White Matter Lesions Defined by Diffusion Tensor Imaging in Older Adults

Age-related cognitive decline classically has been associated with decreased synaptic density and neuron loss. However, growing evidence supports a central role for white matter (WM) changes in cognitive dysfunction associated with both normative and pathological aging. Indeed, sixty-five percent of cognitively normal individuals >75 years of age show WM abnormalities,1,2 including diffuse changes as well as small infarcts,3 and neuroimaging correlates of cognitive performance in elderly individuals have identified WM as a primary site of damage.4-8 While the most common location of WM changes in the adult brain is the periventricular region, some neuroimaging studies of age-related WM changes have highlighted an apparent specific vulnerability of frontal WM fiber systems relative to other brain regions.9,10 Correlation of regional WM hyperintensities with impairment in specific cognitive domains is an area of intense current investigation that is not in complete agreement; however, several studies have observed an association between age-related impairment in executive function or complex processing speed and anterior WM hyperintensities that is either focused on, or at least includes, frontal lobe WM.8,11,12 More recently, WM changes have been investigated using diffusion tensor imaging (DTI), an MRI technique that provides information about WM integrity through measurements of water diffusion and its directional dependence.13,14 Several DTI studies, as well as related MRI measurements of transverse relaxation rates,15 have observed age-associated WM changes that commonly involve prefrontal cortex (PFC), centrum semiovale, and anterior callosal regions, and which are associated with impaired cognitive function (reviewed in 16; 17-22). The disease mechanisms responsible for these WM changes remain elusive, and this has hampered the development of relevant animal models and therapeutic strategies. In fact, it is currently unclear if these DTI measures of WM changes result from demyelination, axonal loss, or other alterations in WM.23 One potential etiology for cerebral WM injury in the elderly is chronic hypoperfusion due to small vessel disease.24,25 Indeed, a number of vascular changes that result in reduced cerebral blood flow, including hypoxia-induced capillary loss, reduced cerebrovascular angiogenesis, and tortuous arterioles, each may contribute to WM damage in older individuals.26,27 However, how such potential hypoperfusion may damage WM in older adults is unclear. A mechanism for hypoperfusion-mediated WM damage in preterm infants has been the recent focus of both experimental models and observational studies using human tissue. This work has identified maturation-dependent vulnerability of oligodendrocyte lineage (OL) cells to injury initiated by ischemia and its associated free radical damage28,29 that results in an initial expansion of the oligodendrocyte precursor pool and reactive astrogliosis.30 Importantly, chronic WM injury triggers maturation arrest of OL cells that are especially vulnerable to recurrent ischemic injury,31 and growing evidence suggests that this OL maturation arrest is linked to the accumulation of the glycosaminoglycan hyaluronan (HA) generated by reactive astrocytes and other cells in lesion microenvironments.29,32,33 Interestingly, a previous study of animal models of both ischemia and Alzheimer's Disease (AD) demonstrated similarly expanded OL cells in adult animals,34 raising the possibility that similar mechanisms may occur in older humans. To determine whether a similar mechanism is potentially operative, and underlies DTI changes associated with aging in frontal WM of older adults, we undertook a multimodal analysis of WM change in human autopsy cases from a population-based cohort where Vascular Brain Injury (VBI) and AD are prevalent. Specifically, we determined the relationships among AD, VBI, DTI-defined changes in WM, free radical injury, and pathological responses by cells in the OL lineage relative to HA accumulation.