Diffusion tensor imaging and histopathological differences in dogs with and without cognitive dysfunction

Abstract Background Canine cognitive dysfunction (CCD) is a progressive neurodegenerative condition in aging dogs that mimics Alzheimer’s disease in humans. While diffusion tensor imaging (DTI) has been used to study white matter changes in human dementia, its role in CCD diagnosis remains unclear. Methods 59 dogs classified into Young (n = 18), Aged (n = 17) and CCD (n = 24) based the Canine Dementia Scale (CADES). DTI data were collected, creating fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD) and radial diffusivity (RD) in four brain regions (corpus callosum, thalamus, internal capsule, hippocampus). All DTI variables were compared among the groups, and correlation between DTI variables and CADES and the Canine Cognitive Dysfunction Rating Scale (CCDR) was evaluated. When available, histopathological examination of the brain was performed to confirm CCD. Results Fifty-nine dogs were prospectively categorized into Young (n = 18), Aged (n = 17), and CCD (n = 24) groups. DTI data (FA, MD, AxD, RD) were extracted from the corpus callosum, thalamus, internal capsule, and hippocampus. Significant group differences were found in all DTI metrics for the corpus callosum, thalamus, and internal capsule, but not the hippocampus, with emphasis on FA in the corpus callosum in CCD dogs and aged dogs (P = .049). Significant negative correlation was identified between CADES and FA in the corpus callosum, thalamus and internal capsule. Postmortem analysis of seven brains showed increased neuroinflammatory morphology (hypertrophic astrocytes, ramified microglia) and tau phosphorylation (T217, T231). A loss of the luxol fast blue stain in the frontal cortex and thalamus was identified but not in hippocampus. Conclusions DTI revealed region-specific microstructural alterations in aging and CCD-affected dogs, particularly in white matter-rich regions like the corpus callosum. FA reductions were associated with both age and cognitive decline severity, supporting its use as a potential imaging biomarker. Histopathology corroborated the presence of neuroinflammation and myelin degradation, further validating the imaging findings. Together, these results support DTI as a promising non-invasive tool for the objective diagnosis and longitudinal monitoring of CCD, with potential translational relevance for human neurodegenerative disease research.