At the outset of this thesis I proposed that the combination of fMRI with MRS could be a beneficial approach in informing understanding of BOLD changes seen in young
APOE-E4 carriers (Shine et al., 2015). I hypothesised that the alteration in PCC ROI BOLD
in the young APOE-E4 carriers could be related to alterations in the biochemistry of this region, assessed via MRS. The work in Chapters 3 and 4 provided novel information that the PCC ROI BOLD response showed a category selective functional-biochemical response for scene perception and scene working memory conditions, which were the tasks in which the young APOE-E4 carriers showed the altered BOLD response in Shine et al. (2015). This achieved my first aim of determining whether functional-biochemical relationships in the PCC can exist specifically for scenes. Despite these findings providing support for my overarching hypothesis of a biochemical alteration underpinning the functional alteration in the young APOE-E4 carriers, there were no MRS differences between young APOE-E4 carriers and non-carriers.
Although this result did not confirm my hypothesis, it does contribute to the literature in two important ways. First, since MRS metabolite differences exist in APOE- E4 carriers over the age of 50, this narrows down the time window to study when MRS changes may arise. Regarding MRS work, future studies should explore PCC MRS changes between the ages of 25 and 50 to identify the earliest metabolic changes that can be assessed in vivo and non-invasively. Second, regarding APOE-E4 carriers at age 18-25, the finding of no MRS metabolite differences between APOE groups indicates that the mechanism behind the altered BOLD response may not be related to MRS biochemistry. More research should be done combining fMRI with other neuroimaging techniques, such as MEG and perfusion imaging, in young APOE-E4 carriers to further investigate why they show an altered BOLD response in the PCC to tasks sensitive to behavioural impairments in AD. If we can better understand the mechanisms related to activity alterations in this AD-vulnerable brain region, we may be able to improve our understanding of why the debilitating disorder of AD may develop, with the ultimate goal being to develop effective strategies and treatments for disease prevention.
References
Aggleton, J. P., Pralus, A., Nelson, A. J. D., & Hornberger, M. (2016). Thalamic pathology and memory loss in early Alzhimer’s disease: moving the focus from the medial temporal lobe to Papez circuit. Brain, 139, 1877–1890. http://doi.org/http://www.brain.oxfordjournals.org/lookup/doi/10.1093/brain/a ww083
Alzheimer’s Association. (2016). 2016 Alzheimer’s Disease Facts and Figures. Retrieved from http://www.alz.org/documents_custom/2016-facts-and-figures.pdf
Alzheimer, A. (1906). Über einen eigenartigen schweren Erkrankungsprozeβ der Hirnrincle. Neurol Central, 25, 1134.
Amaro, E., & Barker, G. J. (2006). Study design in fMRI: Basic principles. Brain and
Cognition, 60(3), 220–232. http://doi.org/10.1016/j.bandc.2005.11.009
Andrews-Hanna, J. R. (2012). The brain’s default network and its adaptive role in internal mentation. The Neuroscientist : A Review Journal Bringing Neurobiology, Neurology
and Psychiatry, 18(3), 251–70. http://doi.org/10.1177/1073858411403316
Andrews-Hanna, J. R., Reidler, J. S., Sepulcre, J., Poulin, R., & Buckner, R. L. (2010). Functional-Anatomic Fractionation of the Brain’s Default Network. Neuron, 65(4), 550–562. http://doi.org/10.1016/j.neuron.2010.02.005.Functional-Anatomic
Anticevic, A., Repovs, G., Shulman, G. L., & Barch, D. M. (2010). When less is more: TPJ and default network deactivation during encoding predicts working memory performance. NeuroImage, 49(3), 2638–2648.
