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Peripheral Biomarkers for Early Diagnosis of Mixed Pathologies in AD/ADRD

用于 AD/ADRD 混合病理早期诊断的外周生物标志物

基本信息

批准号：
10669877
负责人：
SHU G. CHEN
金额：
$ 75.6万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669877
关键词：
Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid beta-Protein Autopsy Biological Assay Biological Markers Biopsy Biopsy Specimen Brain Brain imaging Cadaver Clinic Clinical Collection Consensus Dementia Dementia with Lewy Bodies Deposition Detection Development Diagnosis Diagnostic tests Differential Diagnosis Disease Disease Progression Early Diagnosis Emerging Technologies Goals Immunoassay Lewy Body Dementia Measures Memory Outcome Outcome Study Parkinson Disease Parkinson&apos s Dementia Participant Pathologic Pathology Patient Care Patients Peripheral Persons Positioning Attribute Probability Progressive Supranuclear Palsy Registries Research Resources Sampling Severity of illness Skin Specimen Symptoms Tauopathies Testing Time Validation Visit accurate diagnosis alpha synuclein biobank brain tissue clinical diagnosis clinical practice comorbidity corticobasal degeneration corticobasal syndrome diagnostic assay diagnostic biomarker diagnostic tool early detection biomarkers follow-up illness length improved neuropathology new technology novel marker prion-like prospective protein aggregation recruit sex success synucleinopathy tau Proteins tau aggregation tau-1 therapeutic development

项目摘要

The overall goal of our proposed research is to develop robust premortem biomarkers for accurate and differential diagnosis of Alzheimer's disease (AD), non-AD tauopathies, Lewy body dementia (LBD), and their comorbidities. A pathological hallmark of AD and other tauopathies is the deposition of tau protein aggregates in the brain, whereas in LBD there is accumulation of α-synuclein (aSyn) aggregates. Strikingly, more than half of patients with clinically diagnosed AD or LBD have concomitant tau and aSyn co-pathologies at autopsy. Moreover, patients with mixed tau and aSyn pathologies often suffer from worse clinical outcomes. Currently, it is highly challenging to clinically differentiate AD, LBD, and mixed AD/LBD due to overlapping symptoms. Moreover, co-existence of aSyn pathology also occurs frequently in non-AD tauopathies. Recent advances in brain imaging and immunoassays of amyloid-β and phosphorylated tau (p-tau) have greatly facilitated diagnosis of typical AD. However, these assays fail to identify non-AD tauopathies and mixed AD/LBD. Therefore, alternative measures in easily accessible biospecimens are warranted, especially if they enable simultaneous detection of tau and aSyn aggregates in patients with mixed tauopathies and synucleinopathies. In preliminary studies, we have leveraged the newly emerged technology known as the real-time quaking-induced conversion assay (tau RT-QuIC) for specific detection of tau aggregates in the skin of patients with AD and non-AD tauopathies. In conjunction with recently established aSyn RT-QuIC, we are in a unique position to accurately diagnose patients with mixed tau and aSyn pathologies using easily accessible skin specimens. We hypothesize that skin tau and aSyn detected by RT-QuIC are novel biomarkers for early and differential diagnosis of mixed tauopathies/synucleinopathies in routine clinical practice. We propose to test this hypothesis by pursuing three Aims: 1) Establish dual skin RT-QuIC biomarker assays for mixed tauopathies/synucleinopathies using neuropathologically confirmed cases; 2) Assess skin tau and aSyn detected by RT-QuIC as reliable biomarkers for premortem diagnosis of mixed tauopathies and synucleinopathies; and 3) Evaluate skin tau/aSyn biomarker assays for improving the differential diagnosis of mixed tauopathies/synucleinopathies through longitudinal follow-up. This translational project is supported by rich clinical resources and a strong team of basic and clinical neuroscientists. The successful outcome of our proposal will establish a robust skin-based diagnostic test for mixed pathologies that is prevalent in AD and related dementias, thus facilitating better patient care and development of disease-modifying therapies.

我们提出的研究的总体目标是开发强大的死前生物标志物，用于准确和