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Patients with Parkinson's disease (PD) often show impaired manual dexterity even when being only minimally bradykinetic, suggesting that they may have limb kinetic apraxia (LKA), that is, a loss of fine motor skill not explained by elemental motor deficits. To explore this dissociation, we investigated the differential dopaminergic responsiveness of dexterity and bradykinesia in PD. Twelve patients with PD (4 women, age 64.4 +/- 8.3, mean + SD) and 12 matched healthy controls (64.8 +/- 8.9) were tested twice in ON vs. OFF and 1st vs. 2nd trial, respectively. A coin rotation (CR) task was applied to assess dexterity and a finger tapping (FT) task to assess bradykinesia. Performance was followed by video recording and analyzed by measuring the frequency of CR and FT during three 10-second periods. Statistical analysis was done by a mixed factorial design with group (PD vs. controls) as between-subject factor and medication (ON- vs. OFF-state or 1st vs. 2nd trial), task (FT vs. CR), and handedness (dominant vs. nondominant) as within-subject factors. In patients with PD, regardless of hand involved, dopaminergic treatment only mildly improved CR performance, in contrast to the strong increase in FT scores (up to the level of controls), as demonstrated by the significant triple interaction of the factors group, medication, and task (F(1,22) = 7.9, P = 0.01; eta(2) = 0.26). Furthermore, CR scores were considerably lower, both in OFF and ON, than in normal controls, pointing to a substantial impairment of dexterity in PD (P < 0.001). In conclusion, impaired manual dexterity showing significantly diminished response to dopaminergic treatment suggests that dextrous deficits in PD are related to LKA rather than bradykinesia., ((c) 2007 Movement Disorder Society.)

Effects of the long term, continuous administration of a dopamine agonist on motor response complications attending levodopa therapy were studied in 7 patients with advanced Parkinson's disease under controlled conditions. After a 3-month round-the-clock infusion of lisuride, the duration of antiparkinsonian action of levodopa increased by approximately 90%, and the therapeutic window for the acutely administered dopamine precursor widened by > 300%. These benefits were more than three times greater than those produced by 9 days of continuous levodopa administration. In contrast to the effects on levodopa pharmacodynamics, the continuous infusion of lisuride did not prolong its action, suggesting a lisuride effect on presynaptic as well as postsynaptic dopaminergic mechanisms. These results lend further support to the view that continuous dopamine replacement ameliorates motor fluctuations and peak-dose dyskinesias that complicate standard levodopa regimens. Our findings further suggest that alterations at both presynaptic and postsynaptic levels contributing to these motor complications tend to normalize with the more physiological stimulation afforded by continuous replacement strategies, especially when given chronically.

Somatostatin is consistently diminished in brains of patients with Alzheimer's disease. To evaluate whether pharmacological restoration of this transmitter deficit has therapeutic value, the synthetic analogue octreotide was administered intravenously to 14 Alzheimer patients under double-blind, placebo-controlled conditions. At the highest dose administered, spinal fluid concentrations approximated those found in brains of experimental animals receiving behaviorally effective amounts of the drug. Neuropsychological testing, however, showed no clinically significant improvement. Coadministration of octreotide and physostigmine to 1 patient also failed to improve cognition. Positron emission tomographic studies in 6 patients revealed a generalized decrease in glucose metabolism as a result of octreotide infusion. These findings suggest that stimulation of the somatostatin system has no value in the symptomatic treatment of Alzheimer dementia.

The management of fluctuations in motor function complicating advanced Parkinson's disease with continuously administered dopaminomimetics was studied in 12 patients. In response to 7 to 12 days of round-the-clock intravenous infusions of levodopa, fluctuations in motor performance gradually diminished, ultimately by more than 40%. The beneficial effect persisted for about 6 days after withdrawal of continuous parenteral treatment and resumption of standard oral therapy. Clinical improvement was associated with changes in several pharmacological indices: Acute dose-response studies of intravenous levodopa showed a shift of the curve to the right in the immediate postinfusion phase compared to preinfusion studies; the therapeutic index improved significantly as patients demonstrated about 76% increased beneficial antiparkinsonian response with an equal degree of toxic dyskinetic effects; and the duration of action of levodopa was prolonged by 30%. These results suggest that changes in central dopaminergic mechanisms contributing to motor complications in advanced Parkinson's disease can be modified by procedures that provide continuous dopamine replacement. Presumably these modifications underlie the gradual amelioration of motor fluctuations over several days of round-the-clock therapy. Results of the present study also suggest potential deleterious effects of chronic intermittent oral treatment in the development of motor complications and thus support the role of long-term, continuous administration of dopaminomimetics.

Abnormal involuntary movements complicate the management of a majority of patients with advanced Parkinson's disease. The ability of levodopa to induce dyskinesias and alleviate parkinsonism has generally been considered a continuous dose-dependent pharmacological spectrum. In this study, the acute dose-response profile of intravenously administered levodopa for both inducing dyskinesia and alleviating parkinsonism, and its duration of action on these motor manifestations were evaluated in 52 parkinsonian patients. The minimum dose of levodopa required to produce mild dyskinetic movements was significantly lower in patients with fluctuations in motor response compared with those who had a stable response to standard oral therapy; the minimum dose for antiparkinsonian benefit, however, failed to show significant differences. The rate of disappearance of dyskinetic movements was faster than the rate of reappearance of parkinsonian signs following withdrawal of a steady-state infusion of levodopa. The dissociation of the pharmacodynamic profile of the two major motor effects of levodopa suggests their mediation through two different central pharmacological mechanisms, perhaps involving the two classes of dopamine receptors or other transmitter systems, and could have important implications for the design of future antiparkinsonian agents.