title: Amyloid-β accumulation in the CNS in human growth hormone recipients in the UK.
abstract: Human-to-human transmission of Creutzfeldt-Jakob disease (CJD) has occurred through medical procedures resulting in iatrogenic CJD (iCJD). One of the commonest causes of iCJD was the use of human pituitary-derived growth hormone (hGH) to treat primary or secondary growth hormone deficiency. As part of a comprehensive tissue-based analysis of the largest cohort yet collected (35 cases) of UK hGH-iCJD cases, we describe the clinicopathological phenotype of hGH-iCJD in the UK. In the 33/35 hGH-iCJD cases with sufficient paraffin-embedded tissue for full pathological examination, we report the accumulation of the amyloid beta (Aβ) protein associated with Alzheimer's disease (AD) in the brains and cerebral blood vessels in 18/33 hGH-iCJD patients and for the first time in 5/12 hGH recipients who died from causes other than CJD. Aβ accumulation was markedly less prevalent in age-matched patients who died from sporadic CJD and variant CJD. These results are consistent with the hypothesis that Aβ, which can accumulate in the pituitary gland, was present in the inoculated hGH preparations and had a seeding effect in the brains of around 50% of all hGH recipients, producing an AD-like neuropathology and cerebral amyloid angiopathy (CAA), regardless of whether CJD neuropathology had occurred. These findings indicate that Aβ seeding can occur independently and in the absence of the abnormal prion protein in the human brain. Our findings provide further evidence for the prion-like seeding properties of Aβ and give insights into the possibility of iatrogenic transmission of AD and CAA.
authors.affiliation: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK. diane.ritchie@ed.ac.uk.
authors.forename: Diane L
authors.identifier: 0000-0002-3614-9638
authors.initials: DL
authors.lastname: Ritchie
authors.affiliation: UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Adlard
authors.affiliation: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Peden
authors.affiliation: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lowrie
authors.affiliation: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Le Grice
authors.affiliation: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Burns
authors.affiliation: Centre for Cognitive and Neural Systems, University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Jackson
authors.affiliation: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Yull
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keogh
authors.affiliation: MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Head
authors.affiliation: National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: James W
authors.initials: JW
authors.lastname: Ironside
mesh_terms: D000293:Adolescent; D000328:Adult; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D015331:Cohort Studies; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D019382:Human Growth Hormone / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000072002:Prion Proteins; D012720:Severity of Illness Index; D016896:Treatment Outcome; D006113:United Kingdom / Q000453:epidemiology; D000073359:Exome Sequencing; D055815:Young Adult; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D000072002:Prion Proteins; C000598624:TARDBP protein, human; D016875:tau Proteins; D019382:Human Growth Hormone
keywords: Amyloid β; Cerebral amyloid angiopathy; Human growth hormone; Iatrogenic Creutzfeldt–Jakob disease; Neuropathology; Prion protein