinical research setting next future. Here we review important results on discuss its potential applications future directions.

Language: Английский

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Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease

Nature Medicine, Journal Year: 2019, Volume and Issue: 25(2), P. 277 - 283

Published: Jan. 21, 2019

Language: Английский

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Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 9

Published: Jan. 9, 2019

In the majority of patients multiple sclerosis starts with a relapsing remitting disease (RRMS), which may at later times transform into secondary progressive (SPMS). minority is skipped and show progression from onset (primary MS, PPMS). Evidence obtained so far indicate major differences between RRMS but no essential SPMS PPMS, exception lower incidence in global load focal white matter lesions particular presence classical active plaques. We suggest that MS two types inflammation occur, develop parallel partially independent each other. The first bulk invasion T- B-lymphocytes profound blood brain barrier leakage, predominately affects gives rise to demyelinated other type slow accumulation T-cells B-cells absence damage connective tissue spaces brain, such as meninges large perivascular Virchow Robin spaces, where they form aggregates or most severe cases structures part resembling tertiary lymph follicles. This associated formation subpial cerebral cerebellar cortex, expansion pre-existing diffuse neurodegeneration normal appearing grey matter. dominates acute MS. second already present early stages gradually increases duration patient age. CD8+ T-lymphocytes remain spinal cord resident cells, focally propagate neuroinflammation, when re-encounter their cognate antigen. appear demyelination neurodegeneration, likely by producing soluble neurotoxic factors. Key open questions research are identification target antigen recognized molecular nature inflammatory mediators, trigger damage.

Language: Английский

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Serum neurofilament light levels in normal aging and their association with morphologic brain changes

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Feb. 10, 2020

Abstract Neurofilament light (NfL) protein is a marker of neuro-axonal damage and can be measured not only in cerebrospinal fluid but also serum, which allows for repeated assessments. There still limited knowledge regarding the association serum NfL (sNfL) with age subclinical morphologic brain changes their dynamics normal population. We sNfL by single molecule array (Simoa) assay 335 individuals participating population-based cohort study after mean follow-up time 5.9 years (n = 103). Detailed clinical examination, cognitive testing 3T MRI were performed to assess damage. show that rising more variable >60 indicate an acceleration neuronal injury at higher age, may driven comorbid pathologies. This supported close volume cross-sectional especially longitudinal manner.

Language: Английский

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Blood neurofilament light chain as a biomarker of MS disease activity and treatment response

Neurology, Journal Year: 2019, Volume and Issue: 92(10)

Published: Feb. 9, 2019

Objective

To assess the value of blood neurofilament light chain (NfL) as a biomarker recent, ongoing, and future disease activity tissue damage its utility to monitor treatment response in relapsing-remitting multiple sclerosis.

Methods

We measured NfL samples from 589 patients with sclerosis (from phase 3 studies fingolimod vs placebo, FREEDOMS interferon [IFN]-β-1a, TRANSFORMS) 35 healthy controls compared levels clinical MRI-related outcomes.

Results

At baseline, (pg/mL) were higher than (30.5 27.0 16.9, p = 0.0001) correlated T2 lesion load number gadolinium-enhancing T1 lesions (p < 0.0001, both). Baseline levels, treatment, new or enlarging during predicted at end study (all 0.01). High low baseline associated (estimate [95% confidence interval]) an increased (ratio mean: 2.64 [1.51–4.60]; 0.0006), relapses (rate ratio: 2.53 [1.67–3.83]; 0.0001), brain volume loss (difference means: −0.78% [−1.02 −0.54]; risk confirmed disability worsening (hazard 1.94 [0.97–3.87]; 0.0605). Fingolimod significantly reduced already 6 months (vs placebo 0.73 [0.656–0.813] IFN 0.789 [0.704–0.884]), which was sustained until 0.628 [0.552–0.714] 0.794 [0.705–0.894]; 0.001, both all assessments).

Conclusions

Blood are measures neuroaxonal have prognostic value. Our results support easily accessible evolution response.

