BRC researchers have unexpectedly found amyloid beta protein in autopsy studies of brain tissue from Creutzfeldt-Jakob disease (CJD) patients who had previously been treated with human growth hormone derived from cadaveric pituitary glands.
Professors John Collinge, Simon Mead, Sebastian Brandner and their colleagues from the UCL Institute of Neurology found that in addition to prion disease in all eight brains sampled, four had a moderate or severe build-up of amyloid beta, which is linked to Alzheimer’s disease (AD). The patients were aged 36-51, and none carried gene variants that bring about the early onset of dementia.
Professor Simon Mead, co-author on the paper and Clinical Lead of the NHS National Prion Clinic said: “We noted that there was marked deposition of amyloid beta in blood vessels of the brain, which is a rare finding at this age. Importantly, there were no signs of the tau protein pathology, which is required to make a pathological diagnosis of AD. Whilst the full changes of AD were not seen, we still have to explain why the amyloid beta protein was found to such a degree in the brains of these patients at a young age.”
In order to rule out cross-seeding (amyloid deposits that might trigger deposition of other amyloid proteins) with prion protein as the cause, the study team checked whether the prion protein deposits that are typically associated with CJD were in the same place in the brain as the amyloid beta deposits. This was clearly not the case, suggesting that cross-seeding hadn’t occurred.
Next the study team looked at the frequency of amyloid beta deposits in brain tissue from people who had died of other forms of prion disease. In order to do this the researchers benefitted from The National Prion Monitoring Cohort, a long-term study which involves regular follow-up clinical and psychological assessments to understand how prion diseases affect patients over time. The authors examined a series of 116 patients with other prion diseases and found no evidence of amyloid beta pathology in the brains of patients of a similar age.
Professor Mead said: “We were able to look at brain tissue from a large series of individuals who had died of other forms of prion disease, to see if there were any unusual amyloid beta deposits. The crucial finding was that in the age range 36-51 we didn’t see any significant amyloid beta deposition. The only CJD cases who showed amyloid beta deposition in the age range 50-60 had genetic risk factors for AD, such as being carriers of the APOE4 allele”
These results linked the unexpected amyloid beta deposition with cadaver derived human growth hormone – a product that was withdrawn in 1985, after its link with CJD. The study team’s hypothesis is that amyloid beta protein seeds were present in the cadaver-derived growth hormone treatment.
Describing the value of autopsy tissue derived from a long term observational cohort study Professor Mead said: “This study would have been impossible without BRC funding. Without the NPMC we would not have had the opportunity to engage with patients and families about our research work and the need for autopsy studies. These findings in a small number of patients would not have had any meaning if we hadn’t been able to compare to a large series of patients that had died of prion disease unrelated to the growth hormone”.
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