Evidence for human transmission of amyloid-[beta] pathology and cerebral amyloid angiopathy

Treatment of children with human cadaver-derived growth hormone (c-hGH) contaminated with prions resulted in transmission of Creutzfeldt-Jakob disease (CJD); unexpectedly, in an autopsy study of eight such iCJD patients, the authors found amyloid-[beta] deposition in the grey matter typical of that seen in Alzheimer's disease and amyloid-[beta] in the blood vessel walls characteristic of cerebral amyloid angiopathy, consistent with iatrogenic transmission of amyloid-[beta] pathology in addition to CJD and suggests that healthy c-hGH-exposed individuals may also be at risk of Alzheimer's disease and cerebral amyloid angiopathy. Possible evidence for transmission of Alzheimer's pathology Treatment of children with human cadaver-derived growth hormone (hGH) contaminated with prions resulted in iatrogenic transmission of Creutzfeldt-Jakob disease (iCJD). While such treatment ceased in 1985, CJD has a long incubation time and new cases are still emerging. Unexpectedly, an autopsy study of eight such iCJD patients, aged 36-51 years old, has revealed amyloid-[beta] deposition in the grey matter typical of that seen in Alzheimer's disease and A[beta] in the blood vessel walls characteristic of cerebral amyloid angiopathy. None of these patients had pathogenic mutations or high-risk alleles associated with early onset Alzheimer's disease. Importantly, A[beta] pathology was detected only in prion-infected individuals who received hGH. This is consistent with iatrogenic transmission of A[beta] pathology in addition to CJD, and suggests that healthy hGH exposed individuals may also be at risk of iatrogenic Alzheimer's disease and cerebral amyloid angiopathy. More than two hundred individuals developed Creutzfeldt-Jakob disease (CJD) worldwide as a result of treatment, typically in childhood, with human cadaveric pituitary-derived growth hormone contaminated with prions.sup.1,2. Although such treatment ceased in 1985, iatrogenic CJD (iCJD) continues to emerge because of the prolonged incubation periods seen in human prion infections. Unexpectedly, in an autopsy study of eight individuals with iCJD, aged 36-51 years, in four we found moderate to severe grey matter and vascular amyloid-[beta] (A[beta]) pathology. The A[beta] deposition in the grey matter was typical of that seen in Alzheimer's disease and A[beta] in the blood vessel walls was characteristic of cerebral amyloid angiopathy.sup.3 and did not co-localize with prion protein deposition. None of these patients had pathogenic mutations, APOE [epsilon]4 or other high-risk alleles.sup.4 associated with early-onset Alzheimer's disease. Examination of a series of 116 patients with other prion diseases from a prospective observational cohort study.sup.5 showed minimal or no A[beta] pathology in cases of similar age range, or a decade older, without APOE [epsilon]4 risk alleles. We also analysed pituitary glands from individuals with A[beta] pathology and found marked A[beta] deposition in multiple cases. Experimental seeding of A[beta] pathology has been previously demonstrated in primates and transgenic mice by central nervous system or peripheral inoculation with Alzheimer's disease brain homogenate.sup.6,7,8,9,10,11. The marked deposition of parenchymal and vascular A[beta] in these relatively young patients with iCJD, in contrast with other prion disease patients and population controls, is consistent with iatrogenic transmission of A[beta] pathology in addition to CJD and suggests that healthy exposed individuals may also be at risk of iatrogenic Alzheimer's disease and cerebral amyloid angiopathy. These findings should also prompt investigation of whether other known iatrogenic routes of prion transmission may also be relevant to A[beta] and other proteopathic seeds associated with neurodegenerative and other human diseases.
Author(s): Zane Jaunmuktane [sup.1] , Simon Mead [sup.2] [sup.3] [sup.4] , Matthew Ellis [sup.3] , Jonathan D. F. Wadsworth [sup.2] [sup.3] , Andrew J. Nicoll [sup.2] [sup.3] , Joanna Kenny [...]