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.

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Comments

  1. The evidence to date is that there may be a very small risk of transmission of pathogenic Aβ in the course of neurosurgical procedures, and that over several decades this can lead to the development of cerebral amyloid angiopathy.

    Neurosurgery carries risks, including infection, hemorrhage, neurological deficits, and epilepsy, and it is contemplated only if the likely benefits clearly outweigh those risks. The minimal additional risk of transmission of pathogenic Aβ should not have any bearing on the advisability of a particular procedure. This would apply whether the neurosurgery was for me, someone else, or my child. The same considerations should apply to decisions regarding blood transfusion.

    The kind of studies the field needs include long-term monitoring (which should include autopsy follow-up studies), particularly after blood transfusion and neurosurgery in early life, so that we can obtain more accurate data on the risk and possible manifestations of Aβ transmission. The studies would also determine whether other aggregation-prone neurodegenerative disease-related proteins, such as tau and α-synuclein, are occasionally transmitted from human to human in the course of neurosurgery or blood transfusion. We also need research to clarify mechanisms and modes of transmission, to develop low-cost, high-throughput assays for transmissible proteins, and to optimize procedures for decontamination of equipment.

    View all comments by Seth Love

  2. Since all brain surgery is a form of brain trauma, and brain trauma is associated with risk for AD, it is not possible to separate out this brain-trauma risk from risk associated with surgical instruments contaminated with CNS pathologies.

    View all comments by John Trojanowski

  3. I’m not an expert on this precise topic. That said, we have considered this issue here in France and Professor Duyckaerts, myself, and others participated in a scientific committee that was convened on this topic in 2016. I was asked specifically to focus on the risk associated with preparing and handling fibrillar tau, α-synuclein, Aβ, etc. … The fibrils we prepare have prion-like properties and people may know that my lab is among the four in the world that can amplify seeds present in the brains or peripheral tissues of patients.

    The authors of this manuscript are right. We cannot exclude the possibility of transmission through surgical intervention or tissue transplant (blood being a tissue). We cannot exclude either that scientists may be contaminated by the large amounts of fibrils they prepare, and often sonicate, thus generating aerosols, when we can show that those fibrils trigger pathology in animal models upon injection, in particular in the olfactory bulb in the case of α-synuclein. The only way at this stage to determine what might happen is to establish strict traceability. This might not be possible for blood (an industrial process).

    We need strict and validated cleaning procedures for surgical tools. We established such procedures in my lab for labware. We clean and neutralize the fibrils we most often use with the detergent SDS, but the cleaning procedures must be adapted to the polymorph one is using (see Fig. 4 of Fenyi et al., 2018). In addition, although it is not particularly convenient, we established fragmentation procedures using sonication that do not generate aerosols and we handle large amounts of fibrils in BSL-2 to BSL-3 labs. This is stated in our papers (Fenyi et al., 2019; Van der Perren et al., 2020). I know this is complicated, but this is also the only way to bring the risk to close to zero.

    In general terms, what is useful is the use of disposable tools when possible and limiting the possible propagation among humans by avoiding tissues donated by people who possibly are incubating the disease. We might not be able to bring the risk to zero, but most often the interventions we are discussing here (surgical intervention, organ transplant, including blood) are performed because the person is at risk of dying. Therefore I, as a citizen, consider the risk we take to be acceptable.

    References:

    Fenyi A, Coens A, Bellande T, Melki R, Bousset L. Assessment of the efficacy of different procedures that remove and disassemble alpha-synuclein, tau and A-beta fibrils from laboratory material and surfaces. Sci Rep. 2018 Jul 17;8(1):10788. PubMed.

    Fenyi A, Leclair-Visonneau L, Clairembault T, Coron E, Neunlist M, Melki R, Derkinderen P, Bousset L. Detection of alpha-synuclein aggregates in gastrointestinal biopsies by protein misfolding cyclic amplification. Neurobiol Dis. 2019 Sep;129:38-43. Epub 2019 May 9 PubMed.

