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.

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.

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.

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.

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.

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.

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.

Isolated diaphragmatic tremor: is there a spectrum in "respiratory myoclonus"?

BACKGROUND: Respiratory myoclonus or diaphragmatic flutter is an unusual movement disorder with abnormal diaphragmatic activity, which may be associated with respiratory symptoms. The effects of distracting maneuvers on diaphragmatic activity have not been investigated. METHODS: Two patients with nondisabling abdominal movements of suspected diaphragmatic origin were studied with surface and needle electromyography (EMG). RESULTS: The abdominal movements resulted from isolated, rhythmic diaphragmatic contractions with variable EMG burst duration, suppressibility with breath-holding and distracting maneuvers, and other attributes of volitional control. CONCLUSION: "Respiratory myoclonus" may be a heterogeneous disorder ranging from synchronous movements of the diaphragm and other respiratory muscles associated with respiratory compromise, to diaphragmatic movements under at least some volitional control with no respiratory or functional disability. The latter group could be designated phenomenologically as "isolated diaphragmatic tremor."

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.

A writing device improves writing in primary writing tremor.

Primary writing tremor (PWT) is task-specific and interferes with handwriting. Several reports have shown a beneficial response of this disorder to stereotactic functional neurosurgery. Significant improvement with a writing device was demonstrated with blind rating of handwriting and spiral drawing samples collected before and during its use in nine patients with PWT, suggesting that this therapeutic modality should be tried before considering chronic pharmacotherapy or functional neurosurgery.

Deep brain stimulation of the subthalamic nucleus: effectiveness in advanced Parkinson's disease patients previously reliant on apomorphine.

OBJECTIVES: To assess the efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced Parkinson's disease previously reliant on apomorphine as their main antiparkinsonian medication. METHODS: Seven patients with motor fluctuations despite optimal medical treatment given as predominantly apomorphine infusion (n=6), or intermittent apomorphine injections (n=1) underwent bilateral STN DBS using frameless stereotactic surgery. Standard assessments of parkinsonism and motor fluctuations, using Unified Parkinson's Disease Rating Scale (UPDRS) were performed before and six months after surgery. Assessments were performed both on and off medication, and postoperative with the stimulators switched on and off. RESULTS: Bilateral STN DBS improved motor scores (UPDRS III) by 61% when off medication (p<0.05). Clinical fluctuations (UPDRS IV items 36-39) were reduced by 46.2% (p<0.05). Total daily apomorphine dose was reduced by 68.9% (p<0.05) and apomorphine infusion via a pump was no longer required in four patients. There were no operative complications. Two patients required treatment for hallucinations postoperatively but there was no significant change in mini-mental state examination. CONCLUSIONS: In patients with advanced Parkinson's disease, previously reliant on apomorphine, bilateral STN DBS is an effective treatment to reduce motor fluctuations and enable a reduction in apomorphine use.

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.

Antiparkinsonian action of a delta opioid agonist in rodent and primate models of Parkinson's disease.

The opioid peptides localized in striatal projection neurons are of great relevance to Parkinson's disease, not only as a consequence of their distribution, but also due to the pronounced changes in expression seen in Parkinson's disease. It has long been suspected that increased expression of enkephalin may represent one of the many mechanisms that compensate for dopamine (DA) depletion in Parkinson's disease. Here we demonstrate that a systemically delivered, selective delta opioid agonist (SNC80) has potent antiparkinsonian actions in both rat and primate models of Parkinson's disease. In rats treated with either the D2-preferring DA antagonist haloperidol (1 mg/kg) or the selective D1 antagonist SCH23390 (1 mg/kg), but not a combination of D1 and D2 antagonists, SNC80 (10 mg/kg) completely reversed the catalepsy induced by DA antagonists. In rats rendered immobile by treatment with reserpine, SNC80 dose-dependently reversed akinesia (EC(50) 7.49 mg/kg). These effects were dose-dependently inhibited (IC(50) 1.05 mg/kg) by a selective delta opioid antagonist (naltrindole) and by SCH23390 (1 mg/kg), but not by haloperidol (1 mg/kg). SNC80 also reversed parkinsonian symptoms in the MPTP-treated marmoset. At 10 mg/kg (ip), scores measuring bradykinesia and posture were significantly reduced and motor activity increased to levels comparable with pre-MPTP-treatment scores. Any treatment that serves to increase delta opioid receptor activation may be a useful therapeutic strategy for the treatment of Parkinson's disease, either in the early stages or as an adjunct to dopamine replacement therapy. Furthermore, enhanced enkephalin expression observed in Parkinson's disease may serve to potentiate dopamine acting preferentially at D1 receptors.

