CME Author: Zeena Nackerdien
Study Authors: Silvia A. Purro, Mark A. Farro, et al.
Target Audience and Goal Statement:
Neurologists and gerontologists
The objective is to evaluate the evidence supporting a transmissibility theory of Alzheimer’s disease (AD).
Background and Study Objectives:
AD is the most common cause of dementia among older adults. It is the sixth leading cause of death in the U.S. and the fifth leading cause of death for those ages ≥65. It is also the most expensive disease in America with 2017 estimated direct costs of $259 billion.
Deaths from AD have almost doubled in the last 14 years. While no disease-modifying treatment is available, a better understanding has developed of the neuropathology of AD in recent years. For instance, AD is known to be characterized by extracellular increases of amyloid plaques, which consist of β-amyloid peptide (Aβ), and by intraneuronal accumulation of intracellular neurofibrillary tangles, which are composed mainly of hyperphosphorylated tau (p-tau) protein aggregates. Clumps of Aβ in AD brains are widely regarded as a hallmark of the disease.
Recent studies have pointed out that Aβ and p-tau mimic several major characteristics of cellular prion proteins — proteins that can become infectious and cause neurodegenerative diseases — such as iatrogenic Creutzfeldt-Jakob disease (iCJD). The characteristics include mechanisms of accumulation and propagation, and formation of distinct Aβ and p-tau species.
The notion that abnormal proteins could be transmissible dates back to earlier results, including a 2015 finding of Aβ plaques and cerebral amyloid angiopathy (CAA) in the brains of seven of eight relatively young recipients of cadaver-derived human growth hormone (c-hGH) who had died of iCJD. Because Aβ pathology is hardly ever found in young adults without risk factors for AD or CAA, authors of the 2015 study suggested that the c-hGH used to treat the patients for short stature might have been contaminated with Aβ seeds in addition to misfolded proteins. But experts critiqued the study, stating that in the absence of appropriate controls, the conclusions were premature, since pre-existing and underlying conditions could by themselves give rise to Aβ pathology and abnormal brain structures.
Because the neuropathological features of the disease differed from other prion-disease patients and population controls and, allied with the ability of AD brain homogenates to seed Aβ deposition in animal models, authors of the current study argued that there was a possibility of human-human disease transmission due to c-hGH contamination with Aβ seeds. The investigators sought to confirm earlier findings, as the results would hold implications for the management of AD.
Synopsis and Perspective:
A total of 1,883 patients were treated with c-hGH between 1958 and 1985 in the U.K. and through July 2018, 80 have developed iCJD, with incubation periods in excess of 4 decades. Archived c-hGH batches to which eight patients were exposed in an earlier study were used for seeding studies in mice genetically engineered to express human versions of Aβ.
The 40-residue peptide Aβ (Aβ40) represents the most common Aβ isoform in the brain, while the 42-residue Aβ (Aβ42) is significantly elevated in certain forms of AD. “We show that certain c-hGH batches to which patients with iCJD and Aβ pathology were exposed have substantial levels of Aβ40, Aβ42, and tau proteins, and that this material can seed the formation of Aβ plaques and cerebral Aβ-amyloid angiopathy in intracerebrally inoculated mice expressing a mutant, humanized amyloid precursor protein, stated John Collinge, MD, of University College London (UCL), and colleagues.
While these findings do not demonstrate that AD can be transmitted, they provide experimental evidence for the hypothesis that amyloid beta pathology can be transmitted by iatrogenic means, they wrote in Nature.
“This represents a new way of thinking about AD,” Collinge said at a press briefing. “There may be certain circumstances — hopefully, they’re rare medical circumstances — in which transmission of the pathology can occur.”
Source Reference: Nature, Dec. 13, 2018, DOI:10.1038/s41586-018-0790-y
Study Highlights: Explanation of Findings
In an accompanying editorial, Tien-Phat V. Huynh, a MD-PhD candidate, and David M. Holtzman, MD, of Washington University in St. Louis, commented on the detection of Aβ in all c-hGH samples prepared using the Hartree-modified Wilhelmi (HWP), but not the non-HWP preparations. The editorialists concurred with the investigators that separation techniques used in the latter procedures might have decreased contamination by Aβ. Compared with genetically engineered mice inoculated with recombinant hGH (rhGH), the researchers noted markedly more Aβ plaques and CAA in comparators inoculated with HWP-prepared c-hGH.
“This data indicate that the vials used for human treatment indeed contained amyloid beta material that was competent to seed the accumulation of pathological amyloid,” said Claudio Soto, PhD, of the University of Texas McGovern Medical School at Houston, who was not involved with the study. “This study, added to the previous one, strongly suggests that amyloid beta deposition seen in patients was induced in a manner reminiscent to prions.”
More than 15 years ago, Soto developed a hypothesis that beta-amyloid plaques were a disorder of protein folding, analogous to prion pathology, such that one misfolded amyloid protein could catalyze misfolding of others to form toxic aggregates.
The question still remains whether transmission of Alzheimer’s pathology is restricted to these rare conditions — such as the use of human-derived products for treatment — or can occur under more common medical practices like blood transfusions, Soto told MedPage Today.
Concerns about transfusions have been around for some time, noted Bart De Strooper, MD, PhD, also of UCL. “Several studies using mice that were similarly genetically primed to develop AD-like symptoms have shown that this route of transmission is theoretically possible,” he told the U.K. Science Media Centre.
These findings prompted a large retrospective study in Sweden and Denmark that found no evidence for increased rates of AD or Parkinson’s disease in patients who received blood from donors who went on to develop those diseases. “Those results provided real-world evidence that any such risk is extremely small. Nevertheless, it is worth monitoring these risks,” said De Strooper, who was not involved in the study.
While Collinge emphasized there is no suggestion AD is contagious or transmissible by blood, he noted it’s important to evaluate the risks of iatrogenic transmission of amyloid beta pathology.
“We have now provided experimental evidence to support our hypothesis that amyloid beta pathology can be transmitted to people from contaminated materials,” he said. “It will be important to review risks of transmission of amyloid pathology by other medical procedures still done today, including instruments used in brain surgery, drawing on other research and what we already know about accidental CJD transmission.”
Mice in this study received samples injected directly into their brains, while people who received the c-hGH preparations decades ago had injections intravenously or intramuscularly, observed the editorialists.
It’s worth noting that the stored vials had been maintained at ambient temperature since the mid-1980s, they added. “Their ability to transmit amyloid beta pathology seen in this study corroborates the idea that amyloid beta seeds are remarkably stable,” they noted. “This property of amyloid beta seeds emphasizes the importance of not using biological material prepared from the human central nervous system for injection or transplantation into patients during neurosurgical or medical procedures, unless these materials are adequately screened or there is no other option.”
“Future studies in animals should assess whether the route of administration influences the ability of material containing misfolded amyloid beta to cause brain amyloid beta pathology, and should investigate the minimum amount of material that has pathological effects,”Holtzman and colleague wrote.
The mice in this study were genetically modified to be prone to amyloid beta pathology, but not tau. The samples of human growth hormone people were exposed to also contained tau, Collinge said, and future studies will assess whether the tau in these vials can seed aggregation in other mice.
Whether the seven people who developed Aβ pathology in the earlier study would have manifested clinical symptoms is unclear, as they died prematurely of iCJD. Surveillance of the remaining c-hGH recipients is also needed to rule out possible treatment-related transmission of various brain pathologies.
Original story for MedPage Today by Judy George
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner