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Title: Longitudinal changes in metabolite concentrations and lesion development in EAE and Multiple Sclerosis using 1H-MR Spectroscopy and MRI
Author: Hill, A. M.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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Multiple Sclerosis (MS) is an inflammatory demyelinating disease affecting the grey matter (GM) and white matter (WM) of the central nervous system resulting in progressive neurological deficits and clinical disability. Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS, can be investigated with magnetic resonance (MR) to address the clinical need to understand mechanisms of the MS disease course. However, longitudinal MR studies with EAE are currently under-explored. This thesis investigated longitudinal changes in metabolite concentrations and lesion development, in relation to neurological deficits in EAE, using 9.4T MRI and 1H-MRS and compared the findings using similar methods in early MS. The pre-clinical study assesses five time-points of EAE disease progression. The results suggest that after the immunisation, but before visible signs of neurological deficits, higher N-acetyl-aspartate concentration [NAA] predicts the severity of late-stage neurological deficits in EAE where a lower fractional anisotropy (FA) and histology indicate microstructural deficits. The results correspond with histology markers where EAE animals severely affected by recombinant myelin oligodendrocyte glycoprotein (rMOG), had an increase of mitochondria at the Pre-symptomatic and Onset time-points compared to controls. These findings were compared to a longitudinal analysis of clinically isolated syndrome (CIS) conversion to clinically definite MS (CDMS), where CIS patients with higher [NAA] 1 year after presenting with symptoms, develop a more severe MS disease course at 15 years after the onset of MS. There was also an interaction between new T2-weighted (T2-w) lesions and [tNAA] at 1 year after CIS onset which was the strongest indicator of differences between Relapsing Remitting MS and Secondary Progressive MS disease courses at 15 years. This may suggest that early [tNAA] changes could be used as a biomarker for long-term disease severity. The association between [NAA] and disability-score in EAE, at the Pre-symptomatic time-point, with histological evidence, as well as the interaction between early [NAA] and new T2-w lesions and disability severity and course, suggests that [NAA] may reflect pathological processes relevant to MS disease course and treatment targets.
Supervisor: Ciccarelli, O. ; Smith, K. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available