Jaunmuktane Z, Quaegebeur A, Taipa R, Viana-Baptista M, Barbosa R, Koriath C, Sciot R, Mead S, Brandner S. Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery. Acta Neuropathol. 2018 May;135(5):671-679. Epub 2018 Feb 15 PubMed.

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  1. We have under revision a case of probable transmission of CAA and Aβ deposits by dural graft performed more than 40 years before the occurrence of multiple hematomas.

    As in the other published cases, CAA was almost pure without a significant tauopathy. It is an indication that the tauopathy seen in sporadic Alzheimer's disease is probably not the consequence of the accumulation of Aβ: in the published cases the brain has been in contact with Aβ aggregates for several decades and has not developed tangles.

    The work of Jaunmuktane and colleagues is brilliant. We have checked our files for pure CAA in young people and indeed found a significant number of cases with a history of neurosurgery. I believe those cases 1) will not remain isolated 2) will probably change our perspectives on sporadic Alzheimer's disease.

    View all comments by Charles Duyckaerts

  2. This article presents important experiments in the discussion of iatrogenic transmission of Aβ pathogenesis. It becomes particularly relevant when considering Aβ pathology as the result of transmissibility through neurosurgery. Proteopathic seedig of Aβ to humans with growth hormone from Aβ-containing pituitary glands resulted in significant parenchymal and vascular Aβ pathology (Cali et al., 2018, Table S5). The latter is of some relevance for the current study and the evidence provided for Aβ cerebral amyloid angiopathy (ACA) transmission through neurosurgery.

    Four patients, three in their 30s and one in her 50s, with CAA-related intracerebral hemorrhages, were identified through searching the local pathology archive by Sebastian Brandner and colleagues. All four cases had a history of neurosurgery during childhood. Since CAA occurs sporadically above the age of 55, accounting for 5 percent to 20 percent of spontaneous intracerebral hemorrhages, and since CAA (mainly if not exclusively composed of Aβ40 fibrils) is present in 88 percent of AD cases (Shinohara et al., 2016), young age was crucial for the patient selection. All but one patient had both parenchymal pathology, which as we now know corresponds to fibrillary Aβ42 aggregates, and vascular Aβ-40 pathology.

    The exception, Case 2, had widespread CAA-Aß40 but no parenchymal-Aβ42 deposition. At age 1, this patient was operated on for meningioma and his first hemorrhage occurred 30 years later, at age 31. The bleed had developed within and around the resection cavity, but PiB-PET revealed deposition of fibrillar Aβ, most likely CAA-Aβ40 throughout the brain. The start site of the bleed may reflect the first site of CAA-Aβ40 deposition, and this may possibly shed light on the mechanism of CAA induction and spread as outlined below. Interestingly, the APOE genotype of Case 2 was 2/3. The three remaining cases with CAA-Aβ40 and parenchymal-Aβ42 had APOE genotypes of 3/4 (Cases 1 and 3) and 3/3 (Case 4). That Case 2 did not develop parenchymal-Aβ42 aggregates argues against transmission through neurosurgery, at least for this case.

    As mentioned, iatrogenic Creutzfeldt-Jakob disease with Aβ pathology acquired from inoculation of Aβ-containing growth hormone resulted in significant parenchymal and vascular Aβ pathology (Cali et al., 2018, Table S5). That the same was not observed in Case 2 suggests that the proteopathic seeds did not contain Aβ42, which is very unlikely, or that seeding did not occur and CAA-Aβ40 originated from endogenous Aβ40.

    Regarding formation of parenchymal Aβ42 aggregates from endogenous Aβ42, this may have been delayed by the APOE 2 allele, which affects age at onset in AD families with PS2 mutations but does not prevent AD pathogenesis (Wijsman et al., 2005). On the other hand, the e2 allele has no protective effect in Dutch Cerebral Amyloid Angiopathy but is an established risk factor for hemorrhages in CAA, whereas the e4 allele is a risk factor for both CAA and hemorrhage (Carpenter et al., 2016). 

    How could CAA-Aβ40 aggregation in Case 2 and CAA-Aβ40 as well as parenchymal-Aβ42 aggregation in Cases 1, 2, and 4 be initiated and propagated if proteopathic seeding did not occur through neurosurgery? Since microglia rapidly become activated in response to CNS damage and may stay activated for as long as 17 years after traumatic brain injury (Donat et al., 2017), ASC specks released from microglia could do the cross-seeding and propagation of CAA-Aβ40 and parenchymal-Aβ42 amyloid deposits (Dec 2017 news). That in Case 2 the CAA-mediated bleeding had developed within and around the resection cavity could indicate that at this site the microglia-mediated CAA-Aβ40 deposition has started and became most pronounced. However, as stated by the authors, larger epidemiological studies are needed to confirm or rule out the possibility of transmission of Aβ proteopathic seeds by neurosurgery.

