White matter atrophy and lesion formation explain the loss of structural integrity of white matter in aging

Abstract

The importance of macrostructural white matter changes, including white matter lesions and atrophy, in intact brain functioning is increasingly being recognized. Diffusion tensor imaging (DTI) enables measurement of the microstructural integrity of white matter. Loss of white matter integrity in aging has been reported, but whether this is inherent to the aging process itself or results from specific white matter pathology is unknown. In 832 persons aged 60 years and older from the population-based Rotterdam Study, we measured fractional anisotropy (FA) and directional diffusivities in normal-appearing white matter using DTI. All subjects' DTI measures were projected onto a common white matter skeleton to enable robust voxelwise comparison. With increasing age, multiple regions showed significant decreases in FA or increases in axial or radial diffusivity in normal-appearing white matter. However, nearly all of these regional changes were explained by either white matter atrophy or by white matter lesions; each of which related to changes in distinct brain regions. These results indicate that loss of white matter integrity in aging is primarily explained by atrophy and lesion formation and not by the aging process itself. Furthermore, white matter atrophy and white matter lesion formation relate to loss of integrity in distinct brain regions, indicating the two processes are pathophysiologically different.

Introduction

Intact white matter connections in the brain are important for the processing and integration of information generated by neural networks. Loss of integrity of these white matter pathways is thought to cause loss of “connectivity” and subsequent age-related cognitive decline (O'Sullivan et al., 2001a). There are two distinct macroscopic processes affecting the white matter that are commonly seen in aging and which are readily recognized in both radiologic and pathologic examinations. Firstly, atrophy of white matter dominates brain tissue loss in aging, rather than does loss of grey matter neurons (Meier-Ruge et al., 1992). Secondly, over 90% of elderly persons demonstrate on brain magnetic resonance imaging (MRI) so-called ‘white matter lesions’ (de Leeuw et al., 2001), which pathologically represent signs of ischemic injury (Englund et al., 1988). Although white matter atrophy and white matter lesion formation often coincide and have shared determinants (Ikram et al., 2008), it is still not understood whether these are part of the same pathophysiologic spectrum or whether these are independent processes. Furthermore, it is unknown whether and how these two macroscopic processes are related to loss of microstructural integrity of normal-appearing white matter. Diffusion tensor imaging (DTI) (Basser and Jones, 2002) enables non-invasive quantification of the microstructural integrity of white matter using MRI (O'Sullivan et al., 2001b). DTI measures the amount and directional dependence of microscopic diffusion of water molecules in the brain. In white matter, diffusion is hindered by the high degree of structural organization, resulting in anisotropic movement of water molecules predominantly parallel to the orientation of the fiber tracts. A lower fractional anisotropy (FA) as measured by DTI signifies less anisotropic diffusion and thus lower microstructural integrity (Basser and Jones, 2002). Furthermore, from animal studies, it has been suggested that analysis of directional diffusivities – axial (λ_ax) and radial (λ_rad) diffusivity – may provide additional information on the underlying mechanisms of loss of white matter integrity. Myelin breakdown has been associated with increased diffusivity perpendicular to the white matter tract (λ_rad,), whilst axonal damage is reflected in diffusivity changes parallel (λ_ax) to the primary fiber orientation (Song et al., 2003, Song et al., 2005, Sun et al., 2006).

So far, FA in white matter has been shown to decrease with age (Salat et al., 2005), but it is unknown to what extent this represents concurrent macroscopic changes in white matter, or whether aging itself causes white matter microstructural changes. Furthermore, analysis of regional patterns in FA changes has so far been limited to manually placed regions-of-interest (Salat et al., 2005) or to voxelwise measurement methods, both of which are prone to methodological constraints hindering interpretation and analysis of FA data (Bookstein, 2001, Smith et al., 2006). Tract-based spatial statistics (TBSS) is a new technique for aligning FA images from multiple subjects and constructing a common skeleton of the white matter tracts, enabling robust voxelwise analysis of the microstructural integrity of white matter across subjects (Smith et al., 2006). Using TBSS, we investigated in 832 persons aged 60 years and older from the general population whether white matter atrophy and white matter lesions relate to integrity of normal-appearing white matter independent from aging, and if so, in which brain regions these associations are strongest.