Evidence of altered age-related brain cytoarchitecture in mouse models of down syndrome: a diffusional kurtosis imaging study

Abstract

Mouse models of Down syndrome (DS) exhibit abnormal brain developmental and neurodegenerative changes similar to those seen in individuals with DS. Although DS mice have been well characterized cognitively and morphologically there are no prior reports utilizing diffusion MRI. In this study we investigated the ability of diffusional kurtosis imaging (DKI) to detect the progressive developmental and neurodegenerative changes in the Ts65Dn (TS) DS mouse model. TS mice displayed higher diffusional kurtosis (DK) in the frontal cortex (FC) compared to normal mice at 2 months of age. At 5 months of age, TS mice had lower radial kurtosis in the striatum (ST), which persisted in the 8-month-old mice. The TS mice exhibited lower DK metrics values in the dorsal hippocampus (HD) at all ages, and the group difference in this region was larger at 8-months. Regression analysis showed that normal mice had a significant age-related increase in DK metrics in FC, ST and HD. On the contrary, the TS mice lacked significant age-related increase in DK metrics in FC and ST. Although preliminary, these results demonstrate that DK metrics can detect TS brain developmental and neurodegenerative abnormalities.

Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome

“…In our diffusion MRI study in the Ts65Dn mice, DKI metrics allowed detection of early brain tissue abnormalities, with distinct patterns in age-related microstructural trajectories in frontal cortex, striatum and hippocampus of the Ts65Dn mouse model of DS [89]. We showed that Ts65Dn mice have higher DKI metrics in the frontal cortex compared with normosomic (NS) littermates at 2 months and do not change significantly through 8 months of age.…”

“…Only a few in vivo imaging studies have been published in humans [76–84] or mouse models [85–89] of DS. In humans, positron emission tomography (PET) measurements of β-amyloid burden [77, 79, 81], regional PET measurements of the cerebral metabolic rate for glucose [76] and structural and functional connectivity differences by anatomical and functional magnetic resonance imaging (MRI) studies [78, 80, 82, 84] demonstrate the safety, efficacy, and acceptability of these imaging techniques to study DS-AD progression.…”

“…Thus far, only a few in vivo neuroimaging studies in mouse models of DS have been published using MRI [85–89]. Chen et al [85] reported decreased transverse relaxation time (T2) in the cortical and hippocampal cholinergic circuitry in middle-aged (> 12 months old) Ts65Dn mice, demonstrating the utility of quantitative in vivo MRI for identifying AD-relevant cholinergic changes in animal models of DS.…”

“…Recently, in a study using high-field MRS, investigators reported lower levels of glutamine and higher levels of myo-inositol in the hippocampus of Ts65Dn mice, and elevated myo-inositol has also been found via MRS in humans with DS [87]. Lastly, our group recently published the first diffusion MRI (dMRI) results in Ts65Dn mice, using diffusional kurtosis imaging (DKI) [89]. Diffusion MRI is uniquely positioned for exploring brain tissue microstructure, function and connectivity, and to provide evidence of brain plasticity in vivo , allowing longitudinal assessment of ongoing processes.…”

Memory and hippocampal architecture following short-term midazolam in western diet-treated rats

“…DKI is already yielding promising preliminary results in studies of normal aging and brain diseases [22–30]. Our work on animal models, as well as studies from other groups, have shown that DKI metrics are sensitive to changes in brain microstructural complexity that may be associated with brain development [31], aging [32], Down syndrome [33], amyloid-beta (Aβ) deposition [34], and myelin abnormalities [35]. …”