Microvascular cerebral blood volume changes in aging APP_swe/PS1_dE9 AD mouse model: a voxel-wise approach

Vascular disorders can either be cause or consequence in the pathophysiology of Alzheimer’s disease (AD). To comprehensively characterize the occurrence of vascular impairment in a double transgenic mouse model for AD (APP_swe/PS1_dE9) during aging, we developed a new method to obtain microvascular relative cerebral blood volume (rCBV_micro) maps from gradient echo MR imaging by histogram evaluation and we applied a voxel-wise approach to detect rCBV_micro changes. With this methodology the development of cerebral microvascular impairments can be described in vivo with 0.16 mm isotropic resolution for the whole mouse brain. At 8 months, impaired rCBV_micro appeared in some cortical regions and in the thalamus, which spreads over several sub-cortical areas and the hippocampus at 13 months. With a ROI-based approach, we further showed that hippocampal rCBV_micro in 13-month-old wild-type and APP_swe/PS1_dE9 mice correlates well with capillary density measured with immunohistochemical staining. However, no differences in capillary density were detected between genotypes. The rCBV_micro values showed no significant correlation with amyloid-β (Aβ) plaque deposition, Aβ at blood vessel walls and biochemically measured levels of Aβ_1-40, Aβ_1-42 oligomers and fibrillar forms. These results suggest that rCBV_micro reduction is caused by an impaired vasoactivity of capillaries and arterioles, which is not directly correlated with the amount of Aβ deposition in parenchyma nor blood vessel walls.