Special Issue on new therapeutic approaches to Parkinson disease.

Parkinson's disease (PD) is a common neurodegenerative disorder. Age is the biggest risk factor, with the prevalence rising from 1% in 45-54 year age group to 2-4% in 85 year or older. Population increases have led some to predict that we are facing a 'PD Pandemic' with the prevalence doubling in the next two decades. There is thus an urgent need for effective therapies to reduce disease burden. In this Special Issue of Neuropharmacology invited authors have reviewed current and emerging targets for pharmacological therapy for PD covering the areas of disease modification, i.e. addressing the underlying disease processes, through to symptomatic therapies, whether for motor or non-motor symptoms of the disease. The articles are from leaders in the field and represent preclinical and clinical stages of therapeutic development. The Special Issue highlights that there is ongoing significant activity across all these potential indications and a vast array of targets have been identified and validated to different extents. PD is, and will remain for the foreseeable future, for the neuropharmacologist a significant area of research, in both the preclinical and clinical space.

Two cases of unexpected long-term improvement of Parkinson's disease after subthalamic nucleus deep brain stimulation removal.

Two patients with Parkinson's disease (PD) treated successfully with subthalamic nucleus deep brain stimulation (STN-DBS) for 3-4 years are reported, who demonstrated a persistent improvement following removal of STN-DBS for late infection. Possible hypotheses are discussed--whether a microlesioning effect or a disease-modifying effect of STN-DBS, though neither adequately explain this phenomenon.

Patient perception of dyskinesia in Parkinson's disease.

OBJECTIVE: To evaluate the perception of patients with Parkinson's disease (PD) regarding dyskinesia. DESIGN: Multicentre survey. SETTING: Tertiary referral centres. PATIENTS: Patients with PD participated in a survey: those not on dopaminergic medications (group I), those on dopaminergic medications without dyskinesia (group II) and those on dopaminergic medications with dyskinesia (group III). INTERVENTION: After a short standardised description and explanation of dyskinesia was provided, patients were asked about the nature and source of prior knowledge of dyskinesia. They were then asked about their perceptions of dyskinesia. Patients in group III were also asked about the duration, the severity of dyskinesia and whether their perception of this problem had changed since its appearance. MAIN OUTCOME MEASURES: Level of concern regarding dyskinesia and whether their perception of dyskinesia would have changed their preference of treatment. Results 259 PD patients completed the survey (group I, 52; group II, 102; group III, 105). Patients with dyskinesia were significantly less concerned about dyskinesia than patients without dyskinesia and were more likely to choose dyskinesia over being parkinsonian. Patients who required fewer changes in medications because of dyskinesia were more likely to choose dyskinesia over parkinsonism. CONCLUSION: Patients with PD experiencing dyskinesia are less likely to be concerned about dyskinesia and more likely to prefer dyskinesia over parkinsonian symptoms than patients without dyskinesia.

The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic effects in MPTP-treated macaques.

BACKGROUND: Long-term treatment of Parkinson's disease (PD) with l-DOPA typically leads to development of l-DOPA induced dyskinesia (LID). Amantadine, an NMDA antagonist, attenuates LID, but with limited efficacy and considerable side-effects. NLX-112 (also known as befiradol or F13640), a highly selective and efficacious 5-HT1A receptor agonist, reduced LID when tested in rodent and marmoset models of PD. METHODS: The effects of NLX-112 (0.03, 0.1 and 0.3 mg/kg PO) on established LID evoked by acute challenge with l-DOPA (27.5 ± 3.8 mg/kg PO) were assessed in MPTP-treated cynomolgus macaques. Amantadine (10 mg/kg PO) was tested as a positive control. Plasma exposure of NLX-112 (0.1 mg/kg PO) was determined. RESULTS: NLX-112 significantly and dose-dependently reduced median LID levels by up to 96% during the first hour post-administration (0.3 mg/kg). Moreover, NLX-112 reduced the duration of 'bad on-time' associated with disabling LID by up to 48% (0.3 mg/kg). In contrast, NLX-112 had negligible impact on the anti-parkinsonian benefit of l-DOPA. NLX-112 exposure peaked at ~50 ng/ml at 30 min post-administration but decreased to ~15 ng/ml at 2h. Amantadine reduced by 42% 'bad on-time' associated with l-DOPA, thereby validating the model. CONCLUSION: These data show that, in MPTP-lesioned cynomolgus macaques, NLX-112 exerts robust anti-dyskinetic effects, without reducing the anti-parkinsonian benefit of l-DOPA. These observations complement previous findings and suggest that selective and high efficacy activation of 5-HT1A receptors by NLX-112 may constitute a promising approach to combat LID in PD, providing an alternative for patients in whom amantadine is poorly tolerated or without useful effect.

