A Diagnostic Test for Dementia with Lewy Bodies

路易体痴呆症的诊断测试

基本信息

批准号：
10382153
负责人：
Todd Levine
金额：
$ 123.98万
依托单位：
CND LIFE SCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382153
关键词：
Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease patient Biological Markers Biological Sciences Biopsy Brain CLIA certified Caring Clinical Clinical Trials Clinical Trials Design Confusion Consensus Cost of Illness Cutaneous Data Databases Dementia Dementia with Lewy Bodies Deposition Detection Development Diagnosis Diagnostic Diagnostic tests Disease Disease Management Disease Progression Dopamine Antagonists Early Diagnosis Enrollment Ensure Equipment FYN gene Feasibility Studies Heterogeneity Impaired cognition Individual Laboratories Legal patent Lewy Body Disease Life Expectancy Measures Medical Methodology Modality Nerve Degeneration Nerve Fibers Neurodegenerative Disorders Neurology Neurons Neuropathy Outcome Participant Pathologic Pathology Patient Care Patients Peripheral Peripheral Nervous System Persons Physicians&apos Offices Positioning Attribute Proteins Public Health Punch Biopsy Research Personnel Sensitivity and Specificity Severities Severity of illness Skin Specificity Surrogate Endpoint Symptoms Technology Testing Translating United States Visual accurate diagnostics alpha synuclein autonomic nerve base circulating biomarkers density diagnostic technologies diagnostic tool disease diagnosis effective therapy efficacious treatment imaging approach mild cognitive impairment minimally invasive misfolded protein new technology novel novel therapeutics phase 2 study pre-clinical prevent prognostic synucleinopathy therapy development

项目摘要

SUMMARY The objective of this study is to validate a diagnostic test for distinguishing two types of dementias—dementia with Lewy Bodies (DLB) and Alzheimer’s disease (AD). DLB is the second most common type of dementias after AD, affecting over 1.4 million people in the U.S. and is an aggressive neurodegenerative disease with no effective therapies. Progressive deposition of a misfolded phosphorylated protein, α-synuclein (P-SYN), within the central and peripheral nervous systems leads to neurodegeneration and is a pathological manifestation of this disease. Among 4 “synucleinopathies”—diseases characterized by the abnormal deposition of P-SYN in neurons—DLB is a dementia that is misdiagnosed in over 25% of patients because cognitive decline, one of its prominent clinical symptoms, is also a hallmark of a slower progressing AD. Diagnostic confusion between DLB and AD, particu- larly early in the disease, leads to 1) mistaken symptomatic patient care, which can accelerate cognitive decline, 2) invalid prognostic advice and 3) enrollment of incorrectly diagnosed patients in DLB and AD clinical trials, slowing down the development of treatments. Existing clinical consensus criteria, as well as imaging approaches, are insufficient to formulate precise diagnoses for dementias. These diagnostic challenges translate into an ur- gent unmet medical need for an accurate, reliable and accessible test to distinguish DLB from AD. CND Life Sciences is addressing this need through its core enabling technology, the Syn-One TestTM. This technology is based on a recent discovery that P-SYN deposition can be accurately measured in the skin of DLB patients with >97% sensitivity and specificity. Unlike detection of disease biomarkers, the Syn-One TestTM measures the ac- tual pathology within the autonomic nerve fibers of the skin based on the amount of P-SYN deposition and the extent of cutaneous nerve fiber degeneration. Importantly, the Syn-One TestTM is minimally invasive and is per- formed in 3 mm punch skin biopsies that can be obtained in any physician’s office without specialized equipment. CND Life Sciences’ feasibility studies demonstrated that P-SYN is detected in 100% of patients with confirmed DLB (n=21), and in none of the 18 AD patients, and that the densities of 3 distinct types of cutaneous nerve fibers are different between DLB and AD. In the proposed study, the precision of the Syn-One TestTM in distin- guishing DLB from AD will be optimized through measuring P-SYN deposition in patients with early DLB and AD diagnoses over a 2-year period (Aim 1), ensuring that pathological findings are confirmed by clinical disease diagnoses. Further, the metrics of neuronal degeneration will be defined by measuring the yearly rates of P-SYN deposition and cutaneous nerve fiber degeneration in DLB and AD patients (Aim 2). The results of this study will have an immediate impact on the clinician’s ability to develop appropriate care strategies for dementia patients. Defining the quantitative metrics of the relationship between cutaneous α-synuclein deposition and disease se- verity and progression will aid in the design of clinical trials and accelerate the development of effective therapies.

概括本研究的目的是验证区分两种类型痴呆症的诊断测试——痴呆症路易体 (DLB) 和阿尔茨海默病 (AD) 是仅次于痴呆症的第二常见类型。 AD 在美国影响着超过 140 万人，是一种侵袭性神经退行性疾病，目前尚无有效治疗方法错误折叠的磷酸化蛋白α-突触核蛋白（P-SYN）在中枢内逐渐沉积。而周围神经系统导致神经退行性变，是本病的病理表现。 4 种“突触核蛋白病”——以 P-SYN 在神经元中异常沉积为特征的疾病——DLB 是一种痴呆症，超过 25% 的患者因认知能力下降而被误诊，认知能力下降是其突出的临床症状之一症状，也是 AD 进展缓慢的一个标志，尤其是 DLB 和 AD 之间的诊断混淆。尤其是在疾病早期，会导致 1) 错误的对症患者护理，这会加速认知能力下降， 2) 无效的预后建议和 3) 将错误诊断的患者纳入 DLB 和 AD 临床试验，减缓现有临床共识标准以及影像学方法的发展，这些诊断挑战不足以对痴呆症做出精确的诊断。医学界对准确、可靠且易于使用的测试来区分 DLB 和 CND Life 的需求尚未得到满足。 Science 正在通过其核心支持技术 Syn-One TestTM 来满足这一需求。基于最近的一项发现，可以准确测量 DLB 患者皮肤中的 P-SYN 沉积与疾病生物标志物检测不同，Syn-One TestTM 测量的灵敏度和特异性超过 97%。根据 P-SYN 沉积量和皮肤自主神经纤维内的实际病理学重要的是，Syn-One TestTM 是微创的，并且是永久性的。通过 3 毫米打孔皮肤活检形成，无需专门设备即可在任何医生办公室获得。 CND Life Sciences 的可行性研究表明，100% 的确诊患者中检测到 P-SYN DLB (n=21)，18 名 AD 患者中没有一人出现，并且 3 种不同类型的皮神经的密度 DLB 和 AD 之间的纤维是不同的。在所提出的研究中，Syn-One TestTM 的精度有所不同。通过测量早期 DLB 和 AD 患者的 P-SYN 沉积，可以优化从 AD 中引导 DLB 两年内的诊断（目标 1），确保病理结果得到临床疾病的证实此外，神经退化的指标将通过测量 P-SYN 的年发生率来定义。 DLB 和 AD 患者的沉积和皮肤神经纤维变性（目标 2）。对临床医生为痴呆患者制定适当护理策略的能力产生直接影响。定义皮肤 α-突触核蛋白沉积与疾病之间关系的定量指标真实性和进展将有助于临床试验的设计并加速有效疗法的开发。