Analysis of Lumbar Spine Stenosis Specimens for Identification of Transthyretin Cardiac Amyloidosis

腰椎管狭窄标本分析鉴定运甲状腺素蛋白心脏淀粉样变性

• 批准号: 10637491
• 负责人: MATHEW S MAURER
• 金额: $ 77.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10637491
• 关键词: Affect; Age; Age Years; Aging; Amyloid; Amyloidosis; Artificial Intelligence; Bilateral; Body mass index; Cardiac; Carpal Tunnel Syndrome; Clinical; Congo Red; Data; Denmark; Deposition; Development; Diagnosis; Diphosphates; Disease; Early Diagnosis; Early identification; Elderly; Evaluation; Future; Genes; Grant; Hip region structure; Histocompatibility Testing; Histologic; Individual; Institution; Knee; Mass Spectrum Analysis; Morbidity - disease rate; Mutation; Myocardial dysfunction; Nuclear; Operative Surgical Procedures; Orthopedics; Outcome; Pathologic; Pathology; Patients; Population; Prealbumin; Prevalence; Prospective, cohort study; Protein Precursors; Radionuclide Imaging; Replacement Arthroplasty; Research Personnel; Risk; Sampling; Shoulder; Specimen; Spinal; Spinal Stenosis; Spine surgery; Stains; Techniques; Testing; Time; Tissues; United States; Variant; Vertebral column; age related; biceps brachii muscle; bone; cardiac amyloidosis; clinical practice; cohort; cost effective; cost-effectiveness evaluation; effective therapy; experience; improved outcome; ligamentum flavum; male; mortality; novel; nuclear imaging; programs; rare condition; screening; screening program; tendon rupture

Project Summary/Abstract Transthyretin (TTR) amyloidosis (ATTR) is a form of systemic amyloidosis either caused by mutations in the TTR gene leading to aggregation and variant TTR amyloidosis (ATTRv; v is for variant) or from aggregation of wild type TTR leading to ATTRwt amyloidosis. ATTRwt is becoming the most common form of systemic amyloidosis, principally because of the aging of the population. ATTRwt cardiac amyloidosis (ATTRwt-CA) almost exclusively affects individuals who >60 years and the average age at diagnosis is 77 years. Orthopedic manifestations (carpal tunnel syndrome (CTS) often bilaterally, biceps tendon rupture, joint replacements [hip, knee, and shoulder] and lumbar spinal stenosis (LSS)) are collectively found in >80% of patients with ATTRwt- CA. Affected individuals experience these orthopedic manifestations on 5 to 15 years prior to the diagnosis of ATTR-CA. Our preliminary data from a NIA R21 grant (AG058348) shows that amyloid deposits are a common cause of lumbar spinal stenosis and that a majority but not all amyloid deposits are due to TTR. The presence of TTR amyloid in the lumbar spine could portend ATTR-CA in the future. Accordingly, we propose to conduct a multi-center, prospective cohort study aimed at facilitating identification of individuals with ATTR-CA. The aims of the study are: (1) To identify subjects with previous LSS Surgery who have evidence of TTR amyloid deposits in their spinal specimens and could be at risk for ATTR-CA, and (2) To evaluate for ATTR-CA among those with localized TTR in their spinal tissue. The hypotheses to be tested are (1) that at least 30% of spinal samples will demonstrate amyloid and more than half of those with amyloid will be due to TTR as determined by mass spectrometry and (2) that more than 20% of patients with TTR amyloid deposits in their spine will have scintigraphy evidence of ATTR-CA, 5 to 15 years after spinal surgery as compared to <5% with indeterminant type of amyloid in spinal tissue. We will also evaluate the cost effectiveness of this screening approach. An exploratory aim is to evaluate an artificial intelligence technique for pathologic that can identify amyloid histologically without Congo Red staining. By systematically evaluating older adults with LSS who have previously undergone lumbar spine surgery thorough pathological evaluation for amyloid in surgically obtained tissue, and if amyloid is present, performing tissue typing with mass spectrometry, there's a unique opportunity to identify older adults with ATTR-CA early in the course of the illness. Early identification of affected individuals is key because disease modifying therapies are significantly more effective before significant cardiac dysfunction has occurred. The data collected in the planned studies could change clinical practice. By routinely evaluating LS specimens for amyloid and determining the precursor protein, we could facilitate early identification of those who develop ATTR-CA, a disorder that without recognition and treatment is a progressive, highly morbid, and fatal. However, with programs aimed at screening and early identification of affected individuals, we may be able to dramatically affect positively the outcomes of such patients.

