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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Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report

Brain, Journal Year: 2019, Volume and Issue: 142(6), P. 1503 - 1527

Published: March 22, 2019

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by stereotypical proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC common proteinopathy, associated an amnestic dementia syndrome that mimicked Alzheimer's-type retrospective autopsy studies. distinguished from frontotemporal lobar degeneration pathology based on its epidemiology (LATE generally affects subjects), and relatively restricted neuroanatomical distribution of proteinopathy. In community-based cohorts, ∼25% brains had sufficient burden to be discernible cognitive impairment. Many subjects have comorbid brain pathologies, often including amyloid-β plaques tauopathy. Given the 'oldest-old' are at greatest risk for LATE-NC, advanced age constitute rapidly growing demographic group many countries, has expanding but under-recognized impact public health. For these reasons, working was convened develop diagnostic criteria LATE, aiming both stimulate research promote awareness this pathway dementia. report consensus-based recommendations guidelines diagnosis staging LATE-NC. routine workup anatomically-based preliminary scheme proposed immunohistochemistry tissue three areas, reflecting hierarchical pattern involvement: amygdala, hippocampus, middle frontal gyrus. appears affect medial temporal lobe structures preferentially, other areas also impacted. Neuroimaging studies demonstrated atrophy lobes, cortex, regions. Genetic thus far indicated five genes alleles LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, APOE. The discovery genetic variants indicate shares pathogenetic mechanisms Alzheimer's disease, suggests disease-specific underlying mechanisms. Large gaps remain our understanding LATE. advances prevention, diagnosis, treatment, there urgent need focused vitro animal models. An obstacle clinical progress lack tools, such as biofluid neuroimaging biomarkers, ante-mortem detection Development biomarker would augment observational seeking further define factors, natural history, features well eventual subject recruitment targeted therapies trials.

Language: Английский

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Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease

JAMA Neurology, Journal Year: 2017, Volume and Issue: 74(5), P. 557 - 557

Published: March 28, 2017

Existing cerebrospinal fluid (CSF) or imaging (tau positron emission tomography) biomarkers for Alzheimer disease (AD) are invasive expensive. Biomarkers based on standard blood test results would be useful in research, drug development, and clinical practice. Plasma neurofilament light (NFL) has recently been proposed as a blood-based biomarker neurodegeneration dementias.To whether plasma NFL concentrations increased AD associated with cognitive decline, other biomarkers, evidence of neurodegeneration.In this prospective case-control study, an ultrasensitive assay was used to measure concentration 193 cognitively healthy controls, 197 patients mild impairment (MCI), 180 dementia from the Alzheimer's Disease Neuroimaging Initiative. The study dates were September 7, 2005, February 13, 2012. analysis performed 2016.Associations tested between diagnosis, Aβ pathologic features, CSF neuronal injury, cognition, brain structure, metabolism.Among impairment, dementia, correlated (Spearman ρ = 0.59, P < .001). MCI (mean, 42.8 ng/L) 51.0 compared controls 34.7 (P .001) had high diagnostic accuracy vs (area under receiver operating characteristic curve, 0.87, which is comparable established biomarkers). particularly features. High poor cognition AD-related atrophy (at baseline longitudinally) hypometabolism (longitudinally).Plasma diagnosis cognitive, biochemical, hallmarks disease. This finding implies potential usefulness noninvasive AD.

Language: Английский

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CSF and blood biomarkers for Parkinson's disease

The Lancet Neurology, Journal Year: 2019, Volume and Issue: 18(6), P. 573 - 586

Published: April 11, 2019

Language: Английский

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Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry

The World Journal of Biological Psychiatry, Journal Year: 2017, Volume and Issue: 19(4), P. 244 - 328

Published: Oct. 27, 2017

In the 12 years since publication of first Consensus Paper WFSBP on biomarkers neurodegenerative dementias, enormous advancement has taken place in field, and Task Force takes now opportunity to extend update original paper. New concepts Alzheimer's disease (AD) conceptual interactions between AD dementia due were developed, resulting two sets for diagnostic/research criteria. Procedures pre-analytical sample handling, biobanking, analyses post-analytical interpretation results intensively studied optimised. A global quality control project was introduced evaluate monitor inter-centre variability measurements with goal harmonisation results. Contexts use how approach candidate biological specimens other than cerebrospinal fluid (CSF), e.g. blood, precisely defined. Important development achieved neuroimaging techniques, including studies comparing amyloid-β positron emission tomography fluid-based modalities. Similarly, research laboratory technologies, such as ultra-sensitive methods, raises our hopes further improve analytical diagnostic accuracy classic novel biomarkers. Synergistically, clinical trials anti-dementia therapies energises motivates efforts find optimise most reliable early Finally, published addressing potential cost-effectiveness biomarkers-based diagnosis disorders.

