Amyloid beta pathology in the grey matter and blood vessel walls characteristic of Alzheimer’s disease (AD) and the related cerebral amyloid angiopathy (CAA) is observed in the brains of deceased patients who acquired Creutzfeldt–Jakob disease (CJD) following treatment with prion-contaminated human growth hormone.
Although there is no evidence that human prion disease, AD or CAA is contagious (spread from person to person by direct contact), the study of eight patients, published in this week’s Nature, suggests that amyloid beta (the peptides that form the main components of the amyloid plaques found in the brains of patients with AD) may potentially be transmissible via certain medical procedures.
Human transmission of prion disease has occurred as a result of various medical procedures (iatrogenic transmission), with incubation periods that can exceed five decades.
One such iatrogenic route of transmission was via the treatment in the UK of 1,848 persons of short stature with human growth hormone (HGH) extracted from cadaver-sourced pituitary glands, some of which were inadvertently prion-contaminated. The treatments began in 1958 and ceased in 1985 following reports of CJD among recipients. By the year 2000, 38 of the patients had developed CJD. As of 2012, 450 cases of iatrogenic CJD have been identified in countries worldwide after treatment with cadaver-derived HGH and, to a lesser extent, other medical procedures, including transplant and neurosurgery.
John Collinge, Sebastian Brandner and colleagues at UCL conducted autopsy studies, including extensive brain tissue sampling, of eight UK patients aged 36–51 with iatrogenic CJD. The authors show that in addition to prion disease in all eight brains sampled, six exhibited some degree of amyloid beta pathology (four widespread) and four of these had some degree of CAA. Such pathology is rare in this age range and none of the patients were found to have mutations associated with early-onset AD.
There were no signs of the tau protein pathology characteristic of AD, but the full neuropathology of AD could potentially have developed had the patients lived longer. The authors examined a cohort of 116 patients with other prion diseases and found no evidence of amyloid beta pathology in the brains of patients of similar age range or a decade older who did not receive HGH treatment.
The study suggests that healthy individuals exposed to cadaver-derived HGH may be at risk of iatrogenic AD and CAA, as well as iatrogenic CJD, as they age. Further research is needed to better understand the mechanisms involved, but it seems likely that, as well as prions, the pituitary glands used to make the HGH contained the amyloid beta seeds that caused the amyloid beta pathology observed.
The results should prompt investigation of whether other known iatrogenic routes of prion transmission, including surgical instrument use and blood transfusion, could also be relevant to the transmission of AD, CAA and other neurodegenerative diseases.
Professor Collinge, Director of the MRC Prion Unit at the UCL Institute of Neurology, said: “Our findings relate to the specific circumstance of cadaver-derived human growth hormone injections, a treatment that was discontinued many years ago. It is possible our findings might be relevant to some other medical or surgical procedures, but evaluating what risk, if any, there might be requires much further research. Our current data have no bearing on dental surgery and certainly do not argue that dentistry poses a risk of Alzheimer’s disease.”
Professor Mike Hanna, Director of the UCL Institute of Neurology, said: “This is potentially very important research from the UCL Institute of Neurology Prion research Group lead by John Collinge and Sebastian Brandner. It could inform our understanding of the molecular mechanisms leading to Alzheimer’s disease and will enable new programmes of world leading research in Dementia at the Institute of Neurology, Queen Square.”
About this Alzheimer’s disease research
Source: Harry Dayantis – UCL Image Credit: The image is credited to the NIH and is in the public domain Original Research:Abstract for “Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy” by Zane Jaunmuktane, Simon Mead, Matthew Ellis, Jonathan D. F. Wadsworth, Andrew J. Nicoll, Joanna Kenny, Francesca Launchbury, Jacqueline Linehan, Angela Richard-Loendt, A. Sarah Walker, Peter Rudge, John Collinge and Sebastian Brandner in Nature. Published online September 8 2015 doi:10.1038/nature15369
Evidence for human transmission of amyloid-β pathology 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 prions1, 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-β (Aβ) pathology. The Aβ deposition in the grey matter was typical of that seen in Alzheimer’s disease and Aβ in the blood vessel walls was characteristic of cerebral amyloid angiopathy3 and did not co-localize with prion protein deposition. None of these patients had pathogenic mutations, APOE ε4 or other high-risk alleles4 associated with early-onset Alzheimer’s disease. Examination of a series of 116 patients with other prion diseases from a prospective observational cohort study5 showed minimal or no Aβ pathology in cases of similar age range, or a decade older, without APOE ε4 risk alleles. We also analysed pituitary glands from individuals with Aβ pathology and found marked Aβ deposition in multiple cases. Experimental seeding of Aβ pathology has been previously demonstrated in primates and transgenic mice by central nervous system or peripheral inoculation with Alzheimer’s disease brain homogenate6, 7, 8, 9, 10, 11. The marked deposition of parenchymal and vascular Aβ in these relatively young patients with iCJD, in contrast with other prion disease patients and population controls, is consistent with iatrogenic transmission of Aβ 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 Aβ and other proteopathic seeds associated with neurodegenerative and other human diseases.
“Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy” by Zane Jaunmuktane, Simon Mead, Matthew Ellis, Jonathan D. F. Wadsworth, Andrew J. Nicoll, Joanna Kenny, Francesca Launchbury, Jacqueline Linehan, Angela Richard-Loendt, A. Sarah Walker, Peter Rudge, John Collinge and Sebastian Brandner in Nature. Published online September 8 2015 doi:10.1038/nature15369