Can Aβ Seeds Be Transferred During Neurosurgery?

Could Aβ aggregates clinging to surgical equipment seed pathology in patients' brains? Possibly, according to Sebastian Brandner and colleagues at University College London. Sifting through pathology archives at the National Hospital for Neurology and Neurosurgery (NHNN), the scientists found four adults who had developed cerebral amyloid angiopathy (CAA) at an uncharacteristically young age, mostly in their 30s. Strikingly, all four had undergone brain surgery decades prior. The researchers identified four similar cases in the literature, as well. They claim that during childhood neurosurgery, Aβ from contaminated surgical equipment was transferred into the brain, and seeded the buildup of amyloid in the cerebrovasculature. Brandner and colleagues call for larger studies to address the potential link directly, and for better sterilization of instruments.

  • Researchers identified eight cases of cerebral amyloid angiopathy in young adults.
  • All had had neurosurgery as children.
  • Were they inadvertently inoculated with Aβ aggregates?

The findings are the latest in a recent string of papers linking neurosurgical procedures or tissue transplants to the subsequent appearance of Aβ deposits. However, Colin Masters and Steven Collins at the University of Melbourne wrote in a joint comment to Alzforum, this is the first report that such transfer, if indeed it occurred, could have fatal consequences. Three of four patients identified in biopsy reports died of intracerebral hemorrhages triggered by CAA. The bleeds are what prompted the biopsies in the first place. However, Masters and Collins cautioned that “plausibility gaps,” along with its small size, leave the study far from definitive.

Lary Walker of Emory University in Atlanta acknowledged the possibility that Aβ contamination caused the CAA in these cases, but emphasized that the data are both sparse and complex. “The evidence is highly speculative at this point,” he said. “It is really impossible, with such a small number of cases that are complicated in many ways, to pin down a specific cause of disease.”

Thirty-plus with CAA. Aβ deposits (brown) associated with blood vessel walls in three people in their mid-30s. Diffuse parenchymal plaques also appeared in two of these cases (red arrows), and in one case, CAA affected the capillaries as well (blue arrows). [Courtesy of Jaunmuktane et al., Acta Neuropathologica, 2018.]

Pinning down a cause has been easier for infectious prions (PrP), which can spread from one host to another via neurosurgical and transplant procedures. It is now widely accepted that this route of transmission explains some cases of “iatrogenic” Creutzfeldt-Jakob disease, i.e. iCJD caused by medical procedures. Notably, some children who for years received regular injections of growth hormone extracted from deceased donors (c-HGH) later developed iCJD as young adults.

In 2015, Brandner and colleagues found Aβ pathology in a proportion of those iCJD patients at autopsy, suggesting that Aβ aggregates in the c-HGH batches had entered the brains of recipients as well, and had spread via proteopathic mechanisms (Sep 2015 news). Since then, researchers have detected Aβ pathology in more c-HGH recipients, including those who never developed iCJD (Ritchie et al., 2017; Cali et al., 2018). 

Iatrogenic CJD and Aβ deposits have also cropped up in people who received dural membrane grafts from cadaver donors to replace tissue damaged by injury or malformations in their brains (Jan 2016 news; Hamaguchi et al., 2016). In both the affected c-HGH and dural graft recipients, researchers identified CAA as the predominant form of Aβ pathology, though diffuse parenchymal plaques also appeared in some cases. For the most part, neurofibrillary tangles of tau were not found.

For the current study, first author Zane Jaunmuktane and colleagues asked whether Aβ could be transferred by contaminated neurosurgical equipment. Collins, Masters, and other researchers had demonstrated that PrP can pass between people in this way, and animal studies reported that both PrP and Aβ aggregates stubbornly resisted removal via standard sterilization procedures (Collins et al., 1999; Sep 2014 news; Bonda et al., 2016). Jaunmuktane searched NHNN brain biopsy and autopsy reports between 2002 and 2016 for cases of CAA, and identified 37 patients who had brain biopsies that indicated CAA. Because the incidence of sporadic CAA increases with age, the researchers restricted their investigation to people younger than 55 to eliminate age-related cases, leaving five people. One carried a pathogenic PSEN1 mutation and was excluded, as was another patient with no available genetic or clinical history. This left three patients who had CAA in their 30s and had no known familial AD mutations. They identified a fourth relatively young person with CAA, aged 57, among autopsy reports.

