Randomized, double-blind, placebo-controlled, short-term trial of ropinirole in restless legs syndrome.

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a condition characterized by an urge to move the legs, usually accompanied by lower limb paresthesias. These symptoms worsen at rest, are relieved by activity, and are worse at night. Previous studies have suggested that dopaminergic drugs such as L-dopa and dopamine agonists, as well as benzodiazepines and opioids, can treat RLS successfully. The purpose of this study was to test the clinical efficacy of ropinirole, a D2/D3 agonist, in the treatment of RLS in a double-blind, short-term, placebo-controlled clinical trial. PATIENTS AND METHODS: After undergoing successful open-label titration and dose adjustments with ropinirole for RLS symptoms over a period of 4 weeks, 22 RLS patients (mean age=50.8; mean duration of symptoms=26.1 years) were randomized to receive either placebo (n=13) or ropinirole (n=9) for 2 additional weeks. Outcome measures included assessment of periodic leg movements in sleep (PLMS) recorded with nocturnal polysomnography and RLS symptoms as assessed with the International Restless Legs Syndrome Study Group (IRLSSG) Rating Scale. Secondary outcomes included sleep macroarchitecture. RESULTS: Results indicated that relative to placebo, ropinirole, at a mean dose of 1.4mg HS significantly decreased PLMS and RLS symptoms. Sleep macroarchitecture did not change. Side effects were typical of all dopamine agonists and were dose related. The majority of patients elected to continue treatment with ropinirole upon study completion. CONCLUSIONS: Ropinirole successfully treated long-standing RLS and can be considered a viable short-term treatment for this condition.

Changes in endocrine function after adrenal medullary transplantation to the central nervous system.

Ten patients were studied before and after autologous adrenal medullary transplantation to the central nervous system for Parkinson's disease to determine if the presence of new catecholamine-producing tissue near the hypothalamus would alter hypothalamic or pituitary function, mineralocorticoid levels, or catecholamine production. No clinically apparent ill effects occurred. Changes in endocrine function were largely short-term and transient: at 7-10 days after surgery, urinary catecholamine levels were significantly increased, PRL levels were significantly elevated despite markedly increased serum dopamine levels, and gonadal steroid levels (estradiol and testosterone) were significantly lower despite unchanged basal and stimulated levels of gonadotropins. Dehydroepiandrosterone sulfate was significantly reduced at 7-10 days after surgery and remained low at 3-6 months. Other changes at 3-6 months after surgery included increased stimulated corticotropin levels and reduced serum aldosterone response to upright posture. The changes at 7-10 days were probably due to stress or unilateral adrenalectomy or both; the changes at 3-6 months were likely due to unilateral adrenalectomy. We conclude that unilateral adrenalectomy and autologous adrenal medullary transplantation to the central nervous system does not produce clinically important changes in endocrine function; however, possible adverse consequences of long-term reduction of dehydroepiandrosterone sulfate levels cannot be excluded.

Complications of gamma knife surgery for Parkinson disease.

BACKGROUND: Many medical centers throughout the world offer radiosurgery with the gamma knife (GK) for pallidotomy and thalamotomy as a safe and effective alternative to radiofrequency ablative surgery and deep brain stimulation for Parkinson disease (PD). The reported incidence of significant complications varies considerably, and the long-term complication rate remains unknown. DESIGN: We describe 8 patients seen during an 8-month period referred for complications of GK surgery for PD. RESULTS: Of the 8 patients, 1 died as a result of complications, including dysphagia and aspiration pneumonia. Other complications included hemiplegia, homonymous visual field deficit, hand weakness, dysarthria, hypophonia, aphasia, arm and face numbness, and pseudobulbar laughter. In all patients, lesions were significantly off target. CONCLUSIONS: The 8 patients with PD seen in referral at our center for complications of GK surgery highlight a spectrum of potential problems associated with this procedure. These include lesion accuracy and size and the delayed development of neurological complications secondary to radiation necrosis. Gamma knife surgery may have a higher complication rate than has been previously appreciated due to delayed onset and underreporting. We believe that the risk-benefit ratio of the GK will require further scrutiny when considering pallidotomy or thalamotomy in patients with PD. Physicians using this technique should carefully follow up patients postoperatively for delayed complications, and fully inform patients of these potential risks.