    References:

    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.

    Shinohara M, Murray ME, Frank RD, Shinohara M, DeTure M, Yamazaki Y, Tachibana M, Atagi Y, Davis MD, Liu CC, Zhao N, Painter MM, Petersen RC, Fryer JD, Crook JE, Dickson DW, Bu G, Kanekiyo T. Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease. Acta Neuropathol. 2016 Aug;132(2):225-34. Epub 2016 May 14 PubMed.

    Wijsman EM, Daw EW, Yu X, Steinbart EJ, Nochlin D, Bird TD, Schellenberg GD. APOE and other loci affect age-at-onset in Alzheimer's disease families with PS2 mutation. Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132B(1):14-20. PubMed.

    Carpenter AM, Singh IP, Gandhi CD, Prestigiacomo CJ. Genetic risk factors for spontaneous intracerebral haemorrhage. Nat Rev Neurol. 2016 Jan;12(1):40-9. Epub 2015 Dec 16 PubMed.

    Donat CK, Scott G, Gentleman SM, Sastre M. Microglial Activation in Traumatic Brain Injury. Front Aging Neurosci. 2017;9:208. Epub 2017 Jun 28 PubMed.

    View all comments by Konrad Beyreuther

  3. This study is fragmentary, making it difficult to draw conclusions about the results. That said, it is important to point out the confound brain trauma represents for any study of people who undergo neurosurgery, including placement of dural grafts and the subsequent development of Aβ plaques. To my knowledge, none of the studies on neurosurgery and Aβ deposits report occurrence of neurofibrillary tau tangles. However, brain trauma per se (which neurosurgery represents) is associated with greater likelihood of brain Aβ deposits (Uryu et al., 2002; Smith et al., 2003; Ikonomovic et al., 2004). An episode of neurosurgery followed later by Aβ deposits could therefore be explained by the trauma from the neurosurgery, rather than transmission of AD plaque and tangle pathologies. I think it is irresponsible for the authors to put out incomplete studies that are not definitive but can stoke fear about AD transmission from patients to family members and medical caregivers.

    References:

    Uryu K, Laurer H, McIntosh T, Praticò D, Martinez D, Leight S, Lee VM, Trojanowski JQ. Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci. 2002 Jan 15;22(2):446-54. PubMed.

    Smith DH, Uryu K, Saatman KE, Trojanowski JQ, McIntosh TK. Protein accumulation in traumatic brain injury. Neuromolecular Med. 2003;4(1-2):59-72. PubMed.

    Ikonomovic MD, Uryu K, Abrahamson EE, Ciallella JR, Trojanowski JQ, Lee VM, Clark RS, Marion DW, Wisniewski SR, Dekosky ST. Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury. Exp Neurol. 2004 Nov;190(1):192-203. PubMed.

    View all comments by John Trojanowski

  4. The analysis raises interesting questions about possible links between neurosurgical procedures and CAA, though the numbers are too small to draw strong conclusions. The small numbers also make it hard to disentangle possible mechanisms, including infectious-like spread as suggested by the authors or alternatives such as traumatic effects of specific types of brain surgery at particular patient ages. The data are certainly intriguing and support further studies to replicate and explain the findings.

    View all comments by Steven Greenberg

  5. This is a very interesting small series of CAA patients with hemorrhages at an unusually young age and past neurosurgery during childhood, without apparent genetic risk factors. The authors are right that their study raises the possibility of Aβ transmission via neurosurgery. Obviously, the present study cannot provide definite evidence for this possibility, as is inherent in such retrospective studies and acknowledged by the authors. Moreover, some additional points may confound the presented suggestion of a causal relation between past neurosurgery (by contaminated instruments) and emergence of Aβ pathology.

    1) The histological diagnosis searched for was CAA at age 55 and below at a brain biopsy, usually performed for evacuation of a hematoma, or at autopsy. Five biopsy cases were identified by biopsy, one of whom had no clinical data, another a genetic risk factor, and the remaining three all had past neurosurgery during childhood. Another such patient (57 years old) was identified by autopsy. The association of "young” CAA with past neurosurgery appears striking, but the numbers are really very small, and what is entirely unclear is the frequency and type of pediatric neurosurgery in such an age bracket with or without biopsies, in CAA at all ages (there are no details given about older CAA cases in the studied archive), or in the population at large. The usefulness of the present control group of 50 patients with (vascular) malformations operated at similar age appears very limited.