项目概要/摘要 运甲状腺素蛋白 (TTR) 淀粉样变性 (ATTR) 是一种系统性淀粉样变性，由甲状腺素突变引起 TTR 基因导致聚集和变异 TTR 淀粉样变性（ATTRv；v 代表变异）或来自以下物质的聚集： 野生型 TTR 导致 ATTRwt 淀粉样变性。 ATTRwt 正在成为最常见的系统性形式 淀粉样变性，主要是由于人口老龄化。 ATTRwt 心脏淀粉样变性 (ATTRwt-CA) 几乎只影响 60 岁以上的人群，诊断时的平均年龄为 77 岁。骨科 表现（腕管综合症（CTS），通常是双侧的，二头肌腱断裂，关节置换[髋关节， 膝关节、肩关节和腰椎管狭窄 (LSS)）共同出现在 >80% 的 ATTRwt 患者中 加利福尼亚州。受影响的个体在诊断之前 5 至 15 年就会经历这些骨科表现 ATTR-CA。我们来自 NIA R21 资助 (AG058348) 的初步数据表明淀粉样蛋白沉积物是一种常见的 腰椎管狭窄的原因，大多数但不是全部淀粉样蛋白沉积是由 TTR 引起的。存在感 腰椎中 TTR 淀粉样蛋白的存在可能预示着未来的 ATTR-CA。因此，我们建议进行 一项多中心、前瞻性队列研究，旨在促进 ATTR-CA 患者的识别。这 该研究的目的是：(1) 确定既往接受过 LSS 手术且有 TTR 淀粉样蛋白证据的受试者 沉积在他们的脊柱标本中，并且可能有 ATTR-CA 的风险，并且 (2) 评估其中的 ATTR-CA 脊髓组织中存在局部 TTR 的患者。要检验的假设是 (1) 至少 30% 的脊柱 样本将显示出淀粉样蛋白，并且超过一半的淀粉样蛋白是由于 TTR 确定的 通过质谱分析以及 (2) 超过 20% 的脊柱中存在 TTR 淀粉样蛋白沉积物的患者将 脊柱手术后 5 至 15 年有 ATTR-CA 的闪烁扫描证据，而脊柱手术后的 <5% 脊髓组织中淀粉样蛋白的不确定类型。我们还将评估此次筛查的成本效益 方法。一个探索性的目标是评估一种可以识别病理的人工智能技术 淀粉样蛋白组织学无需刚果红染色。通过系统地评估患有 LSS 的老年人 之前接受过腰椎手术，对手术中的淀粉样蛋白进行彻底的病理评估 获得的组织，如果存在淀粉样蛋白，用质谱法进行组织分型，有一个独特的方法 有机会在病程早期识别患有 ATTR-CA 的老年人。及早识别 受影响的个体是关键，因为疾病修饰疗法在之前明显更有效 已发生明显的心功能障碍。计划研究中收集的数据可能会改变临床 实践。通过常规评估 LS 样本中的淀粉样蛋白并确定前体蛋白，我们可以 促进早期识别 ATTR-CA 患者，这是一种未经识别和治疗的疾病 是一种进行性、高度病态且致命的疾病。然而，通过旨在筛查和早期识别的计划 对于受影响的个体，我们也许能够对这些患者的治疗结果产生显着的积极影响。