    Van der Perren A, Gelders G, Fenyi A, Bousset L, Brito F, Peelaerts W, Van den Haute C, Gentleman S, Melki R, Baekelandt V. The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson's disease, multiple system atrophy and dementia with Lewy bodies. Acta Neuropathol. 2020 Jun;139(6):977-1000. Epub 2020 Apr 30 PubMed.

    View all comments by Ronald Melki

  4. As underlined in this paper, to date, the risk of transmission associated with Aβ pathology during neurosurgery remains uncertain. Data are limited and inconclusive. In my opinion, they are by far insufficient to delay or forgo any necessary neurosurgery regardless of the patient’s age.

    Epidemiological studies will be key to estimate this risk. Prospective cohorts of patients with a medical history of neurosurgery in early life would be useful, keeping in mind that time duration between exposure and potentially transmitted CAA is several decades. A surveillance of early onset CAA with a retrospective checking of prior history of neurosurgery would provide informative data.

    In recent decades, in light of the risk associated with CJD prion transmission, various improvements have been made for prion detection and, notably in neurosurgery, prion decontamination. In France, the systematic use of 134°C autoclaving procedures and inactivating solutions efficient against prions has been adopted.

    Expansion of detection procedures from the prion field to other proteopathic seeds is in progress and it would be probably helpful to assess how procedures designed to eliminate CJD transmission risk are efficient against other amyloids. Developing fundamental research to better understand the nature and the mechanisms of propagation of prions, other proteopathic seeds, and their different strains is a central issue

    View all comments by Stéphane Haïk

  5. How strange that researchers focus on the patients, who get one brain operation each. Largely ignored is a possible risk to neurosurgeons, who all day are exposed to brain after brain, accompanied by glove nicks, sharps penetrations, and cautery smoke plumes.

    Three years ago I called attention to a provocative report that neurosurgeons seemed to have excessive deaths from Alzheimer's compared to other physicians. How long must we wait for epidemiologists and biostatisticians to dig into such data to establish whether transmissibility is occurring?

    See "It’s Time to Find the 'Alzheimer’s Germ,'” Norins LC. ALZgerm.org/whitepaper. 

    References:

    Lollis SS, Valdes PA, Li Z, Ball PA, Roberts DW. Cause-specific mortality among neurosurgeons. J Neurosurg. 2010 Sep;113(3):474-8. PubMed.

    View all comments by Leslie Norins

  6. Lauwers and colleagues present a helpful synopsis of the potential risk of human transmission of β-amyloid pathology by contaminated neurosurgical equipment and blood transfusions. The authors point out that the current evidence to support iatrogenic transmission is weak and often hampered by small cohort sizes, retrospective evaluations, and long disease incubation periods. Despite the low probability of transmission, the authors appropriately suggest adopting proactive safety measures, such as using separate surgical tools for adults and children, enzyme-based detergents for instrument decontamination, and developing large-scale and long-term epidemiological studies to track disease incidence in those who have undergone high-risk medical interventions.

    The authors also propose employing molecular tools, such as protein misfolding cyclic amplification or RT-QuIC, to aid in detection of proteopathic seeds from potentially contaminated materials. In addition to these methods, I would also propose using cell-based seeding assays such as those previously described for tau and α-synuclein (Holmes et al., 2014). These assays are highly sensitive, robust, and facile, and could be adopted by labs with access to cell culture and flow cytometry workflows. Future generations of these cell-based assays may enable multiplexed molecular fingerprinting to identify specific strains across multiple proteopathic seed types simultaneously. If iatrogenic transmission is indeed occurring, correlating specific strains with disease subtypes could offer highly compelling evidence for proteopathic seed propagation. Finally, as we build registries for long-term patient monitoring, it would be fascinating to know if host factors, such as genetic background, could lead to increased risk of acquiring and propagating proteopathic seeds.

