A re-opened case from the history of medicine suggests that “seeds” of a protein that aggregates in the brains of people with Alzheimer’s disease may have been transmitted with human growth hormone, brain covering grafts, or neurosurgical instruments that hadn’t been adequately sterilized – decades ago.
Just in case the media misinterprets the new findings, here’s a crucial caveat from the lead researcher of the new report in Nature, John Collinge, of the University College London Institute of Prion Diseases. He spoke with reporters yesterday:
“Although we generated evidence that Alzheimer’s pathology may be transmissible, there is no suggestion, in our work or in anyone else’s, that Alzheimer’s disease is contagious. You can’t catch it with intimate contact as a carer or a loved one of someone with Alzheimer’s. It is only transmitted as a result of a particular medical procedure.” A condition caused by a procedure is called iatrogenic.
The “proteopathic seeds” of Alzheimer’s disease found their way into a few patients’ brains along with the infectious proteins – aka prions – that cause another brain condition, Creutzfeldt-Jakob disease (CJD).
From 1958 to 1985, approximately 30,000 children with very short stature received human growth hormone (hGH) from the pituitary glands of dead people, a preparation termed cadaveric, or c-hGH. “Thousands of glands were pooled and extracts used to treat the children,” said Dr. Collinge.
In 1985, three of the patients were diagnosed with the extremely rare CJD, when an occasional gland in the mix came from someone incubating CJD. Fortunately, recombinant DNA technology had recently made it possible to mass-produce safe synthetic hormone, which immediately replaced the cadaver source.
By the year 2000, 267 cases of iatrogenic CJD had been identified.
CJD is an invariably fatal, utterly horrific brain disease that progresses in a few months from diminished memory, changes in behavior, loss of coordination, and visual disturbances to blindness, profound weakness, involuntary movements, and coma. Prion diseases like CJD are set into motion when a rare three-dimensional shape of a protein causes copies with the more common shape to contort into the rare form, like a biochemical domino effect.
The new paper continues a story reported in 2015 in Nature that analyzed the brains of 8 people who had died in their 30s or 40s from CJD and had received the cadaveric growth hormone as children or teens. Four had widespread amyloid beta, one of two proteins that builds up in Alzheimer’s disease; 2 had moderate deposits; and one had some of the protein – only one person hadn’t developed the overload.
“The patients must have had a very long incubation. The majority had substantial deposits of amyloid beta protein, both in brain tissue and in the blood vessels,” said Dr. Collinge. The brain blood vessel involvement, also part of Alzheimer’s, is called cerebral amyloid angiopathy, or CAA.
The finding was a surprise, especially in young people. “We couldn’t identify any genetic factors, which led us to hypothesize that the reason they got this is because those growth hormone batches prepared many years ago were from human tissue that may have been contaminated with seeds of beta amyloid, as well as with prions that caused the CJD,” Dr. Collinge said.
Could Alzheimer’s be transmitted? Precedents suggested so. Experiments reported in 1993 injected extracts from Alzheimer’s patients into monkeys and from 2006 into mice, and both species developed brain clog. So in their 2015 paper, the researchers proposed that the hGH had been tainted with Alzheimer’s seeds as well as with the prions that caused CJD. The patients lived long enough for their brains to have accumulated the telltale amyloid beta deposits, which lie between neurons, but not the tau tangles that strangle neurons from within later in the disease.
Dr. Collinge and his team weren’t satisfied with their conclusions in 2015. They hadn’t shown that the hGH had triggered the plugged cerebral blood vessels of CAA, just that both were present. “Given the public health importance, we went on to get experimental evidence to investigate the hypothesis further. That’s the current Nature paper,” he said.
Medical Detectives Recreate the Scene
The researchers were able to get their hands on the very vials of befouled c-hGH that had been injected into the kids who developed CJD. “Fortuitously, an archive at Public Health England had kept old growth hormone, from 30 to 40 years ago, and we were able to identify some of the material with which the 8 patients we reported on 3 years ago were injected. We pieced together some of the batches,” Dr. Collinge said. And what had happened started to become clear.
Back then, hGH was extracted from human pituitary glands in a few ways, with patients typically receiving a mixed bag of the hormone. “We became suspicious of one particular method, called HWP, because everybody in the UK who has developed CJD from this treatment has had at least one set of injections with this method. The preparation didn’t use a chromatography step, which may have allowed protein aggregates through into the purified material,” Dr. Collinge explained.
