Summary of findings published in Nature
The fatal brain disease Creutzfeldt-Jakob disease (CJD) is caused by infectious agents known as prions which are composed of rogue proteins that can grow and spread in the brain. One of the well-known ways people have become infected with prions is following treatment (usually during childhood) with human growth hormone prepared from pituitary glands removed from deceased people, some of whom may have had a prion infection. This type of treatment stopped many years ago (in 1985 in the UK) when the risk of it causing CJD came to light, but several people a year continue to develop this form of CJD because prion infections can take decades to develop. The MRC Prion Unit has been conducting a long-term clinical study on prion diseases in the UK as part of its research to develop effective treatments for these conditions. In the course of this research, we perform detailed studies on brain samples where patients and their families consent to donate tissue for our research. Recently, we looked at eight patients who had developed CJD after treatment with growth hormone. Surprisingly, we found that four had significant or severe changes in their brains normally seen in Alzheimer’s disease (AD) which are very rarely seen in patients of this age group. Two others had more localised changes and only one of the eight had none. These changes are the build-up of protein deposits known as amyloid-beta (or Aß for short). We also showed that pituitary glands from patients that had Aß in their brains often also contained Aß, so we think that Aß as well as prions might have contaminated batches of growth hormone. We and other scientists around the world have suspected for many years that other rogue proteins might sometimes behave like prions and cause disease in a similar way. Indeed experiments from several laboratories have shown that Aß deposits form, after a prolonged period of time, in the brains of some laboratory animals when they are injected with extracts of brain tissue from patients who had died of Alzheimer’s disease. It is therefore thought that Alzheimer protein deposits might act as “seeds” which trigger the formation and spread of more seeds rather like prions do. Up until now there has been no evidence that this has actually happened in humans or whether this would be sufficient to cause Alzheimer’s disease. These new findings suggest transfer of such seeds from some batches of growth hormone to humans has occurred although we do not know whether the protein deposits we saw in the brains would have led on to the full picture of Alzheimer’s disease had these patients lived longer and not died of CJD.
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 by which CJD can rarely be transmitted, but evaluating what risk, if any, there might be requires much further research.
There is absolutely no suggestion from our work that AD is a contagious disease or that there would be any risk to relatives, spouses or carers of patients with AD. Studies in the past have not found any association between AD and blood transfusion.
This work does however contribute to the growing research interest in parallels between prion disease like CJD and Alzheimer’s disease and whether they may share features that might provide insights to advance diagnosis, prevention and treatment in the future.
Background to this research
It has been known for many years that some fatal brain diseases causing dementia are caused by infectious agents called prions. Unlike other infectious agents like viruses and bacteria, prions are only composed of protein and do not have their own genetic material. Prions are formed of long chains of misshapen proteins that can grow in the brain and then divide, forming more prions. This process leads to progressive damage to the brain and is fatal.
Prions also cause diseases in animals (for example scrapie in sheep and bovine spongiform encephalopathy (BSE) or “mad cow disease” in cattle) as well as Creutzfeldt-Jakob disease (CJD) and other human prion diseases. While prions are infectious, they are not contagious in humans – you cannot catch CJD by being in close contact with a sufferer. However, prions can be passed from person to person accidentally by medical and surgical procedures, for example by prion-contaminated surgical instruments or in some cases by blood transfusion although these instances are rare. One form of prion disease, variant CJD, was caused by dietary exposure to BSE.
One of the best known ways prions have accidentally infected humans was by treatment, usually of children of short stature, with injections of growth hormone that was extracted from glands removed from deceased individuals (this is known as human cadaveric pituitary growth hormone or c-hGH). This form of treatment was stopped in 1985 when it was realised that CJD could be transmitted this way. After this time, people needing growth hormone treatment were given a synthetic hormone which does not carry any risk of CJD.
The c-hGH was prepared from large pools of glands, some of which, unknown to those preparing the growth hormone, were thought to have been prion-infected. Worldwide, many thousands of people were given this form of treatment including about 1800 in the UK of whom 77 have so far developed so-called “iatrogenic” CJD (iatrogenic means that it was caused by a medical accident).
