Preserved diffusion MRI measures despite subtle behavioral and hippocampal CA3 alterations in a preclinical model of cerebral small vessel disease

Background Cerebral small vessel disease (CSVD) is a major cause of vascular cognitive impairment, yet early-stage alterations remain insufficiently characterized. This study investigated the relationship between behavioral deficits, hippocampal microstructure, and histopathological changes in a preclinical CSVD model. Methods Male stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar Kyoto (WKY) controls were evaluated at 8, 14, and 42 weeks. Behavioral assessments included open field, novel object recognition, and Morris's water maze. Brain MRI was performed using a 3.0 T system with diffusion tensor imaging (DTI), followed by region-of-interest analysis of the hippocampus. Histological evaluation included hematoxylin and eosin (H&E) and Nissl staining. Results SHRSP demonstrated age-associated behavioral alterations, including reduced locomotor activity (strain × age: p = 0.013), preserved recognition memory at early stages but declined at 42 weeks, and impaired spatial learning with absent acquisition improvement in aged animals. Notably, hippocampal DTI metrics remained unchanged across the examined experimental time points, with no significant effects of strain or age on fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), or radial diffusivity (RD) (all p > 0.25). Whole-brain analyses yielded non-significant findings similarly. Histologically, enlarged perivascular spaces (ePVS) were consistently observed, while microbleeds and hemosiderin deposition were absent. Hippocampal thickness (CA1, CA3, dentate gyrus) was preserved; however, selective neuronal loss was detected in the CA3 subfield of aged SHRSP (42 weeks). Conclusion Behavioral decline was observed despite the absence of detectable hippocampal microstructural alterations using conventional DTI metrics, suggesting that functional impairment may emerge before abnormalities become evident within the sensitivity limits of the current imaging framework. These findings suggest that early CSVD involves subtle cellular and vascular dysfunction not captured by standard imaging, emphasizing the need for more sensitive, network-based, and molecular approaches.

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