. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature. 2015 Sep 10;525(7568):247-50. PubMed.


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  1. This is an interesting and provocative study of brain and pituitary tissue from individuals who died of prion diseases. Between 1958 and 1985 a significant number of young individuals of short stature received growth hormone (GH) isolated from the pituitary glands of human cadavers. Sadly, a small number of these individuals subsequently developed Creutzfeldt-Jakob disease (CJD). The current study focuses on eight of these iatrogenic CJD (iCJD) cases, all of whom died between the ages of 36 and 51, and quantifies Aβ deposition in the brain parenchyma and vasculature. Three out of the eight had significant amounts of vascular deposits (known as congophilic or cerebral amyloid angiopathy, CAA). Moreover, four of the eight had significant Aβ deposits in the parenchyma. Nineteen individuals who died at comparable ages to the eight GH iCJD cases from prion diseases not associated with GH had little or no evidence of CAA or parenchymal Aβ. None of the eight GH iCJD cases (including the four with substantial Aβ) had mutations in genes believed to predispose to AD. Importantly, no neurofibrillary tangles, the other diagnostic lesion of AD, were detected in any of the four iCJD cases with abundant Aβ deposits.

    Overall, the authors interpreted their data to demonstrate iatrogenic transmission of Aβ “pathology” in addition to iCJD. They encouraged: 1) watching for the appearance at autopsy of deposits of Aβ in currently still-living recipients of pituitary extracts; and 2) investigating whether other routes of tissue entry from one human into another, e.g., by transfused blood products or contaminated surgical instruments, could be associated with the development of Aβ deposits.

    Some specific comments:

    1. This paper does not report the transmission of AD or AD pathology, rather it documents the detection of Aβ deposits in individuals at an age when normally such deposits are extremely rare. The fact that the brains of these individuals did not contain neurofibrillary tangles (the other key histological marker of AD) indicates that they did not have AD. Even if they had lived longer, it is uncertain that they would have developed AD. Importantly, there was no mention about any AD-type peri-plaque neuritic dystrophy or microgliosis.

    2. In terms of clinical relevance, the observed CAA may be of more concern than the parenchymal Aβ deposits. This is because the physical buildup of CAA can sometimes lead to micro-hemorrhages and ultimately stroke, whereas it is less clear that just Aβ deposits in the parenchyma have significant functional consequences. However, given that the chances of developing iCJD from prion-contaminated GH injections is low (3.6 percent for U.K. cases, and less than 1 percent for U.S. cases), and only three of eight iCJD cases examined here had CAA, it would appear that the likelihood of developing clinically noticeable CAA may be lower than developing clinical iCJD.

    3. It remains unclear how much Aβ could actually have been expected to be present in the cadaveric pituitaries, how many of the donors would have been likely to have Aβ deposits in their pituitaries, whether the Aβ would be enriched in the final pooled extracts, and how many of the multiple human pituitary extracts each patient received would have contained Aβ. As the authors rightly point out, it will be important to examine the original GH extracts for the presence and forms of Aβ therein.

    4. The results presented are consistent with a prior report of Alzheimer-type neuropathology in a 28-year old patient with iatrogenic Creutzfeldt-Jakob disease after grafting of cadaverous dura mater (Preusser et al., 2006). 

    We conclude that Jaunmuktane et al. have made an intriguing observation that definitely needs detailed follow-up epidemiologically. However, for the broad public, this report is by no means evidence for transmission of AD or even a definite risk of developing AD. This unusual, now-discontinued iatrogenic route via pituitary extracts means the risk to the general public of acquiring AD in any similar fashion is extremely low. In accord, the overwhelming majority of typical AD subjects have not had any exposure to tissue extract injections, dural grafts, or even blood product transfusions, indicating that this prion-like route of acquiring AD is a rare phenomenon, but nonetheless deserving of further scientific study.


    . Alzheimer-type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting. J Neurol Neurosurg Psychiatry. 2006 Mar;77(3):413-6. PubMed.

    View all comments by Dennis Selkoe
  2. This is a simple but fascinating paper. It suggests to me that patients who received cadaveric growth hormone, and who came to autopsy because they were unlucky enough to have been exposed to PrP prions, may have received Aβ seeds along the way as well.

    It is of course unclear whether PrP pathology could somehow trigger Aβ pathology. There is no good evidence for this. Thus, given how common both AD and CAA are, instead it seems likely that some of these donors’ brains (i.e., people who didn’t have prion disease, but did have Aβ accumulation) found their way into the pooled extracts that were given to the patients who ultimately came down with prion disease. This is supported by the investigators’ findings that pituitary glands feature Aβ accumulation.

    The implication, of course, is that many other proteins besides PrP could potentially be infectious. I still highly doubt that in standard medical practice it would be possible to transmit pathology efficiently between individuals. Since we are no longer doing these pooled tissue treatments, which in retrospect seem particularly foolhardy, I would not imagine that we will be seeing a high number of “infected” cases of AD, CAA, or PD. But you never know.

    View all comments by Marc Diamond
  3. The authors made clear they were referring to Aβ transmission and not transmission of Alzheimer’s disease, as none of the patients had clinical AD or the tangles that in addition to Aβ deposits are required to make a postmortem diagnosis of AD. Thus, it is important to emphasize that we reported in a study of nearly 7,700 similarly treated individuals in a NIH/CDC database that there were no cases of AD or PD among them (Irwin et al., 2013). 

    Briefly, we found no evidence to support concerns that AD proteins are transmitted from one person to another.

    Irwin et al. analyzed data from an existing cohort of patients who had received cadaveric human growth hormone (c-hGH) extracted from postmortem pituitary glands via a national program, which was a beneficial treatment for stunted growth, before synthetic hGH was available. Nearly 7,700 patients were treated with c-hGH in the United States between 1963 and 1985. In the mid-1980s, more than 200 patients worldwide who had received c-hGH inadvertently contaminated with prion proteins from affected donor pituitary tissue went on to develop an iatrogenic form of Creutzfeldt-Jakob disease (i-CJD).

    Since then, the cohort has been followed by NIH/CDC investigators to track any additional cases of CJD, with extensive medical histories for patients over the 30-plus years since the c-hGH therapy was stopped. In Irwin et al., we looked for signs of elevated risk of AD and PD among this group and found that none of the c-hGH recipients developed AD or PD, despite the presence of pathological AD (tau, Aβ) and PD (α-synuclein) proteins in pituitary glands from deceased subjects. This clarified that c-hGH recipients were most likely exposed to these neurodegenerative disease proteins linked to AD and PD, but this did not result in transmission of AD or PD from person to person in nearly 7,700 examined subjects in the database described above.


    . Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol. 2013 Apr;70(4):462-8. PubMed.

    View all comments by John Trojanowski

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