Alpha1-adrenoceptors mediate dihydroxyphenylalanine-induced activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaques.

The mechanisms underlying actions of dihydroxyphenylalanine (L-DOPA) in Parkinson's disease remain to be fully elucidated. Noradrenaline formed from L-DOPA may stimulate alpha(1)-adrenoceptors. We assessed the involvement of alpha(1)-adrenoceptors in actions of L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaques. In each animal, the minimal dose of L-DOPA required to alleviate parkinsonian symptoms was defined (12.5-25 mg/kg p.o.). The effects of coadministration of the alpha(1)-adrenoceptor antagonist prazosin ([4-(4-amino-6,7-dimethoxy-quinazolin-2-yl) piperazin-1-yl]-(2-furyl)methanone) on motor activity, parkinsonism, and dyskinesia were assessed. Antiparkinsonian benefit was accompanied by mild dyskinesia. L-DOPA also elicited hyperactivity, i.e., activity greater than that seen in normal animals. Coadministration of prazosin (0.16-0.63 mg/kg p.o.) with L-DOPA did not significantly affect either its antiparkinsonian actions or dyskinesia. However, prazosin significantly and dose-dependently attenuated L-DOPA-induced activity, reducing it to a level equivalent to that of normal animals. More specifically, during periods of pronounced L-DOPA-induced activity, prazosin attenuated the total and duration of activity by 80 and 76%, respectively. These actions of prazosin were expressed in the absence of sedation. Although activation of alpha(1)-adrenoceptors plays no major role in the antiparkinsonian and dyskinetic effects of L-DOPA per se, it does contribute to the induction of hyperactivity. alpha(1)-Adrenoceptors may be involved in pathological responses to L-DOPA treatment, including the dopamine dysregulation syndrome.

Distinct electric potentials in soma and neurite membranes.

Structurally similar voltage-dependent ion channels may behave differently in different locations along the surface of a neuron. A possible reason could be that channels experience nonuniform electrical potentials along the plasmalemma. Here, we map the electrical potentials along the membrane of differentiated N1E-115 neuroblastoma cells with a potential-sensitive dye. We find that the intramembrane potential gradient is indeed more positive in the membranes of neurites than in the membranes of somata. This is not attributable to differences in ion conductances or surface charge densities between the membranes of neurites and somata; instead, it can be explained by differences in lipid composition. The spatial variation in intramembrane electrical potential may help account for electrophysiological and functional differences between neurites and somata.

Clinical practice regarding dopamine-agonist use and driving in Parkinson's disease.

BACKGROUND: Current Health Canada instructions for use of the dopamine agonists (DA), pramipexole and ropinirole, state that Parkinson's disease (PD) patients should be told not to drive. The objective was to assess neurologists' actual clinical practice concerning driving advice they give to PD patients starting a DA. METHODS: An online survey was created consisting of 4 items regarding demographics, 5 regarding PD and driving, and 9 regarding DA use and driving. The survey was distributed to 563 neurologists. RESULTS: In total 96 neurologists (17.9%) responded. 4.4% tell patients with PD not to drive, solely because they are taking a DA. Respondents assess the patient's tendency for excessive daytime sleepiness and sleep attacks after starting a DA more frequently than after starting other dopaminergic drugs (p < 0.001). DISCUSSION: A minor proportion of the clinicians responding to our survey advise PD patients not to drive, solely because they use a DA. Such being the case, we propose that current Health Canada guidelines need revision.

Prevention of osteoporosis in glucocorticoid-treated neurology patients.

