Parkinsonian Disability Research Articles

Effect of the mGlu2 positive allosteric modulator CBiPES on dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset.

Advanced Parkinson's disease (PD) is often complicated by the occurrence of dyskinesia, motor fluctuations and psychosis. To this day, few treatment options are available for each of these phenomena, and they are at times not effective or elicit adverse events, leaving some patients short of therapeutic options. We have recently shown that positive allosteric modulation of metabotropic 2 (mGlu2) receptors with the prototypical positive allosteric modulator (PAM) LY-487,379 is efficacious at alleviating both dyskinesia and psychosis-like behaviours (PLBs), while simultaneously enhancing the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we assessed the effects of CBiPES, a mGlu2 PAM derived from LY-487,379, but with improved pharmacokinetic properties. Six MPTP-lesioned marmosets with reproducible dyskinesia and PLBs were administered L-DOPA in combination with vehicle or CBiPES (0.1, 1 and 10mg/kg), after which their behaviour was rated. CBiPES 10mg/kg reduced global dyskinesia by 60% (P < 0.0001), while peak dose dyskinesia was reduced by 66% (P < 0.001), compared to L-DOPA/vehicle. CBiPES 10mg/kg also diminished global PLBs by 56% (P < 0.0001), while peak dose PLBs were reduced by 64% (P < 0.001), compared to L-DOPA/vehicle. Lastly, CBiPES enhanced the anti-parkinsonian action of L-DOPA, by reducing global parkinsonian disability by 43% (P < 0.01), compared to L-DOPA/vehicle. Our results provide further evidence that mGlu2 positive allosteric modulation may be an approach that could be efficacious for the treatment of dyskinesia, psychosis and motor fluctuations in PD.

Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease

There is a critical need for careful and independent validation of reported symptomatic efficacy and dopaminergic biomarker changes induced by nilotinib in Parkinson disease (PD). To assess safety and tolerability of nilotinib in participants with moderately advanced PD. Secondary and exploratory objectives were to assess its affect on PD disability, pharmacokinetics, cerebrospinal fluid (CSF) penetration, and biomarkers. This was a 6-month, multicenter, randomized parallel-group, double-blind, placebo-controlled trial. Recruitment was from November 20, 2017, to December 28, 2018, and follow-up ended on September 9, 2019. The study was conducted at 25 US sites. The study approached 173 patients, of whom 48 declined, 125 were screened, and 76 who received a stable regimen of PD medications were enrolled (39% screen failure). Participants were randomized 1:1:1 to placebo, 150-mg nilotinib, or 300-mg nilotinib once daily orally for 6 months, followed by 2-month off-drug evaluation. The primary outcomes were safety and tolerability. The tolerability end point was defined as the ability to complete the study while receiving the assigned dose. An active arm was considered tolerable if the percentage of participants meeting the tolerability end point for that group was not significantly lower than the percentage observed in the placebo group. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinson's Disease Rating Scale [MDS-UPDRS], Part II OFF/ON). Exploratory outcomes included serum and CSF pharmacokinetic profile, and CSF dopaminergic biomarkers. At baseline, mean (SD) participants' age was 64.6 (7.5) years, 52 were male (68%), mean (SD) disease duration was 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score was 66.4 (19.3), ON score was 48.4 (16.2), and Montreal Cognitive Assessment score was 27.1 (2.2). The number of participants who completed the study receiving the assigned dose were 21 (84%), 19 (76%), and 20 (77%) in the placebo, 150-mg, and 300-mg arms, respectively. Both active doses had acceptable safety profile. The most common reasons for drug suspension were asymptomatic, dose-dependent elevations of amylase, and/or lipase. Nilotinib, 150 mg and 300 mg, exhibited worse MDS-UPDRS-3 ON scores compared with placebo, achieving significance for nilotinib, 300 mg, at month 1 (P < .01). There was no difference in the change of MDS-UPDRS-3 OFF from baseline to 6 months between groups (P = .17). Cerebrospinal fluid/serum ratio of nilotinib concentration was 0.2% to 0.3%. There was no evidence of treatment-related alteration of dopamine metabolites in the CSF. While we demonstrated acceptable safety and tolerability of nilotinib in our cohort, the low CSF exposure and lack of biomarkers effect combined with the efficacy data trending in the negative direction indicate that nilotinib should not be further tested in PD. ClinicalTrials.gov Identifier: NCT03205488.

