William Bara-Jimenez

Adenosine A2A receptor antagonist treatment of Parkinson’s disease

Background: Observations in animal models suggest that A2A antagonists confer benefit by modulating dopaminergic effects on the striatal dysfunction associated with motor disability. This double-blind, placebo-controlled, proof-of-principle study evaluated the pathogenic contribution and therapeutic potential of adenosine A2A receptor–mediated mechanisms in Parkinson disease (PD) and levodopa-induced motor complications. Methods: Fifteen patients with moderate to advanced PD consented to participate. All were randomized to either the selective A2A antagonist KW-6002 or matching placebo capsules in a 6-week dose-rising design (40 and 80 mg/day). Motor function was rated on the Unified PD Rating Scale. Results: KW-6002 alone or in combination with a steady-state IV infusion of each patient’s optimal levodopa dose had no effect on parkinsonian severity. At a low dose of levodopa, however, KW-6002 (80 mg) potentiated the antiparkinsonian response by 36% (p < 0.02), but with 45% less dyskinesia compared with that induced by optimal dose levodopa alone (p < 0.05). All cardinal parkinsonian signs improved, especially resting tremor. In addition, KW-6002 prolonged the efficacy half-time of levodopa by an average of 47 minutes (76%; p < 0.05). No medically important drug toxicity occurred. Conclusions: The results support the hypothesis that A2A receptor mechanisms contribute to symptom production in PD and that drugs able to selectively block these receptors may help palliate symptoms in levodopa-treated patients with this disorder.

Periodic limb movements in sleep: State-dependent excitability of the spinal flexor reflex

Objective: To test the hypothesis that periodic limb movements (PLMs) are related to spinal flexor reflexes (FRs), the authors compared the state-dependent changes in FR excitability in 10 patients with restless legs syndrome (RLS) and PLMs with those from matched controls. Background: PLM is a disorder of motor control during sleep, frequently occurring in RLS. Clinically, PLMs resemble spinal FRs. Methods: FRs were obtained by electrically stimulating the medial plantar nerve and recording from antagonist leg and thigh muscles bilaterally. Results: Compared with controls, patients had significantly increased spinal cord excitability, as indicated by lower threshold and greater spatial spread of the FR, which was more prominent during sleep. Multiple late responses were seen during sleep in all patients and in some controls at higher threshold. The most prominent of these responses had a very long duration and a latency range of 250 to 800 msec, and because of its close temporal relationship to the FR stimulus, the authors considered it was a late, high-threshold component of the FR (FR3). The authors also found a similarity between the pattern of muscle recruitment and spatial spread of late components of the FR and those of spontaneous PLMs. Conclusions: The results support the hypothesis that PLMs in RLS and FRs share common spinal mechanisms and suggest that PLMs may result from enhanced spinal cord excitability in RLS patients. Because dopaminergic mechanisms are involved in spinal FR control, the results are consistent with the current view that RLS is a disorder of dopaminergic function.

Placebo-controlled study of rTMS for the treatment of Parkinson's disease.

The objective of this study is to assess the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) for gait and bradykinesia in patients with Parkinsons disease (PD). In a double‐blind placebo‐controlled study, we evaluated the effects of 25 Hz rTMS in 18 PD patients. Eight rTMS sessions were performed over a 4‐week period. Four cortical targets (left and right motor and dorsolateral prefrontal cortex) were stimulated in each session, with 300 pulses each, 100% of motor threshold intensity. Left motor cortex (MC) excitability was assessed using motor evoked potentials (MEPs) from the abductor pollicis brevis. During the 4 weeks, times for executing walking and complex hand movements tests gradually decreased. The therapeutic rTMS effect lasted for at least 1 month after treatment ended. Right‐hand bradykinesia improvement correlated with increased MEP amplitude evoked by left MC rTMS after individual sessions, but improvement overall did not correlate with MC excitability. rTMS sessions appear to have a cumulative benefit for improving gait, as well as reducing upper limb bradykinesia in PD patients. Although short‐term benefit may be due to MC excitability enhancement, the mechanism of cumulative benefit must have another explanation.