    In the meantime, I agree with the authors that I would not discourage my patients from undergoing beneficial neurosurgical interventions or blood transfusions. However, as we build patient registries and develop new tools for detection of contaminated materials, we will be even better equipped to counsel our patients appropriately.

    References:

    Holmes BB, Furman JL, Mahan TE, Yamasaki TR, Mirbaha H, Eades WC, Belaygorod L, Cairns NJ, Holtzman DM, Diamond MI. Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):E4376-85. Epub 2014 Sep 26 PubMed.

    View all comments by Brandon Holmes

  7. There are ample clearing mechanisms in the body for proteins such as amyloid. We know that there is a turnover of amyloid, so to speculate that there may be some detrimental effect from tiny amounts of amyloid in the body is stretching the likelihood of probabilities beyond the imaginable. In addition, we should remember that a number of clinical trials in AD patients showed no improvement even though the levels of amyloid in their brains and CSF had been reduced significantly.

    View all comments by Christian Hoelscher

  8. The paper by Lauwers et al. is a timely reminder of the transmissible properties of amyloid fibrils. This is a story that started in the 1960s with the observations of the systemic amyloid researchers using experimental models of what is now known as AA amyloid, an acute-phase protein of hepatic origin. Their original work preceded the discovery of the transmissible PrP protein in CJD/scrapie. Several groups found that systemic amyloidosis could be “enhanced” by injection of a factor derived from and inoculated into sensitized mice (Hultgren et al., 1967; Ranlov, 1967; Werdelin and Ranlov, 1968; Shirahama et al., 1969). Many years later, this “amyloid-enhancing factor” was identified as the AA protein itself, but uncertainty still persists over the conformation of the transmissible subunit: β-rich oligomer or β-stranded amyloid protofibril or fibril (Westermark, 2005; Tasaki et al., 2010). 

    In the 1970s, much effort was expended on comparing the transmissibility of CJD with AD and other neurodegenerative diseases. We came to the conclusion that AD was not transmissible, at least not with clinical and pathological kinetics similar to the replication of the PrP protein as now recognized in CJD (Goudsmit et al., 1980). Of course, those were the days before Aβ, and the more sensitive assays using immunocytochemistry and quantitative immuno-assays for the replication of low levels of Aβ in experimentally inoculated animals were yet to be applied. It would still be worth going back and re-examining these AD-inoculated animals’ brain sections for the amplification of Aβ.

    Which brings us to the 1990s. We described a case of presumptive iatrogenic CJD five years after a dura mater graft (Simpson et al., 1996). The late Donald Simpson was the doyen of Australian neurosurgery, and a close friend of Carleton Gajdusek. I (Colin L. Masters) noted in the pathological report that this case was “unusual” because in addition to the spongiform change of CJD, this 56-year-old recipient also showed abundant Aβ plaques and congophilic angiopathy in the absence of neurofibrillary tangles. This may have been the first example of what we are now debating: transmissible human-to-human Aβ induced by seeding from the dura mater. The article was published in a relatively obscure Australian journal, and probably went unnoticed by the rest of the research community.

    By coincidence, we have now published (today) a paper on the finding that the incidence of intracerebral hemorrhage may be increased in Australian cadaveric pituitary hormone recipients (Alnakhli et al., 2020). Yes, it’s in the same obscure Australian journal as the Simpson et al., 1996, paper. But since it directly addresses the issues that Lauwers et al. raise in The Lancet, maybe it will reach a wider audience. An odds ratio of 2.77 for intracerebral hemorrhage in human cadaveric hormone recipients is worth noting and needs replication in a more robust manner.

    References:

    Hultgren MK, Druet RL, Janigan DT. Experimental amyloidosis in isogeneic x-irradiated recipients of sensitized spleen tissue. Am J Pathol. 1967 Jun;50(6):943-55. PubMed.

