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 Parkinson's disease. The development of motor complications in Parkinson's 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 individual's 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 Parkinson's 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 Parkinson's 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 Parkinson's 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 Parkinson's disease therapy will limit the development of motor complications.

Transdermal dopaminergic D(2) receptor agonist therapy in Parkinson's disease with N-0923 TDS: a double-blind, placebo-controlled study.

N-0923 is a non-ergot, dopaminergic D(2) agonist designed to be transdermally available. It has anti-parkinsonian effects when infused intravenously. An adhesive matrix patch was developed to deliver N-0923 transdermally (N-0923 TDS). In this phase II trial, we evaluated the effectiveness of various doses of N-0923 TDS at replacing levodopa. Eighty-five Parkinson's disease (PD) patients were randomized to placebo or one of four doses of N-0923 TDS for 21 days. Change in daily levodopa dose was the primary efficacy measure. Significantly greater reductions in levodopa dose were achieved as compared to placebo for the two highest doses of N-0923 TDS. Patients treated with 33.5 mg and 67 mg N-0923 TDS decreased levodopa use by 26% and 28%, vs. 7% for placebo. N-0923 TDS was safe and well tolerated.

Intravenous amantadine improves levadopa-induced dyskinesias: an acute double-blind placebo-controlled study.

Experimental evidence suggests that glutamatergic receptor blockade may improve the motor response complications associated with long-term levodopa treatment in Parkinson's disease (PD) patients. Our objective was to evaluate the acute effect of amantadine, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, on levodopa-induced dyskinesias, and to gain further insights into the antidyskinetic mechanism of this drug. Nine PD patients with motor fluctuations and severely disabling peak of dose dyskinesias received their first morning levodopa dose, followed by a 2-hour intravenous amantadine (200 mg) or placebo infusion, on two different days. Parkinsonian symptoms and dyskinesias were assessed every 15 minutes during the infusion and for 3 hours thereafter, while patients were taking their usual oral antiparkinsonian therapy, by means of Unified Parkinson's Disease Rating Scale (UPDRS, motor examination), tapping test, and a modified Abnormal Involuntary Movement Scale (AIMS). Intravenous amantadine acutely improved levodopa-induced dyskinesias by 50%without any loss of the anti-parkinsonian benefit from levodopa. This study confirms the antidyskinetic effect of amantadine and strengthens the rationale for using antiglutamatergic drugs in the treatment of parkinsonian motor fluctuations.

Cardiac sympathetic denervation in Parkinson disease.

BACKGROUND: In Parkinson disease, orthostatic hypotension can result from L-dopa treatment or from sympathetic neurocirculatory failure. The latter is detected by abnormal blood pressure responses to the Valsalva maneuver and can be associated with loss of functional cardiac sympathetic nerve terminals. OBJECTIVE: To determine the frequency of cardiac sympathetic denervation in Parkinson disease, with or without sympathetic neurocirculatory failure, and its association with disease duration, severity, and L-dopa treatment DESIGN: Intergroup comparisons in resting patients. SETTING: National Institutes of Health Clinical Center, Bethesda, Maryland. PATIENTS: 29 patients with Parkinson disease (9 with sympathetic neurocirculatory failure, 10 who had stopped receiving or had never been treated with L-dopa), 24 patients with multiple-system atrophy (17 with sympathetic neurocirculatory failure, 8 receiving L-dopa), 7 patients with pure autonomic failure, 33 controls with episodic or persistent orthostatic intolerance without sympathetic neurocirculatory failure, and 19 normal volunteers. MEASUREMENTS: Beat-to-beat blood pressure responses to the Valsalva maneuver, interventricular septal 6-[18F]fluorodopamine-derived radioactivity, cardiac extraction fraction of [3H]norepinephrine, appearance rate of norepinephrine in coronary sinus plasma (cardiac norepinephrine spillover) and venous-arterial differences in levels of dihydroxyphenylglycol (DHPG) and endogenous L-dopa. RESULTS: Of the 29 patients with Parkinson disease, 9 with sympathetic neurocirculatory failure and 11 without had low septal 6-[18F]fluorodopamine-derived radioactivity (2861 +/- 453 Bq/mL per MBq/kg and 5217 +/- 525 Bq/mL per MBq/kg, respectively). All 6 patients with Parkinson disease and decreased 6-[18F]fluorodopamine-derived radioactivity who underwent right-heart catheterization had a decreased cardiac extraction fraction of [3H]norepinephrine and virtually no cardiac norepinephrine spillover or venous-arterial increments in plasma levels of DHPG and L-dopa. Sympathetic neurocirculatory failure and decreased 6-[18F]fluorodopamine-derived radioactivity were unrelated to disease duration, disease severity, or L-dopa treatment CONCLUSIONS: Many patients with Parkinson disease-including all those with sympathetic neurocirculatory failure-have evidence of cardiac sympathetic denervation. This suggests that loss of catecholamine innervation in Parkinson disease occurs in the nigrostriatal system in the brain and in the sympathetic nervous system in the heart

