DTI and resting state fMRI as biomarker of Alzheimer's disease: Present state and perspectives

Abstract

Background: Alzheimer’s disease can be characterized as a disorder of intracortical connectivity based on the degeneration of specific synapses, neuronal fiber connections and neuron populations. Diffusion tensor imaging detects integrity of intracortical projecting fiber tracts in vivo, resting state functional MRI (rfMRI) tracks the functional connectivity within the so called default mode network (DMN) which is related to the viability of neuronal metabolism and synapses. The DMN involves cortical areas that represent the major predilection sites of AD pathology. Consistently several DTI studies describe decline of intracortical projecting fiber tracts in manifest and predementia stages of AD, such as mild cognitive impairment (MCI). Additionally, DMN connectivity was reduced in AD patients and MCI patients in a range of studies. Here we aimed to determine the potential use of DTI and rfMRI as biological markers of AD for early diagnosis and mapping of disease progression. Methods: In a series of studies we determined (i) longitudinal and multicenter stability of DTI and r fMRI, (ii) the structural basis of cortical functional connectivity and (iii) diagnostic accuracy of DTI and r fMRI markers. We performed a multicenter physical and clinical phantom study, as well as cross-sectional and longitudinal analyses of DTI and fMRI derived measures of structural and functional connectivity in AD patients, subjects with MCI and healthy controls employing region of interest based analysis, as well as multivariate analysis of variance and independent component analysis on a voxel-basis. Results: DMN estimates from rfMRI was stable over different time points. DTI measures of fractional anisotropy showed variation in the range of 5 to 10% based on physical phantom data across different sites. Specific structural networks could be identified underlying functional connectivity in EEG and fMRI data. Diagnostic accuracy of DTI and rfMRI was close or even superior to the accuracy achieved by MRI based volumetric measures in discriminating AD patients and controls. Conclusions: DTI and rfMRI capture important characteristics of AD pathology and their employment in future diagnostic and longitudinal studies will enhance our understanding of the underlying mechanisms of AD pathology.