Cerebral amyloid angiopathy, a rare brain illness, may be caused by prions

A PAPER PUBLISHED in this month’s Annals of Neurology, by Gargi Banerjee and David Werring of University College, London, adds to evidence that prion diseases are more widespread and varied than had been realised. Such diseases are caused by misfolded protein molecules that have the unfortunate property of triggering similar misfolding in others of their kind, and so transmitting their pathological character to previously healthy molecules. They came to public attention in the 1990s, when a variant form of the best known of them, Creutzfeldt-Jakob disease (CJD), was shown to be transmissible from cattle to people. This sparked fears of an epidemic among beef eaters, which fortunately failed to come to pass. Ever since, doctors have kept an eye open for anything similar. Dr Banerjee’s and Dr Werring’s results suggest cerebral amyloid angiopathy (CAA), a haemorrhage-causing illness closely related to Alzheimer’s, may be an example.

The story starts in 2015, when a team led by John Collinge, a neuroscientist at University College who is one of the world’s leading CJD researchers, examined the brains of eight people who had died from the illness after contracting it from human-growth-hormone treatments. Until 1985, when synthetic versions of the molecule became available, growth hormone was extracted from the pituitary glands of cadavers—along with (though this was not known at the time) CJD-causing prions, if such were present. Subsequent mixing of the extracts spread the prions widely. By the time the practice ceased, around 30,000 people had received injections of cadaver-derived growth hormone. By 2012, 450 cases of CJD around the world had been attributed to growth-hormone treatments.

Dr Collinge and his team found that six of the eight brains they examined contained, besides signs of CJD, deposits of amyloid-beta (aB), a protein which forms the plaques that are the principal hallmark of Alzheimer’s disease. In four of the six the deposits were widespread. Oddly, those concerned had died between the ages of 36 and 51—too young to show Alzheimer-related pathology in normal circumstances, given that they did not have genetic mutations linked to the early-onset version of the disease. The researchers concluded that the growth-hormone injections had probably also contained aB, and that this had transmitted amyloid pathology to the unfortunate four, in addition to CJD.

Last December a second piece of evidence emerged. Another team led by Dr Collinge obtained samples of cadaver-derived human growth hormone that had been stored since the 1980s. As they had suspected, they found that those samples which were of the type given to people in Britain who had contracted CJD did indeed contain aB. Moreover, mice genetically engineered to produce human amyloid protein that were injected with material from these samples developed significantly more amyloid plaques than did mice injected with synthetic growth hormone.

In the latest paper, Dr Banerjee and Dr Werring, who are not members of Dr Collinge’s research group, though they collaborate with it, describe three patients admitted to a specialist cerebral-haemorrhage clinic run by Dr Werring. Out of 663 patients referred there since the beginning of 2015, the three described were the only ones under the age of 50 who received a diagnosis of CAA. They were between 34 and 48 years old—and CAA rarely occurs in those under 55.

Intriguingly, the three had something else in common. All had undergone, three to four decades earlier, brain-repair procedures that involved the transplantation from a deceased donor of material from the dura mater, a membrane covering the brain. Dr Banerjee’s and Dr Werring’s study cannot prove that aB carried along with the transplants caused the disease, but both early-onset CAA and dura-mater grafts are rare, so mere coincidence seems unlikely.

On a practical level, Dr Banerjee and Dr Werring suggest that doctors now ask patients with symptoms that might indicate CAA if they have had neurosurgery earlier in life, especially if they are young. Though dura-mater grafts were banned in Britain in 1992, precisely to avoid the risk of prion transmission, some of those affected may not yet have surfaced—and while there is no cure for CAA, there are ways to reduce the risk of haemorrhage if doctors have the right diagnosis.

There is a more general point though. Stanley Prusiner, the neuroscientist who developed and proved prion theory (and also coined the term), has long argued that most neurodegenerative illnesses, Alzheimer’s included, are prion diseases of one sort or another. To many, that seems unlikely, as the only human prion diseases known at the moment all involve the same type of protein as CJD. If CAA, which involves amyloid-beta rather than the CJD protein, also proves prionic, it strengthens the idea that Dr Prusiner is right.