OBJECTIVES: Iatrogenic, including corticosteroid-induced osteoporosis is preventable with administration of osteoprotective biphosphonates. The best medical practice is published in the National Guidelines: UK Osteoporosis Consensus Group (1998, update 2002). We conducted an audit in prednisolone-treated general neurology patients, to assess compliance to national guidelines, raise awareness of osteoporosis prevention, and improve clinical practice in a tertiary neurology referral centre. METHODS AND RESULTS: Preintervention: Of the 48 cases (21 male) identified twenty-nine (61%) received osteoporosis prophylaxis. Nineteen (40%) were given biphosphonates, while 10 (21%) hormone replacement therapy or calcium and Vitamin D. INTERVENTION: Results were presented to the consultant body. Postintervention: Data were collected prospectively on 48 patients (30 male) in year 2001. Thirty-eight (79%) received prophylaxis: 35 (73%) were started on biphosphonates, while 3 (6%) on calcium and Vitamin D. This process was repeated 2 years later to assess sustainability. Of the 48 patients, 44 (92%) received prophylaxis: 41 (86%) were taking biphosphonates, while 3 (6%) calcium and Vitamin D. CONCLUSION: We present an original and complete audit on osteoporosis prophylaxis in a typical population of neurology patients. Though initial results were similar to previous reports, our audit led to significant improvement in clinical practice. National guidelines could not be followed meticulously, as our centre has no regular access to bone densitometry. Our patient population had other risk factors for osteoporosis apart from steroid use. Therefore, we recommend that neurologists in this setting use osteoporosis prophylaxis for all their patients on long-term corticosteroids.

Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study.

The lateral segment of the globus pallidus (GPl) is thought to be overactive in levodopa-induced dyskinesia in PD. Stimulation of cannabinoid receptors in the GPl reduces gamma-aminobutyric acid (GABA) reuptake and enhances GABA transmission and may thus alleviate dyskinesia. In a randomized, double-blind, placebo-controlled, crossover trial (n = 7), the authors demonstrate that the cannabinoid receptor agonist nabilone significantly reduces levodopa-induced dyskinesia in PD.

5-HT(2C) receptor antagonists enhance the behavioural response to dopamine D(1) receptor agonists in the 6-hydroxydopamine-lesioned rat.

Non-dopaminergic therapies are of potential interest in the treatment of Parkinson's disease given the complications associated with current dopamine-replacement therapies. In this study we demonstrate that SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3, 5-tetrahydropyrrol[2,3-f]indole) (20 mg/kg) enhanced the actions of the dopamine D(1) receptor agonist, SKF 82958 ((+)-6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide) (1 mg/kg), in eliciting locomotion in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease. This action was only seen following prior priming with L-DOPA (L-3, 4-dihydroxyphenylalanine). SB 206553 had no effect on rotational behaviour when given alone. 5-HT(2C) receptor antagonists may have potential as a means of reducing reliance on dopamine replacement in the treatment of Parkinson's disease.

The effect of helical pitch and beam collimation on the lesion contrast and slice profile in helical CT imaging.

A model is presented in this paper to describe how the contrast of a reconstructed object and slice sensitivity profile are affected by (1) the table speed or helical pitch, (2) the x-ray collimations, (3) the size of the object, (4) the alignment between the reconstructed slice and the object, (5) the distance of the object from the axis of rotation, and (6) the helical CT reconstruction algorithm employed. This contrast model is validated by both computer simulations and experiments. With this model, the contrast of a reconstructed object, slice sensitivity profile, and the longitudinal MTF can be accurately predicted. The optimal scan strategy and the point of diminishing returns can be determined prior to scanning. Several conclusions can be drawn from this model. First, overlapping reconstruction significantly improves overall scan contrast sensitivity of helical CT. Second, with a given x-ray collimation, low pitch helical scans provide better longitudinal resolutions. Third, with a given volume coverage rate (i.e., a given table speed), narrow collimation high pitch helical scans provide better longitudinal resolutions than wide collimation low pitch ones and therefore are recommended for high-contrast thin-slice applications. A lesion conspicuity model is also established.

Perceptions of risks of smoking and heavy drinking during pregnancy: 1985 NHIS findings.

As part of the Health Promotion and Disease Prevention Questionnaire administered in the 1985 National Health Interview Survey, nearly 20,000 respondents ages 18-44 answered questions about their awareness of the risks of smoking and heavy drinking during pregnancy. In reference to smoking, interviewers asked about miscarriage, stillbirth, prematurity, and low birth weight; in reference to heavy drinking, they asked about miscarriage, mental retardation, low birth weight, and birth defects, as well as fetal alcohol syndrome. For each of these adverse outcomes, a majority of subjects acknowledged increased risk because of smoking or heavy drinking during pregnancy. The range was 66-80 percent of respondents for the four questions on smoking, with the perceived association to smoking strongest for low birth weight. Approximately 84 percent of respondents associated heavy drinking with increased risk for each of the suggested pregnancy outcomes. Smoking seemed to be perceived to pose a lesser risk to pregnancy than heavy drinking. This relative lack of awareness of the pregnancy risks of smoking was more apparent among respondents with less education and more pronounced among blacks than whites. Women were more likely than men to express some opinion on these pregnancy-related questions and were more cognizant than men of the risks. On this limited survey, Americans ages 18-44 were not very knowledgeable about fetal alcohol syndrome. Among the 55 percent who had heard of fetal alcohol syndrome, fewer than one in four correctly identified it as a set of birth defects when offered three possible definitions. It will be interesting to correlate responses to these "knowledge" questions with NHIS data still forthcoming on reported actual smoking and drinking behavior among women respondents who were recently pregnant.