    Ranlov P. The adoptive transfer of experimental mouse amyloidosis by intravenous injections of spleen cell extracts from casein-treated syngeneic donor mice. Acta Pathol Microbiol Scand. 1967;70(3):321-35. PubMed.

    Werdelin O, Ranlov P. Amyloidosis induced in mice by transplantation of casein-sensitized and not-sensitized spleen cells. Acta Pathol Microbiol Scand. 1968;72(1):13-22. PubMed.

    Shirahama T, Lawless OJ, Cohen AS. Heterologous transfer of amyloid--human to mouse. Proc Soc Exp Biol Med. 1969 Feb;130(2):516-9. PubMed.

    Westermark P. Aspects on human amyloid forms and their fibril polypeptides. FEBS J. 2005 Dec;272(23):5942-9. PubMed.

    Tasaki M, Ueda M, Ochiai S, Tanabe Y, Murata S, Misumi Y, Su Y, Sun X, Shinriki S, Jono H, Shono M, Obayashi K, Ando Y. Transmission of circulating cell-free AA amyloid oligomers in exosomes vectors via a prion-like mechanism. Biochem Biophys Res Commun. 2010 Oct 1;400(4):559-62. Epub 2010 Aug 31 PubMed.

    Goudsmit J, Morrow CH, Asher DM, Yanagihara RT, Masters CL, Gibbs CJ Jr, Gajdusek DC. Evidence for and against the transmissibility of Alzheimer disease. Neurology. 1980 Sep;30(9):945-50. PubMed.

    Simpson DA, Masters CL, Ohlrich G, Purdie G, Stuart G, Tannenberg AE. Iatrogenic Creutzfeldt-Jakob disease and its neurosurgical implications. J Clin Neurosci. 1996 Apr;3(2):118-23. PubMed.

    Alnakhli SH, Wand H, Law M, Sarros S, Stehmann C, Senesi M, Klug GM, Simpson M, Lewis V, Masters CL, Collins SJ. Intra-cerebral haemorrhage but not neurodegenerative disease appears over-represented in deaths of Australian cadaveric pituitary hormone recipients. J Clin Neurosci. 2020 Nov;81:78-82. Epub 2020 Sep 29 PubMed. Correction.

    View all comments by Steven Collins

  9. In their comment above, Colin L. Masters and Steven J. Collins rightfully pointed to a report from 1996 of what most likely is the first case of Aβ transmission after a graft of human dura mater material (Simpson et al., 1996). We want to acknowledge here that this report takes precedence over the 74 cases of suspected iatrogenic transmission of amyloid β pathology we recently reviewed.

    In another, very recent publication, Colin L. Masters, Steven J. Collins, and colleagues (Alnakhli et al., 2020) screened the death certificates of 184 individuals who received human cadaveric pituitary hormone treatment before 1985. They found that deaths listed as from "intra-cerebral haemorrhage" were significantly increased compared to the standard population, whereas there was no evidence to support increased deaths from non-prion neurodegenerative diseases such as AD or PD (consistent with previous report from John Trojanowski and colleagues, Irwin et al., 2013). These findings confirms the conclusion from our working group that AD itself is not transmissible iatrogenically.

    References:

    Irwin DJ, Abrams JY, Schonberger LB, Leschek EW, Mills JL, Lee VM, Trojanowski JQ. Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol. 2013 Apr;70(4):462-8. PubMed.

    Simpson DA, Masters CL, Ohlrich G, Purdie G, Stuart G, Tannenberg AE. Iatrogenic Creutzfeldt-Jakob disease and its neurosurgical implications. J Clin Neurosci. 1996 Apr;3(2):118-23. PubMed.

    View all comments by Bart De Strooper

  10. We commend the careful wording in the new paper by Steve Collins and colleagues that reports a significant increase in intracerebral hemorrhage (potentially related to amyloid-β cerebral amyloid angiopathy (CAA)) in a group of c-hGH recipients, but no significant increase in standardized mortality from neurodegenerative diseases other than iatrogenic Creutzfeldt-Jakob disease (iCJD, Alnakhli et al., 2020). 

