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

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