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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Bartha, Robert

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder of the brain that presents as progressive impairment across several cognitive domains. The biological mechanisms underlying the development of AD remain unclear, with amyloid-beta plaques, neurofibrillary tangles, calcium dysregulation, and oxidative stress all contributing to neurodegeneration in AD. Vitamin D (VitD) deficiency, a common condition in the elderly, may modulate these mechanisms and complicate the AD process. Due to this complicated pathogenesis, the diagnosis of AD requires subjective clinical judgement, staging of AD is challenging, and it remains difficult to predict when and who will progress to AD. The purpose of this thesis was to study the metabolic and structural changes of specific brain regions as a consequence of AD alone and under conditions of AD and VitD deprivation. Identification of biological changes underlying the early symptoms of AD will help to identify and stage individuals prior to symptom onset.

In one study, proton magnetic resonance spectroscopy (1H-MRS), diffusion tensor imaging (DTI), and neurospychological testing was used to measure the metabolic and microstructural processes associated with episodic memory impairment. Individuals with AD, mild cognitive impairment (MCI), and normal elderly controls (NEC) were studied. Left hippocampal glutamate and posterior cingulate N-acetyl aspartate concentrations were reduced in MCI and AD compared to NEC. Differences in DTI metrics indicated volume and white matter loss along the cingulum in AD compared to NEC. Metabolic and microstructural changes were also associated with episodic memory performance assessed using Craft Story 21 Recall and Benson Complex Figure Copy. The results of this study suggested that metabolite concentrations may provide insight into the underlying biological processes of AD and increase the confidence of a clinical diagnosis of MCI or AD.

To improve glutamate measurement in future studies, the echo time (TE) for 1H-MRS measurement of glutamate at 7 T was optimized for signal strength and measurement precision in a second study. Time-domain simulations were performed and verified against in vivo and in vitro measurements. The results of this study indicated that TE = 105 ms was optimal for in vivo glutamate measurement at 7 T with the semi-LASER (localization by adiabatic selective refocusing) sequence as this echo time produced the greatest glutamate signal while also producing the lowest measurement coefficient of variation. Use of a long TE will also decrease power deposition and minimize macromolecule contributions to the spectrum.

In a third study, the role of VitD deficiency in AD was comprehensively evaluated in the APPSwe/PS1ΔE9 mouse model of mild AD using 1H-MRS, high-resolution MRI, and spatial memory tasks. VitD deficiency did not change ventricle volume, an MRI marker of neuronal loss, but did result in changes in metabolite concentrations consistent with astrocytosis and gliosis. Overall, VitD deficient mice also performed better or improved on measures of spatial memory than mice on a nutritionally sufficient control diet. The results of this study suggested that VitD deficiency may improve memory by upregulating beneficial reactive astrocytosis in the prodromal stages of AD.

Summary for Lay Audience

Alzheimer's disease (AD) is a brain disorder that causes a progressive decline in memory and thinking. No one knows what gives rise to AD, but it includes abnormal deposits of different proteins, irregular calcium levels, and changes in antioxidant defences. Vitamin D (VitD) deficiency, a common condition in the elderly, could also play a role. Uncertainty of the root cause makes it hard for physicians to diagnose and predict the progress of AD. The purpose of this thesis was to study brain changes due to AD and VitD deficiency.

In one study, brain chemistry and structure in individuals with AD were studied using magnetic resonance imaging (MRI) techniques. Compared to elderly individuals without AD, individuals with AD had lower amounts of glutamate (the chemical responsible for cell communication), which was associated with volume loss and deterioration of structural connections. Changes occurred in the brain circuit responsible for episodic memory, the type of memory affected early in AD. As expected, changes were associated with performance on tests of episodic memory. Therefore, measuring brain chemicals could provide insight into biological processes underlying AD symptoms and increase a physician's confidence in their diagnosis.

In a second study, computer simulations were used to determine the best settings for glutamate measurement. The simulation results were verified against measurements made in a model with a known amount of glutamate and in the human brain. The optimal settings provided the greatest amount of glutamate signal, while also providing the best measurement precision.

In a third study, the role of VitD deficiency was evaluated in mice genetically engineered to reproduce aspects of the early stages of human AD. MRI was also used to measure brain chemistry. Over time, VitD deficiency resulted in brain chemical changes indicative of increased numbers of astrocytes, special cells that support and protect nerve cells in the brain. VitD deficient mice also performed better on tests of memory than mice that were not VitD deficient. The results of this study suggested that VitD deficiency may actually improve memory in the early stages of AD through a beneficial increase in astrocyte numbers.

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