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.

Keywords: Amyloid-β; Aβ; CAA; Cerebral amyloid angiopathy; Decontamination; Head trauma; Intracerebral haemorrhage; Neurosurgery; Prion diseases; Proteopathic seeding; TBI; Transmission; Traumatic brain injury.

Fig. 1

Number of patients with CAA in different age groups over 15-year period from NHNN archive. Histogram showing all patients who underwent surgery, or whose biopsy was reviewed at NHNN during the period from January 2002 to March 2016, and one post-mortem case. In all 37 patients who underwent haematoma evacuation or diagnostic brain biopsy and in one post-mortem case, CAA was histologically confirmed. Cases 1 (#1) and 3 (#3) correspond to the two female patients in the age group 36–40 years, Case 2 (#2) corresponds to the male patient in the age group 30–35, and Case 4 (#4) corresponds to the female patient, aged 57, in whom CAA was diagnosed at autopsy. The two patients in the age group 41–45 correspond to one female patient with a pathogenic mutation in the PSEN1 gene and one male patient with CAA and parenchymal Aβ pathology in whom further clinical details could not be obtained. Orange, female patients and blue, male patients

Fig. 2

Timeline of the clinical history in patients with CAA: The top row indicates the age in years and the two left columns denote all four patients in our study and reports from the literature, with the patient identifier used in the text. In the timeline, light orange indicates the period prior to neurosurgery; light purple the intervals between neurosurgery and CAA diagnosis or first episode of intracerebral haemorrhage. The green lines on the left indicate the time points of neurosurgical interventions. In patient #5, the time point indicating surgery is an estimate. In patients #6 and #7, the purple lines indicate an estimated time point of head trauma. The red lines on the right indicate the age at which the haemorrhage(s) occurred and the black line indicates the age at death. ApoE status for each patient, where available, is indicated in the far right column (NA not available). Patient #9 [49] did not have neurosurgery and no clinical information of surgery is available for patient #10 [8]

Fig. 3

CAA in biopsy and autopsy tissue of the four patients from our cohort. The cortex in case 1 (a, a1) shows widespread CAA, including capillary involvement (blue arrows in a1) and occasional diffuse parenchymal deposits (red arrow in a1). In case 2 (b, b1), there is CAA in leptomeninges and cortex but no diffuse Aβ. In case 3 (c, c1), there are in addition frequent diffuse parenchymal deposits (red arrow in c1). The autopsy case (Patient 4, d, d1–d8) shows widespread CAA in the cerebral leptomeninges and neocortex (d) and focally in the cerebral white matter (d1, WM white matter). In the leptomeninges, there is also focal multinucleated giant cell inflammation (blue arrow in d2). Amyloid angiopathy is also present across the medial temporal lobe, including CA4 hippocampal sub-region (d3), in the putamen (d4), thalamus, including within the haemorrhage (d5) and in the midbrain near the substantia nigra (blue arrow in d6, SN substantia nigra). CAA is also seen in the cerebellar leptomeninges, and to a lesser extent in the cerebellar cortex (d7) and focally in the subcortical cerebellar white matter (d8; GL granule cell layer, ML molecular layer). All sections are immunostained for amyloid-β. Section d2 is double-labelled for amyloid-β (brown) and macrophages (CD68, red). All sections are counterstained with haematoxylin. Scale bar: 450 µm in a, b, c, d; 200 µm in d1, d3, d4, d5, d6, d7, d8 and 50 µm in a1, b1, c1 and d2