NONINVASIVE NEUROCHEMICAL ANALYSIS OF FOCUS EXCITOTOXIC LESIONS IN MODELS OF NEURODEGENERATIVE ILLNESS USING SPECTROSCOPIC IMAGING

Water-suppressed chemical shift magnetic resonance imaging was used to detect neurochemical alterations in vivo in neurotoxin-induced rat mo dels of Huntington's and Parkinson's disease. The toxins were: N-methy l-4-phenylpyridinium (MPP(+)), aminooxyacetic acid (AOAA), 3-nitroprop ionic acid (3-NP), malonate, and azide. Local or systemic injection of these compounds caused secondary excitotoxic lesions by selective inh ibition of mitochondrial respiration that gave rise to elevated lactat e concentrations in the striatum. In addition decreased N-acetylaspart ate (NAA) concentrations were noted at the lesion Site Over time. Meas urements of lactate washout kinetics demonstrated that t(1/2) followed the order: 3-NP approximate to MPP(+) AOAA approximate to malonate wh ich parallels the expected lifetimes of the neurotoxins based On their mechanisms of action. Further increases in lactate were also Caused b y intravenous infusion of glucose. at least part of the excitotoxicity is mediated through indirect glutamate pathways because lactate produ ction and lesion size were diminished using unilateral decortectomies (blockade of glutamatergic input) or glutamate antagonists (MK-801). L esion size and lactate were also diminished by energy repletion with u biquinone and nicotinamide. Lactate measurements determined by magneti c resonance agreed with biochemical measurements made using freeze cla mp techniques. Lesion size as measured with MR, although larger by 30% , agreed well with lesion size determined histologically. These experi ments provide evidence for impairment of intracellular energy metaboli sm leading to indirect excitotoxicity for all the compounds mentioned before and demonstrate the feasibility of small-volume metabolite imag ing for in vivo neurochemical analysis.