Monoamine oxidase A inhibition with moclobemide enhances the anti-parkinsonian effect of L-DOPA in the MPTP-lesioned marmoset.

Whereas monoamine oxidase (MAO) type B inhibitors are used as adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in the treatment of Parkinson's disease (PD), the enzyme MAO type A (MAO-A) also participates in the metabolism of dopamine in the human and primate striatum. Here, we sought to assess the effect of the selective reversible MAO-A inhibitor moclobemide on L-DOPA anti-parkinsonian in the gold standard animal model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We also assessed the effect of moclobemide on L-DOPA-induced dyskinesia and psychosis-like behaviours (PLBs). Experiments were performed in six MPTP-lesioned marmosets chronically treated with L-DOPA and exhibiting stable dyskinesia and PLBs upon each administration. In a randomised within-subject design, animals were administered a therapeutic dose of L-DOPA in combination with moclobemide (0.1, 1 and 10mg/kg) or its vehicle, after which the severity of parkinsonism, dyskinesia, and PLBs was rated by an experienced blinded rater. Moclobemide significantly reduced the global parkinsonian disability (- 36% with 0.1mg/kg, P < 0.05; - 38% with 1mg/kg, P < 0.01; - 47% with 10mg/kg, P < 0.01), when compared with its vehicle. This reduction of parkinsonism was not accompanied by an exacerbation of dyskinesia or PLBs. Reversible MAO-A inhibition with moclobemide appears as an effective way to increase the anti-parkinsonian action of L-DOPA, without negatively affecting dyskinesia or dopaminergic psychosis.

Parkinson's Disease Caregiver Strain in Singapore.

Background: Caregiver strain is recognized globally with Parkinson's disease (PD). Comparatively little is understood about caregiver burden and strain in Asia.Objective: To investigate caregiver strain for families living with PD in Singapore, in light of international data.Methods: Ninety-four caregivers were recruited via people living with idiopathic PD in Singapore. Caregiver strain was assessed using the Zarit Burden Interview (ZBI); health status was assessing using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). PD disability measures were the Unified Parkinson's Disease Rating Scale (UPDRS) and modified Hoehn and Yahr (1967) Scale.Results: Primary caregivers of people living with PD in Singapore were mostly cohabiting spouses, partners or offspring. Around half employed foreign domestic helpers. Mean caregiving duration was 5.9 years with an average of eight hours per day spent in caregiving roles. Most care providers were comparatively healthy. Caregivers reported significant levels of strain which increased with greater level of disability (r = 0.36, n = 94, p < 0.001). Associations were significant between caregiver strain and scores on the UPDRS mentation, behavior, and mood subscales [r = 0.46, n = 94, p < 0.001, 95% CI (0.28, 0.60)]. High scores on the UPDRS activities of daily living subscale were associated with caregiver strain [r = 0.50, n = 94, p < 0.001, CI (0.33, 0.64)].Conclusion: Most caregivers in this Singapore sample reported high levels of strain, despite comparatively good physical function. Caregiver strain in PD spans geopolitical and cultural boundaries and correlates with disease severity. These results support the need for better early recognition, education, and support for caregivers of people living with PD.

Physical Therapy for Freezing of Gait and Gait Impairments in Parkinson Disease: A Systematic Review.

Freezing of gait (FOG) is a major cause of falls and disability in Parkinson disease (PD). As FOG only partially improves in response to dopaminergic medication, physical therapy is an important element of its management. To assess the evidence for the physical interventions for FOG and gait impairments and to establish recommendations for clinical practice. This review follows the guidelines for systematic reviews: the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Systematic search in PubMed, Embase, Physiotherapy Evidence Databases, and CINAHL for randomized controlled trials of PT interventions for FOG in PD patients until April 2018. Twenty randomized controlled trials (RCTs) were reviewed. In 12 RCTs, PT for FOG was assessed, which was the primary outcome measure in nine of these RCTs. In eight RCTs, PT for gait impairment (not targeting specifically FOG) in PD was assessed. The following PT interventions reduce FOG with a good category A recommendation: cueing strategies (P < .05) (visual and auditory); treadmill walking (P < .05); aquatic obstacle training (P < .01); supervised slackline training (P < .05). These interventions can be combined and maintain their efficacy when being applied concurrently: though there is a lack of long-term follow-up studies. The following PT interventions show possible benefit and need further investigations: balance and coordination training; aquatic gait training; sensory (tactile) cues. The treadmill training and auditory and visual cues are effective also for other gait disturbances in PD and improve gait kinematics. Visual and auditory cueing and the treadmill training are effective interventions for FOG and gait impairments in PD patients (evidence level A- according to the European Federation of Neurological Societies). Tactile cues and other specific therapies targeting FOG are probably effective but need further studies.

