A Diagnostic Test for Dementia with Lewy Bodies

总结 本研究的目的是验证一个诊断测试区分两种类型的痴呆-痴呆 路易体（DLB）和阿尔茨海默病（AD）。DLB是第二种最常见的痴呆症， AD影响美国超过140万人，是一种侵袭性神经退行性疾病， 治疗一种错误折叠的磷酸化蛋白，α-突触核蛋白（P-SYN），在中枢神经系统内进行性沉积， 和周围神经系统导致神经变性，是这种疾病的病理表现。 在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%的患者被误诊，因为认知能力下降，其突出的临床表现之一， 症状，也是进展较慢的AD的标志。DLB和AD之间的诊断混淆，特别是 在疾病的早期，导致1）错误的症状患者护理，这可能加速认知能力下降， 2)无效的预后建议和3）在DLB和AD临床试验中招募错误诊断的患者， 减缓了治疗方法的发展。现有的临床共识标准以及成像方法， 不足以对痴呆症做出精确的诊断。这些诊断挑战转化为一个ur- 满足了对准确、可靠和可获得的测试以区分DLB与AD的未满足的医疗需求。CND Life Sciences通过其核心技术Syn-One TestTM来满足这一需求。该技术 基于最近的发现，P-SYN沉积可以在DLB患者的皮肤中准确测量， >97%的灵敏度和特异性。与疾病生物标志物的检测不同，Syn-One TestTM测量的是 基于P-SYN沉积量的皮肤自主神经纤维内的实际病理学 皮肤神经纤维变性程度。重要的是，Syn-One TestTM是微创的， 形成3毫米打孔皮肤活检，可以在任何医生的办公室，没有专门的设备。 CND Life Sciences的可行性研究表明，在确诊的P-SYN患者中，100%检测到P-SYN。 DLB（n=21），18例AD患者中无1例，3种不同类型的皮神经密度 DLB和AD之间的纤维不同。在拟议的研究中，Syn-One TestTM在区分 通过检测早期DLB和AD患者中P-SYN沉积，将DLB从AD中消除的方法优化 2年内的诊断（目标1），确保病理结果得到临床疾病的证实 诊断。此外，将通过测量P-SYN的年发生率来定义神经元变性的度量。 DLB和AD患者的皮肤沉积和皮肤神经纤维变性（目的2）。这项研究的结果将 对临床医生为痴呆症患者制定适当护理策略的能力产生直接影响。 定义皮肤α-突触核蛋白沉积和疾病本身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。

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.