Of the three CAA cases in their 30s, all had suffered brain trauma that required surgery when they were children. A 39-year-old woman had had a severe brain injury at age 1; a 31-year-old man had had a brain tumor removed when he was 1; and a 37-year-old woman had had multiple surgeries to treat developmental problems, including spina bifida, hydrocephalus, and an Arnold-Chiari malformation, in which the cerebellum pushes through the base of the skull. All three developed spontaneous intracerebral hemorrhages in their mid-30s, and the biopsies were taken during removal of resulting hematomas. The two women ultimately died from further hemorrhages; whether the 31-year-old man survived was not reported. Histopathology of the biopsied tissue revealed pervasive CAA in both leptomeningeal and cortical blood vessels in all cases. Parenchymal plaques were not apparent in samples from the 31-year-old man and were sparse in the 39-year-old woman, but diffuse plaques were numerous in the 37-year-old woman, along with several dense plaques. The source of the man’s hemorrhage came from the resection cavity of his tumor, and CAA also surrounded the cavity.

Interestingly, a subsequent PiB-PET scan revealed that the man had fibrillar Aβ throughout the brain. The 37-year old woman carried the R62H variant of TREM2, which is a known risk factor for late-onset AD, as a well as a single copy of the ApoE4 allele. However, the researchers reasoned that neither of these risk alleles was likely to explain her early development of Aβ pathology. None of the patients had neuritic plaques or neurofibrillary tau tangles.

The fourth case of CAA, identified in an autopsy report, was a 57-year-old woman who had been diagnosed with syringomyelia—a condition in which a cyst grows on the spinal cord—at age 17. She had surgery to remove the cyst at age 20. At age 40, she developed a malformation within blood vessels in the right insula, which was surgically treated. Ultimately, she died from a large intracerebral hemorrhage. Postmortem histology revealed widespread CAA as the cause, along with multiple smaller hemorrhages throughout the brain. This woman had extensive parenchymal Aβ deposits, and neurofibrillary tangles confined to the medial temporal lobe. Though she was too old to rule out age-related, sporadic CAA, Brandner told Alzforum that the extent of the CAA pathology was still unusual for someone in her 50s.

The researchers identified six additional cases of CAA in young adults in the literature. All were men who had suffered a single, bone-penetrating traumatic brain injury as children. Clinical history confirmed two of them had had surgery to treat the injury, while in another two cases, surgery was deemed likely to have happened based on neuroimaging. One of the six cases did not have neurosurgery in childhood, and the other one had no clinical history. This left a total of four cases from the literature who had young-onset CAA and a history of likely neurosurgery.

The researchers hypothesized that the three young-onset CAA cases identified in their hospital records and the four in the literature were caused by transfer of Aβ aggregates during their childhood procedures. One potential confounder could be selection bias within the biopsy cases: Perhaps people who undergo biopsies are more likely to have had neurosurgeries in the past, and that could explain why all the young biopsied CAA cases had a history of surgery. However, when the researchers looked through a control group of 50 biopsy records of people in their 20s to 40s who did not have CAA, they found only three of them had definitively had childhood neurosurgical procedures, arguing against a link between biopsy and prior surgery.

Several commentators said that the small number of cases make it difficult to draw strong conclusions about the cause of their CAA. Key information is also missing. Herbert Budka at the Medical University in Vienna pointed out that there is no information on whether the patients received dural grafts—a potential source of Aβ seeds—during their childhood procedures. Others noted that it is unknown if the childhood neurosurgeries took place at institutions that also operate on adults, much less on old adults likely to harbor Aβ pathology that could contaminate surgical equipment.

Others raised the obvious possibility that childhood brain trauma—from the injuries, malignancies, disorders, or even the neurosurgeries themselves—may have triggered the development of CAA, rather than a transfer of Aβ aggregates per se. “The small number [of cases] makes 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,” wrote Steven Greenberg of Massachusetts General Hospital in Boston. “The data are certainly intriguing and support further studies to replicate and explain the findings.”

John Trojanowski of the University of Pennsylvania in Philadelphia cited his and other studies reporting an association between brain trauma and Aβ deposits (Uryu et al., 2002; Smith et al., 2003; Ikonomovic et al., 2004). “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,” Trojanowski wrote. “Brain trauma per se (which neurosurgery represents) is associated with greater likelihood of brain Aβ deposits.” Researchers recently reported Aβ plaque accumulation in people who had a single TBI years prior, though their pathology was fibrillar plaques, not CAA (Feb 2016 news).

The authors cited studies calling into question a potential link between trauma/surgery and CAA. Tau tangles, not Aβ deposits, are the hallmark of chronic encephalopathy (CTE), which is caused by repetitive head trauma, they noted. And while Aβ deposits may occur in about half of people with CTE, they do so primarily in older people, making it unlikely they would appear in 30-somethings as a result of past injury alone (Stein et al., 2015). 

The authors also questioned the proposed link between traumatic brain injury and CAA, noting an autopsy study that found no association between self-reported TBI and CAA, while an amyloid PET study correlated brain trauma and Aβ burden in people with MCI, but not in cognitively normal people (Jul 2016 news; Jan 2014 news). 