Barthel Index and modified Rankin Scale: Psychometric properties during medication phases in idiopathic Parkinson disease.

Independence in activities of daily living (ADL) is one of the most important aspects in planning treatment for people with Parkinson disease (PD). The Barthel Index (BI) and modified Rankin Scale (mRS) are commonly used in neurological diseases. This study was conducted to confirm the validity and reliability of the BI and mRS in PD during ON and OFF medication phases. We included 260 individuals with a diagnosis of idiopathic PD. The disability in ADL was measured by the BI, mRS, Parkinson's Disease Questionnaire-39 (PDQ-39), Unified Parkinson Disease Rating Scale-Activities of Daily Living (UPDRS-ADL), and Schwab and England ADL scale (SE). Test-retest, inter-rater reliability, and internal consistency were assessed by the intra-class correlation (ICC) and Cronbach α coefficients. Dimensionality was evaluated by factor analysis. Convergent validity was assessed by the SE, Berg Balance Scale (BBS), PDQ-39 and UPDRS-ADL. For the 260 participants (187 [71.9%] males; mean [SD] age 60.3 [12.3] years), both the BI and mRS achieved an acceptable level of test-retest and inter-rater reliability (ICC=0.77 to 0.91) in ON and OFF medication phases. The Cronbach α for BI was 0.85 and 0.88, respectively. We found 1 and 2 factors for BI in ON and OFF phases, respectively. Investigation of convergent validity showed moderate to high correlation for the BI with the UPDRS-ADL, SE, PDQ-39 (ADL), BBS and mRS scores in ON and OFF phases (ρ=0.51-0.74) and mRS with SE, UPDRS-ADL, PDQ-39 (ADL) and BBS scores (ρ=0.48-0.82). The BI and mRS showed acceptable validity and reliability to measure the degree of disability in patients with PD in daily activities in both ON and OFF medication phases.

Low Back Pain--Related Disability in Parkinson Disease: Impact on Functional Mobility, Physical Activity, and Quality of Life.

People with Parkinson disease (PD) frequently experience low back pain (LBP), yet the impact of LBP on functional mobility, physical activity, and quality of life (QOL) has not been described in PD. The objectives of this study were to describe body positions and functional activities associated with LBP and to determine the relationships between LBP-related disability and PD motor sign severity, physical activity level, and QOL. The study was a cross-sectional study. Thirty participants with idiopathic PD (mean age=64.6 years [SD=10.3]; 15 women) completed the Revised Oswestry Disability Questionnaire (RODQ), a measure of LBP-related disability. PD motor symptom severity was measured using the Movement Disorder Society-Unified Parkinson Disease Rating Scale Part III (MDS-UPRDS III). The Physical Activity Scale for the Elderly (PASE) was used to measure self-reported physical activity. The Parkinson Disease Questionnaire-39 (PDQ-39) was used to measure QOL. Descriptive statistics were used to characterize LBP intensity and LBP-related disability. Spearman correlations were used to determine relationships between the RODQ and the MDS-UPDRS III, PASE, and PDQ-39. LBP was reported to be of at least moderate intensity by 63.3% of participants. LBP most frequently impaired standing, sleeping, lifting, and walking. The RODQ was significantly related to the MDS-UPDRS III (r=0.38), PASE (r=-0.37), PDQ-39 summary index (r=0.55), PDQ-39 mobility subdomain (r=0.54), and PDQ-39 bodily pain subdomain (r=0.44). Limitations included a small sample of people with mild to moderate PD severity, the fact that RODQ is a less frequently used measure of LBP-related disability, and the lack of a non-PD control group. LBP affected walking, sleeping, standing, and lifting in this small sample of people with mild to moderate PD. Greater LBP-related disability was associated with greater motor sign severity, lower physical activity level, and lower QOL in people with PD.

