D. Bravi

Catechol‐O‐methyltransferase inhibitor tolcapone prolongs levodopa/carbidopa action in parkinsonian patients

The wearing-off phenomenon frequently complicates levodopa therapy of Parkinsons 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 levodopdcarbidopa 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 levodopdcarbidopa 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 levodopdcarbidopa therapy.

No evidence for altered muscle mitochondrial function in Parkinson's disease.

Recent reports indicate that reductions in mitochondrial respiratory chain function occur in substantia nigra, platelets, and muscle from patients with Parkinsons disease. To confirm and further characterise the presence of a generally distributed mitochondrial defect, mitochondrial metabolism was evaluated in muscle obtained from subjects with Parkinsons disease and from normal controls. Oxygen consumption rates in muscle mitochondria represented by complex I, complexes II-III, or complex IV did not differ between the two groups. Likewise, activities of rotenone sensitive NADH cytochrome c reductase, succinate cytochrome c reductase, or cytochrome oxidase in muscle mitochondria were not significantly different between Parkinsonian and control subjects. These findings fail to provide support for a generalised defect in mitochondrial function in Parkinsons disease but do not exclude an abnormality in respiratory function confined to the substantia nigra.

D-cycloserine treatment of Alzheimer disease.

SummaryDegeneration of cortical glutamatergic projections may contribute to the cognitive decline in Alzheimer disease (AD). To evaluate whether 1glutamate system stimulation might confer symptomatic benefit, we administered D-cycloserine, a putative partial indirect agonist at certain N-methyl- D-aspartate (NMDA) glutamate receptors, to 12 patients with probable AD. The patients (seven men, five women) had a mean age of 65 ± 8.4 years; Mini Mental State Examination scores ranged from 15 to 25. A dose escalation phase, in which cycloserine was given in daily oral doses from 25 to 500 mg (total of six dose levels, 1 week per dose), was followed by a “best dose” crossover comparison with placebo under double-blind conditions. The crossover phase consisted of 2 weeks of cycloserine and 2 weeks of placebo, separated by a 1-week washout period. We observed no significant or consistent effect on neuropsychological outcome measures. The results suggest that short-term potentiation of NMDA-mediated glutamatergic transmission may not prove useful in the symptomatic treatment of Alzheimer dementia.

Levodopa peak response time reflects severity of dopamine neuron loss in Parkinson's disease

We measured the time to peak antiparkinson response following injection of levodopa or apomorphine in 57 patients with Parkinsons disease. The peak response time for levodopa fell from 53 ± 6.5 minutes in patients at Hoehn and Yahr stage I-II, and 28 ± 4.8 minutes in those at stage IV (p < 0.0005). There was a significant correlation between levodopa peak response time and symptom duration (r = 0.65; p < 0.0001), but there was no relation between apomorphine peak response time and measures of disease severity. Peak response time to levodopa appears to reflect predominantly the status of compensatory presynaptic dopaminergic mechanisms and thus may provide an index to the degree of dopamine neuron degeneration in parkinsonian patients.

Is early-onset Alzheimer disease a distinct subgroup within the Alzheimer disease population?

Although patients with Alzheimer disease (AD) share major clinical and neurohistologic features regardless of age of onset, the hypothesis that early-onset AD comprises a distinct subgroup remains viable. Most studies addressing this hypothesis find quantitative differences between early- and late-onset AD patients. Early-onset AD is characterized by shorter survival, more rapid cognitive deterioration, greater frequency of language disturbance, more severe and widespread neurochemical abnormalities, and a greater density of neurohistologic lesions. In addition, both the chromosome 14 genetic abnormality and chromosome 21 amyloid precursor protein mutations appear restricted to early-onset familial AD. Age of onset of AD subjects may be relevant to the design of clinical trials. For example, the efficacy of a drug that slows disease progression may be more easily demonstrated in subjects with early-onset disease.

End‐of‐dose dystonia in Parkinson's disease

To evaluate the pathogenesis of end-of-dose dystonia in levodopa-treated patients with Parkinsons disease, we discontinued a steady-state optimal-dose levodopa infusion either abruptly or slowly. Although dystonic signs appeared sooner after sudden levodopa termination, in both situations dystonia emerged only when circulating drug levels had fallen to the same concentration and parkinsonian scores had declined by the same amount. Dystonia onset thus appears to reflect the degree, rather than the rate, of reduction in dopaminergic stimulation, and may involve the preferential interaction of dopamine with a receptor subpopulation that does not mediate its antiparkinsonian efficacy.