Diffusion tensor imaging of the human brain in aging and age-related diseases

Abstract

The human cerebral white matter (WM) consists of neuronal fibers which are involved in many types of cognitive and motor functions. Macroscopic cerebral WM properties, such as volume or lesion load, can be investigated with conventional magnetic resonance imaging (MRI). Recent developments in diffusion tensor imaging (DTI) now allow for the characterization of the microstructure in cerebral WM, providing us another opportunity to explore WM tissue organization in various clinical diseases. The focus of this thesis is the investigation of brain microstructure with DTI in aging and age-related diseases. The thesis consists of five studies, which are described in Chapters two to six. In addition to the discussion of our findings, future research and critical considerations are introduced in Chapter seven.

In Chapter 2, we studied the effect of aging on WM microstructural properties in 145 healthy subjects. Our aim was to identify potential associations between age, gender, and the global and regional fractional anisotropy (FA) and mean diffusivity (MD) using DTI. In total, we studied sixteen regions of interest in both hemispheres to search for regions that display such relationships. In addition, we performed a complementary voxel based analysis, which does not require any a priori hypothesis regarding brain location.

A limiting methodological factor of DTI based voxel based analyses, such as the one presented in the second chapter, is the implicit assumption of “linear correlation” when studying brain regions that relate age with a particular diffusion measure of interest. The objective in Chapter 3 was to develop a more sophisticated approach using higher-order polynomial regression models that could overcome this linearity constraint. To demonstrate the benefits of the new statistical framework, we used a large cohort of 346 healthy subjects.

After our initial studies of aging and DTI in healthy subjects, we explored the potential contribution of vascular risk factors including aging, hypertension, type 2 diabetes mellitus (T2DM), past history of cardiovascular disease, smoking, and inflammation markers such as homocysteine on the WM microstructure in the following chapters. Our main aim in Chapter 4 was to examine potential differences in brain organization in terms of diffusion measures between 40 T2DM patients without cognitive complaints and 97 healthy controls.

Despite previously observed associations between the vascular risk factor homocysteine and macroscopic structural brain changes, it is still unknown whether microstructural associations with brain tissue properties can be observed using clinical routine MRI. The aim of the study presented in Chapter 5 was to investigate such potential relationships between homocysteine levels and microstructural measures in 338 healthy participants, while controlling for several other vascular risk factors. In addition, we studied how the age-related white matter changes (ARWMC) score and the Framingham Stroke Risk Profile (FSRP) were related to these DTI metrics.

Our main aims in Chapter 6 were to investigate the WM microstructure in patients with vascular parkinsonism (VP) using DTI and to examine specific fiber tract involvement with respect to clinical severity. We performed global, voxel-based, and tract-based analyses to compare WM microstructural properties between the two groups.