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Amyloid-Beta Pathology Seen in Brain Tissue of Patients Treated with Prion-Contaminated Growth Hormone: Experts Divided on How to Interpret the Findings

Hiscott, Rebecca

doi: 10.1097/01.NT.0000472961.18425.a7
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Researchers observed amyloid-beta (Abeta) pathology in the postmortem brain tissue of patients who developed Creutzfeldt-Jakob disease following childhood treatment with prion-contaminated cadaveric human growth hormone. The findings offer evidence of iatrogenic transmission of Abeta pathology and suggest that a prion-like mechanism is involved in Alzheimer's disease, according to the researchers. But infectious disease experts are divided over the strength of the evidence.

Amyloid-beta (Abeta) pathology and cerebral amyloid angiopathy (CAA) were evident in the postmortem brain tissue of a small number of patients who developed Creutzfeldt-Jakob disease (CJD) following childhood treatment with prion-contaminated cadaveric human growth hormone (c-hGH), UK researchers reported in the September 9 online edition of Nature.

The finding offers evidence of iatrogenic transmission of Abeta pathology, and “lends support to the idea that so-called ‘prion-like’ mechanisms are important in Alzheimer's disease,” study author Simon Mead, PhD, a consultant neurologist and clinical lead of the UK National Prion Clinic at the National Hospital for Neurology and Neurosurgery in London and an investigator with the UK Medical Research Council (MRC)'s Prion Unit, told Neurology Today in an email.

The finding was widely reported in the scientific and mainstream media, sometimes accompanied by sensationalist headlines claiming evidence of Alzheimer's disease (AD) transmission. But both the study authors and independent infectious disease experts who spoke with Neurology Today emphasized that the findings do not suggest that AD itself is transmissible.

“There is absolutely no suggestion from our work that AD is a contagious disease or that there would be any risk to relatives, spouses, or carers of patients with AD,” Dr. Mead said.

Experts who spoke with Neurology Today praised the study for looking at this unique patient cohort, but some questioned whether the evidence was strong enough to support the researchers' hypotheses.

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Between 1958 and 1985, an estimated 30,000 children with short stature worldwide were treated with human growth hormone extracted from the pituitary glands of cadavers. Some of these c-hGH preparations were later found to be contaminated with misfolded prion proteins, giving rise to cases of iatrogenic Creutzfeldt-Jakob disease. By the year 2000, 38 of the 1,848 UK patients treated with c-hGH had developed CJD, the Nature authors reported. (Growth hormone treatments are now genetically engineered, eliminating the risk of prion contamination.)

Dr. Mead and his colleagues examined the brains of eight patients in the UK's National Prion Monitoring Cohort who received c-hGH in childhood and subsequently died from CJD. The patients were between the ages of 36 and 51 at death, with disease incubation periods ranging from 27.9 to 38.9 years.



The researchers found that four patients had Abeta pathology in the gray matter and blood vessel walls, while two more showed sparse Abeta deposits. There was also widespread cortical and leptomeningeal cerebral amyloid angiopathy in three patients and focal CAA in one.

Abeta has been shown in past research to accumulate in the pituitary glands, a finding Dr. Mead and colleagues replicated in the current study. Given the prevalence of Abeta pathology in the general population, “there have undoubtedly been lots of glands contaminated with Abeta that have gone into these preparations,” the study's corresponding author, John Collinge, MD, a professor of neurology and head of the Department of Neurodegenerative Disease at the University College London Institute of Neurology, director of the university's MRC Prion Unit, and a Fellow of the Royal College of Physicians, said in a telephone news briefing with reporters in September.

“Of course,” he said, “we have no way of knowing if these individuals would have gone on to develop the full features of Alzheimer's disease, because they died of CJD before they had time for that to happen.”

The findings suggest that some healthy adults who received c-hGH in childhood may have a higher risk of Alzheimer's disease, he said.

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This was an observational study, so it offers no definitive proof that the contaminated growth hormone preparations were responsible for the patients' abnormal Abeta pathology, Dr. Mead and colleagues noted. The patients also lacked evidence of neurofibrillary tau tangles, another hallmark of AD. However, none had any of the genetic risk factors that might predispose them to early-onset AD or excessive Abeta deposition, they said.

In order to rule out the possibility that CJD or prion infection itself increased the likelihood of Abeta pathology in these patients, the researchers examined brain tissue from 116 individuals with other prion diseases, including sporadic CJD, variant CJD, and inherited prion disease. However, none had comparable Abeta pathology, they reported.

There was also little overlap of Abeta and prion protein pathology in the brains, suggesting the proteins did not “cross-seed” but rather developed independently, Dr. Mead said.

“We looked very hard at the possibility that this [Abeta pathology] was secondary to their prion disease, but found several lines of evidence against this idea,” he said. “The only other possibility we think is plausible is that amyloid-beta seeds were transmitted by the c-hGH treatment.”

To replicate the Nature findings, Dr. Mead and his colleagues will now attempt to seed Abeta pathology in transgenic mice using archival c-hGH. “This might allow us to better characterize the structure of amyloid-beta seeds, and thereby help work aiming to target them therapeutically and diagnostically,” he said.

