| Author: | Cheng, Wai Yeung |
| Title: | Radio-pathological investigation of myelin loss and oligodendrocyte degeneration using multimodal functional MRI in Alzheimer’s disease |
| Advisors: | Tse, Kai-hei Franki (HTI) |
| Degree: | Ph.D. |
| Year: | 2023 |
| Department: | Department of Health Technology and Informatics |
| Pages: | 243 pages : color illustrations |
| Language: | English |
| Abstract: | Alzheimer's disease (AD) is the most common cause of dementia characterized by excessive amyloid-β plaque formations and cognitive impairment. This neurodegenerative disease exists in two forms: familial AD and sporadic AD. Both are suggested to be triggered by protein misfoldings. Familial and sporadic AD are associated with mutations of the amyloid cascade pathway and biological aging, respectively. However, when abnormal protein aggregations become detectable, the cognitive impairments in the patients are already irreversible. Emerging evidence suggested that myelin loss and oligodendrocyte degeneration are some of the earliest events in both types of AD, but the cellular mechanism remains unknown. By delineating the biological process leading to early myelin loss in AD, new direction towards early disease detection and patient management may be achievable. To fill the gap of knowledge, this study characterizes the myelin pathology of AD among different transgenic mouse model using functional magnetic resonance-based neuroimaging (fMRI), followed by a histopathological examination of the cellular changes. To investigate the robustness of fMRI on demyelination, we first studied the effects of demyelination with cuprizone on amyloid deposition in AD mice models, R1.40 and APP/PS1. mice predisposed for familial AD (R.140 and APP/PS1) between 3 and 4 months old and fed cuprizone for chemically induced demyelination before subjection to multimodal functional MRI. Diffusion kurtosis imaging, magnetic resonance spectroscopy, magnetization transfer and T2 weighted volumetric analysis were performed to study structural and chemical changes of the whole cerebrum. Perpendicular diffusion from white matter tracts was not found between both the treated and untreated wild-types (WT) and R1.40 strain. Histologically, however, mature oligodendrocyte (OL) populations and the myelin protein, MAG, were significantly reduced in the cuprizone mice. No neuronal loss was detected, yet DNA damage stained by 53BP1 was prevalent in both neurons and OLs and more prevalent in cuprizone mice. This unaffected neuron count compared to the decrease in mature OLs indicate the vulnerability of the OLs. Complementary investigation into the more aggressive APP/PS1 strain showed increase diffusivity in the white matter region of the cuprizone treated. Histological analysis showed the selective reduction in mature OLs without effect on the overall OL population. The compromised OL differentiation may contribute to the increased diffusivity through insufficient OL maturation and myelin maintenance. An elevated level of amyloid protein was also observed with cuprizone-mediated demyelination in APP/PS1 strain. Magnetic resonance spectroscopy showed a significant increase of glutamate and glutamine in APP/PS1 mice with or without demyelination. This increase may indicate an excessive activation of glutamate receptors that can result in cell death. Altogether, this study was able to suggest the vulnerability of myelin integrity and OLs to DNA damage and show the potential acceleration of AD progression driven by demyelination. To investigate the effects of the strongest genetic risk factor of sporadic AD, APOE, on the age-related myelin breakdown, a cross sectional age-dependent study of the humanized APOE (hAPOE) knock-in mice was conducted to understand the cellular mechanism underlying common fMRI findings in early sporadic AD. At 6, 10 and 16 months, transgenic mice for Apoe knockout (KO) and isoforms ε3 and ε4 were put into a battery of behavioural, radiological, and histological evaluations. As APOE acts as a lipid transporter around the body and a provider of cholesterol for myelination, we expect lipid-based alterations in myelin and OLs. Observational study showed significant increase in weight of the 10-month hAPOE4 with no such difference in the 6- and 16-month-old and minimal difference in the spontaneous alternation of working memory using Y-maze. Metabolic analysis of the 10-months for food intake and physical activity showed no difference, however, the respiration quotient denoting basal metabolic rate suggests lipids as the main source of energy solely in the hAPOE4 mice compared to proteins in the WT, KO and hAPOE3. No significant changes were found in the diffusivity of 6 months, yet, in 10 months, the anterior cingulate of the hAPOE4 showed insignificant increase of perpendicular diffusivity. The movement of water perpendicular of the white matter tract suggests compromised myelin structures that can result in leaky axons. By 16 months, this difference has stabilized with each diffusivity modality levelled. Nonetheless, the decrease in mature OLs is still prevalent in the hAPOE4 in comparison. Similarly, to the APP/PS1, hAPOE4 showed an increase in glutamate and glutamine levels compared to other cohorts. This comparison may indicate a similar mechanism to acute demyelination seen in the previous study. Statistics with Pearson correlation coefficient showed altered correlations specific to hAPOE4 in reference to its diffusivity with its cellular pathologies that may demonstrate a compensatory effect of a reduction in mature OLs attempting to myelinate more than each cell may be capable of. This event may stress these cells and induce excessive DNA damage. Together, this study was able to correlate the genetic risk factors of AD with the radio-histological effects, providing a basis for future AD diagnosis. |
| Rights: | All rights reserved |
| Access: | open access |
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