During healthy aging, the brain experiences complex structural and biochemical changes, including modification in dendritic morphology, synaptic connectivity (Anderson and Rutledge, 1996), Ca2+ dysregulation (Toescu et al., 2004), gene expression (for review see Burke and Barnes, 2006) and a decrease in the availability and level of neurotransmitters (Roth and Joseph, 1994). Cholinergic and dopaminergic reductions are particularly pronounced compromising motor, attention, and memory processes (Volkow et al., 1998; Braver and Barch, 2002). Furthermore, extensive studies reported that the function of the dopaminergic system gradually declines as we grow older due to degeneration of dopaminergic neurons and receptors (Zaman et al., 2008).

Age-related decreases in white matter integrity appear to be a common process in the brain (Resnick et al., 2003; Stadlbauer et al., 2008). Recent morphological studies using diffusion tensor imaging (DTI, for review see Pierpaoli et al., 1996) in old healthy subjects have consistently shown a correlation between aging and reduction of fractional anisotropy, suggesting a rarefaction of directionally oriented axonal membranes, and increased mean diffusivity reflecting an alteration in cellular membranes and other structures hindering diffusion (Sullivan and Pfefferbaum, 2006).

These age-related differences in white matter integrity are seen throughout the brain, with an increasing magnitude of the difference in anterior white matter structures compared to posterior regions, which most authors refer to as a “anterior–posterior gradient,” with age-related changes occurring earlier in the frontal lobe (Bennett et al., 2010). The corpus callosum represents the largest white matter structure connecting the two hemispheres in the brain. Age-related changes in the topology of the corpus callosum primarily affect the genus; however, recent studies using more sensitive techniques of DTI also demonstrated changes in the splenium (Bastin et al., 2010).

Until now, there is no consensus of the etiology and the functional repercussion of these changes in white matter structure, but recent data from healthy individuals and patients with mild cognitive impairments and dementia converge on highlighting correlations between cognitive performance and fractional anisotropy (Persson et al., 2006), indicating that the decline in white matter might be associated with cognitive impairment.