The role of dopamine agonists in early Parkinson's disease.

Recent evidence from clinical studies suggests an expanded role for dopamine agonists as initial dopaminergic monotherapy in the treatment of Parkinson's disease (PD). The rationale for the use of dopamine agonist monotherapy in early disease is to delay the initiation of levodopa or to decrease the total exposure to levodopa, thereby reducing the motor complications of long-term levodopa therapy. Dopamine agonists, when used alone, rarely promote the development of dyskinesias and motor fluctuations that complicate levodopa treatment. Theoretically, there is potential for a neuroprotective effect by decreasing the oxidative breakdown of dopamine and free radical generation. Because they act on postsynaptic dopamine receptors of the striatum, dopamine agonists act independent of the synthetic dopaminergic enzyme system and are not dependent on degenerating presynaptic neurons in the substantia nigra. This article will review the traditional role of dopamine agonists and will focus on emerging strategies for the treatment of PD, including early monotherapy with dopamine agonists and early combination therapy with dopamine agonists and levodopa.

Progressive supranuclear palsy: neuropathologic and clinical heterogeneity.

To investigate potential heterogeneity in progressive supranuclear palsy (PSP), we examined 13 patients with neuropathologically diagnosed PSP. The clinical diagnosis of PSP was made in eight of these individuals, whereas probable AD was the primary diagnosis in the remaining five. In addition to PSP neuropathology, seven of the 13 patients (54%) showed concomitant pathologic changes of Alzheimer's disease (AD), Parkinson's disease (PD), or both disorders. These observations indicate that AD and PD changes coexist with PSP neuropathology in a substantive proportion of patients and provide further evidence of clinical and neuropathologic heterogeneity in neurodegenerative disorders. Moreover, our results suggest that PSP may be underdiagnosed and deserves more prominence in the differential diagnosis of dementing illness.

Dopaminergic effects on simple and choice reaction time performance in Parkinson's disease.

The present study examined whether premovement central neural processing in Parkinson's disease was related to functional motor disability and plasma L-dopa concentration. Reaction time (RT) performance in simple and choice RT tasks was assessed while plasma L-dopa levels were controlled by continuous IV L-dopa infusion in five parkinsonian patients. Five age-matched controls performed the same RT tasks for comparison. Simple RT for the patients was longer than the normal control RT at all infusion levels (p less than or equal to 0.005). However, choice RT was normal when the patients were "on," but became prolonged as plasma L-dopa levels decreased (p less than or equal to 0.01). The results show that there are abnormalities of premovement central neural processing in Parkinson's disease, and that simple and choice RTs are differentially affected by L-dopa replacement. This suggests that different neural mechanisms may be involved in the processing of these tasks.

Corticobasal degeneration: neuropathologic and clinical heterogeneity.

We investigated clinical and neuropathologic heterogeneity and apolipoprotein E (apoE) genotype in 11 cases of neuropathologically diagnosed corticobasal degeneration (CBD). Although seven of the 11 patients presented with unilateral limb dysfunction, the remaining four patients had less typical presentations including memory loss, behavioral changes, and difficulties with speech or gait. All 11 patients eventually developed extrapyramidal signs as well as cortical features, most commonly apraxia. At autopsy, the brains of seven of the 11 patients exhibited predominant neuronal loss and gliosis of perirolandic cortex; degeneration of more rostral frontal cortex was observed in three of the four patients with atypical clinical presentations. All cases displayed ballooned neurons, tau-positive neuronal and glial inclusions, threads and grains, and nigral degeneration. Six of the 11 cases manifested overlapping neuropathologic features of one or more disorders, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), Parkinson's disease (PD), and hippocampal sclerosis. Interestingly, these six patients all exhibited memory loss early in the course of their illness. The 11 CBD cases exhibited increased frequency (0.32) of the epsilon 4 allele of apoE, relative to control populations; the frequency remained elevated (0.25) even when the three cases with concomitant AD were excluded. Beta-amyloid (A beta) deposition in hippocampus or cortex was present in five of the seven cases with an epsilon 4 genotype. These observations indicate that CBD is a pathologically and clinically heterogeneous disorder with substantial overlap with other neurodegenerative disorders.

