In an attempt to define possible subgroups ofAlzheimer's disease, 21 patients satisfying current clinical diagnostic criteria for this disorder were divided on the basis of progression rates of symptoms. Thirteen patients with relatively rapid intellectual deterioration did not differ from eight patients showing slow progression with respect to global intellectual performance, sex, or age at onset of symptoms. Neuropsychological testing revealed that although the two groups were indistinguishable in verbal or visuospatial functions associated with the parietotemporal cortex, the more rapidly deteriorating group had significantly greater impairment in executive functions attributed to the frontal lobe. PET scans showed equivalent reductions in glucose metabolism in the parietotemporal cortex, but patients with relatively fast progression had significantly greater hypometabolism frontally. These results suggest an association between relatively severe frontal lobe involvement and a rapid clinical course that might have important implications for the development of treatment strategies for patients with Alzheimer's disease.

The wearing-off phenomenon frequently complicates levodopa therapy of Parkinson's disease (PD). These response fluctuations appear when intrasynaptic dopamine concentrations begin to reflect the swings in levodopa availability that attend standard dosing regimens. Drugs that prolong the biologic half-life of levodopa and dopamine should thus prove beneficial. We administered levodopa/carbidopa in combination with single oral doses of tolcapone (Ro 40-7592), an inhibitor of catechol-O-methyltransferase, under controlled conditions to 10 PD patients with the wearing-off phenomenon. Tolcapone prolonged the antiparkinson response to levodopa/carbidopa by about 67% at several doses ranging from 50 to 400 mg (p < 0.05). There was no significant change in the peak levodopa effect on parkinsonian signs or in the severity of dyskinesias. No dose-limiting adverse effects occurred. Multiple daily dosing with tolcapone would thus be expected to safely reduce the wearing-off phenomenon associated with levodopa/carbidopa therapy.

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