First In Vivo Look at Amyloidosis Sparked by Dural Grafts

Evidence for the transmission of Aβ seeds between people keeps accumulating. In the December 31 Annals of Neurology, researchers led by David Werring at University College London describe the cases of three adults with early onset cerebral amyloid angiopathy (CAA) and cortical plaques. As children, all had surgeries that used dura mater derived from cadavers. Two were neurosurgeries, the third a vascular repair, hinting that Aβ seeds might travel through the blood stream to reach the brain, as has been described in mice. Unlike previous case studies, none of the patients developed prion disease.

  • Three people with early onset CAA received dural grafts from cadavers as children.
  • In one case, the dural material was confined to blood vessels.
  • Data provides more evidence for transmission of Aβ seeds, even from blood to brain.

Researchers agreed the findings strengthen earlier data. “This is a fascinating study that adds significantly to the growing body of evidence linking transfer of human brain material to proteinopathies. This requires a re-examination of neurosurgical and interventional procedures and practices in light of the potential transmission of amyloid pathology,” Costantino Iadecola at Cornell University, New York, wrote to Alzforum (full comment below).

In previous studies, researchers discovered amyloid pathology while autopsying cases of Creutzfeldt-Jakob disease (CJD), a rare human prion disorder. Some people with CJD had been treated with pituitary growth hormone isolated from cadavers (Sep 2015 news; Dec 2018 news). Others had received dural grafts (Jan 2016 news). Despite their relatively young age at death, amyloid had accumulated in brain tissue and blood vessels. Charles Duyckaerts and colleagues at Hôpital Pitié-Salpêtrière, Paris, recently reported a fatal case of CAA without CJD in a 46-year-old woman who had received a dural graft transplant at the age of 2 (Hervé et al., 2018). UCL researchers also reported severe early onset CAA in four young adults who had neurosurgery as children, though it was not clear if those patients had received dural grafts (Feb 2018 news). 

The new study provides the first glimpse of graft-associated CAA in living people. First author Gargi Banerjee studies patients with brain hemorrhages seen at the UCL Stroke Research Centre. Three of the 663 patients seen since the beginning of 2015 had sporadic CAA that developed unusually young. Aged 34, 39, and 48, the two men and one woman suffer from repeated seizures, brain microbleeds, and intracerebral hemorrhages. When the older two underwent surgery to relieve hematomas, tissue biopsy revealed CAA in the blood vessels of the brain and in the meninges, as well as some parenchymal plaques. While the youngest was not biopsied, a florbetapir PET scan indicated amyloid plaques scattered throughout her cortex. Doctors also scanned the 39-year-old man with florbetapir and likewise found cortical plaques. Low levels of cerebrospinal fluid Aβ42 in this man and woman corroborated the PET data.

What explained this early onset CAA? None of the three carried any known familial AD mutations, nor had an ApoE4 allele. As children, however, the oldest and youngest patients had dural grafts after brain trauma, in one case to repair a skull fracture and in the other to patch up the choroid plexus. The 39-year-old man did not undergo neurosurgery. Instead, at age 2 he had surgery to remove a vascular lesion in one of his salivary glands. During this procedure, surgeons plugged a branch of the carotid artery using lyophilized dura mater, a relatively common practice to stem leaky vessels. These surgeries occurred in 1980–1982, an average of three decades before they were diagnosed with CAA.

“The intriguing cases described by the authors make a strong case for exposure to cadaveric dural material as a cause of CAA later in life,” Steven Greenberg at Massachusetts General Hospital, Boston, wrote to Alzforum (full comment below). Still, David Knopman at the Mayo Clinic in Rochester, Minnesota, cautioned that these case studies do not prove dural grafts cause early onset CAA. As an alternate explanation, perhaps disruption of the brain’s drainage system during neurosurgery triggered amyloid deposition (full comment below).

The presence of plaques and CAA following vascular surgery particularly intrigued researchers. Iadecola noted that cerebral endothelial cells have been shown to pick up and translocate particles from blood to the brain perivascular space (Lam et al., 2010). “This process could be responsible for transporting [Aβ] ‘seeds’ into the brain after intravascular administration,” he suggested. Researchers have demonstrated such transmission in mouse models (Oct 2010 news; Jul 2014 news). Scientists expressed little worry that blood transfusions might transmit amyloid pathology, however. “It is unclear that species capable of seeding Aβ deposits exist in the blood,” Iadecola said.

Another notable feature in all three cases was the lack of any tau pathology in the cortex, despite the amyloid plaques there. “The data suggest that, as in mice overexpressing mutated APP, Aβ accumulation is not sufficient to induce tau aggregation,” Iadecola noted.

