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

Study Overview
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Brief Summary
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Primary objective: To identify older adults with transthyretin cardiac amyloidosis (ATTR-CA) early in the course of the illness, at a time when disease modifying therapies are most effective. The specific aims of this epidemiologic investigation include: To identify subjects with previous lumbar spinal stenosis (LSS) Surgery who have evidence of transthyretin (TTR) amyloid deposits in spinal specimens and could be at risk for ATTR cardiac amyloidosis. To evaluate for ATTR-CA among those with localized TTR in the spinal tissue. The study will also explore the following: The prevalence of amyloid in lumbar spinal stenosis specimens by Congo Red staining. The prevalence of TTR deposits among subjects with amyloid as determined by mass spectrometry. Evaluation of a novel artificial intelligence technique for that can identify amyloid histologically with standard H&E staining. Difference in ATTR-CA prevalence between subjects with TTR and indeterminate amyloid deposits in subject's spine by myocardial uptake of technetium pyrophosphate scan (Tc99-PYP).

Detailed Description
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This is a multicenter, prospective cohort study aimed at facilitating identification of individuals with ATTR-CA. Investigators will identify subjects with previous LSS surgery who have evidence of TTR amyloid deposits in spinal specimens. Subjects with localized TTR in spinal tissue will be invited to an on-site visit and be evaluated for the presence of clinical manifestations of ATTR cardiac amyloidosis (ATTR-CA). Subjects will undergo nuclear scintigraphy, TTR genetic test, a clinical evaluation, electrocardiogram, and echocardiogram. Quality of life questionnaires will also be administered. Subjects who have myocardial retention of the imaging radiotracer with a Perugini score equal to 2 (uptake equal to bone) or 3 (uptake greater than bone) and confirmation by SPECT or SPECT/CT that the uptake is myocardial in nature and have no evidence of monoclonal proteins will be diagnosed with ATTR-CA. This study is to be conducted at five study sites: Boston Medical Center, Cedars Sinai Medical Center, Cleveland Clinic, Columbia University Irving Medical Center, and Tufts University Medical Center. The Mayo Clinic will serve a Pathology research core to analyze spine specimens. Most of the subjects are expected to complete all the study procedures and questionnaires on a single day. Up to 1663 patients will be consented in this study to have spinal specimens examined for the presence of amyloid by Congo Red at the Mayo Clinic core lab. From the pool of subjects with amyloid detected (which anticipate will be 33% or at least 544), the investigators expect to recruit 163 participants to undergo cardiac phenotyping (Tc99m and cardiac evaluation). Among the 163 participants who undergo cardiac phenotyping, 98 will have TTR as the precursor protein identified by mass spectrometry and 65 will have an indeterminant precursor protein by mass spectrometry.

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

Conditions
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Lumbar Spinal Stenosis, Cardiac Amyloidosis, ATTR Amyloidosis Wild Type, ATTR Gene Mutation, ATTRV122I Amyloidosis, Cardiomyopathy, Hypertrophic

Intervention / Treatment
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* Diagnostic Test: Tc99-PYP or Tc99-HDMP Scan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinically indicated lumbar spinal decompressive surgery that involved removal of the ligamentum flavum 5 to 15 years prior to enrollment. Age >60 years at the time of the surgery. Able to understand and sign the informed consent document after the nature of the study has been fully explained. Exclusion Criteria: Confirmed primary amyloidosis (AL) or secondary amyloidosis (AA). Known TTR amyloidosis. Lumbar surgery for indications other than spinal stenosis. Active malignancy. Impairment from stroke, injury or other medical disorder that precludes participation in the study. Disabling dementia or other mental or behavioral disease. Enrollment in a clinical trial not approved for co-enrollment. Weight >350 lbs. Inability or unwillingness to comply with the study requirements. Nursing home resident. Other reason that would make the subject inappropriate for entry into this study.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| ATTR Negative<br>Participants who have undergone previous lumbar spinal, and/or carpel tunnel surgery will provide medical record data and spinal specimen for analysis of presence of ATTR amyloid. | |
| ATTR Positive<br>Participants who have undergone previous lumbar spinal, and/or carpel tunnel surgery will provide medical record data, spinal specimen, prospective data from cardiac workup with confirmed ATTR amyloid in spinal specimen then undergo cardiac workup for cardiac phenotyping/genotyping. | Diagnostic Test: Tc99-PYP or Tc99-HDMP Scan<br>* Difference in ATTR-CA prevalence between subjects with TTR and indeterminate amyloid deposits in their spine by myocardial uptake of Tc99-PYP.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of subjects with previous LSS surgery who have evidence of TTR amyloid deposits in their spinal specimen and could be at risk for ATTR cardiac amyloidosis | To identify who can be at risk for ATTR Cardiac Amyloidosis. The investigator is going to collect spinal ligamentum flavum specimens and stain with congo red and those who result positive for ATTR amyloid in their spinal specimen will be counted | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of subjects with ATTR-CA among those with localized TTR in their spinal tissue | To evaluate number of subjects with ATTR-CA among those with localized TTR in their spinal tissue. The investigator is going to perform standard of care (SOC) cardiac amyloidosis work up including PYP scan to confirm cardiac phenotype | up to 6 years |