The neural degeneration observed in the striata of patients with Huntington's disease (HD) can be reproduced by excitatory NMDA receptor agonists such as aspartate and glutamate in striatal cell cultures and in striata of vertebrates injected with these substances. Therefore, we decided to investigate the role of aspartate and glutamate in HD. Aspartate, glutamate, glutamine, and phenylalanine were measured in platelets and plasma of HD patients and age- and sex-matched healthy controls (C), using HPLC methods. In HD platelets the mean aspartate concentration was significantly (p < 0.01) increased (8.9 +/- 3.8 (SD) nmol/mg protein, n = 28) compared to C (4.6 +/- 1.4 (SD) nmol/mg protein, n = 24), whereas plasma aspartate was significantly (p < 0.01) decreased in HD (0.092 +/- 0.023 (SD) mg/dl, n = 16) versus C (0.179 +/- 0.109 (SD) mg/dl, n = 21). The increase in platelet aspartate should be a direct or indirect consequence of the dominant gene defect in HD. It might therefore be present in neurons as well, especially since platelets share many characteristics with neurons. Hence, chronically increased release of aspartate with consecutive overstimulation of postsynaptic neurons via NMDA receptors might be responsible for the damage observed in striatal target cells of corticostriatal glutamatergic and aspartatergic projection fibers in HD.