Abstract
The identification of biomarkers of vascular cognitive impairment is urgent for its early diagnosis. The aim of this study was to detect and monitor changes in brain structure and connectivity, and to correlate them with the decline in executive function. We examined the feasibility of early diagnostic magnetic resonance imaging (MRI) to predict cognitive impairment before onset in an animal model of chronic hypertension: Spontaneously Hypertensive Rats. Cognitive performance was tested in an operant conditioning paradigm that evaluated learning, memory, and behavioral flexibility skills. Behavioral tests were coupled with longitudinal diffusion weighted imaging acquired with 126 diffusion gradient directions and 0.3 mm3 isometric resolution at 10, 14, 18, 22, 26, and 40 weeks after birth. Diffusion weighted imaging was analyzed in two different ways, by regional characterization of diffusion tensor imaging (DTI) indices, and by assessing changes in structural brain network organization based on Q-Ball tractography. Already at the first evaluated times, DTI scalar maps revealed significant differences in many regions, suggesting loss of integrity in white and gray matter of spontaneously hypertensive rats when compared to normotensive control rats. In addition, graph theory analysis of the structural brain network demonstrated a significant decrease of hierarchical modularity, global and local efficacy, with predictive value as shown by regional three-fold cross validation study. Moreover, these decreases were significantly correlated with the behavioral performance deficits observed at subsequent time points, suggesting that the diffusion weighted imaging and connectivity studies can unravel neuroimaging alterations even overt signs of cognitive impairment become apparent.
Highlights
Vascular dementia is, after Alzheimer’s disease, the second most common cause of acquired dementia and covers between 25 and 30% of total dementia cases (O’Brien et al, 2003)
We found a significant effect of time [F(4, 70) = 9.265; P < 0.001], though there was no interaction [F(4, 70) = 0.6977; n.s.]. These results revealed no differences in learning and memory skills between the two groups and showed a time effect of learning in both Spontaneously hypertensive rats (SHR) and Wistar rats since fewer trials to re-discriminate were needed over time
In this work we present longitudinal diffusion tensor imaging (DTI) and global network analysis results that are correlated with behavioral data from cognitive flexibility paradigms
Summary
After Alzheimer’s disease, the second most common cause of acquired dementia and covers between 25 and 30% of total dementia cases (O’Brien et al, 2003). Affecting around 30% of the population older than 80 years, the total number of people with dementia worldwide in 2010 was estimated at Abbreviations: SHR, spontaneously hypertensive rats; VCI, vascular cognitive impairment; CSV, cerebral small vessel disease; MRI, magnetic resonance imaging; DTI, diffusion tensor imaging; DWI, diffusion weighted imaging; VOI, volume of interest; ADHD, attention deficit and hyperactivity disorder; WKY, Wistar-Kyoto; CC, corpus callosum; mPFC, medial prefrontal cortex; NAcc, nucleus accumbens; OFC, orbitofrontal cortex; adHpc, antero-dorsal hippocampus; FA, fractional anisotropy; AD, axial diffusivity; RD, radial diffusivity; MD, mean diffusivity; CV, cross-validation. Cognitive decline is characterized by the development of executive dysfunction even before other symptoms, such as memory impairment (O’Sullivan, 2004), become apparent. Identification of early changes associated with later development of dementia is imperative to evaluate the efficacy of any potential pharmacological therapy
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