Chronic Neuroleptic-Induced Parkinsonism Examined With Positron Emission Tomography.

BACKGROUND: Neuroleptic drug-induced parkinsonism (NIP) is a leading cause of parkinsonism, particularly in aging. Based on abnormal dopamine transporter scan results, individuals displaying chronic NIP are often diagnosed with Lewy-body Parkinson's disease (PD), but this assumption needs further substantiation. OBJECTIVE: To quantitate the profile of striatal dopaminergic nerve terminal density in NIP relative to PD. METHODS: We used the positron emission tomography ligand [11 C](+)-dihydrotetrabenazine targeting vesicular monoamine transporter type 2 (VMAT2) binding sites and collected various clinical parameters (motor ratings, olfaction, polysomnography to document rapid eye movement sleep muscle activity, quantitative sensory testing for pain thresholds) possibly predicting binding results in patients older than age 50 living with schizophrenia spectrum disorders under long-term stable antipsychotic drug treatment, with (N = 11) or without (N = 11) chart documention of chronic NIP, and compared them to healthy volunteers (N = 11) and others medicated for PD (N = 12). RESULTS: Striatal VMAT2 binding was dichotomous in the NIP group between those with spared (N = 5) or low (N = 6) PD-like values. Striatal binding reduction in the low VMAT2-NIP group was asymmetric without the gradient of maximal involvement in the posterior putamen typical of PD. Anosmia was the only nonmotor parameter measured matching the abnormal striatal VMAT2 binding status. CONCLUSION: These preliminary observations suggest that striatal VMAT2 binding is abnormal in a fraction of chronic NIP cases and differs in spatial distribution from PD. The possibility of a drug-induced axonopathy and resultant synaptopathy, as well as the evolution of the binding deficit, warrant further longitudinal studies in a large cohort. © 2020 International Parkinson and Movement Disorder Society.

A Focused Update on Tardive Dyskinesia.

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication following chronic exposure to centrally acting dopamine receptor antagonists, mainly of the class of antipsychotics drugs. New generations of antipsychotic drugs reduced its mean prevalence to 20%, but it continues to mar the drug experience and social integration in a significant fraction of patients. The underlying molecular cascade remains elusive, explaining in part why TD management is so often difficult. Protocol variations between experimental laboratories and inter-species differences in the biological response to antipsychotic drugs have added layers of complexity. The traditional dopamine D2 receptor supersensitivity hypothesis was revisited in an experimental nonhuman primate model. Findings in the striatum revealed a strong upregulation of D3, not D2, receptors specific to dyskinetic animals, and indirect evidence suggestive of a link between overactivation of glycogen synthase kinase-3ß signaling and TD. New effective vesicular monoamine transporter type 2 inhibitors alleviating TD have been approved in the USA. They were integrated to an emerging stepwise treatment algorithm for troublesome TD, which also includes consideration for changes in the current antipsychotic drug regimen and recognition of potentially aggravating factors such as anticholinergic co-medications. These advances may benefit TD.

Tardive dyskinesia is associated with altered putamen Akt/GSK-3ß signaling in nonhuman primates.

