Cadaveric pituitary-derived growth hormone delivery influences iatrogenic Alzheimer’s Disease

A recent Nature Medicine study showed that recipients of cadaver-derived pituitary growth hormone (c-hGH) developed biomarker changes in the realm of Alzheimer’s disease (AD). This study indicates the association between c-hGH and AD.

Study: Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone. Image Credit: Gorodenkoff/Shutterstock.comStudy: Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone. Image Credit: Gorodenkoff/Shutterstock.com

Background

Prions are pathogenic agents that induce abnormal folding in prion protein (PrPC) that are abundantly present in the brain. In mammals, prions cause neurodegenerative diseases.

Diverse strains of prions have been identified to exhibit variance in fibril structure. Each structural variation accounts for specific clinicopathological disease phenotypes.

Creutzfeldt–Jakob disease (CJD) is a sporadic condition caused by infectious prions. Besides CJD, all other prion diseases are caused by mutations in the autosomal prion protein gene (PRNP).

The prevalence of acquired or iatrogenic CJD is rare; it may occur due to accidental inoculation during a surgical procedure. Around 200 cases of iatrogenic CJD have been recorded globally that happened as a consequence of c-hGH treatment during childhood.

Previous studies have shown that the use of contaminated gonadotrophin, human cadaveric pituitary-derived growth hormone, and corneal grafting using contaminated neurosurgical instruments can lead to the development of CJD.

In the 1990s, the emergence of a novel CJD variant was documented, which manifested due to dietary exposure to bovine spongiform encephalopathy (BSE).

Human neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, are associated with the accumulation of misfolded host proteins in a ‘prion-like’ fashion.

Previous studies have shown that the transmission of amyloid-beta (Aβ) pathology occurs through iatrogenic routes. A prolonged incubation has been linked to the development of iatrogenic cerebral amyloid angiopathy (CAA), which indicates the risk of developing iatrogenic Alzheimer’s disease after a longer period of latency.

Previous studies have demonstrated that iatrogenic Aβ transmission occurs in patients who received c-hGH treatment. No clinical documents are available that show iatrogenic disease occurs due to Aβ transmission in c-hGH recipients.

About the study

Brain biopsy and postmortem brain tissue samples were collected following standard neurosurgical protocols. The study cohort included individuals with all forms of prion diseases, such as sporadic, inherited, iatrogenic, or variant forms.

It also included individuals who were at a higher risk of developing CJD and those who were treated with c-hGH. Next-generation sequencing (NGS) was performed in all test samples to evaluate the genetic aspect of CJD manifestations, particularly in those who received c-hGH treatment.

Study findings

The majority of studies have revealed that AD is primarily a sporadic condition that occurs in late adult life. However, some studies have indicated its genetic nature by showing that  APP, PSEN1, and PSEN2 gene mutations are linked with AD manifestations.

Taken together, the results suggest that AD is associated with a triad of etiologies, namely, sporadic, inherited, and rare acquired forms, that are related to conventional prion diseases.

Participants who developed symptoms underwent repeated exposure to contaminated c-hGH, over many years. However, the treatment was discontinued many years ago.

The transmissible nature of AD disease in certain circumstances has been documented. Experimental findings indicated the iatrogenic forms of Alzheimer’s disease phenotypically differ from sporadic and inherited forms. 

Previous studies have demonstrated the association between the transmission of Aβ pathology and the manifestation of iatrogenic cerebral amyloid angiopathy (CAA).

Participants with a history of iatrogenic CAA had died due to iatrogenic CJD, and these patients were exposed to c-hGH contaminated with Aβ seeds/tau and CJD prions.

In comparison to CJD manifestations, a higher number of people were found to develop AD. Based on this observation, it could be presumed that Aβ seeds more frequently contaminate c-hGH lots, developed from large pools of cadaveric pituitary glands than CJD prions.

Furthermore, individuals who were exposed to c-hGH and did not develop CJD were at a higher risk of progressing to develop all the pathological features of AD at a longer incubation period than those of iatrogenic CAA developments.

Conclusions

The current study showed that AD has triad etiologies, i.e., iatrogenic (environmentally acquired), late-onset sporadic, and early-onset inherited forms.

The findings imply the possibility of targeting disease-related assemblies as a therapeutic approach.

Even though iatrogenic AD is a rare occurrence, future studies must focus on developing measures to prevent accidental transmissions of pathogenic prions during surgical procedures with contaminated instruments.

Journal reference:
Dr. Priyom Bose

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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