There has been growing interest in recent years as to whether similar disease processes – so called “prion-like mechanisms” are involved in other degenerative brain diseases, notably the commonest form of dementia - Alzheimer’s disease (AD), since they all involve accumulation of protein deposits which appear to spread in the brain. Scientists in several laboratories around the world have shown that the protein deposits seen in AD, known as amyloid-beta or Aß, can be induced in laboratory animals by injecting them in the brain, or even in the abdomen, with extracts of brain tissue from patients who died of AD which contain Aß “seeds”. There has however been considerable scepticism as to whether such experiments are relevant to human diseases.
The new research findings
In the 10th September issue of the journal Nature, we report evidence that suggests accidental transmission of one type of protein deposit characteristic of AD has occurred. For some years, the MRC Prion Unit has been conducting an in depth clinical study of patients affected by the various forms of prion disease in the UK – the National Prion Monitoring Cohort study (NPMC) – to build up a detailed picture of how these diseases progress to pave the way for effective clinical trials of treatments for CJD in the future. This has been a very successful study, and in recent years close to 100% of patients have participated. In a large proportion of these patients (over 60%), consent was given for autopsy and study of samples of brain tissue. These were routinely examined not just for prion disease but using a comprehensive panel of techniques to look at other proteins involved in brain degeneration.
While new occurrences of iatrogenic CJD related to treatment with c-hGH are rare, they do still occur (up to 6 per year) because of the extraordinarily long incubation periods seen in human prion infections which we know (from other work from the MRC Prion Unit on a prion disease called kuru) can span over 50 years. The patients who have developed iatrogenic CJD in recent years will have had incubation periods generally exceeding 30 years. To our surprise, when looking at brain tissue from eight such recent patients where this detailed analysis was possible, we found that in addition to the characteristic signs of CJD, most had deposition of Aß in the brain tissue itself (characteristic of AD) or around blood vessels in the brain (a related condition known as cerebral amyloid angiopathy (CAA) which causes bleeding in the brain). Although these patients had long incubation periods, they were themselves relatively young when they developed CJD, with ages ranging from 36-51 years. While such AD-like pathology is common in the elderly, where AD itself is of course common, it is very rarely seen in this young age group.
Although we have extensive experience in studying CJD over many years, we had not seen this before in other types of CJD. However we felt it important to consider whether the prions in the brain might somehow lead to a build-up of other protein deposits like Aß or indeed whether prions might themselves “seed” formation of Aß deposits. We therefore performed a very extensive study of brain tissue (from well over a hundred patients) with all other forms of prion disease over a wide age range. None of these had similar findings at the same age or even a decade older and there was no evidence that prions might themselves trigger formation of Aß as the prion and Aß deposits were located quite separately from each other.
We therefore concluded that the likely cause of the Aß deposition in these young patients was that the c-hGH with which they were treated as children was contaminated with Aß seeds as well as prions. We had also examined the pituitary glands from individuals who had Aß in their brain tissue and found Aß was often present in the glands too. Since hundreds of thousands of glands went into the preparation of c-hGH over the years, it is inevitable that many will have contained significant amounts of Aß.
Since Aß deposits are common in the elderly and many more glands will have contained Aß than prions, this suggests that those healthy people who have received c-hGH and not developed CJD may nevertheless have been exposed to Aß seeds. This raises the possibility that such individuals might be at increased risk of developing AD or CAA in the years ahead.
If such Aß seeds can be transmitted between individuals like CJD by hormone injections, we also need to consider whether other known routes by which CJD is transmitted might also transmit Aß seeds and lead to “iatrogenic” AD or CAA. These routes include contaminated surgical instruments. It is known that such seeds adhere to metal surfaces. Such protein “seeds” are also involved in other degenerative diseases of the brain such as Parkinson’s disease, tauopathies and motor neurone disease. However at the moment this is speculative and much further research will be required to determine if there is any actual risk of this in practice.
This is a descriptive study of humans: it is not, nor could it be, an experimental study. While this work suggests that the Alzheimer-like pathology in the brains was caused by growth hormone injections contaminated with Aß seeds, it does not prove this.
The characteristic features seen in the brain in patients with AD are deposits of Aß (as plaques outside brain cells and in blood vessels) and abnormal deposits of another protein called tau, forming structures called “neurofibrillary tangles”. The patients we have studied with significant Aß deposits in the brain and blood vessels did not have the full features of AD because abnormal tau deposits were not seen. The relationship between Aß and tau pathology in AD is still controversial but many scientists hold the view, supported by genetic studies, that the Aß changes occur first and the tau pathology develops later, perhaps in response to that. It is known that Aß deposits in the brain occur a decade or more before the patient develops the symptoms of dementia. These patients died of CJD at a relatively young age and it is possible that they would have developed the full features of AD in their brains, and developed the clinical symptoms of AD, had they lived longer. It is also possible that the Aß deposits would not have caused AD. The Aß deposition around blood vessels is however entirely characteristic of that seen in the disease cerebral amyloid angiopathy, which causes bleeding into the brain. The severity of the amyloid angiopathy we saw in some of these patients with iatrogenic CJD suggests that they may have developed bleeds had they lived longer.