Language: Английский

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Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials

JAMA Neurology, Journal Year: 2020, Volume and Issue: 77(9), P. 1132 - 1132

Published: June 8, 2020

Accumulation of disability in multiple sclerosis may occur as relapse-associated worsening (RAW) or steady progression independent relapse activity (PIRA), with PIRA regarded a feature primary and secondary progressive sclerosis.To investigate the contributions vs relapse-independent to overall confirmed accumulation (CDA) assess respective baseline prognostic factors outcomes 2 treatments.Analyses occurred from July 2015 February 2020 on pooled data intention-to-treat population identical, phase 3, multicenter, double-blind, double-dummy, parallel-group randomized clinical trials (OPERA I II) conducted between August 2011 April 2015. In trials, patients relapsing (RMS), diagnosed using 2010 revised McDonald criteria, were 307 trial sites 56 countries; resulting analyzed set.Participants 1:1 receive 600 mg ocrelizumab by intravenous infusion every 24 weeks subcutaneous interferon β-1a 3 times week at dose 44 μg throughout 96-week treatment period.Confirmed was defined an increase 1 more measures (Expanded Disability Status Scale, timed 25-ft walk, 9-hole peg test), after 6 months, classified per temporal association relapses (PIRA RAW).In OPERA II (1656 2096 eligible participants), demographics disease characteristics similar for (mean [SD] age, 37.2 [9.2] 37.1 years; 552 [66.6%] 541 women [65.4%]). After 96 weeks, 12-week composite CDA had 223 (29.6% Kaplan-Meier estimate) 167 (21.1%) ocrelizumab; 24-week 170 (22.7%) taking 129 (16.2%) ocrelizumab. The events main contributors treated (174 [78.0%] 137 [80.6%], respectively) (147 [88.0%] 115 [89.1%], respectively); minority explained RAW (69 390 [17.7%] 52 299 [17.4%], respectively). Very few experienced both (17 [4.4%] 15 [5.0%] CDA). Ocrelizumab (vs β-1a) associated reduced risk (hazard ratio [HR], 0.67) (HR, 0.78) 0.47) events.Most RMS is not overt relapses. This indicates underlying this typical challenges current distinction forms sclerosis. superior preventing PIRA.ClinicalTrials.gov Identifiers: (NCT01247324) (NCT01412333).

Language: Английский

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Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study

The Lancet Neurology, Journal Year: 2022, Volume and Issue: 21(3), P. 246 - 257

Published: Feb. 16, 2022

Language: Английский

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How patients with multiple sclerosis acquire disability

Brain, Journal Year: 2022, Volume and Issue: 145(9), P. 3147 - 3161

Published: Jan. 28, 2022

Patients with multiple sclerosis acquire disability either through relapse-associated worsening (RAW) or progression independent of relapse activity (PIRA). This study addresses the relative contribution relapses to over course disease, how early begins and extent which therapies delay accumulation. Using Novartis-Oxford (NO.MS) data pool spanning all phenotypes paediatric sclerosis, we evaluated ∼200 000 Expanded Disability Status Scale (EDSS) transitions from >27 patients ≤15 years follow-up. We analysed three datasets: (i) A full analysis dataset containing observational randomized controlled clinical trials in were assessed (n = 27 328); (ii) phase 3 8346); (iii) placebo-controlled 4970). determined importance RAW PIRA, investigated role on all-cause using Andersen-Gill models observed impact mechanism disease-modifying time reach milestone levels continuous Markov models. PIRA started disease process, occurred became principal driver accumulation progressive disease. Relapses significantly increased hazard events; following a year (versus without relapses), by 31-48% (all P < 0.001). Pre-existing older age risk factors for incomplete recovery. For placebo-treated minimal (EDSS 1), it took 8.95 until limitation walking ability 4) 18.48 require assistance 6). Treating delayed these times 3.51 (95% confidence limit: 3.19, 3.96) 3.09 (2.60, 3.72), respectively. In relapsing-remitting those who worsened exclusively due events similar length EDSS values compared fastest superimposed relapses. Our confirm that contribute disability, primarily sclerosis. becomes dominant as evolves. are further The use delays accrual years, potential gain being highest earliest stages

Language: Английский

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