Muscle-targeted nutritional support for rehabilitation in patients with parkinsonian syndrome.

We evaluated the efficacy of muscle-targeted nutritional support on the functional outcomes of multidisciplinary intensive rehabilitation treatment (MIRT) in patients with Parkinson disease (PD) or parkinsonism. We conducted a pragmatic, bicentric, randomized (1:1), assessor-blind controlled trial (Protein, Leucine and Vitamin D Enhancing Rehabilitation [PRO-LEADER]; April 2017 to January 2018) in cognitively intact patients with PD or parkinsonism and undergoing a 30-day MIRT. Patients (n = 150) received a standard hospital diet with or without a whey protein-based nutritional supplement enriched with leucine and vitamin D twice daily. The primary efficacy endpoint was the increase in the distance walked during a 6-minute walking test (6MWT). Secondary endpoints were changes in 4-meter walking speed, Timed Up and Go test (TUG), Berg balance scale, handgrip strength, Self-assessment Parkinson's Disease Disability Scale, body weight, and skeletal muscle mass (SMM). Nutritional support resulted in greater increase in the distance walked during 6MWT (mean 69.6 meters [95% confidence interval (CI) 60.7-78.6]) than no support (51.8 meters [95% CI 37.0-66.7]): center-adjusted mean difference, 18.1 meters (95% CI 0.9-35.3) (p = 0.039). Further adjustment for changes in dopaminergic therapy and SMM yielded consistent results: mean difference, 18.0 meters (95% CI 0.7-35.2) (p = 0.043). A meaningful effect was also found for the following secondary endpoints: 4-meter walking speed (p = 0.032), TUG (p = 0.046), SMM, and SMM index (p = 0.029). Six patients discontinued the nutritional therapy due to mild side effects. The consumption of a whey protein-based nutritional formula enriched with leucine and vitamin D with MIRT improved lower extremity function and preserved muscle mass in patients with PD or parkinsonism.Clinicaltrials.gov IDENTIFIER: NCT03124277. This study provides Class I evidence that for patients with parkinsonism undergoing intensive rehabilitation, a whey protein-based nutritional formula enriched with leucine and vitamin D increased distance walked on the 6MWT.

Allosteric and orthosteric activation of mGlu2 receptors to alleviate dyskinesia and psychosis in the parkinsonian marmoset

ObjectiveTo determine the effect of combined allosteric and orthosteric activation of metabotropic glutamate 2 (mGlu2) receptors on L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced psychosis‐like behaviours (PLBs) and dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset model of Parkinson's disease (PD).BackgroundWe have previously demonstrated that activation of mGlu2 receptors via positive allosteric modulation with LY‐487,379 or orthosteric stimulation with LY‐354,740 alleviates PLBs and dyskinesia in experimental parkinsonism. Here, we seek to determine if synergy ensues when mGlu2 positive allosteric modulation and orthosteric stimulation are combined, in the MPTP‐lesioned marmoset.MethodsSix common marmosets were rendered parkinsonian by MPTP injection. Following repeated administration of L‐DOPA/benserazide (L‐DOPA) to elicit stable PLBs and dyskinesia, they were administered acute challenges of LY‐487,379 (1 mg/kg), LY‐354,740 (1 mg/kg), LY‐487,379/LY‐354,740 (each 1 mg/kg) or vehicle, in combination with L‐DOPA, after which the severity of each of PLBs, dyskinesia and parkinsonian disability was rated.ResultsLY‐487,379, LY‐354,740 and LY‐487,379/LY‐354,740 each significantly reduced the severity of the global dyskinesia score, by ≈ 42%, 55% and 64% (each P &lt; 0.001), when compared to L‐DOPA/vehicle. The combination LY‐487,379/LY‐354,740 was significantly more effective than either treatment alone (both P &lt; 0.05). The severity of the global PLB score was also significantly reduced by each of LY‐487,379, LY‐354,740 and LY‐487,379/LY‐354,740, by ≈ 51%, 44% and 56% (each P &lt; 0.001), when compared to L‐DOPA/vehicle. The combination LY‐487,379/LY‐354,740 was significantly more effective than LY‐487,379 (P &lt; 0.01), but not LY‐354,740 (P &gt; 0.05). The benefits on dyskinesia and PLBs were achieved without compromising the therapeutic effect of L‐DOPA on parkinsonism.ConclusionsOur results confirm mGlu2 activation, via both positive allosteric modulation and orthosteric stimulation, is a promising strategy to reduce dyskinesia and psychosis in PD. Moreover, they suggest that the combination of a positive allosteric modulator and an orthosteric agonist may lead to a synergistic effect, thereby providing greater anti‐dyskinetic and anti‐psychotic effects.Support or Funding InformationFonds de Recherche Québec ‐ Santé, Natural Sciences and Engineering Research Council of Canada, Parkinson Canada, Weston Brain Institute, Michael J Fox Foundation for Parkinson's Research, Healthy Brains for Healthy Lives.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Biphenylindanone A, a prototypical mGlu2 positive allosteric modulator, alleviates dyskinesia and psychosis in the parkinsonian marmoset