    Collins and colleagues were cautious to point out the limitations of their study. They note the small sample size and that, like the earlier study by Irwin et al. (Irwin et al., 2013), it was based only on death certificates; living c-hGH recipients (over 90 percent) potentially manifesting the diseases of interest were not ascertained. They considered their findings tentative and supported the need for more detailed epidemiological studies, and we certainly agree.

    With respect to the last comment from Elsa Lauwers and Bart De Strooper, we think it premature to make definitive statements on the lack of transmissibility of Alzheimer’s disease. At the workshop, there was near consensus on the human transmission of amyloid-β pathology and the disease CAA. We agree that human transmission of AD has not yet been confirmed (Jaunmuktane et al., 2015; Purro et al., 2018) and expect that, in any case, it would likely be confined to specialized medical and surgical interventions.

    However, absence of evidence is not evidence of absence. Given the accumulating evidence in experimental models and new human data we recommend renewed efforts in AD epidemiology and long-term monitoring of individuals who may have been inadvertently inoculated with amyloid-β and other proteopathic seeds.

    The parallels, both scientifically and historically, with understanding prion disease are important to emphasize. CJD is universally accepted to be a transmissible dementia, although it is not contagious. However, in reality, only around 1 percent of recognized cases have a known environmentally acquired (“transmitted”) etiology. The large majority of human prion disease cases are sporadic, and nearly all the rest are earlier-onset inherited forms.

    It is also important to appreciate the extraordinary incubation periods possible in acquired human prion diseases. We know from study of kuru, as well as iCJD, that these can exceed five decades (Collinge et al., 2006), and intervals of decades also seem relevant to development of iatrogenic amyloid-β pathology (Jaunmuktane et al., 2015). 

    In our view, we not only must remain open to, but should actively investigate, whether AD epidemiology is similar, with rare iatrogenically acquired forms in addition to the large majority of sporadic and early onset inherited forms. As concluded at the workshop, we should develop improved methods to remove proteopathic seeds from surgical instruments on a precautionary basis (perhaps using a type of simple enzymatic prewash, as was successfully developed for prions), given that a full understanding of the scale of the risks will take years to unravel, along with consideration of new measures to ensure laboratory safety.

    —Peter Rudge and Zane Jaunmuktane are co-authors of this comment.

    References:

    Alnakhli SH, Wand H, Law M, Sarros S, Stehmann C, Senesi M, Klug GM, Simpson M, Lewis V, Masters CL, Collins SJ. Intra-cerebral haemorrhage but not neurodegenerative disease appears over-represented in deaths of Australian cadaveric pituitary hormone recipients. J Clin Neurosci. 2020 Nov;81:78-82. Epub 2020 Sep 29 PubMed. Correction.

    Collinge J, Whitfield J, McKintosh E, Beck J, Mead S, Thomas DJ, Alpers MP. Kuru in the 21st century--an acquired human prion disease with very long incubation periods. Lancet. 2006 Jun 24;367(9528):2068-74. PubMed.

    Irwin DJ, Abrams JY, Schonberger LB, Leschek EW, Mills JL, Lee VM, Trojanowski JQ. Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol. 2013 Apr;70(4):462-8. PubMed.

    Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, Kenny J, Launchbury F, Linehan J, Richard-Loendt A, Walker AS, Rudge P, Collinge J, Brandner S. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature. 2015 Sep 10;525(7568):247-50. PubMed.

    Purro SA, Farrow MA, Linehan J, Nazari T, Thomas DX, Chen Z, Mengel D, Saito T, Saido T, Rudge P, Brandner S, Walsh DM, Collinge J. Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone. Nature. 2018 Dec;564(7736):415-419. Epub 2018 Dec 13 PubMed.

    View all comments by John Collinge

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