Effects of bilateral posteroventral pallidotomy on gait of subjects with Parkinson disease.

BACKGROUND: Most studies documenting the effect of pallidotomy on parkinsonian gait have reported unilateral surgery and used qualitative scales or timed tests that only provide measures of walking speed. OBJECTIVE: To document the effect of bilateral posteroventral pallidotomy on the walking patterns of patients with Parkinson disease (PD). DESIGN: Case series of gait evaluations performed 1 month before and 1 month after surgery, with antiparkinson medication withheld for 8 hours overnight. SETTING: Movement analysis laboratory of a clinical research center. PATIENTS: Consecutive sample of 8 men and 3 women with a diagnosis of PD scheduled for bilateral pallidotomy. INTERVENTION: Bilateral posteroventral pallidotomy. MAIN OUTCOME MEASURES: A 3-dimensional motion-capture system allowed calculation of temporal and spatial measurements and joint angular displacements of the lower extremities and trunk during gait. RESULTS: Pallidotomy significantly increased average walking speed from 0.214 statures/s preoperatively to 0.440 statures/s postoperatively (where stature indicates body height) (P = .03). A faster postoperative walking speed was achieved almost exclusively by increasing average stride length from 0.24 to 0.47 statures (P = .03) rather than changing average gait cycle time (1.32 to 1.37 seconds; P = .08). A forward stepwise multiple regression analysis (P<.001) revealed that 96% of the change in stride length postoperatively could be explained by the combination of changes in foot-floor angle, knee, and hip excursion during gait. CONCLUSIONS: Bilateral posteroventral pallidotomy was associated with a 2-fold increase in walking speed. Previous studies have demonstrated that walking speed is an important indicator of locomotor performance and level of disability in patients with PD, so the increase in postoperative walking speed likely provided a functional benefit.

Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study.

BACKGROUND: In a recent acute study, amantadine was found to have antidyskinetic effect against levodopa-induced motor complications in patients with Parkinson disease. The longevity of this effect was not addressed but is of interest in light of the controversy in the literature regarding the duration of amantadine's well-established antiparkinsonian action. OBJECTIVE: To determine the duration of the antidyskinetic effect of amantadine in advanced Parkinson disease. DESIGN: One year after completion of an acute, double-blind, placebo-controlled, crossover study, patients returned for re-evaluation of motor symptoms and dyskinesias using a nonrandomized, double-blind, placebo-controlled follow-up paradigm. SETTING: National Institutes of Health Clinical Center. PATIENTS: Seventeen of the original 18 patients with advanced Parkinson disease complicated by dyskinesias and motor fluctuations participated in this study; 1 was lost to follow-up. Thirteen of the 17 individuals had remained on amantadine therapy for the entire year. INTERVENTIONS: Ten days prior to the follow-up assessment, amantadine was replaced with identical capsules containing either amantadine or placebo. MAIN OUTCOME MEASURES: Parkinsonian symptoms and dyskinesia severity were scored using standard rating scales, while subjects received steady-state intravenous levodopa infusions at the same rate as 1 year earlier. RESULTS: One year after initiation of amantadine cotherapy, its antidyskinetic effect was similar in magnitude (56% reduction in dyskinesia compared with 60% 1 year earlier). Motor complications occurring with the patients' regular oral levodopa regimen also remained improved according to the Unified Parkinson's Disease Rating Scale (UPDRS-IV). CONCLUSION: The beneficial effects of amantadine on motor response complications are maintained for at least 1 year after treatment initiation.

Pallidal activity during dystonia: somatosensory reorganisation and changes with severity.