Spatial discrimination is abnormal in focal hand dystonia

Background: In patients with focal hand dystonia, abnormal digit representations in the primary somatosensory cortex (S1) could be the result of enlarged and overlapping receptor fields, as suggested by an animal model of dystonia. A possible clinical correlate of this S1 abnormality is a disturbed spatial discrimination capability. Objective: To test the hypothesis that somatosensory spatial discrimination is abnormal in focal hand dystonia. Methods: Seventeen patients with focal hand dystonia underwent a quantitative evaluation of somatosensory spatial frequency (gap detection, JVP domes, applied to the distal phalanx of the index finger) and single-touch localization (Von Frey monofilaments, applied to the middle phalanx of the index finger). Results: Compared with control subjects, patients had a decreased performance in both the gap detection (p = 0.004) and the localization (p = 0.013) tasks. The extent of spatial frequency abnormality correlated with age in both groups. Conclusions: These findings, together with a previously shown temporal discrimination deficit, support a role for sensory dysfunction in the pathophysiology of dystonia.

Sensory discrimination capabilities in patients with focal hand dystonia

To explore the concept that dystonia may result from dysfunction of the sensory system, 14 patients with focal hand dystonia were tested during two somatosensory discrimination tasks. Compared with controls, patients had a higher threshold in a task involving discrimination of two electric stimuli closely related temporally, an abnormality that correlated with the degree of severity of dystonia. There was no significant difference in a single‐touch, gross localization task. The possible relevance of these findings to the pathogenesis of dystonia is discussed. Ann Neurol 2000;47:377–380

Effects of serotonin 5‐HT1A agonist in advanced Parkinson's disease

Intermittent stimulation of striatal dopaminergic receptors seems to contribute to motor dysfunction in advanced Parkinsons disease (PD). With severe dopaminergic denervation, exogenous levodopa is largely decarboxylated to dopamine in serotonergic terminals. If 5‐HT1A autoreceptors regulate dopamine as well as serotonin release, in parkinsonian patients inhibition of striatal serotonergic neuron firing might help maintain more physiological intrasynaptic dopamine concentrations and thus ameliorate motor fluctuations and dyskinesias. To evaluate this hypothesis, effects of a selective 5‐HT1A agonist, sarizotan, given orally at 2 and 5 mg twice daily to 18 relatively advanced parkinsonian patients, were compared with baseline placebo function during a 3‐week, double‐blind, placebo‐controlled, proof‐of‐concept study. Sarizotan alone or with intravenous levodopa had no effect on parkinsonian severity. But at safe and tolerable doses, sarizotan coadministration reduced levodopa‐induced dyskinesias and prolonged its antiparkinsonian response (P ≤ 0.05). Under the conditions of this study, our findings suggest that 5‐HT1A receptor stimulation in levodopa‐treated parkinsonian patients can modulate striatal dopaminergic function and that 5‐HT1A agonists may be useful as levodopa adjuvants in the treatment of PD.

Sensory training for patients with focal hand dystonia

Some patients with focal hand dystonia have impaired sensory perception. Abnormal sensory processing may lead to problems with fine motor control. For patients with focal hand dystonia who demonstrate sensory dysfunction, sensory training may reverse sensory impairment and dystonic symptoms. We studied the efficacy of learning to read braille as a method of sensory training for patients with focal hand dystonia. Sensory spatial discrimination was evaluated in 10 patients who had focal hand dystonia and 10 age‐ and gender‐matched controls with a spatial acuity test (JVP domes were used in this test). Clinical dystonia evaluation included the Fahn dystonia scale and time needed to write a standard paragraph. Each individual was trained in braille reading at the grade 1 level for 8 weeks, between 30 and 60 minutes daily, and was monitored closely to ensure that reading was done regularly. Both controls and patients demonstrated improvement on the spatial acuity test. Patients showed a significant mean difference from baseline to 8 weeks on the Fahn dystonia scale. Sixty percent of the patients shortened the time they needed to write a standard paragraph. Improved sensory perception correlated positively with improvement on the Fahn dystonia scale. We conclude that training in braille reading improves deficits in spatial discrimination and decreases disability in patients with focal hand dystonia.

Continuous transdermal dopaminergic stimulation in advanced Parkinson's disease.

