Parkinson's disease (PD) is a functionally devastating, common neurological disorder, producing slow, clumsy bodily movements, muscular rigidity and tremor, as well as impaired balance and cognition in many instances. There is no clear consensus about the etiology (ies) of the condition, and researchers are exploring genetic, environmental and endogenous neurochemical hypotheses. There is much postmortem biochemical evidence from PD brain that iron-promoted oxidative stress, producing lipid peroxidative damage particularly in the substantia nigra (SN) of the midbrain, the chief site of neuronal loss in PD, is involved in the premature death of those cells. However, the clinical significance of iron accumulation in SN, or elsewhere in basal ganglia (e.g., putamen [PUT] or globus pallidus [GP] in PD, has not been defined in living human subjects. This is because earlier MRI studies at 1.5 Tesla seeking to measure brain iron content have not found a consistent relationship between nonspecific T2 relaxation and either PD severity or quantitative measurements of the metal in brain tissue postmortem. To test the hypothesis, in living patients, that iron-promoted oxidative brain damage is an important mechanism in the pathogenesis of PD, the need now is to: 1) establish a more specific MRI measure of brain iron context which distinguishes PD from non-PD subjects; and 2) relate that measure to PD motoric severity. The research we propose will meet these needs because we have demonstrated in preliminary studies that MRI at 3 Tesla has allowed the calculation of a parameter, R2', the relaxation rate due to magnetic field inhomogeneities, derived from measurements of T2 and T2', that is more specific for brain tissue iron. This is because, having developed a technique to correct for global magnetic field inhomogeneities, the R2' parameter we calculate will now reflect only microscopic inhomogeneities, such as those produced by iron and other paramagnetic substances. The further specificity for iron depends on the fact that other paramagnetic ions (i.e., Mn, Cu, Zn) are either unchanged in PD SN, PUT or GP, are orders of magnitude less concentrated than iron, or are far less parmagnetic than iron to contribute significantly to R2'. Moreover, we have shown a clear relationship between asymmetries in SN R2' and asymmetries in motor impairment in PD, as assessed by simple reaction time measurements. These novel methods will permit us, for the first time, to test the hypotheses that SN, PUT or GP iron context is related to the pathogenesis and motor severity of PD. We will test the disease specificity of our findings by studying patients with multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and MPTP-parkinsonism. The fulfillment of these research goals will provide a noninvasive method for the sequential, objective evaluation of PD (and, perhaps, MSA, PSP AND MPTP-parkinsonism) progression during future therapeutic drug trials for one or more of these disorders. We are committed to this work, which we believe offers hope for better understanding of PD, MSA, PSP and MPTP-parkinsonism, devastating neurological disorders.
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