Validating MRI Measures of Disease Stage and Progression in Alzheimer’s Disease

Abstract

Currently no absolute diagnostic marker exists for Alzheimer’s disease (AD). Therefore, better non-invasive methods are needed to identify the risk of developing AD, staging the disease, and measuring its progression. The ideal biomarker would be a direct in vivo measurement of plaque and tangle burden, and promising results toward this objective have been reported in nuclear medicine (Klunk et al. 2002; Small et al. 2002). Until such direct measures have been thoroughly validated, however, other approaches must be employed. This chapter will review the literature supporting the position that indirect measures of AD can be valid biomarkers of disease stage and progression. It seems logical that indirect measures of disease can be valid biomarkers provided that changes in the measurement are empirically proven to track with independent measures of disease stage and progression, and that a plausible biological link exists between change in the measurement and progression of the disease itself. Magnetic resonance imaging (MRI) is a highly flexible imaging modality capable of measuring a number of different biologic parameters, for example, anatomic structure, metabolite concentration, proton diffusion, tissue perfusion, etc. All these tissue properties have been evaluated to some extent with MRI as potential diagnostic features of AD. The most widely studied MRI parameter in AD, however, is anatomic structure. Brain morphometry — specifically volume — is arguably the most straightforward of all tissue parameters measurable by MRI. Measurements of tissue volume are highly reliable and also have a strong, plausible biologic link to the pathologic progression of AD. In fact, loss of neurons and synaptic pruning, which are the substrates of cerebral atrophy, are felt to be more closely linked with the clinical progression of AD than plaque and tangle density (Fig. 1).