NIA Weighs in on Neurodegenerative Disease Transmissibility

An expert panel convened by the NIH found little evidence that Alzheimer’s, Parkinson’s, and similar neurodegenerative diseases can be transmitted in a prion-like fashion, such as after contact with biological specimens or contaminated surgical instruments. Still, writing in the October Journal of Neuropathology and Experimental Neurology, the panel, led by Matthew Frosch, Massachusetts General Hospital, Boston, consider current research on this topic inadequate and recommend that critical questions be studied so any risk of iatrogenic spread can be truly assessed. The panel broadly agrees with a whitepaper a European working group recently published on the topic (Sep 2020 news). 

Toxic forms of amyloid-β, tau, and α-synuclein can act as seeds to coax misfolding and aggregation of normal versions of these proteins in healthy brains. For example, injecting minuscule amounts of toxic Aβ into mouse brain prompts rampant formation of amyloid plaques months later (Oct 2011 news). Researchers have long asked if this could happen in people too. Possibility turned reality when a series of papers documented unusually young cases of cerebral amyloid angiopathy, an Aβ-based disease of the vasculature, among people who had come in contact with Aβ-contaminated tissue and medicines decades earlier (Sep 2015 news; Jan 2016 news; Hervé et al., 2018; Jan 2019 news). These cases were exceedingly rare and linked to medical practices that have since been dropped or changed. Even so, they raised the question of whether neurodegenerative disease might spread via contaminated surgical instruments, or even blood or plasma, and working groups in the EU and U.S. set out to address it.

In this new paper, first author David Asher, U.S. Food and Drug Administration, Silver Spring, Maryland, and colleagues review current knowledge about proteopathic seeding of Aβ, α-synuclein, and tau, the three proteins that have been most studied in this regard. They conclude there is no evidence that tau can be transmitted among people. The evidence for Aβ and α-synuclein transmissibility is limited to surgical grafts and growth hormone formulations that are no longer in use. Nevertheless, the authors acknowledge that there is little data to go on. “Thus, while no clear data currently suggest a public health risk to individuals or physicians, this issue has not been deeply explored,” they note.

To better assess risk of such transmission, Asher and colleagues call for more rigorous characterization of proteopathic seed infectivity, stability, distribution in the body, e.g., brain versus blood, inactivation methods, and likely exposure in the environment.

“We fully support the recommendations by Asher and colleagues for further investigations regarding the molecular identity of proteopathic seeds and their potential transmission between humans, whether in a research setting or during a medical procedure,” commented Elsa Lauwers of KU Leuven, Belgium, and colleagues, authors of the EU whitepaper (see full comment below).—Tom Fagan

Comments

  1. Asher and colleagues present the conclusions from a working group convened by the National Institute on Aging to evaluate the potential risk of handling proteopathic seeds associated with neurodegenerative diseases. They provide a concise and informative review of key features of three type of seeds (Aβ, tau, and α-synuclein): their misfolding and polymerization propensity, the stability of the resulting aggregates, their ability to “propagate” along neural systems, and the conditions under which they can be transmitted between individuals, including between species.

    We consider this review an excellent complement to the recent publication by our own, similar working group (Lauwers et al., 2020), where we focused on human transmission and, given the available literature, essentially on Aβ seeds. Importantly, both groups concluded that even though iatrogenic transmission of proteopathic seeds can occur under very specific conditions, there is no evidence for such transmission of a neurodegenerative disease other than Creutzfeld-Jakob disease.

    We fully support the recommendations by Asher and colleagues for further investigations regarding the molecular identity of proteopathic seeds and their potential transmission between humans, whether in a research setting or during a medical procedure.

    References:

    Lauwers E, Lalli G, Brandner S, Collinge J, Compernolle V, Duyckaerts C, Edgren G, Haïk S, Hardy J, Helmy A, Ivinson AJ, Jaunmuktane Z, Jucker M, Knight R, Lemmens R, Lin IC, Love S, Mead S, Perry VH, Pickett J, Poppy G, Radford SE, Rousseau F, Routledge C, Schiavo G, Schymkowitz J, Selkoe DJ, Smith C, Thal DR, Theys T, Tiberghien P, van den Burg P, Vandekerckhove P, Walton C, Zaaijer HL, Zetterberg H, De Strooper B. Potential human transmission of amyloid β pathology: surveillance and risks. Lancet Neurol. 2020 Oct;19(10):872-878. Epub 2020 Sep 16 PubMed.

    View all comments by Elsa Lauwers View all comments by Giovanna Lalli View all comments by Bart De Strooper

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References

News Citations

  1. Could Contaminated Scalpels Seed Amyloidosis?
  2. Seeds of Destruction—Prion-like Transmission of Sporadic AD?
  3. Alzheimer’s Transmission Between People? Amyloid Plaques in Hormone Recipients Hint at Prion-like Spread
  4. News Brief: More Evidence for Aβ Spread Between People
  5. First In Vivo Look at Amyloidosis Sparked by Dural Grafts

Paper Citations

  1. Hervé D, Porché M, Cabrejo L, Guidoux C, Tournier-Lasserve E, Nicolas G, Adle-Biassette H, Plu I, Chabriat H, Duyckaerts C. Fatal Aβ cerebral amyloid angiopathy 4 decades after a dural graft at the age of 2 years. Acta Neuropathol. 2018 May;135(5):801-803. Epub 2018 Mar 5 PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. Asher DM, Belay E, Bigio E, Brandner S, Brubaker SA, Caughey B, Clark B, Damon I, Diamond M, Freund M, Hyman BT, Jucker M, Keene CD, Lieberman AP, Mackiewicz M, Montine TJ, Morgello S, Phelps C, Safar J, Schneider JA, Schonberger LB, Sigurdson C, Silverberg N, Trojanowski JQ, Frosch MP. Risk of Transmissibility From Neurodegenerative Disease-Associated Proteins: Experimental Knowns and Unknowns. J Neuropathol Exp Neurol. 2020 Nov 1;79(11):1141-1146. PubMed.

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