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.

项目总结/摘要 甲状腺素运载蛋白（TTR）淀粉样变性（ATTR）是一种系统性淀粉样变性，由甲状腺素受体（TTR）基因突变引起。 TTR基因导致聚集和变体TTR淀粉样变性（ATTRv; v是变体）或来自 野生型TTR导致ATTRwt淀粉样变性。ATTRwt正在成为最常见的系统性 淀粉样变性，主要是因为人口老龄化。ATTRwt心脏淀粉样变性（ATTRwt-CA） 几乎只影响60岁以上的人，诊断时的平均年龄为77岁。骨科 表现（腕管综合征（CTS）通常是双侧的，二头肌肌腱断裂，关节置换[髋， 膝关节和肩关节]和腰椎管狭窄症（LSS））共同发现于>80%的ATTR患者。 约受影响的人在诊断前5至15年经历这些骨科表现， ATTR-CA。我们来自NIA R21基金（AG 058348）的初步数据显示，淀粉样蛋白沉积是一种常见的 这是腰椎管狭窄症的原因，大多数但不是所有的淀粉样蛋白沉积是由于TTR。存在 TTR淀粉样蛋白在腰椎中的表达可能预示着ATTR-CA的未来。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。的 本研究的目的是：（1）识别有TTR淀粉样蛋白证据的既往LSS手术受试者 沉积在他们的脊柱标本，并可能在ATTR-CA的风险，和（2）评估ATTR-CA之间 脊髓组织中有局部TTR的患者。待检验的假设是（1）至少30%的脊柱 样本将显示淀粉样蛋白，超过一半的淀粉样蛋白将是由于TTR确定 （2）超过20%的脊柱中TTR淀粉样蛋白沉积的患者， 在脊柱手术后5 - 15年，有ATTR-CA的血管造影证据，相比之下， 脊髓组织中不确定类型淀粉样蛋白。我们亦会评估这项检查的成本效益 approach.一个探索性的目的是评估人工智能技术的病理，可以识别 淀粉样蛋白组织学无刚果红染色。通过系统评估患有LSS的老年人， 既往接受过腰椎手术，对手术中的淀粉样蛋白进行了彻底的病理学评估 获得组织，如果淀粉样蛋白存在，用质谱法进行组织分型， 有机会在疾病早期识别患有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 发生了严重的心脏功能障碍。在计划的研究中收集的数据可能会改变临床 实践通过常规评估LS标本的淀粉样蛋白和确定前体蛋白，我们可以 促进早期识别那些谁开发ATTR-CA，一种疾病，没有识别和治疗， 是一种渐进的高度病态的致命疾病然而，随着旨在筛查和早期识别的计划的实施， 我们也许能够极大地积极影响这些患者的结果。