Juvenile Parkinson's disease with REM sleep behavior disorder, sleepiness, and daytime REM onset.

We describe an unmedicated patient with juvenile PD with difficulties maintaining wakefulness and the atonia of REM sleep. Laboratory testing showed enhanced muscle activity in REM sleep consistent with a history of dream enactment behavior (i.e., REM sleep behavior disorder) and daytime sleepiness, and REM-sleep onsets on multiple sleep latency testing. The results emphasize the potential role of dopamine and basal ganglia circuits in the modulation of activated behavioral states (e.g., wakefulness and REM sleep).

Electrophysiologic analysis of early Parkinson's disease.

We have been interested in the application of quantitative measures of motor performance as a possible means of early detection of Parkinson's disease. To assess motor function, we have measured movement time (the physiologic correlate of bradykinesia) and reaction time (simple and directional choice) with an upper limb motor task, and tremor with accelerometry and electromyographic recordings. In this report we describe preliminary data from a Parkinson's disease patient group with symptoms of fewer than 2 years' average duration (compared with an age- and gender-matched normal control group) which indicate that precise, quantitative tests of motor function can detect the slight deviations from normal that are present in early Parkinson's disease. It appears that tests of bradykinesia are most sensitive, and detection of rest tremor is most specific. These tests may be applicable in screening individuals who are suspected of having or are "at risk for" Parkinson's disease and other related disorders.

Genome-wide scan for Parkinson's disease: the GenePD Study.

A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine beta-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.

Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2beta-carbo-1'-fluoro-2-propoxy-3beta-(4-chlorophenyl)tr opanes. Ligands for the imaging of dopamine transporters by positron emission tomography.

2beta-(R)-Carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((R)-FIPCT, R-6) and 2beta-(S)-carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((S)-FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2beta-carbo-R-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (R-12) and 2beta-carbo-S-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (S-12) followed by treatment with no carrier-added potassium[(18)F]fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [(3)H]WIN 35428 and [(3)H]citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [(18)F](R)-FIPCT and [(18)F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [(18)F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [(18)F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT for DAT indicate [(18)F](R)-FIPCT and [(18)F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.

Evaluation of carrier detection of Duchenne muscular dystrophy using carbonic anhydrase III and creatine kinase.

Carbonic anhydrase III (CAIII) and creatine kinase (CK) were measured in plasma samples from a series of females at-risk as carriers of Duchenne muscular dystrophy and compared with control groups. Both plasma CAIII and CK levels were raised in a proportion of carriers. Although measurement of CAIII and CK was no more successful in identifying carriers than CK alone, CAIII could fulfill a useful confirmatory role, particularly for cases with a marginally elevated CK or where the sample is poorly preserved. The difference between the CK and CAIII results could indicate biochemical heterogeneity in the expression of Duchenne muscular dystrophy.

Fetal plasma carbonic anhydrase III in prenatal diagnosis of Duchenne muscular dystrophy.

Carbonic anhydrase III (CAIII), a skeletal-muscle-specific enzyme which is elevated in the plasma of Duchenne muscular dystrophy (DMD) patients, was measured by radioimmunoassay in fetal plasma in order to evaluate its application to prenatal diagnosis of DMD. Using fetoscopy, pure fetal blood samples were taken at 17-24 weeks gestation from 25 fetuses at risk for DMD and from 78 control fetuses. Care was taken in the handling and storage of all samples. Normal sons were born in eight cases at risk for DMD. The CAIII levels in the infants were not significantly different from those of the control infants. Pregnancies were terminated in the remaining 17 at-risk cases. The CAIII levels in the fetuses were significantly different (p = 0.0034) from those of the control fetuses, although the distributions overlapped. Based on prior maternal risk, seven affected fetuses were expected in the terminated group; five had CAIII levels at or above the 95th centile of the control range. It is suggested that measurement of CAIII achieves partial discrimination between affected fetuses and their normal at-risk brethren.