Future directions in CT technology.

Progress in helical CT acquisition and processing over the last 5 years has lead to new applications and new requirements. Recent progress to meet these requirements is discussed in this article. The potential of future acquisition developments and their potential to further import application are explored.

Juvenile offenders and accurate perception of time.

In the present study, 72 juvenile offenders and 24 high school boys with no criminal history were tested on how accurately they could estimate the passage of 15-, 30-, 60-, and 120 sec. periods of time. Hypotheses predicted significant differences between the accuracy of time estimations by juvenile offenders and high school students across and among all four trials and also between trials of time estimation by 24 violent juvenile offenders and 24 nonviolent juvenile offenders across and among the trials. Analysis indicated that these mostly Hispanic juvenile offenders produced significantly less accurate time estimations than nonoffending high school students, but no significant differences were found between estimates by violent juvenile and nonviolent juvenile offenders. The results are consistent with previous research indicating that deficits in ego functioning may be associated with the presence of maladaptive and antisocial behavior.

Palliative care for advanced Parkinson disease: an interdisciplinary clinic and new scale, the ESAS-PD.

UNLABELLED: Palliative care provides a holistic approach to symptom relief using a multidisciplinary team approach to enhance quality of life throughout the entire course of a particular illness. The care team consists of movement disorders neurologist, a palliative care physician, a wound care nurse, a spiritual counselor and a care coordinator. Palliative care concepts were applied to a group of advanced Parkinson disease (PD) patients in a dedicated Palliative Care Clinic. METHODS: A modified Edmonton Symptom Assessment System Scale for PD (ESAS-PD) was developed and applied to 65 PD patients at their initial consultation and following recommended interventions. Scores were compared to those of metastatic cancer patients reported in the palliative care literature. RESULTS: The ESAS-PD scores significantly improved after the interventions (56 and 40 respectively, p = 0.0001). The most improved items were constipation, dysphagia, anxiety, pain and drowsiness. ESAS-PD scores were not significantly different from metastatic cancer patients' ESAS scores. CONCLUSIONS: ESAS-PD is a quick, effective scale for assessment of late stage PD symptoms. Scores are sensitive to intervention, and therefore have potential clinical utility for physicians and other healthcare providers. Advanced PD patients have a similar degree of symptoms as metastatic cancer patients, respond to treatment in a similar way, and therefore should have access to palliative care services.

Multisensory determinants of orientation perception in Parkinson's disease.

Perception of the relative orientation of the self and objects in the environment requires integration of visual and vestibular sensory information, and an internal representation of the body's orientation. Parkinson's disease (PD) patients are more visually dependent than controls, implicating the basal ganglia in using visual orientation cues. We examined the relative roles of visual and non-visual cues to orientation in PD using two different measures: the subjective visual vertical (SVV) and the perceptual upright (PU). We tested twelve PD patients (nine both on- and off-medication), and thirteen age-matched controls. Visual, vestibular and body cues were manipulated using a polarized visual room presented in various orientations while observers were upright or lying right-side-down. Relative to age-matched controls, patients with PD showed more influence of visual cues for the SVV but were more influenced by the direction of gravity for the PU. Increased SVV visual dependence corresponded with equal decreases of the contributions of body sense and gravity. Increased PU gravitational dependence corresponded mainly with a decreased contribution of body sense. Curiously however, both of these effects were significant only when patients were medicated. Increased SVV visual dependence was highest for PD patients with left-side initial motor symptoms. PD patients when on and off medication were more variable than controls when making judgments. Our results suggest that (i) PD patients are not more visually dependent in general, rather increased visual dependence is task specific and varies with initial onset side, (ii) PD patients may rely more on vestibular information for some perceptual tasks which is reflected in relying less on the internal representation of the body, and (iii) these effects are only present when PD patients are taking dopaminergic medication.