Thrombolysis in experimental cerebral amyloidangiopathy and the risk of secondaryintracerebral hemorrhage

Background Intracerebral hemorrhage (ICH) is the most adverse event of thrombolytic therapy in ischemic stroke (IS). In cerebral amyloid angiopathy (CAA), accumulation of amyloid- β results in cerebral microbleeds and a higher risk for spontaneous lobar ICH. Although thrombolysis may be performed in CAA-affected patients suffering acute IS, there is still little knowledge available regarding the risk for thrombolysis-associated ICH both in patients and from experimental studies. Methods We investigated the effect of recombinant tissue plasmin activator (rtPA) on experimental IS in the APP23-transgenic (tg) mouse model of CAA (n=18) and wildtype (wt) littermates (n=15). Focal IS was induced in 26 months old mice by temporal occlusion of the left middle cerebral artery (MCA, filament-model). Animals were treated with 10 mg/kg rtPA 30 min after MCA occlusion (MCAo). 24 hours after MCAo a functional score was assessed and the mice were sacrificed for histological analysis. Results APP23-tg mice and controls did not differ regarding mortality (4/18 APP-tg, 3/15 wt; p=0.754), histologically assessed infarct volume (32.5±24.9 mm3 vs. 26.2±28.9 mm3; p=0.57) and functional neurological deficit (3±0.6 vs. 2.6±1; p=0.33). From all mice undergoing surgery one mouse in each group had to be excluded from analysis because of no infarct after MCAo. The APP23 genotype was associated with a higher risk for ICH in the infarct area (9/13 vs. 3/12; p=0.027). For histological evaluation of ICH severity, a score with adjustment for numbers and size was established. We 1 found a positive correlation with infarct size and ICH-severity in APP23-tg mice but not controls (p=0.012). Conclusion To our knowledge, we present the first rodent study evaluating the risk of ICH after stroke thrombolytic therapy in a mouse model of CAA. Our results suggest a significantly higher risk for ICH in the CAA-affected brain. However, increasing severity of ICH with infarct size was neither associated with a higher mortality nor worse functional outcome. Furthermore, although in general vascular amyloid deposits in old APP23-tg mice are severe, no ICHs were observed outside of the area of infarction.