*4.5. Sex- and Brain-Region-Dependent Asymmetry in the MRI-ASL Regional Cerebral Blood Flow*

Brain structural and functional asymmetry in health/disease is an emerging field. The neurodegeneration of subcortical structures is not symmetric, with neuroimaging studies reporting volumetric regional, hemispheric asymmetries. Thus, asymmetric hippocampal atrophy has been recently reported in normal aging, mild cognitive impairment, and AD [62]. A whole-brain analysis revealed increased neuroanatomical asymmetries in dementia for the hippocampus and amygdala and is proposed as a powerful imaging biomarker [63]. At the translational level, hippocampal asymmetry was important in rodents for acquiring spatial reference memory, retaining working memory [64], and some features of non-spatial learning [65]. At the neurochemical and molecular levels, left–right hippocampal asymmetry has been demonstrated for the glutamatergic system [65]. We have just provided the first evidence of brain atrophy asymmetry in male 3xTg-AD mice, thus modeling that found in human patients with AD [50]. However, little is known about the alterations in CBF hemisphere asymmetries. In the present work, the MRI-ASL rCBF results unveiled, for the first time, the asymmetry between left–right hemispheres in the female's cortex, in the hippocampus of control males, and 3xTg-AD females, as well as in the striatum of control females. Therefore, the present results show asymmetry between left–right hemispheres in the 3xTg-AD model and aging mice, in both sexes (but mostly in females) and in cortical and subcortical structures. Moreover, to ensure that these detected asymmetries in rCBF measurements were not affected by differences in mice's

head positioning (rotation respect to the sagittal plane) or differences in signal-to-noise ratio (SNR) or contrast-to-noise ratio (CNR) between hemispheres, a SNR/CNR quality check analysis was performed that showed no statistically significant differences among the experimental groups (data not shown). This modeling will be useful for the translational development and assessment of the preventive/ therapeutic interventions and those of the risk factors and hazards and monitoring disease progression.
