The brains of aged mice are characterized by altered tissue diffusion properties and cerebral microbleeds

Abstract

Background: Brain aging is a major risk factor in the progression of cognitive diseases including Alzheimer's disease (AD) and vascular dementia. We investigated a mouse model of brain aging up to 24 months old (mo). Methods: A high field (11.7T) MRI protocol was developed to characterize specific features of brain aging including the presence of cerebral microbleeds (CMBs), morphology of grey and white matter, and tissue diffusion properties. Mice were selected from age categories of either young (3 mo), middle-aged (18 mo), or old (24 mo) and fed normal chow over the duration of the study. Mice were imaged in vivo with multimodal MRI, including conventional T2-weighted (T2W) and T2*-weighted (T2*W) imaging, followed by ex vivo diffusion-weighted imaging (DWI) and T2*W MR-microscopy to enhance the detection of microstructural features. Results: Structural changes observed in the mouse brain with aging included reduced cortical grey matter volume and enlargement of the brain ventricles. A remarkable age-related change in the brains was the development of CMBs found starting at 18 mo and increasing in total volume at 24 mo, primarily in the thalamus. CMBs presence was confirmed with high resolution ex vivo MRI and histology. DWI detected further brain tissue changes in the aged mice including reduced fractional anisotropy, increased radial diffusion, increased mean diffusion, and changes in the white matter fibers visualized by color-coded tractography, including around a large cortical CMB. Conclusions: The mouse is a valuable model of age-related vascular contributions to cognitive impairment and dementia (VCID). In composite, these methods and results reveal brain aging in older mice as a multifactorial process including CMBs and tissue diffusion alterations that can be well characterized by high field MRI.

Age-dependent gray matter demyelination is associated with leptomeningeal neutrophil accumulation

“…Furthermore, the nonremitting clinical course was accompanied by leptomeningeal inflammation, gray matter demyelination, axonal damage, synapse loss, and disruption of the glial limitans, as well as brain atrophy and accumulation of NfL in the serum, all hallmarks of PMS. In the absence of EAE, as we did not observe a decrease in brain volume with age, which is in contrast to the findings of Taylor et al ( 33 ). However, Taylor et al examined brain volume in 24-month-old C57BL/6 mice, whereas our old SJL/J mice were 8 months old.…”

Longitudinal manganese‐enhanced magnetic resonance imaging of neural projections and activity

“…Previous work on development using MRI without contrast demonstrated that brain development involves dramatic volumetric changes 240,241 . Similarly, in aging, multiple parameter MRI without contrast also found volumetric and structural changes 242 . Systemic MEMRI greatly improves anatomical contrast for analysis of brain volume changes.…”

“…240,241 Similarly, in aging, multiple parameter MRI without contrast also found volumetric and structural changes. 242 Systemic MEMRI greatly improves anatomical contrast for analysis of brain volume changes. MEMRI can be performed longitudinally over short and long time periods without deleterious effects.…”

The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice

“…In rodents, VBM has demonstrated similar trends to that reported in human studies. Many studies regarding aging in rodents (mice and rats) primarily focus on cortical structures and somehow neglect subcortical regions of the brain, such as basal ganglia ( Hammelrath et al, 2016 ; Taylor et al, 2020 ; Asan et al, 2021 ). Our structural data points toward changes in striatum over time, with bilateral increases in mGMD observed in lateral portions of dorsal striatum, medial portions of nucleus accumbens, and bilateral reduction in mGMD in globus pallidus.…”