How concerning are these findings for people who had neurosurgery in the 1980s? Only a single brand of dural graft, Lyodura, has been associated with CJD (Brooke et al., 2004). Werring and colleagues don’t know if these three cases had this type of graft. About 400 people in the U.S. and 1,172 people in Australia received Lyodura grafts in the mid ’80s (Brown et al., 2000). However, in many countries, poor record-keeping makes it impossible to track recipients. Werring and colleagues noted that the U.K. keeps no records on this.

The majority of Lyodura grafts were used in Japan, where an estimated 20,000 people per year received them between 1983 and 1987. Masahito Yamada at Kanazawa University noted that Japan has more than 60 percent of the known instances of CJD following dura mater exposure (Hamaguchi et al., 2013). Japan maintains a CJD Surveillance Committee to track these cases. So far, they have identified 154 (Ae et al., 2018). Yamada and colleagues examined 16 of them postmortem, finding significantly more subpial amyloid plaques and CAA in them than in 21 age-matched cases of sporadic CJD (Hamaguchi et al., 2016). The severity of CAA correlated with the length of time since the dural graft, Yamada said. It is unclear how many other cases of CJD or early onset CAA might arise. Yamada noted there are also no records in Japan of who received such grafts, but a nationwide survey of CAA has identified some additional early onset cases.

Researchers believe that modern neurosurgical techniques are safer. Dural grafts from cadavers were banned in 1992 in the U.K., and in 1997 in Japan. “There is currently no evidence for transmission of either CAA or Alzheimer’s disease by mechanisms other than direct exposure to human brain preparations, and therefore no reason to think that dangerous exposures are currently ongoing,” Greenberg noted.—Madolyn Bowman Rogers

Comments

  1. The intriguing cases described by the authors make a strong case for exposure to cadaveric dural material as a cause of CAA later in life. It’s reasonable to think this was due to direct β-amyloid seeding, but dura is not thought to contain large amounts of β-amyloid and the original dura materials aren’t available for testing, so other mechanisms remain possible. Either way, these cases certainly widen our appreciation for the spectrum of mechanisms that can trigger CAA.

    There is currently no evidence for transmission of either CAA or Alzheimer's disease (the brain’s two beta-amyloidoses) by mechanisms other than direct exposure to human brain preparations, and therefore no reason to think that dangerous exposures are currently ongoing. These results nonetheless shine a light on ways these diseases could be transmissible and act as an incentive to continue to broaden the search for epidemiological risk factors for CAA and AD.

    View all comments by Steven Greenberg

  2. This set of three cases is interesting and raises concerns for people who had dural transplants before the practice ended. That said, these cases do not prove causality, and the authors acknowledge alternative hypotheses. One might have proposed it was the disruption of the glymphatic system that occurred at the time of the initial treatment of the brain lesions, and not the subsequent application of the dural transplant. Such an alternative explanation is probably excluded by case No. 2 in the article, who was treated with embolization with lyophilized dura. With the caveat that causality remains speculative, the findings provide novel insights into the biology of beta-amyloidosis, namely that abnormally configured β-amyloid structures might be able to retain their ability to self-template and propagate along perivascular pathways, and that at least among these cases, the β-amyloid abnormalities manifested as vascular amyloid, leaving uncertain whether the β-amyloid propagated in the brain parenchyma.

    View all comments by David Knopman

  3. Assuming that the human material transplanted or injected contained Aβ species, these data provide further evidence of Aβ seeding in humans, with widespread diffusion not only in blood vessels as CAA, but also as amyloid plaques.

    I find it fascinating that cerebral blood vessels are specifically targeted by this pathogenic process, which may provide further evidence of the critical role that the cerebral vasculature plays in Aβ clearance. The localization to the meninges also may suggest involvement of the meningeal lymphatics in this process. 

    As discussed previously at Alzforum (Dec 2018 news), the data suggest that precautions should be taken in neurosurgical procedures to avoid seeding through surgical instruments. Considering the long incubation time, procedures in pediatric cases and young individuals should receive particular attention to this issue. 

    As for Aβ in the blood, preclinical data suggest that this needs to be in small, soluble, non-covalent aggregates for most efficient seeding. Therefore, it will depend on the state of aggregation of Aβ in blood. Platelet and macrophages do produce Aβ, and this peptide is transported into the circulation, but it is unclear that it exists in seeding-promoting species in blood. However, Aβ has been shown to bind and aggregate on the surface of red blood cells (Hashimoto et al., 2015). 

