Seeds of neuroendocrine doubt

Feeney, Claire; Scott, Gregory; Cole, James R.; Sastre, Magdalena; Goldstone, Anthony P.; Leech, Robert

doi:10.1038/nature18602

Cited by 9 publications

(9 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The transmissibility of CAA, and potentially Alzheimer’s disease, by iatrogenic routes raises important public health issues and would also indicate a clear shift in understanding their aetiology and suggest new approaches to prevention and treatment 2 . Alternative interpretations of our findings have been proposed 14,15 , although we have not considered these to be as plausible as the human transmission hypothesis 16,17 . Given the potential public health importance of our findings, we proceeded to examine experimentally whether c-hGH batches to which these patients were exposed contained viable Aβ seeding activity, albeit after storage for more than 30 years.…”

contrasting

confidence: 77%

Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone

Purro

Farrow

Linehan

et al. 2018

Nature

146

104

View full text Add to dashboard Cite

We previously reported1 the presence of amyloid-β protein (Aβ) deposits in individuals with Creutzfeldt–Jakob disease (CJD) who had been treated during childhood with human cadaveric pituitary-derived growth hormone (c-hGH) contaminated with prions. These relatively young individuals with such treatment-induced (iatrogenic) CJD (iCJD), unlike other prion-disease patients and population controls, showed marked deposition of grey-matter and vascular Aβ; this finding, allied with the ability of Alzheimer’s disease brain homogenates to seed Aβ deposition in laboratory animals, led us to argue that the implicated c-hGH batches might have been contaminated with Aβ seeds as well as with prions. However, this was necessarily an association, and not an experimental, study in humans and causality could not be concluded. Given the public health importance of our hypothesis, we proceeded to identify and biochemically analyse archived vials of c-hGH. Here we show that certain c-hGH batches to which patients with iCJD and Aβ pathology were exposed have substantial levels of Aβ1–40, Aβ1–42 and tau proteins, and that this material can seed the formation of Aβ plaques and cerebral Aβ−amyloid angiopathy in intracerebrally inoculated mice expressing a mutant, humanized amyloid precursor protein. These results confirm the presence of Aβ seeds in archived c-hGH vials and are consistent with the hypothesized iatrogenic human transmission of Aβ pathology. This experimental confirmation has implications for both the prevention and the treatment of Alzheimer’s disease, and should prompt a review of the risk of iatrogenic transmission of Aβ seeds by medical and surgical procedures long recognized to pose a risk of accidental prion transmission2,3.

show abstract

contrasting

confidence: 77%

Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone

Purro

Farrow

Linehan

et al. 2018

Nature

146

104

View full text Add to dashboard Cite

show abstract

“…Questions have been raised on the clinical background of the patients included in the study by Jaunmuktane et al, suggesting that the pre-existing and underlying conditions causing hGH deficiency in this patient cohort “could by themselves lead to Aβ pathology and abnormal brain structure” [15]. In the 33 patients analysed for Aβ deposits in this study, we found no clinical history or neuropathological evidence of traumatic brain injury as the cause of the hGH deficiency.…”

Section: Discussionmentioning

confidence: 53%

“…Of the 13 hGH recipients who had brain tumours, three had received post-operative radiotherapy (Online Resource Table 2), none of whom had Aβ deposition in the CNS. In addition, no evidence of the more generalised disorders that can be associated with Aβ deposition in the CNS (as suggested by Feeney et al [15]) such as epilepsy, fragile X syndrome, Down’s syndrome or Parkinson’s disease were found (Online Resource Table 2). Furthermore, the morphology and distribution of Aβ lesions and relative lack of phospho-tau pathology argue against an underlying traumatic aetiology for the Aβ pathology reported in this study.…”

Section: Discussionmentioning

confidence: 98%

“…There is also evidence of phospho-tau and α-synuclein accumulation in the pituitary gland in aging; α-synuclein can also be detected in the pituitary gland in Parkinson’s disease and Lewy body dementia [23, 25]. However, the claim for Aβ transmission in 4/8 UK hGH-iCJD cases has been questioned in view of the possibility of underlying CNS disorders in these patients that might predispose to Aβ accumulation, casting “seeds of neuroendocrine doubt” [15]. Furthermore, Aβ has been reported to co-localise with PrP amyloid deposits in the CNS in patients with sCJD and various forms of inherited human prion diseases [9, 27, 44, 49], raising further doubts about the significance of Aβ deposition in hGH-iCJD.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Amyloid-β accumulation in the CNS in human growth hormone recipients in the UK

et al. 2017

View full text Add to dashboard Cite

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1703-0) contains supplementary material, which is available to authorized users.

show abstract

“…This important finding strongly argues for human-to-human transmission of an Aβ-related condition independently from the PrP Sc seeding process. Nonetheless, whether the neuroendocrine deficiency may favor the Aβ pathology in some cases is still unknown [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study

Calì

Cohen

Haїk

et al. 2018

acta neuropathol commun

View full text Add to dashboard Cite

The presence of pathology related to the deposition of amyloid-β (Aβ) has been recently reported in iatrogenic Creutzfeldt-Jakob disease (iCJD) acquired from inoculation of growth hormone (GH) extracted from human cadaveric pituitary gland or use of cadaveric dura mater (DM) grafts.To investigate this phenomenon further, a cohort of 27 iCJD cases – 21 with adequate number of histopathological sections – originating from Australia, France, Italy, and the Unites States, were examined by immunohistochemistry, amyloid staining, and Western blot analysis of the scrapie prion protein (PrPSc), and compared with age-group matched cases of sporadic CJD (sCJD), Alzheimer disease (AD) or free of neurodegenerative diseases (non-ND).Cases of iCJD and sCJD shared similar profiles of proteinase K-resistant PrPSc with the exception of iCJD harboring the “MMi” phenotype. Cerebral amyloid angiopathy (CAA), either associated with, or free of, Thioflavin S-positive amyloid core plaques (CP), was observed in 52% of 21 cases of iCJD, which comprised 37.5% and 61.5% of the cases of GH- and DM-iCJD, respectively. If only cases younger than 54 years were considered, Aβ pathology affected 41%, 2% and 0% of iCJD, sCJD and non-ND, respectively. Despite the patients’ younger age CAA was more severe in iCJD than sCJD, while Aβ diffuse plaques, in absence of Aβ CP, populated one third of sCJD. Aβ pathology was by far most severe in AD. Tau pathology was scanty in iCJD and sCJD.In conclusion, (i) despite the divergences in the use of cadaveric GH and DM products, our cases combined with previous studies showed remarkably similar iCJD and Aβ phenotypes indicating that the occurrence of Aβ pathology in iCJD is a widespread phenomenon, (ii) CAA emerges as the hallmark of the Aβ phenotype in iCJD since it is observed in nearly 90% of all iCJD with Aβ pathology reported to date including ours, and it is shared by GH- and DM-iCJD, (iii) although the contributions to Aβ pathology of other factors, including GH deficiency, cannot be discounted, our findings increase the mounting evidence that this pathology is acquired by a mechanism resembling that of prion diseases.Electronic supplementary materialThe online version of this article (10.1186/s40478-017-0503-z) contains supplementary material, which is available to authorized users.

show abstract

Seeds of neuroendocrine doubt

Cited by 9 publications

References 14 publications

Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone

Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone

Amyloid-β accumulation in the CNS in human growth hormone recipients in the UK

Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study

Contact Info

Product

Resources

About