Nutritional and Metabolic Diseases

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Amyloidosis

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Immunoglobulin Light-chain Amyloidosis

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AL Amyloidosis

Familial Transthyretin Amyloidosis

Biopsy of ligamentum flavum tissue during spinal stenosis surgery sent to pathology for amyloid-specific analysis

During clinically-scheduled spinal stenosis surgery, ligamentum flavum tissue (which may contain surrounding tissue and subcutaneous fat) that is removed during the procedure will be sent to pathology to be analyzed with amyloid-specific staining.

Biopsy

Mazen A Hanna, MD

The investigators will prospectively evaluate for the presence of amyloid deposits in ligamentum flavum (yellow ligament) tissue samples obtained from patients undergoing spinal stenosis surgery. Patients who have tissue that stains positive for amyloid will be referred to an amyloidosis specialist.

Similar to carpal tunnel syndrome, spinal stenosis is associated with systemic amyloidosis and presents earlier than cardiac amyloidosis symptoms - 21-45% of ATTR patients and case reports in AL patients. The investigators' recent study found that 10% of older patients undergoing carpal tunnel release surgery were positive for amyloidosis, with 20% of that group presenting with cardiac involvement. 70% of the amyloid-positive group had a history of spinal stenosis and 40% required surgical intervention. Surgical intervention for spinal stenosis could provide an opportunity to screen for amyloidosis through yellow ligament (ligamentum flavum) biopsy.

This study will look at the prevalence of amyloidosis in patients undergoing surgical intervention for non-congenital spinal stenosis and spondyloarthropathy. The investigators hypothesize that 10% of such patients will be positive for amyloidosis.

Ligamentum flavum tissue (may contain surrounding tissue and subcutaneous fat)

Screening for Systemic Amyloidosis Via the Ligamentum Flavum

Incidence of amyloid deposits in removed ligamentum flavum tissue of older patients undergoing spinal stenosis surgery

The Cleveland Clinic

Principle Investigator

Heart and Blood Diseases

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

Cardiomyopathies

Disease Progression

Amyloid Neuropathies, Familial

Amyloid Neuropathies

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Amyloid Neuropathy

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Doxycycline

Curcumin

Ursodeoxycholic Acid

Ursodoxicoltaurine

Diflunisal

1.) To evaluate the relative amount of misfolded ATTR oligomers in asymptomatic ATTR amyloid genetic carriers and correlate their levels with clinical symptoms and outcomes.

1. Determine if misfolded ATTR oligomers are elevated compared to healthy control data obtained by Scripps during probe development
2. Describe the levels longitudinally
3. Determine if treatment with ATTR-specific medications (examples: diflunisal, doxycycline, ursodiol, tauroursodeoxycholic acid (TUDCA), green tea extract, curcumin, tafamidis, inotersen, patisiran) lead to reduction in the probe levels in those with elevated levels at baseline

This study measures circulating, misfolded ATTR oligomers in asymptomatic ATTRm amyloidosis genetic carriers longitudinally over five years.

Recent advances in genetic testing have allowed for pathogenic mutation identification in family members of affected individuals prior to onset of symptoms. While the presence of mutation and the corresponding TTR kinetic stability have been directly linked to disease development, the molecular drivers of tissue specific degeneration have not been defined. We hypothesize that soluble misfolded TTR oligomer species may be circulating within the blood of these patients possibly years prior to amyloid deposition and could serve as an early biomarker and/or driver for disease development. In this line, The Scripps Research Institute has developed a peptide-based probe that specifically labels and integrates into misfolded TTR oligomers allowing the relative circulating concentration in the bloodstream to be determined. Longitudinal monitoring of untreated, asymptomatic TTR amyloid genetic carriers utilizing the Scripps probe is likely to provide novel insight into early disease progression. We also plan to utilize the Scripps probe to monitor disease progression in TTR amyloid genetic carriers currently undergoing treatment by observing how treatments affect the circulating misfolded TTR oligomers. Through enhanced understanding of early disease progression and treatment efficacy, our hope is to limit amyloid accumulation in cardiac and nerve tissue and delay the development of the invariably fatal TTR amyloid cardiomyopathy/neuropathy.

Monitoring of Early Disease Progression in Hereditary Transthyretin Amyloidosis

Change (%) for oligomer level at the time of TTR amyloid symptoms compared to baseline

Change (%) for oligomer level at the time of ATTR specific medication changes compared to baseline

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Screening for Systemic Amyloidosis Via the Ligamentum Flavum	NCT03923920	Amyloid Amyloidosis Spinal Stenosis Transthyretin A... Primary Amyloid...	Biopsy	50 Years -	The Cleveland Clinic
Monitoring of Early Disease Progression in Hereditary Transthyretin Amyloidosis	NCT03431896	Amyloidosis Amyloid Amyloid Neuropa... Amyloid Cardiom... Amyloid - Prima... Transthyretin A... AL Amyloidosis		-	The Cleveland Clinic

Spots Global Cancer Trial Database for transthyretin amyloidosis