Neurochemical Signatures for the Evaluation of Disease State and Therapeutic Strategies in Neurodegenerative Diseases: a Magnetic Resonance Spectroscopy Study

Abstract: Magnetic Resonance Spectroscopy (MRS) allows for the quantification of neurotransmitters, antioxidants, energy-metabolism, membrane components and cellular viability markers present in the brain. This technology has been used in preclinical studies and later extended to be used in humans, where it offers an attractive non-invasive approach complementary to other anatomical imaging modalities (e.g. MRI). In this thesis, MRS was used for the evaluation of disease state and therapeutic strategies in models of neurodegenerative diseases based on the expression of human alpha-synuclein or huntingtin proteins. Impaired brain energy-metabolism was observed as result of an increased alpha-synuclein load in cortical neurons in the rat, while the expression of mutant huntingtin (mHTT) in the striatum of the BACHD mouse model of Huntington’s disease (HD) caused neurotransmitter reduction and an antioxidant response. In addition, MRS was used to evaluate the outcome of two therapeutic approaches by reversing the detrimental effects of mHTT expression in the striatal cells using the BACHD model. In particular there was a recovery in amino acid concentrations in the striatum. The results presented here show the versatility of MRS for the identification of neurochemical markers of disease state in animal models. Furthermore, MRS is of particular value in the evaluation of new therapeutic strategies, where specific neurochemical markers can be used in the follow-up of control and treatment groups in a non-invasive and longitudinal design.

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