Language: Английский

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Neurofilaments: neurobiological foundations for biomarker applications

Brain, Journal Year: 2020, Volume and Issue: 143(7), P. 1975 - 1998

Published: March 13, 2020

Interest in neurofilaments has risen sharply recent years with recognition of their potential as biomarkers brain injury or neurodegeneration CSF and blood. This is the context a growing appreciation for complexity neurobiology neurofilaments, new specialized roles synapses developing understanding mechanisms responsible turnover. Here we will review neurofilament proteins, describing current structure function, including recently discovered evidence synapses. We explore emerging degradation clearance methods future elucidation kinetics turnover humans. Primary pathogenesis human diseases be described. With this background, then critically supporting use concentration measures neuronal degeneration. Finally, reflect on major challenges studies intermediate filaments specific attention to identifying what needs learned more precise confident interpretation neurodegeneration.

Language: Английский

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Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

Biomedicines, Journal Year: 2019, Volume and Issue: 7(4), P. 97 - 97

Published: Dec. 9, 2019

Despite all scientific efforts and many protracted expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or abandoned in the last decade. The most probable explanations failures disease-modifying treatments (DMTs) AD may include late initiation during course development, inappropriate dosages, erroneous selection targets, mainly an inadequate understanding complex pathophysiology AD, which necessitate combination rather monotherapy. Clinical trials’ methodological issues also criticized. Drug-development research is aimed to overcome these drawbacks. Preclinical prodromal populations, as well traditionally investigated populations representing stages are included recent trials. Systematic use biomarkers staging preclinical a single primary outcome trials regularly integrated. application amyloid, tau, neurodegeneration biomarkers, including biomarkers—such Tau positron emission tomography, neurofilament light chain (blood Cerebrospinal fluid (CSF) biomarker axonal degeneration) neurogranin (CSF synaptic functioning)—to allows precise AD. Additionally, Bayesian statistics, modifiable trial designs, simulators enrich methodology. Besides, therapy regimens assessed above-mentioned diagnostic statistical advances, recently integrated relevant studies treatments. Their experiential theoretical origins better equip potentially successful drug-development strategies.

Language: Английский

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Molecular biomarkers of Alzheimer's disease: progress and prospects

Disease Models & Mechanisms, Journal Year: 2018, Volume and Issue: 11(5)

Published: May 1, 2018

The neurodegenerative disorder Alzheimer's disease is characterised by the formation of β-amyloid plaques and neurofibrillary tangles in brain parenchyma, which cause synapse neuronal loss. This leads to clinical symptoms, such as progressive memory deficits. Clinically, these pathological changes can be detected cerebrospinal fluid with imaging, although reliable blood tests for plaque tangle pathologies remain developed. Plaques often co-exist other pathologies, including aggregates transactive response DNA-binding protein 43 Lewy bodies, but extent contribute severity currently unknown. In this 'At a glance' article poster, we summarise molecular biomarkers that are being developed detect its related pathologies. We also highlight use include critical appraisal challenges associated applying diagnostic prognostic purposes disorders, their prodromal phases.

Language: Английский

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Making brain–machine interfaces robust to future neural variability

Nature Communications, Journal Year: 2016, Volume and Issue: 7(1)

Published: Dec. 13, 2016

A major hurdle to clinical translation of brain-machine interfaces (BMIs) is that current decoders, which are trained from a small quantity recent data, become ineffective when neural recording conditions subsequently change. We tested whether decoder could be made more robust future variability by training it handle variety sampled months previously collected data as well synthetic perturbations. developed new multiplicative recurrent network BMI successfully learned large neural-to- kinematic mappings and became with larger datasets. When non-human primate preclinical model, this was under disabled state-of-the-art Kalman filter based decoder. These results validate strategy in accumulated history effectively harnessed, may facilitate reliable daily use reducing retraining downtime.

Language: Английский

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Plasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 11, 2021

Abstract Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. We therefore tested if plasma measurements amyloid-β (Aβ)42/40, phospho-tau217 (P-tau217), neurofilament light (NfL) together predict clinical deterioration 435 CU individuals followed for an average 4.8 ± 1.7 years the BioFINDER study. A combination all three basic demographics best predicted change cognition (Pre-Alzheimer’s Clinical Composite; R 2 = 0.14, 95% CI [0.12–0.17]; P < 0.0001) subsequent AD dementia (AUC 0.82, [0.77–0.91], 0.0001). In a simulated trial, screening algorithm combining would reduce required sample size by 70% (95% [54–81]; 0.001) with as trial endpoint, 63% [53–70], endpoint. ATN show usefulness populations could make large trials more feasible cost-effective.

Language: Английский

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