ObjectiveTo determine the effect of the prototypical and selective metabotropic glutamate 2 (mGlu2) receptor positive allosteric modulator (PAM) biphenylindanone A (BINA) on L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced psychosis‐like behaviours (PLBs) and dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset model of Parkinson's disease (PD).BackgroundPsychosis and dyskinesia undermine the quality of life of as many as 50–95% of patients with advanced PD. Available therapies are few, and they may elicit important side effects. We have recently demonstrated that activation of mGlu2 receptors with another prototypical PAM, LY‐487,379, reduces both PLBs and dyskinesia in the MPTP‐lesioned primate. Here, we seek to determine the effects of PAM BINA on these 2 treatment‐related complications, in the MPTP‐lesioned marmoset.MethodsSix common marmosets (Callithrix jacchus) were rendered parkinsonian by MPTP injection. Following repeated administration of L‐DOPA/benserazide (L‐DOPA) to elicit stable PLBs and dyskinesia, they were administered acute challenges of BINA (0.1, 1 and 10 mg/kg) or vehicle, in combinaison with L‐DOPA after which the severity of PLBs, dyskinesia and parkinsonian disability was rated.ResultsBINA (0.1, 1 and 10 mg/kg) significantly reduced the severity of peak dose PLBs, by ≈33.3%, ≈ 55.6 and ≈ 61.1% (P &lt; 0.05, P &lt; 0.01 and P &lt; 0.01), respectively when compared to L‐DOPA/vehicle. Severity of peak dose dyskinesia was also reduced, by ≈ 28.9%, ≈ 52.3 and ≈57.8% (P &lt; 0.05, P &lt; 0.01 and P &lt; 0.01), respectively, when BINA (0.1, 1 and 10 mg/kg) was added to L‐DOPA, compared to L‐DOPA/vehicle. The anti‐psychotic and anti‐dyskinetic effects of BINA were achieved without interfering with the therapeutic effect of L‐DOPA on parkinsonian disability.ConclusionsBINA is the second mGlu2 PAM that was effective at alleviating PLBs and dyskinesia in the gold‐standard animal model of PD, the parkinsonian primate. The results presented here further add to the increasing data suggesting that mGlu2 positive allosteric modulation may be effective to diminish both PD psychosis and L‐DOPA‐induced dyskinesia.Support or Funding InformationFonds de Recherche Québec ‐ Santé, Parkinson Canada, Natural Sciences and Engineering Research Council of Canada, Weston Brain Institute, Michael J Fox Foundation for Parkinson's Research, Healthy Brains for Healthy Lives.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Dopamine compartmentalization, selective dopaminergic vulnerabilities in Parkinson's disease and therapeutic opportunities.

Progressive depletion of selected dopamine neurons is central to much Parkinson's disease (PD) disability. Although symptomatic treatments can ameliorate the disabilities that this neuronal depletion causes, no current strategy is documented to slow these losses. There is substantial evidence that dopamine in intracytoplasmic/extravesicular neuronal compartments can be toxic. Here, I review evidence that supports roles for dopamine compartmentalization, mediated largely by serial actions of plasma membrane SLC6A3/DAT and vesicular SLC18A2/VMAT2 transporters, in the selective patterns of dopamine neuronal loss found in PD brains. This compartmentalization hypothesis for the dopamine cell type specificity of PD lesions nominates available drugs for amelioration of damage arising from miscompartmentalized dopamine and raises cautions in using other drugs.