Bai, X., Edden, R. A. ., Gao, F., Wang, G., Wu, L., Zhao, B., … Barker, P. B. (2014). Decreased γ-aminobutyric acid levels in the parietal region of patients with Alzheimer’s disease. Journal of Magnetic Resonance Imaging : JMRI, 00, 1–6. http://doi.org/10.1002/jmri.24665
Barense, M. D., Henson, R. N. A. a, Lee, A. C. H. H., & Graham, K. S. (2010). Medial temporal lobe activity during complex discrimination of faces, objects, and scenes: Effects of viewpoint. Hippocampus, 20(3), 389–401. http://doi.org/10.1002/hipo.20641
Baslow, M. H., Dyakin, V. V, Nowak, K. L., Hungund, B. L., & Guilfoyle, D. N. (2005). 2- PMPA , a NAAG Peptidase Inhibitor , Attenuates Magnetic Resonance BOLD Signals in Brain of Anesthetized Mice. Journal of Molecular Medicine, 26, 1–16. http://doi.org/10.1385/JMN
Bateman, R. J., Xiong, C., Benzinger, T. L. S., Fagan, A. M., Goate, A., Fox, N. C., … Morris, J. C. (2012). Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. The New England Journal of Medicine, 367(9), 795–804. http://doi.org/10.1056/NEJMoa1202753
Bates, T. E., Strangward, M., Keelan, J., Davey, G. P., Munro, P. M., & Clark, J. B. (1996). Inhibition of N-acetylaspartate production: implications for 1H MRS studies in vivo.
Neuroreport, 7(8), 1397–1400.
Batra, N. A., Seres-Mailo, J., Hanstock, C., Seres, P., Khudabux, J., Bellavance, F., … Le Melledo, J. M. (2008). Proton Magnetic Resonance Spectroscopy Measurement of Brain Glutamate Levels in Premenstrual Dysphoric Disorder. Biological Psychiatry,
63(12), 1178–1184. http://doi.org/10.1016/j.biopsych.2007.10.007
Bero, A. W., Yan, P., Roh, J. H., Cirrito, J. R., Stewart, F. R., Raichle, M. E., … Holtzman, D. M. (2011). Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nature Neuroscience, 14(6), 750–6. http://doi.org/10.1038/nn.2801
Binnewijzend, M., Schoonheim, M., Sanz-Arigita, E., Wink, A., van der Flier, W., Tolboom, N., … Barkhof, F. (2012). Resting-state fMRI changes in Alzheimer’s disease and mild cognitive impairment. Neurobiology of Aging, 33(9), 2018–28.
Bird, C. M., Chan, D., Hartley, T., Pijnenburg, Y. a, Rossor, M. N., & Burgess, N. (2010). Topographical short-term memory differentiates Alzheimer’s disease from frontotemporal lobar degeneration. Hippocampus, 20(10), 1154–69. http://doi.org/10.1002/hipo.20715
Born, R., & Bradley, D. (2005). Structure and Function of Visual Area Mt. Annual Review of
Neuroscience, 28(1), 157–189.
http://doi.org/10.1146/annurev.neuro.26.041002.131052
Boy, F., Evans, C. J., Edden, R. A. E., Lawrence, A. D., & Singh, K. D. (2011). Dorso-lateral prefrontal γ-amino butyric acid in men predicts individual differences in rash impulsivity. Biological Psychiatry, 70(9), 866–872. http://doi.org/10.1016/j.biopsych.2011.05.030.
Braak, H., & Braak, E. (1991). Neuropathological stageing of Alzheimer-related changes.
Acta Neuropathologica, 82, 239–259.
Braak, H., & Braak, E. (1995). Staging of Alzheimer’s Disease-Related Neurofibrillary Changes. Neurobiology of Aging, 16(3), 271–278.
Braak, H., & Del Tredici, K. (2012). Where, when, and in what form does sporadic Alzheimerʼs disease begin? Current Opinion in Neurology, 25(6), 708–714. http://doi.org/10.1097/WCO.0b013e32835a3432
Braak, H., Thal, D. R., Ghebremedhin, E., & Tredici, K. Del. (2011). Stages of the Pathologic Process in Alzheimer Disease : Age Categories From 1 to 100 Years, 70(11), 960– 969.
Buchhave, P., Minthon, L., Zetterberg, H., Wallin, A. K., Blennow, K., & Hansson, O. (2012). Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Archives of General