Although we found no evidence that prion and Aß deposits co-localised, arguing against the idea that prions might trigger or promote Aß accumulation, we cannot formally exclude this.
It is possible that prions and Aß seeds purified together when growth hormone was extracted from pituitary glands. If this were the case, those healthy individuals who received injections many years ago and who do not develop CJD may be at lower risk of developing Aß pathology than our study would otherwise suggest. Further research will be required to investigate this.
Does this work mean that I can catch Alzheimer’s disease from someone?
No, we have not found any evidence that Alzheimer’s disease can be spread between people by normal contact like touching, kissing, sexual or other contact with body fluids and there is no suggestion of risk to relatives, spouses or carers including nursing staff. Our findings relate to the specific circumstance of cadaver-derived human growth hormone injections, a form of treatment that was discontinued many years ago.
I am about to have a blood transfusion or surgery, should I reconsider because of the potential risk of iatrogenic Alzheimer’s disease?
No, it is important you continue with the plans for treatment, guided by your own GP or hospital doctors looking after you. At present we have no evidence that Alzheimer’s disease can be spread by these procedures, and those studies which have looked at this matter in the past have been reassuring. Whilst we believe that more research is needed in this area, the fact that research is planned should not be a cause for alarm.
I am about to have dental surgery, should I be concerned?
No. Our findings have no bearing on dental surgery and certainly do not suggest that dentistry poses a risk of Alzheimer’s disease.
How do I know if I received cadaver-derived human growth hormone injections?
All individuals treated with contaminated hormone were informed in the late 1980s about the possibility of developing iatrogenic CJD so if you did receive this type of treatment you should already know. The contaminated hormone was withdrawn from use in the UK in 1985, any treatments that began after this date will have used synthetic hormone only and this cannot have been contaminated in the same way. If you remain uncertain please speak to your doctor. If your doctor is unsure they can contact Dr Peter Adlard at the UCL Institute of Child Health in London on 020 7404 0536. Dr Adlard is responsible for keeping records of all people treated in the UK with c-hGH and provides advice about c-hGH treatment and the risk of CJD and counselling support to this group.
I/my relative/partner/friend was treated with cadaver-derived human growth hormone and are concerned about these new findings and want to discuss further, how can we get help?
The National Prion Clinic is happy to assist if we can. Please contact us via our helpline number. If necessary your GP could refer you to the clinic in London for assessment. Counselling services are also available through the Clinic from nurses who are expert in this group of conditions. We will be able to liaise with your GP and local services. We apologise if we are unable to respond straight away. We may need to take your number and call you back later. Alternatively, you can contact us by email.
Why was cadaver-derived human growth hormone used at all?
At the time (from 1959) it was the only way to obtain hormones to treat or manage problems caused by their deficiency. The risks of transmitting CJD were not fully understood at that time. Purification methods were used that were thought to minimise the chances of spread of known infections.
Might Alzheimer’s disease be transmitted by blood transfusion or use of other blood products?
Our research only relates to treatment by injection with cadaver-derived human growth hormone. Research studies published in the past have looked at this question but failed to find any evidence that would suggest blood transfusion is a risk.
Does this research work help develop treatments for Alzheimer’s disease?
It is possible that it might. Our work lends support to the idea that rogue Aß proteins are the root cause of Alzheimer’s disease. Many experimental treatments are in development by pharmaceutical companies which are designed to target forms of Aß proteins. Our work suggests that this strategy is broadly correct, although the timing of treatment and exactly which type of rogue Aß proteins to target remain important outstanding questions. Prions can be very effectively studied in the laboratory because animals and cells can become infected. Our work should encourage efforts to develop similar ways to study the prion-like properties of Aß proteins, which may have implications for the testing of new treatments.
I/my relative/partner/friend was treated with cadaver-derived human growth hormone and would like to help with research
We are planning further research and are very grateful for any help with this. Please contact us via the helpline number and we can speak further about our research.