A woman with progressive, medically intractable right upper limb dystonia underwent a pallidotomy with only transient improvement. During the procedure her dystonia became more severe as she repeatedly made a fist to command in order to provoke dystonia transiently (movement provoked dystonia). Comparisons within cells in the internal segment of the globus pallidus (Gpi) disclosed that the firing rate was the same at rest, with making a fist, and during movement provoked dystonia. However, the firing rate compared between cells decreased significantly throughout the procedure as the patient made a fist repeatedly. During the second half of the procedure the firing rate of cells in the Gpi was similar to that in hemiballismus. The proportion of cells in the GPi which responded to sensory stimulation was significantly higher in dystonia (53%) than in hemiballismus (13%). These results suggest that pallidal activity can correlate inversely with the severity of dystonia, perhaps due to activity dependent changes in neuronal function resulting from repeated voluntary movement.

Pallidotomy for hemiballismus: efficacy and characteristics of neuronal activity.

A patient with unremitting, medically intractable hemiballismus underwent a pallidotomy that abolished his involuntary movements. Firing rates of cells in the internal segment of the globus pallidus (GPi) recorded during this procedure were significantly lower than those observed during pallidotomy for Parkinson's disease, either "on" or "off" medication. Firing patterns in hemiballismus were characterized by low-frequency modulation of the firing rate. These results are consistent with the hyperkinetic model, which suggests that hemiballismus results from decreased inhibition of the pallidal relay nucleus of the thalamus by the GPi. The efficacy of surgery in the case of hemiballismus demonstrates that pallidotomy can be an effective treatment for this condition and suggests that patterned neuronal activity in the GPi is important in the mechanism of hyperkinetic disorders.

Effects of supra-threshold levodopa doses on dyskinesias in advanced Parkinson's disease.

The levodopa (LD) dose-antiparkinsonian response relationship becomes progressively steeper with advancing Parkinson's disease (PD). To establish the dose-response profile for the dyskinesiogenic effect of LD, we administered intravenous LD over a wide dose range to 25 patients with advanced PD. As expected in these patients with nonexistent therapeutic windows, the threshold doses (TD) for both motor effects were similar. Just around the TD, the relationship between LD dose and the magnitude of antiparkinsonian and dyskinesiogenic responses inclined steeply, reaching a plateau above 1.5 x TD. Response duration, however, continued to increase. The findings suggest that attempts to ameliorate dyskinesias in advanced PD patients by giving smaller, more frequent LD doses may be counter-productive due to shorter motor responses, more "off" time, and dose failures, while some may, in fact, benefit from higher LD doses to assure a full response and prolong its duration.

Modulation of levodopa-induced motor response complications by NMDA antagonists in Parkinson's disease.

The complex dopamine-glutamate interactions within the basal ganglia are disrupted by chronic nigrostriatal denervation and standard replacement therapy with levodopa. Acute N-methyl-D-aspartate (NMDA) receptor blockade is able to overcome the changes in dopamine D1- and D2-dependent responses and the progressive shortening in the duration of response induced by long-term exposure to levodopa in 6-hydroxydopamine-lesioned rats. Preliminary results further suggest that NMDA receptor blockade can counteract levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned non-human primates and parkinsonian patients without substantially altering the motor benefit derived from levodopa. These results appear to be in accordance with our 2-deoxyglucose studies in 6-hydroxydopamine-lesioned rats showing that NMDA receptor blockade can attenuate many of the changes in synaptic activity induced by levodopa, particularly in the striatopallidal complex. Taken together, our observations suggest that abnormal glutamate transmission or dysregulation of NMDA receptor-mediated mechanisms contribute to levodopa-induced motor response complications. Additional preclinical and clinical experiments need to be completed with well tolerated glutamate antagonists to determine the full potential of glutamate receptor blockade as a long-term strategy against levodopa-related motor response complications in Parkinson's disease.

Cortical and subcortical chemical pathology in Alzheimer's disease as assessed by multislice proton magnetic resonance spectroscopic imaging.