    In this regard, the case described in this paper in which the seeding may have occurred through intra-arterial administration is of particular interest. Grutzendler and colleagues described a process through which cerebral endothelial cells can pick up and translocate particles from blood to the brain perivascular space (Lam et al., 2010). Inasmuch as Aβ seeds were contained in the embolization material, this process could be responsible for transporting the “seeds" into the brain after intravascular administration. 

    The remarkable parenchymal spread of the process is also noteworthy. Whether this process is facilitated by the diffusion along perivascular spaces, uptake by brain cells, spread through neural pathways, or convective flow remains to be established. But it suggest that the process is not compartmentalized to the meninges or vessels. 

    The seeming lack of tau pathology, as in other cased previously described, is also noteworthy. Limitations of the study notwithstanding, the data suggest that, as in mice overexpressing mutated APP, Aβ accumulation is not sufficient to induce tau aggregation. It would be of interest to determine the phosphorylation state of tau in the biopsies. It is also notable that the cases were not ApoE4 carriers, a genetic variant that promotes Aβ accumulation and reduces vascular clearance. 

    The limitations of the study are clearly stated in the paper. However, this is a fascinating study that adds significantly to the growing body of evidence linking transfer of human brain material to proteinopathies, and requires a re-examination of neurosurgical and interventional procedures and practices in light of potential transmission of amyloid pathology. 

    References:

    Hashimoto M, Hossain S, Katakura M, Al Mamun A, Shido O. The binding of Aβ1-42 to lipid rafts of RBC is enhanced by dietary docosahexaenoic acid in rats: Implicates to Alzheimer's disease. Biochim Biophys Acta. 2015 Jun;1848(6):1402-9. Epub 2015 Mar 14 PubMed.

    Lam CK, Yoo T, Hiner B, Liu Z, Grutzendler J. Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization. Nature. 2010 May 27;465(7297):478-82. PubMed.

    View all comments by Costantino Iadecola

  4. The three cases reported by Banerjee et al. confirm in living patients what had been initially suspected by postmortem studies: the prevalence of β-amyloid pathology (both cerebral amyloid angiopathy and diffuse deposits) was found abnormally high in patients with a history of receiving dural grafts (Frontzek et al., 2016; Cali et al., 2018; Kovacs et al., 2016; Hamaguchi et al., 2016; Iwasaki et al., 2018; Hervé et al., 2018). The induced cerebral amyloid pathology was symptomatic, causing cerebral hematomas in at least in one patient (Hervé et al., 2018). The transmission of β-amyloid pathology through Aβ-contaminated, cadaver-derived, human growth hormone has been proven experimentally (Purro et al., 2018), and the same mechanism is probably at work with dural grafts. There is, today, little doubt that β-amyloid pathology can be transmitted.

    In case No. 2, embolization with lyophilized cadaveric dura was probably the cause of the contamination. The vascular route of contamination is intriguing. How does the pathology spread from the embolus of the external carotid artery to the rest of the cerebrovascular system linked to the internal carotid artery? This involves retrograde spread of the external carotid system to the carotid bifurcation and anterograde spread into the internal carotid system (implausible!), or passage from the external carotid artery to the dura mater and from there to the internal carotid system. It should be noted, however, that an ischemic stroke during the procedure suggests that material had reached the internal carotid system. How the pathology of β-amyloid propagates from the vascular system to the cerebral parenchyma is another unresolved issue. One last point to emphasize: There is no transmission of tau pathology and it does not develop despite prolonged contact of the brain with β-amyloidosis. 

    References:

    Frontzek K, Lutz MI, Aguzzi A, Kovacs GG, Budka H. Amyloid-β pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting. Swiss Med Wkly. 2016;146:w14287. Epub 2016 Jan 26 PubMed.

    Cali I, Cohen ML, Haik S, Parchi P, Giaccone G, Collins SJ, Kofskey D, Wang H, McLean CA, Brandel JP, Privat N, Sazdovitch V, Duyckaerts C, Kitamoto T, Belay ED, Maddox RA, Tagliavini F, Pocchiari M, Leschek E, Appleby BS, Safar JG, Schonberger LB, Gambetti P. Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study. Acta Neuropathol Commun. 2018 Jan 8;6(1):5. PubMed.

    Kovacs GG, Lutz MI, Ricken G, Ströbel T, Höftberger R, Preusser M, Regelsberger G, Hönigschnabl S, Reiner A, Fischer P, Budka H, Hainfellner JA. Dura mater is a potential source of Aβ seeds. Acta Neuropathol. 2016 Jun;131(6):911-23. Epub 2016 Mar 25 PubMed.

