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(HealthNewsDigest.com) – A retrospective study examined the health records of nearly 1.5 million patients in Sweden and Denmark to see whether those who received blood from donors who later developed neurodegenerative disorders eventually came down with the disorders themselves. The conclusion: “[N]o evidence of transfusion transmission of dementia, Alzheimer disease or Parkinson disease.”
“To me, it’s a very strong negative study that convincingly shows that concerns that these neurological disorders could be transmitted by blood donation are not valid,” said Michael P. Busch, MD, PhD, an author of the research, which was recently published in the Annals of Internal Medicine. Busch is codirector of the San Francisco–based Blood Systems Research Institute, which specializes in studying transfusion-transmitted infectious diseases.
Colin Masters, MD, cohead of the neurodegeneration division of Australia’s Florey Institute of Neuroscience and Mental Health and a pioneer in the genetics and proteopathy of AD, said he was “very reassured” by the results, noting they “coincide with one’s clinical impressions that blood transfusions are not a major risk factor for the more common neurodegenerative diseases.”
Masters, a professor at the University of Melbourne who was not connected with the research, called it “a major study from the Swedish and Danish blood transfusion databases, probably the largest ever conducted.” Rating the strength of its conclusions on a scale of 1 to 10, he described them as “very substantial, at least a 9.”
The finding comes at a time when researchers, still struggling with the etiology of AD, PD, and certain other neurodegenerative diseases, are focusing on the growing possibility that the misfolded proteins that characterize them can be passed along, in some circumstances, to other humans.
Such misfolded proteins are the underlying contagion in rare disorders likeCreutzfeldt-Jakob disease (CJD), fatal familial insomnia, and the newly linked multiple system atrophy. In these diseases, aberrant proteins called prions touch off a chain reaction of misfolding throughout the brain.
Once they gain a foothold in neural tissue, prions act like Svengali, relentlessly inducing molecules like the normal cell-surface protein PrPC to refold using the prions’ deviant structure as a model. The resulting dysfunctional proteins then aggregate into large clumps that the body cannot clear. Eventually, the brain tissue becomes pitted, like a sponge, and death inevitably follows.
One of prions’ most insidious properties is their transmissibility both from cell to cell and from person to person. Creutzfeldt-Jakob disease has been transmitted via brain surgery with insufficiently autoclaved instruments used previously on patients with CJD.
Both AD and PD share characteristics with prion diseases. For example, in AD, aberrant proteolytic processing of amyloid precursor protein (APP), a naturally occurring brain molecule whose normal function is not well understood, producesamyloid beta (Aβ) protein fragments. Certain isoforms of Aβ are prone to misfolding and act prionlike in that they can seed the aggregation and accumulation of Aβ into sticky plaques that may inhibit transmission between neurons, especially those responsible for cognition and memory. In PD, the relevant protein is α-synuclein, whose deviant form aggregates into Lewy bodies that interfere with multiple brain functions. Perhaps most tellingly, small concentrations of these 2 aggregates, called oligomers, are directly toxic to healthy neurons and can jump from cell to cell, as in prion disorders.
Scientists believe these transformations are present in the brains of people likely to develop AD and PD well before symptoms appear. There is some evidence that donor tissue from such as-yet asymptomatic carriers may promote development of neurodegenerative pathology in recipients. Autopsies of the brains of 8 people who died of CJD decades after receiving human growth hormone (hGH) extracted from the pituitary glands of cadavers found that 6 not only had prion damage but also had the amyloidosis seen in AD, even though none were older than 51 years when they died or had mutations associated with early-onset AD. Such infectivity was not found in an earlier study that used a database listing US recipients of cadaver hGH to see if AD or PD appeared on the death certificates of any of the 796 deceased.
Conversely, when Stanley B. Prusiner, MD, who won the Nobel Prize for his trailblazing work in prions, and his colleagues injected Aβ aggregates into miceengineered for AD susceptibility and studied them in vivo using advanced imaging technology, they found the aggregates “self-propagated” in the manner of prions. The group went so far as to call it “compelling evidence” that Aβ aggregates areprions.
Given the emerging possibility that misfolded proteins in AD and PD may be transmissible and behave similarly to prions, a critical question to Busch was whether a blood donor with AD or PD brain changes who was asymptomatic could pass along a misfolded brain protein or other toxic agent to the recipient, starting the cascade of events that leads to disease many years later.
Such a grim prospect arose when unpublished reports surfaced that transgenic mice had shown plaque progression after infusion of Aβ aggregates parenterally, Busch explained. Such transmission “would be analogous to blood transfusion,” he says, “and could potentially create substantial anxiety in the transfusion community.”
It occurred to Busch that the Scandinavian Donations and Transfusions (SCANDAT2) database might be useful to test the premise. The database was assembled from computerized records maintained in Swedish and Danish blood banks since 1968 and 1981, respectively, and the data were then linked with nationwide health registers, creating long-term follow-up information on the health care of all transfusion donors and recipients through 2012.
“It’s by far the most comprehensive database in the world currently,” said Busch, who collaborated with Gustaf Edgren, MD, PhD, research group leader at the Department of Epidemiology and Biostatistics at Sweden’s Karolinska Institutet and principal Swedish investigator at SCANDAT2.
Their study was designed to ascertain the risk of acquiring a neurodegenerative disease from an affected donor using 2 different yardsticks: increased disease concordance between donors and recipients, or excess disease occurrence among all recipients of blood from a particular donor.
Of the 1 465 845 patients whose records were reviewed, 2.9% received at least 1 unit of blood from a donor diagnosed with a neurodegenerative disorder within 20 years after donation. Follow-up of recipients began 6 months after the first transfusion to allow those already seriously ill with 1 of the targeted disorders but undiagnosed at the time to present with the disease. After excluding such recipients, the remainder were followed until a diagnosis of AD, PD, another dementia, or the study’s December 31, 2012, cut-off date.
The researchers’ key finding was no disease concordance between donors and recipients, and similarly, no excess occurrence of disease beyond normal statistical incidence in all recipients of blood from 1 donor.
“What we did was measure the hazard ratio, which asks what the probability is of developing, say, Alzheimer’s from a donor who later developed it, compared with the probability of getting Alzheimer’s after getting blood from a donor who never developed it,” Busch said. “The hazard ratios were all essentially 1.0, which means there is no difference in the incidence rates.”
An important control in the study, Busch noted, was a sensitivity component to prove the validity of the team’s methodological approach.
“We chose to look at hepatitis C transmission between donors and recipients in the same database,” he explained. “We found there was significantly increased risk—the hazard ratio was 8—of getting hep C from a blood donor who was later diagnosed. But after 1992, the year when the hep C virus was discovered and began to be screened for in the blood supply, there was none. This told us that our analytical method was sensitive.”
Busch said the value of the study lies in helping to obviate the need for agencies like the US Food and Drug Administration to devise blood screening tests for AD and other neurodegenerative diseases.
“A negative finding may not be real exciting to the lay press,” he said. “But it preempts potential fear, heavy investment, and onerous effort in screening technologies.”
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