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Thrombolysis in experimental cerebral amyloid angiopathy and the risk of secondary intracerebral hemorrhage

Reuter, Björn and Grudzenski, Saskia and Handwerker, E and Meairs, S and Heiler, P and Schad, L and Staufenbiel, Matthias and Hennerici, Michael P and Fatar, Marc (2014) Thrombolysis in experimental cerebral amyloid angiopathy and the risk of secondary intracerebral hemorrhage. Stroke, 45 (8). pp. 2411-2416. ISSN 0039-2499

Abstract

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.

Item Type: Article
Keywords: CAA, transgenic mice, APP23, stroke, rtPA, thrombolysis, ICH, amyloid angiopathy
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/10711

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