Intrastriatal cografts of autologous adrenal medulla and sural nerve in MPTP-induced parkinsonian macaques: behavioral and anatomical assessment.

To examine the effects of autologous sural nerve and adrenal medullary tissue intrastriatal cografts upon voluntary motor performance in parkinsonism, a non-human primate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model was employed to quantitatively assess skilled hand movements. Motor performance was studied in normal, MPTP-induced parkinsonian, and then cografted states. Reaction and movement times were prolonged and variability increased in experimental and control animals in the parkinsonian state. Animals undergoing autologous cografts demonstrated improved motor performance whereas the control animal continued in a chronic, stable parkinsonian state. Intrastriatal cografts of autologous adrenal medullary tissue and sural nerve resulted in good to excellent chromaffin cell survival. The mechanism of the restoration of function in the cografted monkeys remains to be determined.

Polymer-encapsulated PC-12 cells demonstrate high-affinity uptake of dopamine in vitro and 18F-Dopa uptake and metabolism after intracerebral implantation in nonhuman primates.

Intracranial implantation of polymer-encapsulated PC-12 cells has been shown to improve motor behavioral performance in animal models of Parkinson's disease. The purpose of this blinded study was to examine whether such improvement is associated with the active uptake and metabolism of dopamine precursors by intracerebrally implanted polymer-encapsulated PC-12 cells. In an in vitro experiment we demonstrate that 3H-dopamine uptake by PC-12 cells was 10(8) fmol/min x 10(6) cells, and that this uptake can be specifically blocked 88% by the addition of 10nM of nomifensine. In the in vivo experiments, polymer-encapsulated PC-12 cells were implanted in four MPTP-treated monkeys into the left deep parietal white matter (R1) or left striatum (R2-4). A fifth MPTP-treated monkey (R5) served as a control and received left striatal implants of empty capsules. 18-F-Dopa Positron Emission Tomography (PET) imaging was performed on each monkey before and after implantation surgery by blinded investigators. PET images obtained 5-13 wk after implantation demonstrated well delineated focal areas of high 18F-dopa uptake in R1, R2, and R4. The focal area of high 18F-dopa uptake in R1 precisely coregistered on a brain magnetic resonance image to the site of implantation. R3 (in whom the polymer-encapsulated PC-12 cells demonstrated poor cell survival upon explantation) and R5 (empty capsules) failed to demonstrate any area of increased 18F-dopa uptake in their PET images. Histological examination of the host brain revealed no sprouting of dopaminergic nerve terminals around the implantation sites of the polymer-encapsulated PC-12 cells. These results indicate that the previously noted behavioral improvement after intrastriatal implantation of polymer encapsulated PC-12 cells is at least in part due to their highly specific uptake and metabolism of dopamine precursors. Furthermore, these data suggest that polymer-encapsulated PC-12 cells can store, reuptake, and functionally replenish dopamine and therefore, may be an effective treatment for Parkinson's disease.

Effect of adrenal-caudate transplantation on CSF levels of salsolinol sulfate in patients with Parkinson's disease.

The main objective of this study was to determine whether the activation of dopaminergic pathways through adrenal-caudate transplantation stimulates the production of the dopamine cyclic metabolite salsolinol in CSF of patients with Parkinson's disease. Salsolinol sulfate in CSF samples was assayed by radioenzymatic technique. The outcome of this study revealed that the replacement of degenerative nigrostriatal neurons with new dopamine-producing cells by adrenal brain transplants resulted in significant increase in CSF concentration of salsolinol sulfate as compared to preoperative levels.