Brandner told Alzforum that despite the small number of patients and gaps in their health records, his finding should at least spur larger studies. Both a broader search for young CAA cases at different institutions and a search for cases of white-matter hyperintensities on MRI scans—a possible indicator of CAA—could flag young people for further investigation. They could at least be asked whether they had had neurosurgery, he suggested.

In the meantime, Brandner suggested hospitals ramp up sterilization procedures of neurosurgical equipment, because current protocols may not fully remove protein aggregates. Complete removal of aggregates, or using disposable equipment when possible, should further reduce the already very low risk of transfer, Brandner told Alzforum. “Any instrument that comes into contact with the brain should be pristine,” Walker said.—Jessica Shugart

Comments

  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.

    Duyckaerts C, Sazdovitch V, Ando K, Seilhean D, Privat N, Yilmaz Z, Peckeu L, Amar E, Comoy E, Maceski A, Lehmann S, Brion JP, Brandel JP, Haïk S. Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology. Acta Neuropathol. 2018 Feb;135(2):201-212. Epub 2017 Nov 22 PubMed.

    Collins S, Law MG, Fletcher A, Boyd A, Kaldor J, Masters CL. Surgical treatment and risk of sporadic Creutzfeldt-Jakob disease: a case-control study. Lancet. 1999 Feb 27;353(9154):693-7. PubMed.

    López FJ, Ruiz-Tovar M, Almazán-Isla J, Alcalde-Cabero E, Calero M, de Pedro-Cuesta J. Risk of transmission of sporadic Creutzfeldt-Jakob disease by surgical procedures: systematic reviews and quality of evidence. Euro Surveill. 2017 Oct;22(43) PubMed.

    Brown P, Preece MA, Will RG. "Friendly fire" in medicine: hormones, homografts, and Creutzfeldt-Jakob disease. Lancet. 1992 Jul 4;340(8810):24-7. PubMed.

    Will RG, Matthews WB. Evidence for case-to-case transmission of Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry. 1982 Mar;45(3):235-8. PubMed.

    Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX, Roth K, Aguzzi A, Staufenbiel M, Walker LC, Jucker M. Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12926-31. PubMed.

    Baker HF, Ridley RM, Duchen LW, Crow TJ, Bruton CJ. Induction of beta (A4)-amyloid in primates by injection of Alzheimer's disease brain homogenate. Comparison with transmission of spongiform encephalopathy. Mol Neurobiol. 1994 Feb;8(1):25-39. PubMed.

    Brown P, Gibbs CJ Jr, Rodgers-Johnson P, Asher DM, Sulima MP, Bacote A, Goldfarb LG, Gajdusek DC. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol. 1994 May;35(5):513-29. 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.

    View all comments by Steven Collins View all comments by Colin Masters

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References

News Citations

  1. Alzheimer’s Transmission Between People? Amyloid Plaques in Hormone Recipients Hint at Prion-like Spread
  2. News Brief: More Evidence for Aβ Spread Between People
  3. Bad Seeds—Potent Aβ Peptides Instigate Plaques, Won’t Be Fixed
  4. Traumatic Brain Injury: Aβ Ensues, but Not Quite Alzheimer’s
  5. Brain Trauma Linked to Parkinson’s, Not Alzheimer’s
  6. Does a Blow to the Head Mean More Amyloid Down the Road?

Mutations Citations

  1. TREM2 R62H

Paper Citations

  1. 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.
  2. 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.
  3. 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.
  4. Collins S, Law MG, Fletcher A, Boyd A, Kaldor J, Masters CL. Surgical treatment and risk of sporadic Creutzfeldt-Jakob disease: a case-control study. Lancet. 1999 Feb 27;353(9154):693-7. PubMed.
  5. Bonda DJ, Manjila S, Mehndiratta P, Khan F, Miller BR, Onwuzulike K, Puoti G, Cohen ML, Schonberger LB, Cali I. Human prion diseases: surgical lessons learned from iatrogenic prion transmission. Neurosurg Focus. 2016 Jul;41(1):E10. PubMed.
  6. 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.
  7. 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.
  8. 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.
  9. Stein TD, Montenigro PH, Alvarez VE, Xia W, Crary JF, Tripodis Y, Daneshvar DH, Mez J, Solomon T, Meng G, Kubilus CA, Cormier KA, Meng S, Babcock K, Kiernan P, Murphy L, Nowinski CJ, Martin B, Dixon D, Stern RA, Cantu RC, Kowall NW, McKee AC. Beta-amyloid deposition in chronic traumatic encephalopathy. Acta Neuropathol. 2015 Jul;130(1):21-34. Epub 2015 May 6 PubMed.

Further Reading

Papers

  1. Johnson VE, Stewart W, Smith DH. Traumatic brain injury and amyloid-β pathology: a link to Alzheimer's disease?. Nat Rev Neurosci. 2010 May;11(5):361-70. PubMed.

Primary Papers

  1. 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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