White Matter Microstructural Integrity and Cognitive Function in a General Elderly Population

Abstract

The role of cerebral white matter in cognitive decline is increasingly being recognized owing to advances in the noninvasive imaging of structural white matter changes, including atrophy and white matter lesions, with magnetic resonance imaging (MRI).¹ Loss of white matter reportedly starts much later in life than gray matter loss^2,3 but in the elderly population may substantially contribute to whole-brain atrophy.^2,4 There is evidence from both imaging and postmortem studies that age-related white matter breakdown, such as myelin loss, is more widespread in persons with dementia.^3,5 Intact white matter connections are important for integration of information from large-scale networks in the brain.⁶ The “disconnection hypothesis” postulates that loss of structural integrity of white matter connections will lead to a loss of integration of these networks and consequently a decline in performance on cognitive tasks.⁷ This is further supported by the fact that white matter lesions, which are thought to disrupt tract organization, are related to cognitive decline and functional disability.⁸ However, white matter lesions have a variable expression with regard to cognition and functional ability and can often be detected to some degree in cognitively intact people.⁹ Also, correlational pathologic studies have found that the degree of axonal and myelin damage within white matter lesions with similar appearance on conventional MRI is highly variable.¹⁰ It may thus be that in their effect on cognition some white matter lesions are worse than others, which cannot be deferred from the mere number or volume of lesions. Measures reflecting microstructural integrity of white matter may provide additional information, beyond macrostructural changes, on the relation between white matter and cognition. Diffusion tensor imaging (DTI) is an MRI technique that enables the measurement of diffusion of water molecules within the brain.¹¹ In normal white matter, the motion of water molecules is restricted by the parallel-oriented fibers and diffusion is therefore highly anisotropic. Degradation of the microstructural organization in white matter is accompanied by changes in measurable DTI parameters, more specifically by a decrease in fractional anisotropy (FA) and an increase in mean diffusivity (MD). There is pathologic evidence that FA and MD correlate directly with the amount of myelin in the white matter and to a lesser extent also to axonal count.¹² Animal studies have suggested a primary role of axonal membranes rather than presence of myelin in anisotropy.¹³ Diffusion tensor imaging therefore provides a noninvasive assessment of white matter microstructural integrity and as such may be used to quantify the severity of tract disruption caused by white matter lesions and white matter atrophy. Furthermore, results from animal studies have indicated that analysis of directional diffusivities—axial (λ_ax) and radial (λ_rad) diffusivities—may provide additional information on the potential underlying pathophysiology of the white matter changes. In these studies, myelin breakdown related to increased diffusivity perpendicular to the white matter tract (λ_rad,), while axonal damage was reflected in diffusivity changes parallel (λ_ax) to the primary fiber orientation.¹⁴