Senile Systemic Amyloidosis

A major focus of research in the Gerry Laboratory is the study of senile systemic amyloidosis (SSA), an age-related type of amyloid disease caused by deposition of the plasma protein, transthyretin (TTR).  Unlike familial TTR-associated forms of amyloid (ATTR) which SSA groupfeature TTR gene mutations and amyloid-forming TTR mutant proteins, SSA is a late onset disease that is acquired, not inherited; mutations in the TTR gene are not a cause of SSA. 

While in SSA the amyloid deposits accumulate in extracellular compartments of tissues and organs throughout the body, the heart is usually the dominant site of involvement.  The presence of amyloid in the heart disrupts normal cellular processes and tissue functioning.  SSA, frequently diagnosed as a restrictive cardiomyopathy, is most commonly reported in men over the age of 60 years and symptoms include congestive heart failure, arrhythmias, and conduction defects. 

A definitive diagnosis of SSA relies on histologic analysis of a biopsy sample from the affected site, i.e. myocardium ideally, but subcutaneous fat or rectal samples are also used. Currently, the etiology of cardiac amyloidosis in SSA remains undefined, the diagnosis of SSA is problematic (there are no biomarkers and disease identification requires the exclusion of all other types of systemic amyloidosis), no accurate measure of disease progression in cardiac amyloidosis is available, and there are no treatment options for patients with SSA. Our research on SSA is aimed at offering contributions and improvements in each of these areas.

With partial support through grant funding from the National Institute on Aging at the National Institutes of Health (1R01 AG031804-01A2), we are conducting a cross-sectional and longitudinal (5-year) study of patients with SSA evaluated at our center.

Patients with SSA are invited to participate in this study.

The goals of this study are to: 

  1. Detail the biochemical nature of circulating and deposited forms of TTR in patients with SSA,
  2. Accurately characterize the clinical features of SSA in a large clinical population,
  3. Correlate disease progression to serum markers uniquely present in SSA samples. 

Our research is also aimed at defining factors that promote the instability or amyloid-forming potential of TTR, i.e. initiators of SSA disease onset.  At the same time, we are focused on identifying factors that stabilize TTR as these would inhibit aggregation, thereby protecting against disease onset.  Results from these latter investigations should provide a platform for designing therapeutic agents.

Important Contributions to SSA Research:
  • We have precisely detailed the primary structures of TTR purified from the serum and cardiac amyloid deposits of patients diagnosed with SSA.  Our results demonstrated that TTR circulating in blood was quite different from the fibrillar, deposited forms of TTR in the SSA samples.
  • We have found that high molecular weight forms of TTR are present in blood samples from patients with SSA.  In addition, we have gathered data suggesting that there are differences between SSA and age-matched control samples with respect to several molecular chaperones, clusterin (in serum) and αB-crystallin (in tissue).  Preliminary studies provide evidence that serum levels of TTR and clusterin in patients with SSA may be lower than normal levels.
  • Further studies in this area have indicated that clusterin may be important in the pathobiology of SSA.  Specifically, we have reported that clusterin is abundantly present in cardiac tissue with amyloid deposits from patients with SSA, and more precisely, that the clusterin appears to be associated with TTR in the fibrils.