Possible transfusion transmitted cerebral amyloid angiopathy: evaluation of transmission of Aβ using the RADAR repository

PROJECT SUMMARY/ABSTRACT
Cerebral amyloid angiopathy (CAA) is a common cause of spontaneous intracerebral hemorrhage (ICH), with a
case fatality rate of 30-50%. CAA is characterized by aggregation of likely misfolded deposits of amyloid β (Aβ)
in the cerebral vasculature, leading to vascular weakening and repeated, unprovoked ICH. Over the past decade
evidence has been accumulating that Aβ exhibits prion-like properties, being overtly transmissible in
experimental settings through a range of different parenteral routes. More pressingly, still, parenteral iatrogenic
Aβ transmissibility, leading to CAA development, has also been demonstrated in humans, following neurosurgery
and in patients treated with cadaveric human growth hormone. Given that prions are readily transfusion
transmissible, this raises the disconcerting possibility that CAA and its related Aβ-associated conditions, are
potentially transfusion transmissible. A large, bi-national, retrospective cohort study using the Swedish-Danish
SCANDAT transfusion database found that 0.1% of transfused patients in Sweden and Denmark received red-
cell units from blood donors who later suffered repeated, unprovoked ICH, and that these patients were at a
near-3-fold increased risk of themselves suffering an unprovoked ICH, as compared to patients who did not
receive red-cell units from affected blood donors. Under the hypothesis that the observed association was driven
by Aβ transmission and CAA development in affected donors and recipients, the clinical implications could be
very large, especially considering that Aβ aggregation is also strongly associated with Alzheimer’s disease.
However, external replication of these preliminary findings, ideally with biochemical and mechanistic
corroboration, is urgently needed. We therefore propose to utilize the existing NHLBI REDS Allogeneic Donor
and Recipient (RADAR) repository, with samples from both blood donors and pre- and post- transfusion samples
of transfused, to (a) investigate the prevalence of Amyloid β pathology through measures of the associated
pTau217 protein among blood donors, and (b) investigate the possibility that amyloid β is transfusion-
transmissible from affected donors to their transfused patients.

Grant Number: 5R21HL175170-02
NIH Institute/Center: NIH
Principal Investigator: MICHAEL BUSCH