The UK researchers sent the implicated vials and some others as distractors to co-author Dominic Walsh at Harvard. He conducted blinded analyses that found significant quantities of amyloid beta and tau, the hallmarks of Alzheimer’s, in all the HWP vials – and not in any of the others.
But finding the Alzheimer’s proteins in the old growth hormone preps didn’t shed light on how they got there. The next step: inject the seeds into animals to see what happens.
That idea led to experiments using mice genetically modified to produce human amyloid precursor protein, which is trimmed to yield the peptide that gunks up the Alzheimer’s brain. Co-authors Takashi Saito and Takaomi Saido, at the RIKEN Center for Brain Science in Wako, Japan engineered the animals.
“We injected the mice with preparations of the ancient pituitary hormone from the limited number of HWP vials,” directly into their brains, said Dr. Collinge. The researchers also set up several controls:
- injecting other mice with synthetic hGH to rule out the hormone causing the accumulating amyloid beta
- injecting non-GM mice
- giving mice extracts from the brains of people who’d died of Alzheimer’s.
When the mice were killed many months later and their brains examined, the results were astonishing: only the mice injected with material from the suspect HWP batches developed pathology, exactly as if they’d received bits of amyloid plaques and plugged blood vessels from Alzheimer’s patients.
“These experiments reproduced the pathology and formally confirmed the seeding activity. I was rather amazed that we could seed so easily from this material that had sat around as dry powder for 30 to 40 years,” concluded Dr. Collinge.
In both the mice and the patients, CJD had proved lethal before the Alzheimer’s had progressed to tau deposits.
Do Dura Mater Grafts and Surgical Instruments Spread Seeds Too?
Human growth hormone may not be the only route to Alzheimer’s seeding.
After the 2015 paper appeared, the researchers began receiving reports from colleagues that implicated CJD in patients who’d received grafts of the dura mater, the membrane enclosing the brain and spinal cord. The CJD prions arose beneath the grafts, which were used as patches in neurosurgeries. Might amyloid beta seeds show up too?
The risk of developing CJD from dura grafts is even lower than from hGH. The study from 2000 found that only 0.3% to 4.4% of patients given pooled growth hormone acquired CJD compared to 0.02% to 0.05% of those receiving dura mater grafts.
A third route of transmission of CJD, and possibly amyloid beta, is through instruments used in neurosurgery. Again, it’s rare.
From 1998 through 2012, only 19 cases of iatrogenic CJD linked to exposure to contaminated surgical instruments were reported to the CDC. Two were eye surgeries and 17 introduced electrodes and other tools into the brain during diagnostic procedures. The hospitals had cleaned and reused instruments, and 11 of the 19 facilities couldn’t track down the implicated devices. The contaminations took place before 1976. Again, a long incubation period.
A report from May 2018 extends the surgical instrument connection to CAA, the blood vessel manifestation of Alzheimer’s. The researchers described four patients who suffered brain bleeds due to CAA three decades after undergoing neurosurgeries as children or teens, adding to three other known cases. “These findings raise the possibility that amyloid beta pathology may be transmissible, as prion disease is, through neurosurgical procedures,” the researchers concluded.
Dr. Collinge agrees, but with caution. “Any risk would be very small and I wouldn’t discourage anyone from having neurosurgery. It’s also important that we do further research and develop new ways of removing these seeds from instruments to prevent any transmission from this route.”
Prevention Going Forward and Clarity Looking Back?
“Given the lack of disease-modifying therapeutics for Alzheimer’s disease and other distressing and fatal neurodegenerative conditions, it will be important to consider introducing improved methods for removing proteopathic seeds from surgical instruments on a precautionary basis,” ends the new report in Nature.
In an accompanying News and Views, Tien-Phat V. Huynh and David M. Holtzman, from Washington University in St. Louis, argue that the remarkable stability of the proteopathic seeds “emphasizes the importance of not using biological material prepared from the human central nervous system for injection or transplantation into patients, unless these materials are adequately screened or there is no other option. Similarly, it is crucial that surgical instruments that come into contact with the human brain are appropriately treated to remove seeds of misfolded forms of peptides and proteins such as amyloid beta, tau or prion protein.”
While efforts going forward will reduce the risk of iatrogenic CJD towards zero, it might also be interesting to examine health records going backwards to demonstrate or rule out that people who have or have died of Alzheimer’s disease were more likely to have had neurosurgery. It’s possible that the saga of the ultra-rare iatrogenic CJD may be pointing to a similar origin of a much more prevalent brain disease, Alzheimer’s.