Intravenously administered gadolinium based contrast agent as a novel approach to longitudinally measure ventricular brain clearance with magnetic resonance imaging in an Alzheimer´s disease model
Luisa Müller, Tobias Lindner, Stefan Polei, Katerina Deike‐Hofmann, Alexander Radbruch, Angela Kuhla, Stefan Teipel- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Amyloidopathy, one pathological hallmark of Alzheimer’s disease (AD), results from dysbalanced amyloid‐β production and clearance. Therefore, disruptions in brain clearance may have a pivotal role as pathogenic drivers. Transgenic mice models of AD may serve to develop and establish minimally invasive in vivo measurement methods to observe brain clearance longitudinally.
Method
We used magnetic resonance imaging (MRI) with intravenously administered gadolinium‐based contrast agent (GBCA) on a 7T small animal ultrahighfield MRI scanner to determine brain clearance efficacy. Imaging sessions were performed longitudinally in n = 9 APPswe/PS1dE9 (tg) mice and n = 9 wild type (wt) littermates at 6, 9 and 12 months of age with a scan protocol consisting of a highly T2w Inv. Rec. RARE (FLAIR) sequence. For a subsample of n = 6 wt and n = 6 tg at 9 and 12 months we used an additional T1w RARE sequence for evaluation of parenchymal changes. Both protocols were carried out every 5‐6.5 minutes for a total of 180 minutes. We determined mean voxel values in manually delineated volumes of interest in ventricles (in T2w images) and brain parenchyma (T1w images) using PMOD software.
Result
We created intensity‐time‐curves and measured slopes for signal increase and decrease, derived from fitting with a model consisting of an exponential convoluted with another exponential and used to normalize area under the curve (AUC) values (Figure 1A‐C). Repeated measurements ANOVA revealed no differences in normalized AUC values regarding age in both lateral (p = 0.568, F(2, 28) = 0.577), 3rd (p = 0.306, F(1.903, 26.64) = 1.232) and 4th ventricles (p = 0.181, F(1.345, 18.83) = 1.924) and also no differences regarding genotype in both lateral (p = 0.684, F(1,16) = 0.172), 3rd (p = 0.737, F(1,16) = 0.117) and 4th ventricle (p = 0.186, F(1,16) = 1.910). Measurements of parenchymal clearance capacity are still ongoing and first results will be presented at the conference.
Conclusion
Our first results showed no measurable difference in the brain clearance efficacy. This could have two possible reasons. Either ventricular clearance measurements are not sensitive enough to measure AD related changes in brain clearance or the used pathogenetic model shows no changes in clearance efficacy. Our still ongoing analyses of parenchymal brain could help to elucidate further on this question.