Two recent reports have suggested that neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease and Huntington’s disease, may be transmissible through medical procedures, raising troubling questions about the safety of common practices such as surgery, transplantation and blood transfusion.
The initial report was an incidental finding by researchers at Queen Square, London, who were investigating iatrogenic Creutzfeldt-Jakob disease (CJD) (Jaunmuktane et al. Nature 2015;525:247-250). Over 200 CJD deaths have occurred in patients who received growth hormone derived from pituitary glands obtained from human cadavers that had been contaminated with pathogenic prions. The autopsy study of patients aged 36-51 years found grey-matter and vascular beta-amyloid pathology consistent with AD in four of 8 subjects. None of the subjects had known genetic risk factors for early-onset AD. No or minimal amyloid pathology was seen in a comparator series of 116 patients with other prion diseases.
Intracerebral injection of beta-amyloid seeds has been shown to induce senile plaque formation in animal models (Rosen et al. J Neurochem 2012;120:660-666). While amyloid seeding has not been demonstrated in humans, the Queen Square researchers concluded that the extent of beta-amyloid deposition in the parenchyma and vasculature was consistent with iatrogenic transmission of beta-amyloid.
The British tabloids were quick to pick up on the story (Daily Mail: Can you Catch Alzheimer’s?), but transmission is theorized to be by invasive medical procedures rather than person-to-person contact. (For a podcast of researcher Dr. John Collinge go to www.nature.com/nature/podcast/index-2016-03-17.html).
Then earlier this year, a second study found similar findings (Frontzek et al. Swiss Med Weekly; free full text at www.smw.ch/content/smw-2016-14287/). The autopsy study examined seven subjects who died of iatrogenic CJD after dural grafting. Over 200 CJD deaths have been reported following dural grafts obtained from cadavers. Subjects were aged 28-63 years and had received the graft 11-25 years before death. In 5 of 7 subjects (71%), beta-amyloid was detected in meningeal vessels as cerebral amyloid angiopathy (CAA), and as grey-matter plaques. No tau pathology was observed. In comparison, CAA was found in 1 of 21 (5%) and parenchymal deposits in 5 of 21 (24%) age-matched subjects with sporadic CJD in the Swiss and Austrian Human Prion Diseases registries. Only iatrogenic CJD subjects had both CAA and grey-matter plaques.
These findings have prompted other centres, such as the U.S. National Prion Disease Pathology Surveillance Center at Case Western Reserve University in Cleveland, Ohio, and the Pitié-Salpêtrière Hospital in Paris, France, to re-examine their CJD tissue banks for evidence of beta-amyloid pathology.
It is well-established that prion diseases are transmissible via tainted meat (BSE), cannibalism (kuru), and tissue transplants (CJD). Whether beta-amyloid seeding indicates that AD is transmissible will require further study. But it has raised the question of whether neurodegenerative conditions are prion-like diseases. Prion (proteinaceous infectious particle) diseases, also called transmissible spongiform encephalopathies (TSE), include bovine spongiform encephalopathy (BSE) in cattle (variant CJD), scrapie in goats and sheep, and chronic wasting disease in deer and elk. Human prion diseases include CJD and its variants; kuru; heritable etc. prion diseases caused by mutations in the PRNP gene include Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia.
Prion diseases are believed to develop following the transformation of the normal prion protein (PrPc) to a misfolded form (PrPSc), which propagates and accumulates in the central and peripheral nervous systems. It is unclear how PrPc undergoes conversion to a pathogenic form; one possible mechanism is that PrPSc serves as a template, inducing neighbouring PrP proteins to misfold (for a review see Burchell & Panegyres. ImmunoTargets and Therapy 2016:5 57-68; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC4970640/pdf/itt-5-057.pdf). These misfolded proteins then aggregate to form amyloids.
There is some evidence to support the idea that AD is a prion-like disease. Both beta-amyloid and tau aggregates have been shown to propagate in a prion-like manner (Jucker & Walker. Nature 2013;501:45-51; Clavaguera et al. Proc Natl Acad Sci USA 2013;110):9535-9540). Alpha-synuclein behaves in a similar fashion (Amschl et al. BMC Neurosci 2013;14:1-14), although iatrogenic transmission has not been reported to date. Some researchers have even proposed that prion diseases be considered as a spectrum of neurodegenerative conditions. These conditions – including AD, PD, tauopathies, amyotrophic lateral sclerosis and Huntington’s disease – are characterized by misfolded proteins, or what has been recently called “malignant proteins (Walker & Jucker. Cerebrum 2016;2016;pii: cer-04-16; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC4938261/pdf/cer-04-16.pdf).
A more immediate implication is whether there is a need to improve sterilization methods to prevent the transmission of prions during transplantation or other surgical procedures. This issue requires further study.
Dr. Catherine Brodeur: Prion-like transmission of beta-amyloid and tau has been described and discussed in international conferences on Alzheimer’s disease over the past few years. Although some believe it is not possible, we should keep in mind that the pathogenesis of AD is still under debate and that an infectious-like process may be, at least in part, responsible for the disease.