    2) Since there are already some more suggestive hints for Aβ transmission via dural grafting, there is the possibility that some cases actually received such grafts during the past neurosurgery, as was rather common decades ago, without obvious data in the presently available medical records. Indeed, the authors mention "no confirmatory evidence of dural grafts.” However, past clinical data given in the paper are sparse: the report of case 1 does not specify type and location of the brain injury suffered, but describes only multiple cranioplasties (bone replacement). The report of case 2 mentions only operation of a "brain tumor, reportedly a meningioma," at age 1. Case 3 had spinal neurosurgery and ventricular shunting. Case 4 also had spinal neurosurgery, with widespread cerebral CAA at autopsy.

    3) The brunt of cerebral Aβ pathology after dural grafting was described by us (ref. 28 of the present paper) at, or near to, the lesioned brain area underneath the graft. The present case reports do not allow such a topographical analysis.

    View all comments by Herbert Budka

  6. We were the first to describe the association of brain Aβ deposition (both as parenchymal plaques and cerebral amyloid angiopathy, CAA) and iatrogenic Creutzfeldt-Jakob Disease (iCJD) related to dura mater grafting many years ago (Australian Communicable Disease Intelligence publication, A case of Creuzfeldt-Jakob disease associated with a human dura mater graft, 1989; Simpson et al., 1996), but, as Aristotle noted, “one swallow does not a summer make.” Starting in 2016, approximately 20 years after our early reports, a rapid succession of papers has shown this association in a total of 34 recipients of dura mater grafts in persons from many countries (Frontzek et al., 2016; Hamaguchi et al., 2016; Kovacs et al., 2016; Cali et al., 2018). In addition, the apparent transmission and propagation of Aβ in the brains of recipients of growth hormone extracted from cadaveric pituitary glands has been recently reported by a number of groups (Cali et al., 2018; Jaunmuktane et al., 2015; Ritchie et al., 2017; Duyckaerts et al., 2018). 

    In this setting of growing concern regarding the possible transmissibility of Alzheimer’s disease (AD) and related disorders such as CAA comes this description of eight potential such cases (four from their own hospital archives and four from a literature search). Jaunmuktane et al. describe patients experiencing often fatal intracerebral hemorrhages from neuropathologically confirmed CAA some 20–30 years after neurosurgery, postulating that these patients represent examples of transmission of Aβ through neurosurgical instruments. Is the summer now made?

    Obviously the answer is “no” and a lot more epidemiological and other work needs to be done. Evidence supporting that surgical instruments can transmit prion disease has accumulated over many years and includes large epidemiological studies and meta analyses (Collins et al., 1999; López et al., 2017), detailed look-back studies to ensure plausibility of direct case-to-case transmission through neurosurgery (Brown et al., 1992; Will et al., 1982) and bioassays to confirm prion infectivity of the offending instruments despite routine sterilization between surgery (Brown et al., 1992). Although it now appears highly likely that Aβ can serve as a prion-like proteopathic seed when introduced into the brains of recipients (Frontzek et al., 2016; Hamaguchi et al., 2016; Kovacs et al., 2016; Cali et al., 2018; Jaunmuktane et al., 2015; Ritchie et al., 2017; Duyckaerts et al., 2018) and can even resist modest sterilization measures in experimental models (Eisele et al., 2009), published AD animal transmission experiments (Baker et al., 1994; Brown et al., 1994) and epidemiological studies of recipients of cadaveric growth hormone (Irwin et al., 2013) have been negative to date for evidence supporting the induction of overt disease; hence, the potential importance of the report by Jaunmuktane and colleagues.

    The speculation by these authors would have been strengthened if “plausibility gaps” could have been tightened, such as confirmation that the neurosurgical instruments employed on the very young pediatric patients included in their series had been verified as being used for CNS neurosurgery in adults with AD, especially in close temporal proximity. While uncertainty around this important issue persists, we await results of ongoing investigations with considerable interest.

    References:

    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.

    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.

    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.

    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.

    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.

    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.

    Ritchie DL, Adlard P, Peden AH, Lowrie S, Le Grice M, Burns K, Jackson RJ, Yull H, Keogh MJ, Wei W, Chinnery PF, Head MW, Ironside JW. Amyloid-β accumulation in the CNS in human growth hormone recipients in the UK. Acta Neuropathol. 2017 Aug;134(2):221-240. Epub 2017 Mar 27 PubMed.

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    View all comments by Colin Masters

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