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Independent infectious disease experts who spoke with Neurology Today were somewhat divided over the findings. Thomas Wisniewski, MD, director of the Center for Cognitive Neurology at New York University (NYU) Langone Medical Center and the Lulu P. and David J. Levidow professor of neurology and a professor of pathology and psychiatry at NYU, praised the work as an “elegant study” conducted in a unique patient cohort.

“I think it gives quite conclusive evidence that amyloid-beta pathology can be transmissible from person to person under certain limited circumstances,” he said. “The drawback of the study is that it's in very few cases, but their interpretation of the data is, I think, very sound.” He added that the robust findings in numerous animal models lend further credence to the results.

The paper “highlights the importance of this prion-like mechanism in all neurodegenerative disorders,” Dr. Wisniewski said, and suggests that “therapies that specifically target these species of pathological protein aggregates are the ones that are most likely to be effective in the future.”

“It's really unusual to see this much Abeta deposition in people that young who do not carry the APOE [apolipoprotein] e4 allele,” said Lary C. Walker, PhD, who coauthored an editorial accompanying the study in Nature. Dr. Walker's research has shown that Abeta pathology can be seeded in transgenic mice by inoculating them with brain tissue from humans with AD. “Between the evidence from animal experiments and the evidence from the control cases, it seems fairly likely that a prion-like seeding process is taking place in these patients,” he said.

The findings may also have implications for neurosurgical practices, Dr. Wisniewski said. “Abeta, like the prion protein, does bind to metals such as surgical instruments. How much of a potential risk that is [for Abeta transmission] has not been addressed,” he said. “Given the emergence of this data, I think it behooves us to see if this is a real risk or not.”

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But other experts questioned the strength of the findings. “Yes, the transmission of Abeta pathology to humans is in theory possible, albeit by unnatural means...but is not substantiated by this Nature paper,” said Carlo Condello, PhD, an assistant professor of neurology in the Institute for Neurodegenerative Diseases at the University of California, San Francisco (UCSF). He argued that “while experimental evidence for this in animal models is robust,” the small number of patients studied in the Nature paper weakens the findings.

Dr. Condello noted that the four patients with widespread Abeta pathology were older than those without the pathology. “We know that people are likely developing [Abeta] deposits in their brains two or three decades prior to being diagnosed with Alzheimer's,” he said. “So if most people are coming to the clinic in their late 60s or 70s with significant cognitive decline and memory loss, it is very likely that their brains 20 or 30 years ago — in the 40s and 50s range — might have had some early levels of Abeta.” It is therefore less surprising that these four patients showed more significant Abeta deposits, he said.

“Alternative explanations like poor clearance mechanisms in any diseased or injured brain might be contributing to elevated Abeta levels,” Dr. Condello added. He cited a paper published in September in the Journal of Neuropathology and Experimental Neurology, in which Steven J. DeArmond, MD, PhD, and colleagues found mild to moderate levels of Abeta in 46 of 266 sporadic CJD patients, including several patients in their early 50s. This suggests “that CJD pathology can indirectly drive increases in Abeta deposition,” Dr. Condello said.

John Q. Trojanowski, MD, PhD, a professor of pathology and laboratory medicine and co-director of the Penn Center for Neurodegenerative Disease Research at the University of Pennsylvania, likewise questioned the findings in light of his own research in patients with iatrogenic CJD, as well as numerous epidemiology research studies from the past decade.

Dr. Trojanowski and colleagues reported in JAMA Neurology in 2013 that there was “no evidence to support concerns that AD proteins are ‘infectious’ or transmitted from one person to another,” he said.

Given the small number of patients in the Nature paper, “it's just not very compelling evidence of Abeta transmission,” Dr. Trojanowski said. It is possible that the four patients with widespread Abeta pathology were simply “outliers” compared with others in their age group, he said.

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Another infectious disease expert suggested that both camps may be right.

“One of the big questions that comes out of the Nature paper is whether the [CJD] prion induced Abeta pathology or whether Abeta pathology itself is prion-like and was seeded, or whether it was a little bit of both. The authors felt their data was strongly suggestive of direct seeding, as opposed to what they called ‘cross-seeding,’” said Michael Geschwind, MD, PhD, a neurologist at the UCSF Memory and Aging Center and an associate professor of neurology and the Michael J. Horner chair in neurology at the UCSF School of Medicine. Dr. Geschwind specializes in the assessment and treatment of rapidly progressive dementias, including prion diseases such as CJD.

But the two concepts are not mutually exclusive, he said. “I do think there's an abundance of evidence that these proteins can seed within the brain, and it's certainly plausible that some of the Abeta pathology we're seeing [in this paper] could have been from direct seeding. But there's a growing body of evidence suggesting that there's also a cross-relationship between prion disease or PrP [prion-related protein] scrapie and Abeta, and maybe even tau. There may be interactions between these proteins, or the mechanisms may be similar.”

Dr. Geschwind said the Nature study was “clever” and “important,” but emphasized that more research needs to be done to replicate and validate the findings. And in the meantime, he advised researchers and clinicians against overzealously interpreting the findings.

“There can be a fine line between caution and being over-cautious, interfering with our ability to do research in a facile, reasonably priced manner and deliver patient care,” he said. “Until we really have good evidence that these [Abeta proteins] are transmissible through standard medical procedures...we have to proceed cautiously about how far we want to extend prion precautions to other neurodegenerative diseases.”

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