BACKGROUND: Multislide proton magnetic resonance spectroscopic imaging (1H-MRSI) permits the simultaneous acquisition of N-acetylaspartate (NA), choline (Cho), creatine/phosphocreatine (Cre), and lactate (Lac) signal intensities from four 15-mm slices divided into 0.84-ml single-volume elements. NA is inferred to be a neuron-specific molecule, whereas Cho mainly reflects glycerophosphocholine and phosphocholine, compounds involved in phospholipid metabolism. OBJECTIVE: To assess whether 1H-MRSI could detect a regional pattern of cortical and subcortical involvement in the brain of Alzheimer's disease (AD) patients. METHODS: 1H-MRSI was performed in 15 patients with probable AD and 15 age-matched healthy controls. Regions of interest (ROIs) were selected from frontal (FC), temporal (TC), parietal (PC), occipital, and insular cortices, subcortical white matter (WM), and thalamus. RESULTS: In AD patients, we found a significant reduction of NA/Cre in the FC, TC, and PC and a significant reduction of Cho/Cre in the WM. CONCLUSIONS: This 1H-MRSI study of AD patients shows a regional pattern of neuronal damage in the associative cortices, as revealed by significant reduction of NA/Cre in the FC, TC, and PC, and regional derangement of phospholipid metabolism, as revealed by significant reduction of Cho/Cre in the WM.

Effect of the putative dopamine D1 agonist and D2 antagonist FCE 23884 on Parkinson's disease.

The ergoline derivative FCE 23,884 acts as a dopamine D1 agonist in untreated parkinsonian animals and as a D2 antagonist in animals whose dopamine system is intact or levodopa treated. To evaluate whether this dual action might benefit patients with Parkinson's disease (PD) who have developed levodopa-induced dyskinesias, the motor effects of FCE 23,884 were examined in seven such individuals using a double-blind, placebo-controlled design. At doses up to the maximum tolerated dose (3.5 +/- 0.5 mg), FCE 23,884 monotherapy did not affect parkinsonian severity. On the other hand, coadministration of FCE 23,884 with a mildly dyskinetic dose of levodopa, infused intravenously under steady-state conditions, reduced the antiparkinson response by 54 +/- 19% and tended to diminish dyskinesia severity. The results thus fail to suggest any useful role for FCE 23,884 in the symptomatic treatment of PD. Although D2 receptor blockade provided by FCE 23,884 antagonizes both the antiparkinson and dyskinesigenic responses to levodopa, the degree of D1 receptor stimulation appears insufficient to ameliorate parkinsonian symptomatology.

Motor effects of the partial dopamine agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (preclamol) in Parkinson's disease.

The motor effects of the partial dopamine agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3-PPP, preclamol] were evaluated in nine patients with Parkinson's disease using a double-blind, placebo-controlled design. (-)-3-PPP monotherapy had an antiparkinsonian effect in five of nine patients at a mean dose of 37 +/- 10 mg intramuscularly. The co-administration of (-)-3-PPP and a mildly dyskinetic dose of levodopa, infused intravenously at steady-state, resulted in complete suppression of dyskinesias and reemergence of parkinsonian signs in two of seven patients. These dopamine antagonist effects of (-)-3-PPP occurred at relatively low (2.5 and 5 mg) doses. Our results suggest that partial dopamine agonists can exert agonist or antagonist activity in parkinsonian patients depending on concurrent dopaminergic tone. Although this dual action of (-)-3-PPP and other partial agonists could be therapeutically important on theoretical grounds, the small number of patients manifesting a clinically significant response and the frequently inconsistent effects could indicate that this class of agents may have relatively limited clinical utility.

Fluctuations in plasma levodopa and motor responses with liquid and tablet levodopa/carbidopa.

To evaluate the ability of orally administered liquid levodopa/carbidopa (LD/CD) to stabilize plasma levodopa levels and reduce motor response fluctuations in Parkinson's disease, five patients received LD/CD hourly, as standard tablets or as an aqueous solution on two separate days in a double-blind, placebo-controlled, cross-over design. Except for a slightly earlier peak plasma levodopa level, no significant advantage of the liquid formulation over tablet therapy was found. However, liquid LD/CD could be helpful in quickly resolving "off" states and by facilitating small dose adjustments that are not possible with tablets.

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 Parkinson's 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.

Topographic mapping of human motor cortex with transcranial magnetic stimulation: Homunculus revisited.

The purpose of this study was to non-invasively evaluate the homuncular organization of the motor cortex in man. We used transcranial magnetic stimulation to induce motor evoked potentials (MEP's) in Abductor Pollicis Brevis (APB) and Biceps Brachii (BB) muscles of 10 healthy volunteers. The practicality and accuracy of magnetic stimulation to scalp sites one cm apart was increased by the application to the scalp of a flexible nylon grid with grid size of 1x1 cm. Responsive scalp sites collectively contributed to distinct but overlapping muscle representational areas for the two muscles. The topography of these motor maps along and slightly anterior to the central fissure corresponds to the homuncular configuration as described by Penfield and Boldrey in 1937.