Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery

Abstract

Amyloid-β (Aβ) is a peptide deposited in the brain parenchyma in Alzheimer’s disease and in cerebral blood vessels, causing cerebral amyloid angiopathy (CAA). Aβ pathology is transmissible experimentally in animals and through medical procedures in humans, such as contaminated growth hormone or dura mater transplantation in the context of iatrogenic prion disease. Here, we present four patients who underwent neurosurgical procedures during childhood or teenage years and presented with intracerebral haemorrhage approximately three decades later, caused by severe CAA. None of these patients carried pathogenic mutations associated with early Aβ pathology development. In addition, we identified in the literature four patients with a history of neurosurgical intervention and subsequent development of CAA. These findings raise the possibility that Aβ pathology may be transmissible, as prion disease is, through neurosurgical procedures.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1822-2) contains supplementary material, which is available to authorized users.

Early onset cerebral amyloid angiopathy following childhood exposure to cadaveric dura

“…In keeping with the few previous reports, 8,9 our patients first developed neurological symptoms approximately 3 to 4 decades after exposure to cadaveric dura (range = 27-37 years), suggesting a long incubation period. The association between CAA and endovascular embolization with cadaveric dura suggests that Aβ seeds might be transmitted without direct neurosurgical brain exposure.…”

“…8,36 However, many of these cases also underwent neurosurgical intervention and, in our series, case 2 had no prior history of either direct head trauma or neurosurgical intervention. A recent neuropathological case series 8 describing Aβ transmission following childhood neurosurgery (n = 4) reported that no dura was used in 1 case, and that its use was unlikely (although not completely excluded) in the other 3, so our study cannot exclude transmission via neurosurgical or neurovascular instrumentation.…”

“…Lyophilized cadaveric dura embolization material has been suggested to potentially transmit iCJD, 19,20 and experimental intravenous injection of Aβ seeds causes CAA. 8,9 There are 2 potential explanations for these observations. 8,9 There are 2 potential explanations for these observations.…”

“…21 In 2 of our cases (Cases 1 and 2), there was evidence of significant amyloid angiopathy distant from the site of presumed transmission; this is in keeping with previously reported cases of suspected iatrogenic CAA, where widespread disease is observed on neuropathological examination. 8,9 There are 2 potential explanations for these observations. First, although prions do spread along defined neuroanatomical pathways, there is evidence that they can reach specific target regions despite different initial sites of inoculation 22 ; in the case of Aβ, the target might be the cerebral and leptomeningeal vasculature, resulting in widespread disease of these vessels regardless of transmission method.…”

“…1 Initially described in iatrogenic Creutzfeldt-Jakob disease (iCJD), [1][2][3][4][5][6][7] probable Aβ transmission in the absence of iCJD has been reported following administration of cadaveric human growth hormone, 3 childhood neurosurgery, 8 and cadaveric dural graft insertion. 1 Initially described in iatrogenic Creutzfeldt-Jakob disease (iCJD), [1][2][3][4][5][6][7] probable Aβ transmission in the absence of iCJD has been reported following administration of cadaveric human growth hormone, 3 childhood neurosurgery, 8 and cadaveric dural graft insertion.…”