Associations between modifiable risk factors and white matter of the aging brain: insights from diffusion tensor imaging studies

Abstract

There is increasing interest in factors that may modulate white matter (WM) breakdown and, consequentially, age-related cognitive and behavioral deficits. Recent diffusion tensor imaging studies have examined the relationship of such factors with WM microstructure. This review summarizes the evidence regarding the relationship between WM microstructure and recognized modifiable factors, including hearing loss, hypertension, diabetes, obesity, smoking, depressive symptoms, physical (in) activity, and social isolation, as well as sleep disturbances, diet, cognitive training, and meditation. Current cross-sectional evidence suggests a clear link between loss of WM integrity (lower fractional anisotropy and higher mean diffusivity) and hypertension, obesity, diabetes, and smoking; a relationship that seems to hold for hearing loss, social isolation, depressive symptoms, and sleep disturbances. Physical activity, cognitive training, diet, and meditation, on the other hand, may protect WM with aging. Preliminary evidence from cross-sectional studies of treated risk factors suggests that modification of factors could slow down negative effects on WM microstructure. Careful intervention studies are needed for this literature to contribute to public health initiatives going forward.

Keywords: Aging; Diffusion tensor imaging; Modifiable– risk factor; White matter.

Fig. 1

Modifiable factors linked to adverse health outcomes. A range of modifiable factors have been linked to adverse health outcomes in aging, including cognitive decline and dementia (Debette and Markus, 2010, Prins and Scheltens, 2015). A substantial body of work has implicated the brain in this pathway. For years, researchers have focused on the mediating role of gray matter in the relationship between lifestyle factors and health outcomes. However, it has become increasingly clear that white matter structure is an important mediator too. For instance, white matter macrostructural alterations, such as hyperintensities, are well-known to increase risk for dementia and stroke (Debette and Markus, 2010). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Isotropic and anisotropic diffusion and the tensor model. The diffusion trajectory (top row) of water is different in the presence or absence of barriers. The tensor model describes water diffusion at each voxel (bottom row). In the model, water diffusion is characterized by its 3 principal eigenvectors and their associated eigenvalues (λ1, λ2, λ3). The DTI parameters—FA, MD, RD, and AxD—can be computed from the eigenvalues of the tensor. Fractional anisotropy (FA) reflects the shape of the tensor and has higher values with more ellipsoid shape tensors (i.e., with anisotropic diffusion—bottom right). Mean diffusivity (MD) is the magnitude of diffusion and can be computed by averaging the eigenvalues of the tensor [(λ1 + λ2 + λ3)/3]. Radial diffusivity (RD) reflects the diffusion perpendicular to the long axis of the tensor and can be computed by averaging eigenvalues λ2 and λ3 [(λ2 + λ3)/2]. Axial diffusivity (AxD) reflects the diffusion along the long axis of the tensor and is equal to λ1. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

White matter tracts that are particularly sensitive to the identified modifiable factors. For each colored tract, factors are listed that have shown to be consistently associated with decline and/or protection of its integrity. These tracts have been implicated in various cognitive processes (Madden et al., 2012) and their integrity typically declines with age, suggesting a pathway whereby changing exposure to the factors could possibly prevent or slow age-related WM breakdown and cognitive decline. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)