Investigating disturbances of brain 5-HT systems by experimental MRI and SPECT neuroimaging

Ruest, Torsten (2009) Investigating disturbances of brain 5-HT systems by experimental MRI and SPECT neuroimaging. PhD thesis, University of Glasgow.

Abstract

Depression is one of the most common causes of periods of disability. There is evidence suggesting that the serotonin system is involved in the pathophysiology of depression. It has been suggested that synaptic serotonin levels are reduced in depressed patients, and that pharmacological blockade with antidepressants of the serotonin transporter (SERT) would result in alleviated symptoms of depression by enhancing serotonin neurotransmission. Since depression can be treated with antidepressants that target SERT, and a recently discovered 5-HTT gene-linked polymorphic region (5-HTTLPR) of the SERT gene has been shown to predispose to depression, the SERT assumes a key role in depression. Traditionally, depression severity was assessed using psychological testing of patients. However in the last 20 years, neuroimaging techniques using magnetic resonance imaging (MRI) of brain structures and molecular single photon emission computed tomography (SPECT) evolved which appear promising to better understand the pathophysiology at the tissue level. However, preclinical data on abnormalities that involve the serotonin system are limited.

The studies presented in this thesis attempt to shed more light on the feasibility of using the novel MRI technique diffusion tensor imaging (DTI), and SPECT to detect disturbances of the serotonin system. Firstly, in order to elucidate the capabilities of DTI as a research tool in the detection of conceivably mild changes in white matter involving the serotonin system, a mouse model of life-long SERT deficiency was studied. Secondly, in order to validate DTI image processing methodology, a mouse model with reportedly profound myelin dysfunction was examined. Histology techniques were applied to the same mouse brains in order to explore the tissue correlate of the DTI signal changes. Thirdly, as myelin was hypothesised to interact with the serotonin system, in vitro autoradiography of SERT in mice with widespread hypomyelination was conducted in order to test this hypothesis. Lastly, in a rat model of SERT depletion, the relative abilities of a well established SPECT radioligand, [125I]βCIT (2β-carbomethoxy-3β-(4-iodophenyl)tropane), and a relatively novel SERT tracer, [123I]ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) were examined using micro-SPECT.

The data demonstrate that DTI did not detect any changes in white matter organisation in SERT-deficient mice. Surprisingly, subtle changes in white matter microstructure were detected in mice that were haploinsufficient for SERT, i.e. heterozygous null mice, displaying a 50 % SERT reduction compared to WT as detected using DTI. On the other hand, profound hypomyelination was detected using DTI in another mouse model with white matter pathology, and correlations between DTI and histopathological markers were present, indicating that this technology provides good indications of severe pathology, while small changes, if present, may be missed. In addition, the SERT availability appeared not to be affected in mice with widespread hypomyelination. While post mortem autoradiography of SERT-depleted rats showed widespread reductions in SERT binding using dedicated specific SERT ligands, micro-SPECT using [125I]βCIT and [123I]ADAM did not show any differences. [125I]βCIT delivered good quality brain SPECT images, however analysis of [123I]ADAM scans was hampered by the poor definition of structures.

Thus this thesis provides important information on the feasibility, and sensitivity of current neuroimaging modalities. In addition, methodological flaws and uncertainties in the current literature were identified, which underpins the need for improving and standardising methodological approaches, particularly in SPECT imaging.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: MRI, DTI, SPECT, Depression, 5-HT, Serotonin, SERT, Serotonin Transporter, Pelizaeus-Merzbacher Disease, PMD
• Subjects: R Medicine > R Medicine (General); R Medicine > RB Pathology; R Medicine > RZ Other systems of medicine; Q Science > Q Science (General)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Supervisor's Name: Dewar, Dr. Deborah
• Date of Award: 2009
• Depositing User: Mr Torsten Ruest
• Unique ID: glathesis:2009-935
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 11 Aug 2009
• Last Modified: 10 Dec 2012 13:28
• URI: https://theses.gla.ac.uk/id/eprint/935