Microvascular cerebral blood volume changes in aging APPswe/PS1dE9 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 (APPswe/PS1dE9) during aging, we developed a new method to obtain microvascular relative cerebral blood volume (rCBVmicro) maps from gradient echo MR imaging by histogram evaluation and we applied a voxel-wise approach to detect rCBVmicro 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 rCBVmicro 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 rCBVmicro in 13-month-old wild-type and APPswe/PS1dE9 mice correlates well with capillary density measured with immunohistochemical staining. However, no differences in capillary density were detected between genotypes. The rCBVmicro values showed no significant correlation with amyloid-β (Aβ) plaque deposition, Aβ at blood vessel walls and biochemically measured levels of Aβ1-40, Aβ1-42 oligomers and fibrillar forms. These results suggest that rCBVmicro 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.

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The author acknowledges Dr. Giulio Gambarota, Dr. Carmen Capone, Carola Janssen, Michiel Kleinnijenhuis and Xiaotian Fang for their technical and scientific assistance in writing this manuscript. The research leading to these results has received funding from the EU FP7 project LipiDiDiet, Grant Agreement No 211696 and was supported by NWO investment grants nr 91106021 and BIG (VISTA).

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There are no actual or potential conflicts of interest to report for any of the authors.

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Correspondence to Amanda J. Kiliaan.

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Video 1. Representative 3D reconstruction of macrovasculature rCBVmacro mask in three-dimensional view identifies the major surrounding and perforating brain arteries and vein

Supplementary material 1 (MPEG 3934 kb)

Supplementary material 1 (MPEG 3934 kb)

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Zerbi, V., Jansen, D., Dederen, P.J. et al. Microvascular cerebral blood volume changes in aging APPswe/PS1dE9 AD mouse model: a voxel-wise approach. Brain Struct Funct 218, 1085–1098 (2013).

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  • Alzheimer’s disease
  • APP/PS1 mice
  • Cerebral blood volume
  • Amyloid-β
  • Voxel-wise analysis