BACKGROUND: Tardive dyskinesia is a delayed and potentially irreversible motor complication arising from chronic exposure to antipsychotic drugs. Interaction of antipsychotic drugs with G protein-coupled receptors triggers multiple intracellular events. Nevertheless, signaling pathways that might be associated with chronic unwanted effects of antipsychotic drugs remain elusive. In this study, we aimed to better understand kinase signaling associated with the expression of tardive dyskinesia in nonhuman primates. METHODS: We exposed capuchin monkeys to prolonged haloperidol (n = 10) or clozapine (n = 6) treatments. Untreated animals were used as controls (n = 6). Half of haloperidol-treated animals (5) developed mild tardive dyskinesia similar to that found in humans. Using Western blots and immunochemistry, we measured putamen total and phosphorylated protein kinase levels associated with canonical and noncanonical signaling cascades of G protein-coupled receptors. RESULTS: Antipsychotic drugs enhanced pDARPP-32 and pERK1/2, but no difference ws observed in phosphoprotein kinase levels between dyskinetic and nondyskinetic monkeys. On the other hand, comparison of kinase levels between haloperidol-treated dyskinetic and nondyskinetic monkeys indicated that dyskinetic animals had lower GRK6 and ß-arrestin2 levels. Levels of pAkt and pGSK-3ß were also reduced, but only haloperidol-treated monkeys that developed tardive dyskinesia had reduced pGSK-3ß levels, whereas pAkt levels in dyskinetic animals positively correlated with dyskinetic scores. Interestingly, double immunofluorescence labeling showed that putamen dopamine D3 receptor levels were upregulated and that D3/pAkt colocalization was enriched in haloperidol-treated animals displaying tardive dyskinesia. CONCLUSIONS: Our results suggest that upregulation of putamen dopamine D3 receptor and alterations along the noncanonical GRK6/ß-arrestin2/Akt/GSK-3ß molecular cascade are associated with the development of tardive dyskinesia in nonhuman primates. © 2019 International Parkinson and Movement Disorder Society.

Upregulation of dopamine D3, not D2, receptors correlates with tardive dyskinesia in a primate model.

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication arising in patients chronically exposed to centrally active dopamine D2 receptor antagonists, including antipsychotic drugs and metoclopramide. The classical dopamine D2 receptor supersensitivity hypothesis in TD, which stemmed from rodent studies, lacks strong support in humans. To investigate the neurochemical basis of TD, we chronically exposed adult capuchin monkeys to haloperidol (median, 18.5 months; n = 11) or clozapine (median, 6 months; n = 6). Six unmedicated animals were used as controls. Five haloperidol-treated animals developed mild TD movements, and no TD was observed in the clozapine group. Using receptor autoradiography, we measured striatal dopamine D1, D2, and D3 receptor levels. We also examined the D3 receptor/preprotachykinin messenger RNA (mRNA) co-expression, and quantified preproenkephalin mRNA levels, in striatal sections. Unlike clozapine, haloperidol strongly induced dopamine D3 receptor binding sites in the anterior caudate-putamen, particularly in TD animals, and binding levels positively correlated with TD intensity. Interestingly, the D3 receptor upregulation was observed in striatonigral neurons. In contrast, D2 receptor binding was comparable to controls, and dopamine D1 receptor binding was reduced in the anterior putamen. Enkephalin mRNA widely increased in all animals, but to a greater extent in TD-free animals. These results suggest for the first time that upregulated striatal D3 receptors correlate with TD in nonhuman primates, adding new insights to the dopamine receptor supersensitivity hypothesis. The D3 receptor could provide a novel target for drug intervention in human TD.

Clinimetric evaluation of the Simpson-Angus Scale in older adults with schizophrenia.

OBJECTIVE: Parkinsonism (or Parkinson's syndrome [PS]) remains common in patients exposed to antipsychotic drugs. One clinical tool used in its detection and follow-up, the Simpson-Angus Scale (SAS), has been under revision lately. We further examined the discriminative power of the SAS to detect PS and its efficacy as a measure of PS intensity in chronic schizophrenia. METHODS: Fifty-six outpatients between 50 and 75 years of age, under stable antipsychotic drug therapy, provided consent to undergo an evaluation along the SAS and Unified Parkinson's Disease Rating Scale III motor subsection, split according to the presence or absence of PS defined in the UK Parkinson's Disease Society Brain Bank (UKPDSBB) criteria or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. RESULTS: The identification rate for PS was 39.3% based on UKPDSBB criteria applied to the Unified Parkinson's Disease Rating Scale III, compared with 62.5% and 87.5% according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and SAS cutoff value greater than 0.3, respectively. Median SAS scores for PS and PS-free participants were comparable. The SAS yielded high sensitivity (90.9%) but low specificity (17.7%). κ Values generally revealed only slight agreement between the group allocation provided by the SAS and the UKPDSBB criteria. Receiver operating characteristic curve for screening performance of the SAS provided poor prediction of subject status. CONCLUSIONS: The SAS lacks specificity and constitutes an imperfect detection and measurement tool for PS in older adults. Raising the cutoff score would avoid inflation in PS identification. The scale is probably best used as a measure of change relative to baseline score following an intervention, but results should be interpreted with caution.

