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 prions. 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 angiopathy and did not co-localize with prion protein deposition. None of these patients had pathogenic mutations, APOE ε4 or other high-risk alleles associated with early-onset Alzheimer's disease. Examination of a series of 116 patients with other prion diseases from a prospective observational cohort study 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 homogenate. 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.
Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
Zane
Z
Jaunmuktane
Medical Research Council Prion Unit, Queen Square, London WC1N 3BG, UK.|Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.|National Prion Clinic, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
Simon
S
Mead
Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Matthew
M
Ellis
Medical Research Council Prion Unit, Queen Square, London WC1N 3BG, UK.|Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Jonathan D F
JD
Wadsworth
Medical Research Council Prion Unit, Queen Square, London WC1N 3BG, UK.|Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Andrew J
AJ
Nicoll
Medical Research Council Prion Unit, Queen Square, London WC1N 3BG, UK.|National Prion Clinic, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
Joanna
J
Kenny
Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Francesca
F
Launchbury
Medical Research Council Prion Unit, Queen Square, London WC1N 3BG, UK.
Jacqueline
J
Linehan
Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Angela
A
Richard-Loendt
MRC Clinical Trials Unit at University College London, 125 Kingsway, London WC2B 6NH, UK.
A Sarah
AS
Walker
Medical Research Council Prion Unit, Queen Square, London WC1N 3BG, UK.|National Prion Clinic, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
Peter
P
Rudge
Medical Research Council Prion Unit, Queen Square, London WC1N 3BG, UK.|Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.|National Prion Clinic, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
John
J
Collinge
Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.|Medical Research Council Prion Unit, Queen Square, London WC1N 3BG, UK.|Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Sebastian
S
Brandner
D000328:Adult; D000483:Alleles; D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism*; D001344:Autopsy; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D016657:Cerebral Amyloid Angiopathy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007562:Creutzfeldt-Jakob Syndrome / Q000150:complications / Q000209:etiology* / Q000378:metabolism; D004340:Drug Contamination; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D066128:Gray Matter / Q000378:metabolism / Q000473:pathology; D019382:Human Growth Hormone / Q000008:administration & dosage*; D006801:Humans; D007049:Iatrogenic Disease; D008875:Middle Aged; D011328:Prions / Q000008:administration & dosage / Q000378:metabolism; D012307:Risk Factors
D016229:Amyloid beta-Peptides; D011328:Prions; D019382:Human Growth Hormone