Levels ofpros-methylimidazoleacetic acid: Correlation with severity of Parkinson's disease in CSF of patients and with the depletion of striatal dopamine and its metabolites in MPTP-treated mice

Abstract

The cerebrospinal fluid (CSF) levels of pros-methylimidazoleacetic acid (p-MIAA) in thirteen medication-free patients with mild to moderate Parkinson's disease were highly correlated (Spearman's rho = 0.749, p less than 0.005) with the severity of signs of the disease as scored on the Columbia University Rating Scale. Levels of p-MIAA in males (n = 8) and females (n = 5) were each significantly correlated with scores of severity (rho = 0.78, p less than 0.05 and rho = 1.0, p less than 0.05, respectively). In C57BL/6 mice treated with 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP), levels of p-MIAA were significantly correlated with the depleted levels of dopamine (r = 0.85, p less than 0.01), homovanillic acid (r = 0.79, p less than 0.02), 3,4-dihydroxyphenylacetic acid (r = 0.84, p less than 0.01) and norepinephrine (r = 0.91, p less than 0.002) in striatum, but not in cortex of the same mice. No such correlations were observed in either striatum or cortex of saline-treated control mice. Mean levels of p-MIAA in CSF did not differ significantly between patients and age-matched controls; and mean levels of p-MIAA in striatum did not differ between MPTP-treated mice and controls. The simplest hypothesis to account for these strong correlations in the absence of differences in mean levels of p-MIAA is that accumulation of p-MIAA [or process(es) that govern its accumulation] influences a failing nigrostriatal system. It is also possible (in analogy with findings in other diseases and with other drugs) that measurements of the putative metabolite(s) of p-MIAA may distinguish the patients and the MPTP-treated mice from their respective controls. Elucidation of the processes that regulate formation and disposition of p-MIAA in brain and information on the neural effects of p-MIAA, its precursors and its putative metabolites may yield insight into factors that regulate the progression of Parkinson's disease, and may shed additional light on the cause(s) of this disease.