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Skin biomarkers for diagnosing and characterizing AD and ADRD

用于诊断和表征 AD 和 ADRD 的皮肤生物标志物

基本信息

批准号：
10673714
负责人：
SHU G. CHEN
金额：
$ 75.78万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673714
关键词：
Age Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid beta-Protein Animal Model Animals Area Autopsy Biochemical Biological Assay Biological Markers Biopsy Biopsy Specimen Blinded Brain Brain Injuries Brain imaging Cadaver Cerebrospinal Fluid Clinical Clinical Trials Creutzfeldt-Jakob Syndrome Dementia Deposition Detection Development Diagnosis Diagnostic tests Differential Diagnosis Disease Disease Progression Early Diagnosis Exhibits Goals Histologic Human Hypersensitivity skin testing Immunoassay Individual Lewy Body Dementia Measures Mutation Neurodegenerative Disorders Outcome Study Parkinson Disease Pathologic Patients Peripheral Pick Disease of the Brain PrP PrPSc Proteins Prion Diseases Prions Progressive Supranuclear Palsy Protein Isoforms Radioactivity Recombinants Sampling Severity of illness Site Skin Skin Tissue Specimen Spinal Puncture Tauopathies Technology Testing Time Treatment Efficacy alpha synuclein brain tissue corticobasal degeneration diagnostic biomarker early detection biomarkers misfolded protein mouse model neurobehavioral neuropathology novel marker outcome prediction potential biomarker pre-clinical predict clinical outcome prion-like protein aggregation protein misfolding cyclic amplification sex tau Proteins tau aggregation therapeutic evaluation

项目摘要

ABSTRACT Alzheimer's disease (AD) and AD-related dementias (ADRD) such as Lewy body dementia (LBD) are all associated with deposition of misfolded protein aggregates in the brain including tau in AD and non-AD tauopathies, and α-synuclein (αSyn) in LBD. Currently, a definite diagnosis of these disorders relies on the histological and biochemical examination of the brain for the misfolded proteins. Development of reliable and sensitive assays for these misfolded proteins in easily accessible peripheral specimens is critical for early or differential diagnosis, determination of disease severity, and evaluation of therapeutic efficacy in clinical trials. Interestingly, brain tau and αSyn aggregates exhibit prion-like aggregation seeding activity, which can be specifically detected by two highly sensitive amplification assays including real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA). They have been proved to be highly sensitive for detection of misfolded proteins in the brain and/or cerebrospinal fluid in prion disease (PrD), AD, or PD (Atarashi et al., 2011; Peden et al., 2012; Foutz et al., 2017; Orrú et al., 2015; Saijo et al., 2017; Kraus et al., 2018). Using RT-QuIC/PMCA, we were able to detect prion and αSyn aggregates in the skin of individuals with PrD or PD (Orrú et al., 2017; Wang et al., 2019; 2020). Remarkably, our preliminary results have shown that prions-like tau- seeding activity is detectable by RT-QuIC and PMCA in skin of AD patients but not in normal controls. Thus, we hypothesize that skin tau-seeding activity detected by RT-QuIC and PMCA is a novel biomarker for diagnosing, characterizing, and predicting outcomes of AD and non-AD tauopathies and for differentiating AD from LBD. To test this hypothesis, the following four Aims will be pursued: (1) Establish the tau-seeding activity in autopsied skin samples as a biomarker for POSTMORTEM diagnosis and characterization of AD using RT-QuIC/PMCA assays; (2) Assess skin tau-seeding activity as a biomarker for PREMORTEM diagnosis, characterization, and predicting clinical outcomes of AD; (3) Determine skin tau-seeding activity as a biomarker for differentiating AD from non-AD tauopathies, and from LBD, a common ADRD; and (4) Determine whether skin tau-seeding activity is detectable at an asymptomatic stage by RT-QuIC/PMCA in animal models of AD tauopathies. We believe that the successful implementation of this project will develop RT-QuIC/PMCA assays of skin tau-seeding activity as a biomarker for diagnostic testing and evaluating clinical trials across AD, non-AD tauopathies, and LBD.

摘要