Usefulness of a modified questionnaire as a screening tool for swallowing disorders in Parkinson disease: A pilot study.

To determine the correlation between our questionnaire scores and two standard Parkinson's disease (PD) disability scores [Unified Parkinsons' Disease Rating Scale (UPDRS) and Hoehn and Yahr (H and Y)], and to study the correlation between the various subgroups of our dysphagia screening questionnaire. This study was conducted at a movement disorder clinic in a tertiary care hospital in Kochi, Kerala. This was a cross-sectional observational study. A questionnaire was developed comprising 11 items, keeping in mind the most relevant swallowing issues in PD patients. The questions were subdivided into four groups representing the different stages of swallowing. Reliability and validity studies were conducted for the questionnaire. Corresponding UPDRS and H and Y scores were documented on the same day. Mean and standard deviation (SD) values of the scores in each group and the correlation between scores (Pearson correlation coefficient) were done. Responses were obtained from 106 PD patients (67 males, 39 females), with a mean age of 66.9 years (SD, 8.62). Our questionnaire score showed a high coefficient of variation (145%) compared to the UPDRS and H and Y scores. There was also moderate correlation between our questionnaire score and the two standard scores with a significant P value. Finally, the highest mean scores were for questions from group A and the least for questions from group D. The association between worsening motor symptoms and swallowing difficulties has been documented in this study. The oral stage of swallowing remains the most affected in PD, which can be recognized early using our questionnaire.

Levodopa/carbidopa intestinal gel infusion and weight loss in Parkinson's disease.

Weight loss (WL) is a frequent yet under-recognized complication of levodopa/carbidopa intestinal gel (LCIG) infusion, as well as a milestone of Parkinson's disease (PD) disability progression. The complex association between WL, poor nutritional status, motor complications and PD progression, however, remains unclear. Consecutive consenting patients with PD treated with LCIG (n=44; PD duration, 18.3±6.5years) were enrolled in an open-label observational study assessing the extent of WL occurring during LCIG treatment. As secondary aims, we correlated the nutritional status, as detected by the Mini Nutritional Assessment, with the severity of motor symptoms [Movement Disorder Society Unified Parkinson's Disease Rating Scale part III], motor complications (Unified Parkinson's Disease Rating Scale part IV), activities of daily living (Schwab and England scale), cognitive impairment (Mini Mental State Examination), depression (Beck Depression Inventory), difficulties in feeding (Edinburgh Feeding Evaluation in Dementia Questionnaire) and levodopa equivalent daily dose (LEDD). There was an average WL of 9.9±10.5% (7.6±7.1kg) over an LCIG treatment period of 51.6±28.5months. The extent of WL correlated with the percentage of the waking day spent with dyskinesia (P<0.05). The nutritional status correlated with motor symptom severity (P<0.01), dysphagia (P<0.01) and LEDD (P<0.01). Weight loss may occur in patients with PD undergoing LCIG in correlation with the percentage of the waking day spent with dyskinesia. Regardless of the extent of WL, the nutritional status correlated with higher LEDD, as well as with indices of disease progression, such as motor symptom severity and dysphagia.

Nefazodone reduces dyskinesia, but not psychosis-like behaviours, in the parkinsonian marmoset.

Nefazodone is an anti-depressant that interacts with a wealth of pharmacological targets, including some that may exert anti-dyskinetic and anti-psychotic effects in Parkinson's disease (PD), notably serotonin 1A and 2A receptors. In this study, we sought to determine the effect of nefazodone on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Six common marmosets developed parkinsonism following administration of MPTP, after which they were treated chronically with L-DOPA to induce stable dyskinesia and PLBs. In behavioural experiments, nefazodone (0.01, 0.1 and 1mg/kg) or vehicle was administered in combination with L-DOPA and its effects on dyskinesia, PLBs and parkinsonian disability were assessed. The addition of nefazodone 0.01, 0.1 and 1mg/kg to L-DOPA reduced the severity of peak dose dyskinesia by ≈ 21%, ≈ 39% and ≈ 42% (all P < 0.05), while it did not have any significant effect on PLBs, when compared to L-DOPA/vehicle. Parkinsonian disability was not affected by any dose of nefazodone. Our results suggest that nefazodone may be effective to alleviate L-DOPA-induced dyskinesia in PD, while it may not exert any beneficial effect on dopaminergic psychosis.

