Alzheimer\u27s 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
