Voxel mirrored homotopic connectivity (VMHC) rs-fMRI in the clinical differential diagnosis of Alzheimer's disease (AD), mild cognitive impairment (MCI), vascular dementia (VD), and its relationship with brain atrophy, cerebral blood flow and amyloid binding

Abstract

The impact of dementia is accelerating with an aging population all over the world. Traditionally, diagnosis of dementia has relied on presentation of clinical symptoms, including memory and cognitive deficits, which were related to interhemispheric dysfunction. Hippocampal atrophy in structural imaging, together with pathological biomarkers including amyloid-β (Aβ) protein, tau protein and neurofibrillary tangles have been developed recently to aid in dementia diagnosis. With the development of resting state functional MRI (rs-fMRI), in-vivo study of interhemispheric functional connectivity (IFC) has become feasible through voxel mirrored homotopic connectivity (VMHC) analysis. In this thesis, VMHC rs-fMRI was evaluated for its diagnosis efficacy in Alzheimer’s disease (AD), Mild Cognitive Impairment (MCI) and Vascular Dementia (VD). In addition, its relationship with brain atrophy, cerebral blood flow and amyloid binding were evaluated in exploring the pathophysiology of dementia. A cohort of 58 subjects (16 AD, 29 MCI, 13 VD) were recruited from the memory clinic of the university hospital, and 25 health controls (HC) were also recruited for comparison. MRI images including rs-fMRI, arterial spin labeling (ASL) and T1 weighted images were acquired for all subjects. [18F]flutemetamol PET images were acquired only for three diseased groups. In the VMHC rs-fMRI analysis, aberrant IFC was found in AD, MCI and VD when compared to HC. To differentiate AD, MCI and VD from HC, combining regional VMHC value of relevant brain regions in ROC analysis achieved accuracy of 92%, 83% and 87% respectively. VMHC was demonstrated to be a reliable diagnostic tool to characterize different types of dementia. In the [18F]flutemetamol study, AD showed high amyloid-β (Aβ) protein deposition in brain regions where IFC attenuated with negative correlation. MCI with amyloid (AmyMCI) showed both medium and high Aβ deposition in different regions. High Aβ deposition attenuated IFC, whereas medium Aβ deposition promoted IFC. MCI without amyloid (NamyMCI) showed low Aβ deposition and promoted IFC. VD showed no correlation between IFC and Aβ deposition. In MR perfusion study, arterial spin labelling (ASL) was used to investigate the cortical cerebral blood flow (CBF). Impaired CBF in AD and AmyMCI showed relationship to Aβ deposition, whereas Hypoperfusion in NamyMCI showed relationship to macrovascular complications. Lowered CBF in VD was likely related to the interaction of both macrovascular complications and microangiopathy. For MRI volumetry, AD showed extensive atrophy in most brain regions, but it was not related to the attenuated IFC. In AmyMCI, both positive and negative correlation was found between atrophy and IFC, indicating brain atrophy promoted IFC. VD showed significant medial temporal atrophy with large white matter lesions, suggesting alteration in IFC related to brain atrophy and vascular comorbidities. In conclusion, VMHC rs-fMRI allows in-vivo study of IFC, and it is demonstrated to be a reliable diagnostic tool in differential diagnosis of AD, MCI and VD. Through studying the relationship between VMHC and brain atrophy, CBF and Aβ binding individually, our understanding in pathophysiology in dementia has been improved.