Neuroimaging Biomarkers Predict Brain Structural Connectivity Change in a Mouse Model of Vascular Cognitive Impairment

Abstract

Background and purpose: Chronic hypoperfusion in the mouse brain has been suggested to mimic aspects of vascular cognitive impairment, such as white matter damage. Although this model has attracted attention, our group has struggled to generate a reliable cognitive and pathological phenotype. This study aimed to identify neuroimaging biomarkers of brain pathology in aged, more severely hypoperfused mice.

Methods: We used magnetic resonance imaging to characterize brain degeneration in mice hypoperfused by refining the surgical procedure to use the smallest reported diameter microcoils (160 μm).

Results: Acute cerebral blood flow decreases were observed in the hypoperfused group that recovered over 1 month and coincided with arterial remodeling. Increasing hypoperfusion resulted in a reduction in spatial learning abilities in the water maze that has not been previously reported. We were unable to observe severe white matter damage with histology, but a novel approach to analyze diffusion tensor imaging data, graph theory, revealed substantial reorganization of the hypoperfused brain network. A logistic regression model from the data revealed that 3 network parameters were particularly efficient at predicting group membership (global and local efficiency and degrees), and clustering coefficient was correlated with performance in the water maze.

Conclusions: Overall, these findings suggest that, despite the autoregulatory abilities of the mouse brain to compensate for a sudden decrease in blood flow, there is evidence of change in the brain networks that can be used as neuroimaging biomarkers to predict outcome.

Keywords: biomarkers; diffusion tensor imaging; hypoperfusion; magnetic resonance imaging; mouse; neuroimaging; vascular cognitive impairment.

Figure 1.

Cerebral blood flow (CBF) and morphological changes in the hypoperfused brain. A, Representative CBF maps and angiography reconstructions showing increases in Circle of Willis tortuosity in hypoperfused mice. B, CBF over time (means±SD) in sham (n=10) and hypoperfused (n=11) groups. C, % hippocampal size in both groups.

Figure 2.

Brain metabolite concentrations in response to hypoperfusion. A, A representative spectrum from the striatum of a hypoperfused mouse. B, Metabolite concentrations (mmol/L) from sham and hypoperfused mice (means±SD). Ala indicates alanine; GABA, γ-aminobutyric acid; Glc, glucose; Gln, glutamine; Glu, glutamate; GPC, glycerophosphocholine; GSH, glutathione; Ins, myo-inositol; Lac, lactate (sham [n=5] and hypoperfused [n=6]); NAA, N-acetylaspartate; PCh, phosphocholine; and Tau, taurine.

Figure 3.

The effects of hypoperfusion on diffusion tensor imaging (DTI) indices. Quantitative fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) maps from 2 representative animals per group (calibration bars correspond to quantitative values). A, FA; (B) MD; (C) AD; and (D) RD (means±SD) in both groups.

Figure 4.

Graph theory revealed microstructural network changes in the hypoperfused brain. Representative reconstructions of the corpus callosum from 2 animals in each group. A, Global efficiency; (B) modularity, (C) transitivity, and (D) local efficiency in both groups.

Figure 5.

White matter integrity and astrogliosis in the hypoperfused brain. Luxol blue, GFAP, and Iba1 stained tissue sections from the corpus callosum of a representative animal in each group (dotted line outlines the corpus callosum [cc]. v indicates ventricles.

Figure 6.

The effects of hypoperfusion on spatial learning and short-term recognition memory. A, Escape latency and (B) swim speed of both groups during the Morris water maze place task (means±SD). C, Discrimination ratio of both groups in the second trial of the novel object recognition (NOR) task before and at 4-wk post-surgery (>0.5 indicates increased exploration of the novel object).