Diffusion tensor imaging in the early diagnosis of Alzheimer's disease

Abstract

Early diagnosis of Alzheimer’s disease (AD) is indispensable for the future success of disease-modifying interventions. Given the recent advances in neuroimaging technology, considerable efforts are underway to identify early diagnostic imaging markers of AD by studying in-vivo cerebral grey matter (GM) damage in AD. By contrast, the evaluation of in-vivo cerebral white matter (WM) degradation in patients with early AD is still in its infancy, although animal and post-mortem studies have demonstrated WM pathological changes are widespread and even precede GM alterations in the AD brain. Diffusion tensor imaging (DTI) can provide useful information regarding microstructural WM changes in-vivo, thus may permit earlier diagnosis of AD from the perspective of WM abnormalities. The overall objective of this thesis is to investigate in-vivo microstructural WM changes as measured by DTI in individuals with amnestic mild cognitive impairment (aMCI) at a high risk of developing AD. Microstructural WM integrity was first examined in the whole sample of aMCI subjects, then in different stages of aMCI, finally in cognitively normal individuals who are destined to develop aMCI. In the whole aMCI group, widespread microstructural WM changes were observed in distributed brain regions, particularly in the medial temporal lobe known to be preferentially vulnerable in AD. Further analysis using fibre tracking technique revealed that disrupted microstructural integrity of the fornix linking the hippocampus contributed more to episodic memory dysfunction than did hippocampal atrophy in aMCI. Additional analysis showed that microstructural WM damage began in the fornix in the early stage of aMCI before spreading to the uncinate fasciculus and the parahippocampal cingulum in the later stage of aMCI. Fornical damage in the early stage of aMCI was found to be independent of hippocampal atrophy. Moreover, in cognitively normal individuals who subsequently developed aMCI during 2-year follow-up, substantial WM alterations consistent with AD were reported in the absence of GM atrophy. The results from this thesis improve our understanding of in-vivo WM changes in the earlier preclinical stages of AD. DTI may enable us to make an earlier and more accurate diagnosis of AD in the near future.