Mapping in Vivo Neurotransmitter Concentrations in the Human Brain with 3D MR Spectroscopic Imaging: Alterations in Manganese-induced Movement Disorders

Ruoyun Ma, Purdue University

Abstract

Gamma-aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the brain. It plays vital roles in the basal ganglia direct and indirect pathways, which modulate various motor and cognitive functions by relaying signals to the thalamus and then projecting to the cortical area for the execution. The basal ganglia pathways have been observed to be disrupted in movement disorders such as idiopathic Parkinson’s disease (IPD) and manganese (Mn)-induced parkinsonism. Previous work from our group demonstrated elevated thalamic GABA levels in IPD patients as well as in a group of workers with high exposure to manganese (Mn). There is a gap in human in vivo research to find biomarkers of neurotoxic effect that can inform occupationally safe levels of exposure to Mn. Therefore, following our previous research, investigating the human GABAergic and glutamergic system under Mn exposure, as well as its association with motor and cognitive functions would help with both understanding the mechanism of how Mn intoxication disturbs the neurotransmitter system and finding a marker for the early detection Mn neurotoxicity. Using both single voxel MEGA-PRESS and MEGA-LASER 3-dimentional magnetic resonance spectroscopic imaging (MRSI) techniques, the dissertation work, for the first time, is able to study Mn neurotoxicty by investigating in vivo GABA concentration maps in the central brain area. This in return allows to study the association between neurotransmitter levels in different brain areas and i) individual exposure levels, ii) brain Mn deposition and iii) motor functions that have been observed to be impaired in IPD patients. The dissertation work has been accomplished in three steps. First, two subgroups of welders with different exposure levels, as well as unexposed control workers were recruited. The group of welders with higher exposure showed a significant increase of thalamic GABA levels by 45%, as well as significantly worse performance in general motor function. However, welders with lower exposure did not differ from the controls in GABA levels or motor performance. Further, in welders the thalamic GABA levels were best predicted by past-12-months exposure levels and were influenced by the Mn deposition in the substantia nigra and globus pallidus. Importantly, both thalamic GABA levels and motor function displayed a non-linear pattern of response to Mn exposure, suggesting a threshold effect. Second, to move the neurotransmitter measurement from a localized single-voxel MEGA-PRESS acquisition to a larger brain coverage with higher resolution using MEGA-LASER 3D MRSI, an automated brain-structure-specific approach for the quantification of the MRSI-measured brain metabolite levels from structures of interest was developed. To cross-validate this approach with the single voxel MRS technique, MRSI data from a central brain area and single voxel MRS data from the thalamus were acquired on 21 healthy subjects. The main metabolites measured by the two techniques are highly correlated between the two techniques. Finally, the MEGA-LASER 3D MRSI technique combined with the brain-structure-specific approach was then applied to a pilot study with 10 controls and 11 welders, with the structures of interest including the thalamus, putamen, caudate and globus pallidus. Individual exposure levels, brain Mn deposition and general motor function were examined. Further, a more specific motor function known as response selection, which is deeply involved with the GABAergic system in the basal ganglia and has been found to be affected in IPD patients, was tested through a modified version of the Simon task. In addition, a longitudinal study was performed to follow up the welders we recruited for step 1 with the same measurements as described in step 1. Due to more usage of respirators and increased ventilation at the factory, the exposure levels of welders recruited in this step were significantly reduced. Further, no difference in GABA levels or R1 values in any brain region was found in this study. The general motor function and response selection function did not differ either between welders and controls. These findings from the pilot study are in line with our main longitudinal study. However, Mn potentially affects the response selection function by a subtle modulation of GABA levels in the putamen, reflected by partial regression between Simon task and GABA levels from several all measured brain regions after multiple comparison correction. In conclusion, my dissertation work, for the first time, enabled studying the effect of Mn neurotoxicity using in vivo GABA mapping in several brain structures of the human brain. The feasibility and user-friendliness of this new methodology is enhanced with an automatic brain-structure-specific approach for the quantification of brain metabolite levels from structures of interest. (Abstract shortened by ProQuest.)

Degree

Ph.D.

Advisors

Dydak, Purdue University.

Subject Area

Medical imaging

COinS