The highly selective 5-HT2A antagonist EMD-281,014 reduces dyskinesia and psychosis in the l-DOPA-treated parkinsonian marmoset

Blockade of serotonin 2A (5-HT2A) receptors is regarded as an anti-dyskinetic and anti-psychotic strategy in Parkinson's disease (PD). However, the 5-HT2A antagonists tested so far exhibited affinity for other receptors, which might have played a role in their action. EMD-281,014 is the most selective 5-HT2A antagonist available, with approximately 2,000-fold selectivity over serotonin 2C (5-HT2C) receptors. EMD-281,014 was previously tested in the clinic and has high translational potential. In the present study, we assessed the effect of EMD-281,014 on dyskinesia and psychosis in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. We first determined the pharmacokinetic profile of EMD-281,014 in the marmoset, after which doses leading to clinically-relevant plasma levels (0.01, 0.03 and 0.1 mg/kg) or vehicle were administered to MPTP-lesioned marmosets, in combination with L-3,4-dihydroxyphenylalanine (l-DOPA). The effects of EMD-281,014 on dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were then evaluated. When added to l-DOPA, EMD-281,014 (0.03 and 0.1 mg/kg) reduced peak dose dyskinesia, by 41.8% and 54.5% (P < 0.05 and P < 0.001), when compared to l-DOPA/vehicle. EMD-281,014 (0.03 and 0.1 mg/kg) also significantly reduced the severity of peak dose PLBs, by 42.5% and 45.9% (P < 0.05 and P < 0.001), when compared to vehicle. The anti-dyskinetic and anti-psychotic effects of EMD-281,014 were achieved without interfering with l-DOPA anti-parkinsonian action. Our results suggest that highly-selective 5-HT2A receptor blockade with EMD-281,014 is an effective way to alleviate both dyskinesia and psychosis in PD, without adversely affecting parkinsonian disability.

Predictors of Disability in Parkinson Disease: Motor vs. Cognitive Impairment Using MMSE vs. MoCA (P2.054)

Predictors of Disability in Parkinson Disease: Motor vs. Cognitive Impairment Using MMSE vs. MoCA (P2.054)

The feasibility and positive effects of a customised videogame rehabilitation programme for freezing of gait and falls in Parkinson\u2019s disease patients: a pilot study

BackgroundFreezing of gait and falls represent a major burden in patients with advanced forms of Parkinson’s disease (PD). These axial motor signs are not fully alleviated by drug treatment or deep-brain stimulation. Recently, virtual reality has emerged as a rehabilitation option for these patients. In this pilot study, we aim to determine the feasibility and acceptability of rehabilitation with a customised videogame to treat gait and balance disorders in PD patients, and assess its effects on these disabling motor signs.MethodsWe developed a customised videogame displayed on a screen using the Kinect system. To play, the patient had to perform large amplitude and fast movements of all four limbs, pelvis and trunk, in response to visual and auditory cueing, to displace an avatar to collect coins and avoid obstacles to gain points. We tested ten patients with advanced forms of PD (median disease duration = 16.5 years) suffering from freezing of gait and/or falls (Hoehn&Yahr score ≥ 3) resistant to antiparkinsonian treatment and deep brain stimulation. Patients performed 18 training sessions during a 6–9 week period. We measured the feasibility and acceptability of our rehabilitation programme and its effects on parkinsonian disability, gait and balance disorders (with clinical scales and kinematics recordings), positive and negative affects, and quality of life, after the 9th and 18th training sessions and 3 months later.ResultsAll patients completed the 18 training sessions with high feasibility, acceptability and satisfaction scores. After training, the freezing-of-gait questionnaire, gait-and-balance scale and axial score significantly decreased by 39, 38 and 41%, respectively, and the activity-balance confidence scale increased by 35%. Kinematic gait parameters also significantly improved with increased step length and gait velocity and decreased double-stance time. Three months after the final session, no significant change persisted except decreased axial score and increased step length and velocity.ConclusionsThis study suggests that rehabilitation with a customised videogame to treat gait and balance disorders is feasible, well accepted, and effective in parkinsonian patients. These data serve as preliminary evidence for further larger and controlled studies to propose this customised videogame rehabilitation programme at home.Trial registrationClinicalTrials.gov NCT02469350.