    Hamaguchi T, Taniguchi Y, Sakai K, Kitamoto T, Takao M, Murayama S, Iwasaki Y, Yoshida M, Shimizu H, Kakita A, Takahashi H, Suzuki H, Naiki H, Sanjo N, Mizusawa H, Yamada M. Significant association of cadaveric dura mater grafting with subpial Aβ deposition and meningeal amyloid angiopathy. Acta Neuropathol. 2016 Aug;132(2):313-5. Epub 2016 Jun 17 PubMed.

    Iwasaki Y, Imamura K, Iwai K, Kobayashi Y, Akagi A, Mimuro M, Miyahara H, Kitamoto T, Yoshida M. Autopsied case of non-plaque-type dura mater graft-associated Creutzfeldt-Jakob disease presenting with extensive amyloid-β deposition. Neuropathology. 2018 Oct;38(5):549-556. Epub 2018 Aug 6 PubMed.

    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.

    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 Charles Duyckaerts

  5. Dr. Iadecola is on point to suggest precautions be taken to avoid "infectious amyloid" seeding into patients through neurosurgical instruments. But what about dangers to neurosurgeons themselves, who risk O.R. exposure to brain tissue via glove nicks from sharps, aerosols, and cautery "smoke" particles? It is noteworthy that Alzheimer's is a leading cause of death for these specialists (Lollis et al., 2010). It is time to stop asserting transmission cannot occur and instead support research to definitively determine if it does.

    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

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References

News Citations

  1. Alzheimer’s Transmission Between People? Amyloid Plaques in Hormone Recipients Hint at Prion-like Spread
  2. Confirmed: Human Pituitary Extract Linked to Amyloidosis Contains Aβ Seeds
  3. News Brief: More Evidence for Aβ Spread Between People
  4. Can Aβ Seeds Be Transferred During Neurosurgery?
  5. Peripheral Aβ Seeds CAA and Parenchymal Amyloidosis
  6. Does Aggregated Aβ Pass Directly From Blood to Brain?

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.
  2. Lam CK, Yoo T, Hiner B, Liu Z, Grutzendler J. Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization. Nature. 2010 May 27;465(7297):478-82. PubMed.
  3. Brooke FJ, Boyd A, Klug GM, Masters CL, Collins SJ. Lyodura use and the risk of iatrogenic Creutzfeldt-Jakob disease in Australia. Med J Aust. 2004 Feb 16;180(4):177-81. PubMed.
  4. Brown P, Preece M, Brandel JP, Sato T, McShane L, Zerr I, Fletcher A, Will RG, Pocchiari M, Cashman NR, d'Aignaux JH, Cervenáková L, Fradkin J, Schonberger LB, Collins SJ. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology. 2000 Oct 24;55(8):1075-81. PubMed.
  5. Hamaguchi T, Sakai K, Noguchi-Shinohara M, Nozaki I, Takumi I, Sanjo N, Sadakane A, Nakamura Y, Kitamoto T, Saito N, Mizusawa H, Yamada M. Insight into the frequent occurrence of dura mater graft-associated Creutzfeldt-Jakob disease in Japan. J Neurol Neurosurg Psychiatry. 2013 Oct;84(10):1171-5. Epub 2013 Apr 17 PubMed.
  6. Ae R, Hamaguchi T, Nakamura Y, Yamada M, Tsukamoto T, Mizusawa H, Belay ED, Schonberger LB. Update: Dura Mater Graft-Associated Creutzfeldt-Jakob Disease - Japan, 1975-2017. MMWR Morb Mortal Wkly Rep. 2018 Mar 9;67(9):274-278. PubMed.
  7. Hamaguchi T, Taniguchi Y, Sakai K, Kitamoto T, Takao M, Murayama S, Iwasaki Y, Yoshida M, Shimizu H, Kakita A, Takahashi H, Suzuki H, Naiki H, Sanjo N, Mizusawa H, Yamada M. Significant association of cadaveric dura mater grafting with subpial Aβ deposition and meningeal amyloid angiopathy. Acta Neuropathol. 2016 Aug;132(2):313-5. Epub 2016 Jun 17 PubMed.

Further Reading

Primary Papers

  1. Banerjee G, Adams ME, Jaunmuktane Z, Alistair Lammie G, Turner B, Wani M, Sawhney IM, Houlden H, Mead S, Brandner S, Werring DJ. Early onset cerebral amyloid angiopathy following childhood exposure to cadaveric dura. Ann Neurol. 2019 Feb;85(2):284-290. Epub 2019 Jan 17 PubMed.

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