Amyloid-ß Pathology Induced by Contaminated Cadaver-Derived Growth Hormone

Dr. Andersen is Chief Resident in Neurology, New York Presbyterian Hospital, Weill Cornell Medical College. Dr. Fink is Louis and Gertrude Feil Professor and Chair, Department of Neurology, Weill Cornell Medical College.

Dr. Andersen and Dr. Fink report no financial relationships relevant to this field of study.

SYNOPSIS: Cadaveric pituitary-derived growth hormone that previously was known to transmit Creutzfeldt-Jakob disease (CJD) also contains ß-amyloid. Growth hormone vials from cases associated with amyloid plaques in CJD patients cause amyloid plaque formation and cerebral amyloid angiopathy when injected intracranially into mice.

SOURCE: Purro SA, Farrow MA, Linehan J, et al. Transmission of amyloid-ß protein pathology from cadaveric pituitary growth hormone. Nature 2018;64:415-419.

Iatrogenic exposure to prion proteins can occur through medical or surgical interventions and result in fatal prion disease after incubation for decades. Thousands of children diagnosed with short stature between 1958 and 1985 were injected with cadaveric human growth hormone (c-hGH). Batches of c-hGH were contaminated with prion proteins from patients who died from Creutzfeldt-Jakob disease (CJD), resulting in iatrogenic transmission of CJD in more than 200 patients to date. Cases associated with c-hGH continue to rise because of the prolonged incubation period.¹ Intriguingly, examination of postmortem brain tissue from these tragic cases of CJD has raised concerns of potential transmissibility of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA).

In 2015, investigators reported unexpected pathologic findings in the brains of eight patients, ages 36-51 years, who recently had died from c-hGH-induced CJD. In addition to CJD pathology, four contained severe gray matter amyloid β (Aβ) pathology; two others had focal Aβ plaques. Three of these eight patients also had widespread vascular amyloid deposition, fulfilling diagnostic criteria for CAA. Genetic testing found no AD susceptibility mutations. In contrast, 19 age-matched patients from a series of patients who died from other prion diseases (sporadic and variant CJD or inheritable prion diseases) showed no amyloid pathology. These researchers hypothesized that misfolded Aβ from patients with AD and/or CAA had contaminated batches of c-hGH and that native Aβ in young patients had been seeded to misfold.² Soon after, several groups reported cerebral hemorrhages from CAA in young patients, decades after dural grafts were placed.^3-5

Purro et al first characterized many batches of c-hGH that had been safely stored by Public Health England. All patients who developed CJD received c-hGH from a batch that was isolated by the Hartree-modified Wilhelmi procedure (HWP).¹ Remarkably, Aβ and tau levels within the HWP-derived vials were comparable to levels found in the brains of patients with AD, despite storage at ambient temperature for decades. Aβ and tau were undetectable in c-hGH vials extracted by other methods.⁶

Knock-in mice expressing human amyloid precursor protein gene were used for transmission experiments. Mice were injected intracerebrally with saline, recombinant hGH, brain homogenate from AD patients, or from two archival vials of c-hGH isolated by HWP. By four months of age, mice injected with Aβ-containing c-hGH vials developed CAA, and to a lesser extent, Aβ plaques in gray matter. Mice injected with brain homogenate from AD patients developed robust CAA and AD pathology. Notably, no plaques developed in mice injected with saline or recombinant hGH at four months of age.⁶

COMMENTARY

These findings provide additional evidence for “seeding” activity as a potential mechanism of disease progression in AD and CAA. First, the authors add to a well-established body of evidence that Aβ can participate in seeding — aggregates of Aβ induce pathologic conformational change in normally folded forms of Aβ, exponentially propagating plaque formation.⁷ The potential for seeding of Aβ plaques after storage of vials for decades at ambient temperature is especially provocative. However, the connection between seeding of plaques, neuronal dysfunction, and AD has not been established. To begin, Aβ plaque burden, while part of the neuropathologic diagnosis of AD, does not correlate with memory impairment in AD.⁸ Rather, soluble Aβ oligomers contribute more directly to neuronal dysfunction and clinical impairment.^9,10 Previous work has demonstrated that plaques are diverse in aggregate composition and only sometimes are accompanied by Aβ oligomers.¹⁰ In addition, the authors did not find tau aggregates in the brains of c-hGH-induced CJD patients (although an analogous study on CJD from c-hGH from France did).¹¹ Given the six patients who died from c-hGH-induced CJD with Aβ plaque deposition in gray matter succumbed prematurely from a more severely dementing disease, it is unknown if AD eventually could have developed through contaminated Aβ seeding.

In contrast, vascular Aβ plaques were induced more robustly by injection of c-hGH into the mice in this study. Since CAA is diagnosed pathologically, clear demonstration of vascular Aβ plaque was sufficient for the diagnosis of iatrogenic CAA. Purro et al demonstrated the potential of Aβ-contaminated batches of c-hGH to cause CAA and some pathologic features of AD; however, gray matter plaque formation does not equate to AD.

With the memory of c-hGH-induced CJD in more than 200 patients worldwide and hundreds of thousands of patients with AD and CAA, the authors argued for the evaluation of the risks of iatrogenic transmission of CAA and possibly AD through surgical instruments by measurement of Aβ. Aggregates or plaques are unlikely to be resistant to current sterilization methods, but testing has not been conducted to confirm effectiveness. With a long disease incubation period in CAA and AD, young patients who undergo neurosurgical procedures may be at risk for development of disease decades after surgery.

REFERENCES

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