Anti-Parkinsonian and anti-dyskinetic profiles of two novel potent and selective nociceptin/orphanin FQ receptor agonists.

We previously showed that nociceptin/orphanin FQ opioid peptide (NOP) receptor agonists attenuate the expression of levodopa-induced dyskinesia in animal models of Parkinson's disease. We now investigate the efficacy of two novel, potent and chemically distinct NOP receptor agonists, AT-390 and AT-403, to improve Parkinsonian disabilities and attenuate dyskinesia development and expression. Binding affinity and functional efficacy of AT-390 and AT-403 at the opioid receptors were determined in radioligand displacement assays and in GTPγS binding assays respectively, conducted in CHO cells. Their anti-Parkinsonian activity was evaluated in 6-hydroxydopamine hemi-lesioned rats whereas the anti-dyskinetic properties were assessed in 6-hydroxydopamine hemi-lesioned rats chronically treated with levodopa. The ability of AT-403 to inhibit the D1 receptor-induced phosphorylation of striatal ERK was investigated. AT-390 and AT-403 selectively improved akinesia at low doses and disrupted global motor activity at higher doses. AT-403 palliated dyskinesia expression without causing sedation in a narrow therapeutic window, whereas AT-390 delayed the appearance of abnormal involuntary movements and increased their duration at doses causing sedation. AT-403 did not prevent the priming to levodopa, although it significantly inhibited dyskinesia on the first day of administration. AT-403 reduced the ERK phosphorylation induced by SKF38393 in vitro and by levodopa in vivo. NOP receptor stimulation can provide significant albeit mild anti-dyskinetic effect at doses not causing sedation. The therapeutic window, however, varies across compounds. AT-403 could be a potent and selective tool to investigate the role of NOP receptors in vivo.

Therapeutic Strategy of Targeting Astrocytes for Neuroprotection in Parkinson's Disease.

Parkinson's disease (PD) is one of common neurodegenerative diseases, which shows motor symptoms including tremor, bradykinesia, rigidity and postural instability. It also involves non-motor symptoms such as cognitive impairment, mental manifestation, autonomic disorder and sensory disturbance. Although treatments to improve the motor disability in PD are being assessed at present, the main challenge remains that is the development of neuroprotective or disease-modifying treatments. Therefore, it is desirable to find approaches that can inhibit the progression of dopaminergic neurodegeneration. Astrocytes are known to play an important role in the maintenance of the neuronal environment and exert neuroprotective effects. Additionally, astrocyte dysfunction increases the susceptibility of neurons to cytotoxicity. We have demonstrated neuroprotective approaches in parkinsonian models in various studies targeting astrocytes. In this article, we summarize the neuroprotective function of astrocytes in the brain, involvement of astrocyte dysfunction in neurodegeneration, and experimental approaches to dopaminergic neuroprotection. We review findings reported in several papers including our own studies. We also address target molecules and pivotal pathways in astrocytes for dopaminergic neuroprotection. The review discusses new promising therapeutic strategies to prevent dopaminergic neurodegeneration in PD.

Trazodone alleviates both dyskinesia and psychosis in the parkinsonian marmoset model of Parkinson's disease.

Trazodone is a clinically available anti-depressant that exhibits affinity for serotonin 1A and 2A receptors, as well as for alpha-adrenoceptors, suggesting that it may be useful to treat L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis that are encountered in advanced Parkinson's disease (PD). Here, we investigated the anti-dyskinetic and anti-psychotic effects of trazodone in the parkinsonian non-human primate. 6 common marmosets were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Following repeated administration of L-DOPA to induce stable dyskinesia and psychosis-like behaviours (PLBs), trazodone (0.1, 1 and 10mg/kg) or vehicle was administered in combination with L-DOPA and its effects on dyskinesia, PLBs and parkinsonism were determined. The addition of trazodone 10mg/kg to L-DOPA reduced peak dose dyskinesia by≈39% (P<0.01) and peak dose PLBs by≈17% (P<0.01). However, parkinsonian disability was significantly worsened by trazodone 10mg/kg (P<0.05) and duration of anti-parkinsonian action was diminished by≈21% (P<0.05). Our results suggest that trazodone may be effective in alleviating L-DOPA-induced dyskinesia and psychosis in PD, but its deleterious effect on motor function is a concern and may limit its tolerability and usefulness in clinical settings.