Small vessel disease and/or atherosclerosis produce microvascular and parenchymal inflammation in white matter and results in vascular cognitive impairment (VCI). We have performed bilateral carotid artery stenosis in hypertensive rats (SHR) to better understand disease pathology, targets for intervention and markers.
Hypothesis: Complex cognitive deficits and diffuse fiber tract changes relevant to human VCI can be quantified and validated for future use.
Methodology: We performed a series of behavioral assays to test declarative memory and executive functioning in stenosis compared to sham surgery SHR. Behavioral assays included T-maze decision making and alternation, novel object recognition (NOR) and active place avoidance (APA). MRI (DTI, DWI, Arterial Spin Labeling; ASL) and FDG-PET imaging was done in Corpus Callosum (CC). Histology-immunohistochemistry included measurements of microglia (Iba-1), astrocytes (GFAP) and Luxol fast blue (for myelin) in CC.
Results: Stenosis resulted in consistent executive function decision making (T-maze) deficits (p<0.05) and impaired complex cognitive performance (APA). No significant differences occurred between sham and stenosis animals in NOR and T-maze alternation. DTI analysis indicated significant (p<0.05) changes in the CC of stenosis compared to sham SHR including: (1) decreased fractional anisotropy, (2) increased radial diffusivity, and (3) unchanged axial diffusivity. MRI ASL revealed significant (p<0.05) decreases in white matter perfusion. No significant changes were seen in FDG-PET. In summary, stenosis animals exhibited increased white matter glial cell inflammation related to demyelination and lost cognition. The inflammatory microglia phenotype was verified using TNFα plus Iba-1 double staining. CC changes were significantly (p<0.05) greater in the anterior, periventricular forebrain.
Conclusion: We have successfully modeled the behavioral, imaging and histologic profile of human VCI in the rat. Currently pre/mature oligodendrocyte changes are being evaluated. This approach provides future opportunities to localize forebrain white matter changes using MR imaging parameters as markers for monitoring VCI demyelination/pathology and intervention.