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.

项目摘要/摘要 经硫代蛋白（TTR）淀粉样变性（ATT）是一种系统性淀粉样变性的一种形式，或者是由突变引起的 TTR基因导致聚集和变体TTR淀粉样变性（ATTRV； V是变体）或来自聚集 野生型TTR导致Attrwt淀粉样变性。 attrwt正在成为系统的最常见形式 淀粉样变性，主要是由于人口的老化。 attrwt心脏淀粉样变性（attrwt-Ca） 几乎完全影响> 60岁的人，诊断年龄的平均年龄为77岁。骨科 表现形式（腕管综合征（CTS）通常是双侧，二头肌肌腱破裂，关节置换[臀部， 膝盖，肩部]和腰椎狭窄（LSS）统称为80％的Attrwt-患者 大约受影响的人在诊断之前的5至15年经历了这些骨科表现 attr-ca。我们来自NIA R21赠款（AG058348）的初步数据表明，淀粉样蛋白沉积是常见的 腰椎狭窄的原因，大多数但并非所有淀粉样蛋白沉积物都是由于TTR引起的。存在 腰椎TTR淀粉样蛋白的未来可能会预示Attr-Ca。因此，我们建议进行 一项多中心的前瞻性队列研究，旨在促进对Attr-CA个体的识别。这 该研究的目的是：（1）确定具有TTR淀粉样蛋白证据的先前LSS手术的受试者 在其脊柱标本中的沉积物，可能有ATTR-CA的风险，（2）评估ATTR-CA 那些在其脊柱组织中局部TTR的人。要测试的假设是（1）至少30％ 样品将证明淀粉样蛋白，淀粉样蛋白的一半以上将是由于TTR所致 通过质谱和（2），超过20％的TTR淀粉样蛋白沉积患者的脊柱将 脊柱手术后5到15年，有闪光照相证据，而<5％ 脊柱组织中淀粉样蛋白的不确定类型。我们还将评估本筛查的成本效益 方法。探索性目的是评估可以识别的病理学的人工智能技术 淀粉样蛋白在组织学上，无刚果红染色。通过系统地评估LSS的老年人 先前已经接受了腰椎手术的腰椎手术彻底的淀粉样蛋白病理评估 获得的组织，如果存在淀粉样蛋白，则用质谱法进行组织，则有一个独特的 在疾病过程中，有机会识别患有ATTR-CA的老年人。早期识别 受影响的个体是关键 发生了严重的心脏功能障碍。计划研究中收集的数据可能会改变临床 实践。通过常规评估淀粉样蛋白的LS标本并确定前体蛋白，我们可以 促进早期识别患有Attr-CA的人，这种疾病是没有识别和治疗的疾病 是一种进步，高度病态和致命的。但是，旨在筛查和早期识别的计划 在受影响的个体中，我们可能能够对此类患者的结果产生积极影响。