Quantitative Magnetic Resonance Imaging to investigate the pathophysiology of Alzheimer’s disease

: implications for clinical trials and non-pharmacological interventions

Abstract

The publications included in this PhD thesis are a small selection of the outputs from Marco Bozzali’s research over a 15-year timeframe. The studies are linked to each other by a common theme: using neuroimaging and neurophysiological techniques to investigate the pathophysiology of Alzheimer’s disease (AD), with the potential of identifying prognostic measures and targets for intervention. The first work (Bozzali et al., 2002) was the second paper ever published using diffusion-imaging to assess white matter (WM) damage in AD brains. Abnormalities were identified in anatomical locations fitting well with the cognitive impairments observed in AD. The second work (Bozzali et al., 2006) describes an early longitudinal investigation assessing the impact of grey matter (GM) loss on AD progression. A group of mild-cognitive-impairment (MCI) patients were recruited and MRI scanned at baseline, together with AD patients and healthy subjects (HS). MCI patients were followed-up for 2 years, and reclassified as MCIconverters and non-converters. When using voxel based morphometry (VBM) to compare baseline scans of MCI against AD patients and HS, MCI-converters, but not MCI-non-converters revealed a pattern of GM atrophy similar to that observed in AD. This indicates a prognostic value for GM atrophy with implications for patient stratification. The third work (Gili et al., 2011) assessed changes in GM atrophy and brain disconnection across AD evolution, using VBM and resting-state fMRI. Disconnection was observed in the medial-temporal lobes (MTLs) and posterior-cingulate cortex (PCC) of both, AD and MCI patients. GM atrophy was detected in the MTLs of both patient groups and in the PCC of AD but not MC patients. This demonstrates how brain disconnection contributes to AD progression, whose importance is reflected by the contents of publication 4 and 5. The fourth work (Bozzali et al., 2015) investigated how cognitive reserve (CR) may modulate AD symptoms. A detailed questionnaire was validated and used to collect lifestyle information from HS and patients with AD and MCI. Education was found modulating functional brain connectivity (FBC) (assessed by resting-state fMRI) in the PCC, fitting with the pathophysiological model hypothesized in Gili et al. (2011). The fifth work, based on previous own studies, hypothesized that repetitive transcranial-magnetic-stimulation (rTMS) could be used to modulate FBC with improvements in AD symptoms. We set up a clinical-trial (double-blind, sham-controlled) including AD patients who underwent a daily rTMS-/sham-stimulation of their PCC for 2 weeks. rTMS (compared to sham) induced a selective improvement in episodic memory and consistent changes of FBC.

Date of Award	2021
Original language	English
Awarding Institution	University of Brighton
Supervisor	Pietro Ghezzi (Supervisor)