Traumatic experiences and the mental health of Senegalese refugees.

The purpose of our study was to conduct a preliminary investigation into the experiences and mental health of Senegalese refugees. Although research has established that refugees are more prone to psychiatric illnesses than the general population, little has been written about West African refugees. Our focus was on adult refugees (18 years of age and older) from the Casamance region of Senegal. A total of 80 participants (39 women, 41 men) were randomly selected from refugee camps in The Gambia. The Harvard Trauma Questionnaire and the Hopkins Symptom Checklist-25 were used to assess levels of traumatization and mental health status. Typical of refugees of war, participants reported suffering a large number of various traumas. High prevalence rates of anxiety, depression, and posttraumatic stress disorder were also found in this group. A substantial mental health problem exists within the Senegalese refugee population that may signify a potential human crisis.

Mu- and delta-opioid receptor antagonists reduce levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease.

Long-term treatment of Parkinson's disease with levodopa is complicated by the emergence of involuntary movements, known as levodopa-induced dyskinesia. It has been hypothesized that increased opioid transmission in striatal output pathways may be responsible for the generation of dyskinesia. In this study, we have investigated the effect of blockade of opioid peptide transmission on levodopa-induced dyskinesia in a primate model of Parkinson's disease-the MPTP-lesioned marmoset. Coadministration of nonselective and mu- or delta-subtype-selective opioid receptor antagonists with levodopa resulted in a significant decrease in dyskinesia. There was no attenuation of the anti-parkinsonian actions of levodopa. These data suggest that specific mu- or delta-opioid receptor antagonists might be applicable clinically in the treatment of levodopa-induced dyskinesia in Parkinson's disease.

Neural mechanisms underlying peak-dose dyskinesia induced by levodopa and apomorphine are distinct: evidence from the effects of the alpha(2) adrenoceptor antagonist idazoxan.

Dyskinesia, secondary to dopamine replacement therapy, is the major complication of currently available therapies for Parkinson's disease. Alpha(2) adrenoceptor antagonists, such as idazoxan, can significantly reduce levodopa-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, nonhuman primate model of Parkinson's disease and in human. This action of adrenoceptor antagonists may involve blockade of the actions of noradrenaline synthesised from levodopa. We hypothesise that, because dopamine receptor agonists, such as apomorphine, cannot be metabolised to produce noradrenaline, activation of adrenoceptors may not be involved in dyskinesia produced by such agents. If this were the case, idazoxan would not be expected to reduce apomorphine-induced dyskinesia. MPTP-lesioned marmosets with stable dyskinesia induced by prolonged levodopa therapy were given an acute challenge with apomorphine (0.3 mg/kg subcutaneously) or levodopa (8.0 mg/kg orally), these doses produced equivalent peak-dose dyskinesia. Idazoxan (2.5 mg/kg p.o.), or vehicle, was then administered with either apomorphine or levodopa. Idazoxan abolished levodopa-induced dyskinesia but did not affect apomorphine-induced dyskinesia (P < 0.05 and P > 0.05, respectively, Wilcoxon matched pairs test). Idazoxan also extended the anti-parkinsonian actions of levodopa but did not affect those of apomorphine. The pharmacological characteristics of the neural mechanisms underlying levodopa-induced dyskinesia and apomorphine-induced dyskinesia in parkinsonism thus appear to be distinct, at least with respect to the involvement of alpha(2) adrenoceptors. Specifically, levodopa, but not apomorphine-induced dyskinesia, involves activation of adrenoceptors. This finding may have major implications for understanding dyskinesia and should be borne in mind when designing clinical studies in which levodopa or dopamine receptor agonist challenges are employed to assess potential anti-dyskinetic properties of drugs.

5-HT2C receptor binding is increased in the substantia nigra pars reticulata in Parkinson's disease.

The involvement of abnormalities in nondopaminergic transmitter systems in Parkinson's disease is noteworthy because of the complications, such as dyskinesia, associated with long-term dopamine replacement therapy. The output regions of the basal ganglia, the substantia nigra pars reticulata, and the medial segment of the globus pallidus are overactive in Parkinson's disease but underactive in dyskinesia. 5-HT2C receptors are localized in these regions and are excitatory. A 5-HT2C receptor binding assay using [3H]-mesulergine and SB 200646A to define nonspecific binding was applied to postmortem tissue from patients with Parkinson's disease and from age-matched control patients. [3H]-mesulergine binding was increased in the substantia nigra pars reticulata by 108% in Parkinson's disease tissue as compared with control tissue. These data suggest abnormalities of 5-HT2C transmission in the basal ganglia of patients with Parkinson's disease.