The objective of the study was to determine the safety and efficacy of increasing doses of Rotigotine CDS in patients with advanced Parkinsons disease. The development of motor complications in Parkinsons disease has been linked to intermittent stimulation of dopamine receptors. Continuous, noninvasive, dopaminergic stimulation has not been available to date. Rotigotine CDS is a lipid-soluble D2 dopamine agonist in a transdermal delivery system that could fill this void. This inpatient study consisted of a 2-week dose escalation phase followed by a 2-week dose maintenance phase at the highest dose (80 cm2). Each individuals L-Dopa dose was back-titrated as feasible. The primary outcome measure was L-Dopa dose, and secondary outcome measures included early morning “off”–L-Dopa Unified Parkinsons Disease Rating Scale motor scores by a blinded evaluator and motor fluctuation data obtained from patient diaries (“on” without dyskinesia, “on” with dyskinesia, and “off”). Seven of 10 subjects provided data that could be evaluated. There were two administrative dropouts, and one individual was eliminated from the study because of recrudescence of hallucinations. The median daily L-Dopa dose decreased from 1,400 to 400 mg (p = 0.018, Wilcoxon test). Unified Parkinsons Disease Rating Scale motor scores were unchanged. Although diary variables improved in most individuals, only the reduction in “off” time attained statistical significance. Adverse effects were mild and consisted mainly of dopaminergic side effects and local skin reactions. The data suggest that Rotigotine CDS is an effective treatment for advanced Parkinsons disease and permits patients to substantially lower L-Dopa doses without loss of antiparkinsonian efficacy. Full-scale controlled clinical trials are warranted. In addition to potential therapeutic benefits, this drug can be used to test the hypothesis that continuous dopaminergic stimulation from the initiation of Parkinsons disease therapy will limit the development of motor complications.

Translating A2A antagonist KW6002 from animal models to parkinsonian patients

Improving the translation of novel findings from basic laboratory research to better therapies for neurologic disease constitutes a major challenge for the neurosciences. This brief review of aspects of the development of an adenosine A2A antagonist for use in the management of Parkinson’s disease (PD) illustrates approaches to some of the relevant issues. Adenosine A2A receptors, highly expressed on striatal medium spiny neurons, signal via kinases whose aberrant activation has been linked to the appearance of parkinsonian signs after dopaminergic denervation and to the motor response complications produced by dopaminomimetic therapy. To assess the ability of A2A receptor blockade to normalize certain of these kinases and thus benefit motor dysfunction, the palliative and prophylactic effects of the selective antagonist KW6002 were first evaluated in rodent and primate models. In hemiparkinsonian rats, KW6002 reversed the intermittent l-dopa treatment-induced, protein kinase A-mediated hyperphosphorylation of striatal α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor GluR1 S845 residues and the concomitant shortening in motor response duration. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys, coadministration of KW6002 with daily apomorphine injections acted prophylactically to prevent dyskinesia onset. These and related preclinical observations guided the design of a limited, randomized, controlled, proof-of-concept study of the A2A antagonist in patients with moderately advanced PD. Although KW6002 alone or in combination with a steady-state IV infusion of optimal-dose l-dopa had no effect on parkinsonian severity, the drug potentiated the antiparkinsonian response to low-dose l-dopa with fewer dyskinesias than produced by optimal-dose l-dopa alone. KW6002 also safely prolonged the efficacy half-time of l-dopa. The results suggest that drugs capable of selectively blocking adenosine A2A receptors could confer therapeutic benefit to l-dopa–treated parkinsonian patients and warrant further evaluation in phase II studies. They also illustrate a strategy for successfully bridging a novel approach to PD therapy from an evolving research concept to pivotal clinical trials.

Neuroimaging of neuronal circuits involved in tic generation in patients with Tourette syndrome

Objective: To identify brain regions generating tics in patients with Tourette syndrome using sleep as a baseline. Methods: We used [15O]H2O PET to study nine patients with Tourette syndrome and nine matched control subjects. For patients, conditions included tic release states and sleep stage 2; and for control subjects, rest states and sleep stage 2. Results: Our study showed robust activation of cerebellum, insula, thalamus, and putamen during tic release. Conclusion: The network of structures involved in tics includes the activated regions and motor cortex. The prominent involvement of cerebellum and insula suggest their involvement in tic initiation and execution.