Stereotaxic intrastriatal implantation of human retinal pigment epithelial (hRPE) cells attached to gelatin microcarriers: a potential new cell therapy for Parkinson's disease.

Human retinal pigment epithelial (hRPE) cells are dopaminergic support cells in the neural retina. Stereotaxic intrastriatal implantation of hRPE cells attached to gelatin microcarriers (Spheramine) in rodent and non-human primate models of Parkinson's disease (PD) produces long term amelioration of motor and behavioral deficits, with histological and PET evidence of cell survival without immunosuppression. Long-term safety in cynomologous monkeys has also been demonstrated. Six H&Y stage III/IV PD patients were enrolled in a one-year, open-label, single center study to evaluate the safety and efficacy of Spheramine (approximately 325,000 cells) implanted in the most affected post-commissural putamen. All patients tolerated the implantation of Spheramine well and demonstrated improvement. At 6, 9, and 12 months post-operatively, the mean UPDRS-Motor score "off", the primary outcome measure, improved 33%, (n = 6), 42% (n = 6), and 48% (n = 3), respectively. No "off-state" dyskinesias have been observed. Based on these preliminary results, Spheramine appears to show promise in treating late stage PD patients.

Disruptive nocturnal behavior in Parkinson's disease and Alzheimer's disease.

Disruptive nocturnal behavior, often referred to as sundowning, is a commonly encountered clinical problem in most forms of dementia. This study compared disruptive nocturnal behavior in patients with Alzheimer's disease (AD) and Parkinson's disease (PD). Questionnaire data were collected from 60 AD and 48 PD caregivers. Respondents were asked to record the typical time of day when any of seven disruptive behaviors were evidenced in their patients, if at all. Two scores were computed: (1) a sundowning score (number of nocturnal disruptive behaviors, range 0-7), and (2) a total score (number of disruptive behaviors without regard to time, range 0-7). Results indicated PD patients were more likely than AD patients to exhibit disruptive nocturnal behavior. The dose, timing, or number of years on antiparkinsonian medication were not related to nocturnal disruptive behavior within the PD patient group. These findings raise the possibility that sundowning in PD patients may be a manifestation of dopaminergic depletion within the basal ganglia or other abnormalities involving the cholinergic, serotoninergic and/or noradrenergic systems in the brainstem.

The role of motor cortex in the pathophysiology of voluntary movement deficits associated with parkinsonism.

The characteristic motor deficits of parkinsonism result from dysfunction of the nigrostriatal dopaminergic system of the basal ganglia. These subcortical deficits must ultimately be expressed at the cortical and spinal motoneuron levels to result in the difficulty with initiation and execution of movements seen in parkinsonism. This article describes the neuronal activity of two motor cortical regions, the primary motor cortex (MI) and supplementary motor area (SMA), which receive the majority of basal ganglia outputs related to movement control through the ventral lateral thalamus. The kinematics and electromyographic characteristics of stimulus-initiated and self-initiated normal and parkinsonian movements are described, and the possible relation of SMA and MI task-related neuronal activity to the parkinsonian movement deficits is reviewed.

Electrophysiologic analysis of early Parkinson's disease.

We have been interested in the application of quantitative measures of motor performance as a possible means of early detection of Parkinson's disease. To assess motor function, we have measured movement time (the physiologic correlate of bradykinesia) and reaction time (simple and directional choice) with an upper limb motor task, and tremor with accelerometry and electromyographic recordings. In this report we describe preliminary data from a Parkinson's disease patient group with symptoms of fewer than 2 years' average duration (compared with an age- and gender-matched normal control group) which indicate that precise, quantitative tests of motor function can detect the slight deviations from normal that are present in early Parkinson's disease. It appears that tests of bradykinesia are most sensitive, and detection of rest tremor is most specific. These tests may be applicable in screening individuals who are suspected of having or are "at risk for" Parkinson's disease and other related disorders.