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

项目摘要/摘要 转甲状腺素(TTR)淀粉样变性(ATTR)是一种系统性淀粉样变性，由基因突变引起 导致聚集和变异型TTR淀粉样变性(ATTRv；v代表变异型)的Ttr基因或来自 导致ATTRUT淀粉样变性的野生型TTR。ATTRUPT正在成为系统性疾病最常见的形式 淀粉样变性，主要是由于人口老龄化。心脏淀粉样变性(ATTRUT-CA) 几乎只影响60岁的患者，确诊时的平均年龄为77岁。骨科 临床表现(腕管综合征(CTS)通常为双侧腕管综合征，二头肌腱断裂，关节置换[髋关节， 膝、肩)和腰椎管狭窄症(LSS)共同存在于80%的ATT；患者中。 加州。受影响的患者在确诊前5至15年出现这些骨科表现 属性-CA。我们从NIA R21基金(AG058348)获得的初步数据显示，淀粉样沉积是一种常见的 大多数(但不是全部)淀粉样物沉积是由于腰椎管狭窄症引起的。他的存在 腰椎TTR淀粉样蛋白的表达可能预示着未来的ATTR-CA。因此，我们建议进行 这是一项多中心的前瞻性队列研究，旨在促进识别患有ATTR-CA的个体。这个 这项研究的目的是：(1)确定那些曾经接受过LSS手术的受试者是否有TTR淀粉样变的证据 在他们的脊柱标本中沉积，并可能面临ATTR-CA的风险，以及(2)评估以下人群中的ATTR-CA 脊椎组织中有局限性TTR者。需要检验的假设是：(1)至少30%的脊椎 样本将显示淀粉样蛋白，超过一半的淀粉样蛋白样蛋白将归因于已确定的TTR 通过质谱仪和(2)超过20%的脊柱中有TTR淀粉样沉积的患者将 脊柱手术后5至15年内有ATTR-CA的核素扫描证据，相比之下，有5%的患者 脊椎组织中不确定类型的淀粉样蛋白。我们还将评估这项筛查的成本效益 接近。一个探索性的目标是评估一种用于病理检查的人工智能技术，该技术可以识别 组织学未见刚果红染色的淀粉样蛋白。通过系统地评估患有LSS的老年人 曾接受过腰椎手术，并在手术中对淀粉样蛋白进行了病理评估 获得的组织，如果淀粉样蛋白存在，用质谱仪进行组织分型，有唯一的 在疾病病程早期识别患有ATTR-CA的老年人的机会。及早识别 受影响的个体是关键，因为在此之前，疾病修正疗法明显更有效 已经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 练习一下。通过常规评估LS样本的淀粉样蛋白和测定前体蛋白，我们可以 促进早期识别那些罹患ATTR-CA的人，这是一种没有得到识别和治疗的疾病 是一种进步的，高度病态的，致命的。然而，随着旨在筛查和早期识别的计划 对于受影响的个体，我们可能能够显著地影响这类患者的结局。

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.