Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease

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

Published: April 3, 2020

Abstract Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate performance CSF p-tau217 as a AD comparison to p-tau181. In Swedish BioFINDER cohort ( n = 194), shows stronger correlations with positron emission tomography (PET) tracer [ 18 F]flortaucipir, and more accurately identifies individuals abnormally increased F]flortaucipir retention. Furthermore, longitudinal increases are higher compared better correlate uptake. P-tau217 correlates than PET measures neocortical amyloid-β burden distinguishes dementia from non-AD neurodegenerative disorders. Higher between corroborated independent EXPEDITION3 trial 32). The main results validated using different immunoassay. These findings suggest that might be useful diagnostic work up AD.

Language: Английский

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Biomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies

Molecular Psychiatry, Journal Year: 2020, Volume and Issue: 26(1), P. 296 - 308

Published: April 6, 2020

Language: Английский

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Immune Signaling in Neurodegeneration

Immunity, Journal Year: 2019, Volume and Issue: 50(4), P. 955 - 974

Published: April 1, 2019

Language: Английский

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Plasma p-tau181 accurately predicts Alzheimer’s disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline

Acta Neuropathologica, Journal Year: 2020, Volume and Issue: 140(3), P. 267 - 278

Published: July 27, 2020

The neuropathological confirmation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFT) remains the gold standard for a definitive diagnosis Alzheimer's disease (AD). Nowadays, in vivo AD is greatly aided by both cerebrospinal fluid (CSF) positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation restricted high cost, limited accessibility invasiveness. We recently developed high-performance, ultrasensitive immunoassay quantification phosphorylated at threonine-181 (p-tau181) plasma, which identifies pathophysiology with accuracy. However, it unclear whether plasma p-tau181, measured years before death, can predict eventual AD, successfully discriminates from non-AD dementia pathologies. studied unique cohort 115 individuals longitudinal blood collections clinical evaluation 8, 4 2 prior to assessment death. results demonstrate that p-tau181 associates better neuropathology Braak staging than 8 post-mortem. Moreover, while all patients had during life, proved discriminate pathologies accuracy (AUC = 97.4%, 95% CI 94.1-100%) even Additionally, trajectory was assessed patients. found main increases occurred between death later plateauing. In contrast, controls exhibited minor, albeit significant, up until Overall, our study demonstrates predictive specific post-mortem examination. These data add further support use aid management primary care recruitment trials.

Language: Английский

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Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative

Molecular Psychiatry, Journal Year: 2020, Volume and Issue: 26(2), P. 429 - 442

Published: Oct. 26, 2020

Language: Английский

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A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: March 31, 2020

Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout AD its continuum. Large-scale genome-wide association studies point out several genetic variants - TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, HLA-DRB5-HLA-DRB1 potentially linked to neuroinflammation. Most these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins cell turn-over, synaptic activity, lipid metabolism, vesicle trafficking. Proteomic indicate that a plethora interconnected aberrant molecular pathways, set off perpetuated by TNF-α, TGF-β, IL-1β, receptor protein Microglia astrocytes key cellular drivers regulators Under physiological conditions, they important for neurotransmission homeostasis. In AD, there is turning pathophysiological evolution where glial cells sustain an overexpressed inflammatory response synergizes with amyloid-β tau accumulation, drives synaptotoxicity neurodegeneration self-reinforcing manner. Despite strong therapeutic rationale, previous trials investigating compounds anti-inflammatory properties, including non-steroidal drugs (NSAIDs) did not achieve primary efficacy endpoints. It conceivable study design issues, lack diagnostic accuracy biomarkers target population identification proof-of-mechanism may partially explain negative outcomes. However, recent meta-analysis indicates potential biological effect NSAIDs. this regard, candidate fluid neuroinflammation under analytical/clinical validation, i.e. MCP-1, IL-6, TNF-α complexes, YKL-40. PET radio-ligands investigated accomplish in-vivo longitudinal regional exploration Biomarkers tracking different pathways (body matrixes) along brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal-spatial dynamics between other mechanisms. Robust biomarker-drug co-development pipelines expected enrich large-scale testing new-generation active, directly or indirectly, on targets displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), AL003 (anti-CD33 antibody). As next step, taking advantage breakthrough multimodal techniques coupled systems biology approach path pursue developing individualized strategies targeting framework precision medicine.

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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The functions and clinical application potential of exosomes derived from adipose mesenchymal stem cells: a comprehensive review

Stem Cell Research & Therapy, Journal Year: 2019, Volume and Issue: 10(1)

Published: Aug. 7, 2019

Exosomes are extracellular membranous nanovesicles that mediate local and systemic intercellular communication by transporting proteins or nucleic acids (DNA RNA) into target cells, thus altering the behaviors of recipient cells. Recent studies have revealed these vesicles play a critical role in many biological functions, such as cell proliferation, immune regulation, nerve regeneration, cancer. Adipose-derived stem cells (ADSCs) now considered multipotent abundant tool field therapy regenerative medicine. ADSCs can produce secrete exosomes, which inherit multiple functions Therefore, this review, we will introduce characteristics exosomes derived from (ADSC-Exos), describe their different processes, summarize latest research achievements, limitations cell-free therapy, provide further insights clinical application potential for treatment certain diseases.

Language: Английский

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The “rights” of precision drug development for Alzheimer’s disease

Alzheimer s Research & Therapy, Journal Year: 2019, Volume and Issue: 11(1)

Published: Aug. 31, 2019

There is a high rate of failure in Alzheimer’s disease (AD) drug development with 99% trials showing no drug-placebo difference. This low success delays new treatments for patients and discourages investment AD development. Studies across programs multiple disorders have identified important strategies decreasing the risk increasing likelihood programs. These experiences provide guidance optimization The “rights” include right target, drug, biomarker, participant, trial. target identifies appropriate biologic process an therapeutic intervention. must well-understood pharmacokinetic pharmacodynamic features, ability to penetrate blood-brain barrier, efficacy demonstrated animals, maximum tolerated dose established phase I, acceptable toxicity. biomarkers participant selection biomarkers, engagement supportive modification, side effect monitoring. hinges on identification (preclinical, prodromal, dementia). Severity mechanism both role defining participant. trial well-conducted clinical biomarker outcomes collected over period time, powered detect clinically meaningful difference, anticipating variability introduced by globalization. We lack understanding some critical aspects biology action that may affect even when are adhered to. Attention disciplined will increase success, decrease risks associated development, enhance attract investment, make it more likely therapies become available those or vulnerable emergence AD.

Language: Английский

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Genetics of Alzheimer’s disease: where we are, and where we are going

Current Opinion in Neurobiology, Journal Year: 2019, Volume and Issue: 61, P. 40 - 48

Published: Dec. 18, 2019

Alzheimer's disease (AD) has a very strong genetic component, whose characterization become an essential part of efforts to understand the pathophysiological processes disease. Thanks systematic use high-throughput approaches over last 10 years, more than 40 genes/loci have been linked AD risk. Although some these signals are likely be false positives, this knowledge shed new light on pathogenesis and, in particular, major role microglia. However, our genetics is far from complete, and larger diverse studies required. Lastly, post-GWAS analyses will needed make sense information without focusing too much what we think know about

Language: Английский

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