Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.666871
Title: Investigation of the neuronal marker N-acetylaspartate as a potential biomarker for neurological diseases
Author: Marsh, Samuel
ISNI:       0000 0004 5358 0408
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2015
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Abstract:
N-acetylaspartate (NAA) is known to be present in high concentrations throughout the whole CNS. It is believed to have four basic functions in the brain; an organic osmolyte, a source of acetate for myelin synthesis, an energy source and a precursor for N-acetylaspartate-glutamate (NAAG). Because of NAA’s ability to be measured both in vivo and ex vivo as well as its high concentration it is believed that it has potential to be used as a biomarker for neuronal loss/dysfunction. The present studies were utilised to develop the potential of NAA as a biomarker using a variety of techniques and neurological diseases both in pre-clinical and human post-mortem studies. Using phencyclidine (PCP) to induce schizophrenia-like symptoms we showed that reductions in the levels of NAA in the frontal cortex and ventral hippocampus are observed in a post-mortem analysis of rat brain tissue. This reduction is not ameliorated following chronic administration of the atypical antipsychotic olanzapine. A deficit in cell density in the frontal cortex was also found following cresyl violet staining. Again this deficit was not ameliorated following chronic administration of atypical antipsychotic olanzapine. With in vivo analysis using Magnetic Resonance Spectroscopy (MRS) we replicated these findings 6 weeks post PCP treatment. This neuronal dysfunction was supported with behavioural data showing a deficit in the PCP group in the novel object recognition (NOR) task. Following behavioural testing a post-mortem analysis was undertaken on the cohort mirroring the reduction in NAA using the HPLC method of analysis in the frontal cortex. Following High Pressure Liquid Chromatography (HPLC) analysis of human brain samples provided by the Stanley Foundation we found a reduction in the level of NAA in human schizophrenic brain tissue when compared to controls. These deficits were found in the frontal cortex and further support the findings in the preclinical experiments. In the final studies we focused on a preclinical rat model of relevance to Alzheimer’s disease. Using acute administration of soluble Amyloid Beta(Aβ)1-42 oligomers we demonstrated a model of early stage Alzheimer’s. We observed a cognitive deficit in the NOR task however no reduction in NAA in the brain regions examined. These finding are indicative of a synaptic dysfunction however no neuronal dysfunction at the early stage of the disease. Taken together, these findings suggest that NAA shows promise as a biomarker for neuronal dysfunction in neurological diseases that can be used in pre-clinical and clinical setting with both in vivo and ex vivo applications. We also demonstrate the potential translational use of NAA as a biomarker for assessing treatment efficacy in relation to the underlying pathological changes in the brain.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.666871  DOI: Not available
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