Characterizing structural neuroimaging biomarker changes in the canine model of Alzheimer’s disease
Jessica A. Noche, Margo F. Ubele, Kathy Boaz, Jennifer L. Mefford, Erin D. Jones, Katie McCarty, Beverly Meacham, Jeffrey Smiley, Laszlo G. Puskas, David K Powell, Lorena Sordo, Stasia A. Bembenek Bailey, Michael J. Phelan, Christopher M. Norris, Elizabeth Head, Craig E.L. Stark- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
The aging beagle is an exceptional model for longitudinal preclinical studies of Alzheimer’s disease due to their endogenous accumulation of beta‐amyloid plaques linked to cognitive impairment in aging, human‐like metabolisms, and ability to undergo serial neuroimaging. However, studies that use standardized analysis methods for evaluating longitudinal changes to neuroimaging biomarkers in this model are lacking. Here, neurostructural changes were characterized from longitudinal neuroimaging of middle‐aged beagles under chronic calcineurin inhibitor (CNI) treatment.
Method
T1‐weighted structural images were collected from 3T MRI at baseline and annually for 3 years from 43 middle‐aged beagles (6.47 +/‐ 1.1 years old) in an environmental enrichment paradigm under a chronic low dose of Tacrolimus (n = 15), Q134R (n = 14) or placebo (n = 14). Tissue segmentation and normalization to a group template for atlas‐based statistics were performed using Advanced Normalization Tools (ANTs) where atrophy rates were assessed from 27 bilateral cortical and subcortical regions of interest (ROIs). The auxiliary log‐Jacobian determinant images derived from non‐linear timepoint‐to‐template warps in ANTs were used to conduct whole‐brain, deformation‐based morphometry in AFNI.
Result
Among the brain structures examined with both ROI‐based and voxel‐based measures, the pregenual gyrus within the frontal lobe exhibited a distinct acceleration in atrophy. In contrast, the volume of the hippocampus was selectively preserved over the three years. Neither atrophy rate nor the preservation of hippocampal volume was modified by chronic CNI treatment.
Conclusion
Structural analysis from serial MRI in the beagle model of AD revealed that age‐related brain atrophy is accelerated within the frontal lobe, an area susceptible to early beta‐amyloid deposition in canines, and is unaltered by CNI treatment. Furthermore, the maintenance of hippocampal volume over time across all groups warrants further investigation into the effects of environmental enrichment on altering the trajectory of hippocampal structural decline. The novel application of robust longitudinal neuroimaging analysis methods in canines offers a novel framework for evaluating canine brain aging characterics and for monitoring treatment‐related structural alterations in preclinical intervention studies.