Recent advances in brain imaging technology permit noninvasive analyses of metabolic, vascular, and structural changes associated with normal and pathological aging. In addition to improved image acquisition devices, computer technology and software development have also advanced, producing more sophisticated methods for analyzing brain imaging data. Techniques such as manual-based region of interest (ROI) planimetry and voxel-based morphometry (VBM), widely used in humans, indicate that biological characteristics such as age, sex, and underlying pathology contribute significantly to the variability in brain aging.
In addition to in vitro neuropathological measures, we have used several imaging protocols to examine brain aging in the dog model. In the remaining section, the application of MRI to study structural, pathological, and cerebrovascular markers of aging in the dog brain will be discussed.
Age-related changes in global and focal brain volume Our initial work with MRI involved using manual ROI planimetry to evaluate changes in brain and ventricular volume as a function of age. Standard quantitative procedures involved meticulously tracing brain regions of interest on multiple slices to compare differences in brain volume across subject cohorts (Figure 35.7).
This revealed that aged dog brains show increased cortical atrophy, ventricular dilation, decreased total brain volume, and decreased frontal lobe volume (Su et al., 1998; Tapp et al., 2004a). Age-related decreases in frontal lobe volume were associated with increased beta-amyloid deposition and impaired executive function (Tapp et al., 2004a).
An alternate method of assessing volumetric brain changes in aging is VBM. VBM permits rapid voxel-by-voxel comparisons of local gray and white matter brain regions without the need for a priori selection of ROIs and is highly sensitive to volumetric differences in normal and pathological aging (Tisserand et al., 2004). Despite its popularity in human brain imaging, application of VBM for mapping brain aging in animal models is less common. We recently developed a VBM procedure for analyzing regional brain aging in the dog (Tapp et al., 2005b). The initial steps of this procedure are time consuming and require the creation of standardized dog brain templates and a priori probability maps; but once
complete, rapid voxel-by-voxel comparisons of gray and white matter volumetric changes in the aging dog brain are possible. Using this technique, we found a number of age and sex dependent changes in gray and white matter volume in the dog (Figure 35.8).
Age-related reductions in gray matter volume were observed bilaterally in the frontal gyrus, orbitalis gyrus, ectosylvian gyrus, olfactory bulb, and superior olivaris nucleus in the brainstem. Unilaterally, gray matter loss occurred in the proreal gyrus, sylvian gyrus, suprasylvian gyrus, cerebellum, and brainstem nuclei with advancing age. The effects of age on brain volume, however, differed in male and female dogs; decreased frontal lobe volume was more predominant in males, and decreased temporal lobe volume was more common in females. Similar patterns were observed in white matter brain regions as well. Age-related white matter loss was largely bilateral and included the internal capsula (including a small portion of the genu of the corpus callosum), white matter tracts of the anterior cingulate (anterior fascia cinguli), and the alveus of the hippocampus. Decreases in the volume of the internal capsula were more frequent in males, whereas atrophy of the alveus of the hippocampus occurred primarily in female dogs. The VBM results not only validated earlier findings of frontal lobe atrophy in aging dogs but extended these findings and suggested that brain aging in the dog, like humans, varies regionally and differs between males and females.
Progressive lesion formation in the aging dog brain A second useful application of MRI is the ability to monitor longitudinal changes in the brain of aging dogs. Serial MRI (sMRI) techniques allow images collected longitudinally to be quantified at the individual level instead of using cross-sectional images to compare differences between young and old groups. In sMRI, images are co-registered using a goodness-of-fit function to align images collected at different time points into a unified stereotaxic space. In humans, sMRI studies are difficult to conduct due to attrition rates and long intervals required to observe significant changes in brain morphology— problems not encountered with dogs. sMRI procedures used in the dog to monitor lesion formation revealed that aging is associated with an increased frequency of a specific type of lesion resembling small lacunes (Su et al., 2005). The majority of lesions observed in the dog brain were located in the frontal cortex and caudate nucleus (Figure 35.9). This is consistent with other evidence that
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