07 Feb 2013

Mounting evidence suggests that toxic proteins that cause Alzheimer's, Parkinson's, and other neurodegenerative diseases spread from neuron to neuron in a slow crawl through the brain. That news has sparked some concern among the media and the general public: Could these proteins pass between people, too? Highly unlikely, concluded scientists led by John Trojanowski, University of Pennsylvania, in a paper in the February 4 JAMA Neurology. Data from a large cohort of patients treated with human growth hormone from cadaver preparations suggest that injection of brain material does not spread Alzheimer’s (AD) or Parkinson’s disease (AD).

“This should help to eliminate any unnecessary concern that either disease can be transmitted from one human to another,” said Lary Walker, Emory University, Atlanta, Georgia. “If the diseases cannot be transmitted even under these relatively permissive conditions, then they are almost certainly not contagious under everyday circumstances.”

Abnormal proteins, such as Aβ and tau in AD (see ARF related news story and ARF news story), α-synuclein in PD (see ARF related news story), and TDP-43 in amyotrophic lateral sclerosis (ALS) (see Polymenidou and Cleveland, 2011), all creep through the brain along cell connections, corrupting healthy protein along the way. That rotten apple effect resembles prions that cause spongiform encephalopathies, such as mad cow disease and scrapie in farm animals, and Creutzfeldt-Jakob disease (CJD) and kuru in humans. They can be caused by exposure to contaminated brain material. If these prions can move within people and infect them, might these “prion-like” proteins do the same?

Trojanowski and colleagues looked for the answer in a group of more than 6,100 people who, through the U.S. National Hormone and Pituitary Program (NHPP), had received extracts prepared from pooled human cadaver pituitary glands. Until 1985, patients suffering from a shortage of human growth hormone received these preparations via intramuscular injection. In the 1980s, an outbreak of CJD passed to 200 of these people worldwide. Since 22 of them were included in the NHPP group, the scientists figured that if any other “prion-like” proteins could pass between people, this cohort provided the best chance of seeing it happen.

Before diving in, first author David Irwin and colleagues wanted to know if the pituitary gland contains any of the toxic proteins in question at all. Using immunostaining techniques, the researchers found small to moderate amounts of pathological tau, Aβ, and α-synuclein in the glands of both healthy and diseased autopsy brains (10 controls, nine patients with AD, two with progressive supranuclear palsy, eight with PD, and six with ALS). No evidence surfaced of any ALS-related proteins—TDP-43, FUS, and ubiquilin. Given these findings, and a relatively high prevalence of AD and PD in the general population, it is likely that patients treated with pituitary extracts did receive pathological tau, Aβ, and α-synuclein in their injections, wrote the authors.

Did those peptides take hold once injected? To find out, Irwin and colleagues pored over the death certificates of 769 people in the NHPP cohort. Neither AD nor PD appeared on any of them, suggesting injection of disease proteins does not cause these diseases. On the other hand, three people in the NHPP had died of ALS, surpassing the expected number for this sample. Despite that, the authors concluded that injections were probably not the cause. For one thing, pituitary samples lacked ALS-linked proteins, so they probably were not transferred in the first place. Plus, since the three ALS cases were diagnosed without modern techniques—one without an autopsy and another without TDP-43 analysis—scientists cannot be sure the diagnoses were accurate.

Of course, ALS proteins could have existed in the examined pituitary glands below levels detectable by immunohistochemistry, said Pierluigi Gambetti, Case Western Reserve University, Cleveland, Ohio. For that reason, the heightened number of ALS cases could raise a red flag—albeit a small one. Continued surveillance of the cohort, which Trojanowski and colleagues recommend, will help probe the potential infectivity of ALS further, Gambetti said.

Trojanowski used this study to distinguish non-prion from prion proteins. “Although cell-to-cell spread occurs with all of these disease proteins, the lack of infectivity seems to be a distinguishing feature of α-synuclein, tau, and Aβ that separates them from infectious prions,” Trojanowski told Alzforum. “It should considerably allay concerns that Alzheimer’s and Parkinson’s are infectious.”

Gambetti agreed to a point. “The lack of infected people does not discount the potential for infectivity,” he told Alzforum.

Could it simply take a longer incubation time before these neurodegenerative diseases show up? After all, many of the people in this cohort died young. Possibly, said Trojanowski, though more than half of the deceased patients survived past 15 years post-treatment and died without signs of neurodegenerative disease. Many patients are still alive 25 years past their treatment. Nevertheless, most of these people are only now on the cusp of the age when the prevalence of sporadic disease begins to jump up (around 60 years), so Trojanowski plans to repeat the study in five years to check on them.

It is also possible that some patients could be in the early asymptomatic phase of diseases, conceded the authors. For those people in this cohort who died without an autopsy, the authors do not know if they had subclinical pathology at the time of death. The research group will continue to review clinical and autopsy records of NHPP patients who die with neurodegenerative disease symptoms, Trojanowski said.—Gwyneth Dickey Zakaib

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References

News Citations

1. Aβ Sufficient for Seeding—But Is It a Prion? 23 Jun 2012
2. Mice Tell Tale of Tau Transmission, Alzheimer’s Progression 3 Feb 2012
3. Toxic Synuclein Corrupts Native in Wild-Type Mice 16 Nov 2012

Paper Citations

1. Polymenidou M, Cleveland DW. The seeds of neurodegeneration: prion-like spreading in ALS. Cell. 2011 Oct 28;147(3):498-508. PubMed.

Further Reading

Papers

1. Polymenidou M, Cleveland DW. The seeds of neurodegeneration: prion-like spreading in ALS. Cell. 2011 Oct 28;147(3):498-508. PubMed.

News

1. Chicago—ALS Protein SOD1 Painted as Disease Template 29 Dec 2012
2. Do Tau "Prions" Lead the Way From Concussions to Progression? 26 Nov 2012
3. Mice Tell Tale of Tau Transmission, Alzheimer’s Progression 3 Feb 2012
4. Keystone: Tau, Huntingtin—Do Prion-like Properties Play a Role in Disease? 14 Mar 2009
5. Aβ Sufficient for Seeding—But Is It a Prion? 23 Jun 2012
6. Synthetic Synuclein Corrupts Native Along Mouse Brain Networks 26 Apr 2012
7. Toxic Synuclein Corrupts Native in Wild-Type Mice 16 Nov 2012

Webinars

1. “Network Epicenters” in Healthy Connectome Predict Dementia 16 Apr 2012
2. Seeded Aggregation and Transmissible Proteopathy—Creepy Stuff Not Just for Prions Anymore? 30 Sep 2009