Impacts of ADHD Symptomatology on the Response to Cognitive-Behavioural Therapy with Gilles de la Tourette Syndrome Patients.

(1) Background: Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. Attention deficit and hyperactivity disorder (ADHD) is a common comorbidity of TS that adds further impairment. Cognitive-behavioural therapy (CBT) has shown efficacy in treating tics, yet its effectiveness in individuals with TS and comorbid ADHD remains unclear. Also, it is suggested that ADHD characteristics like executive dysfunction and inattention could hinder the response to CBT. This study aims to compare the response to CBT for tics and its maintenance six months post-therapy among TS individuals with and without ADHD symptoms. (2) Methods: In this study, 55 TS participants who completed 14-week CBT for tics were split into high (TS+) or low (TS-) ADHD symptomatology groups. Outcomes were evaluated using the Yale Global Tic Severity Scale (YGTSS) regarding global tic severity and motor and vocal tic frequency post-CBT and at a 6-month follow-up. (3) Results: No significant group difference was found regarding improvements post-CBT (n = 55), nor the maintenance six months later (n = 45). (4) Conclusions: ADHD symptoms may not hinder the response to CBT or its maintenance, suggesting that TS individuals with ADHD symptoms may not require specialized CBT interventions.

Haloperidol-induced striatal Nur77 expression in a non-human primate model of tardive dyskinesia.

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication arising in patients chronically exposed to antipsychotic drugs. As several modern (so-called atypical) antipsychotic drugs are common offenders, combined with the widening clinical indications for prescription as well as exposure of vulnerable individuals, TD will remain a significant drug-induced unwanted side effect. In addition, the pathophysiology of TD remains elusive and therapeutics are difficult. Based on rodent experiments, we have previously shown that the transcriptional factor Nur77 (also known as nerve growth factor inducible gene B or Nr4a1) is induced in the striatum following antipsychotic drug exposure as part of a long-term neuroadaptive process. To confirm this, we exposed adult capuchin (Cebus apella) monkeys to prolonged treatments with haloperidol (median 18.5 months, N = 11) or clozapine (median 6 months, N = 6). Six untreated animals were used as controls. Five haloperidol-treated animals developed mild TD movements similar to those found in humans. No TD was observed in the clozapine group. Postmortem analysis of Nur77 expression measured by in situ hybridization revealed a stark contrast between the two drugs, as Nur77 mRNA levels in the caudate-putamen were strongly upregulated in animals exposed to haloperidol but were spared following clozapine treatment. Interestingly, within the haloperidol-treated group, TD-free animals showed higher Nur77 expression in putamen subterritories compared with dyskinetic animals. This suggests that Nur77 expression might be associated with a reduced risk of TD in this experimental model and could provide a novel target for drug intervention.

Relevance of animal models to human tardive dyskinesia.

Tardive dyskinesia remains an elusive and significant clinical entity that can possibly be understood via experimentation with animal models. We conducted a literature review on tardive dyskinesia modeling. Subchronic antipsychotic drug exposure is a standard approach to model tardive dyskinesia in rodents. Vacuous chewing movements constitute the most common pattern of expression of purposeless oral movements and represent an impermanent response, with individual and strain susceptibility differences. Transgenic mice are also used to address the contribution of adaptive and maladaptive signals induced during antipsychotic drug exposure. An emphasis on non-human primate modeling is proposed, and past experimental observations reviewed in various monkey species. Rodent and primate models are complementary, but the non-human primate model appears more convincingly similar to the human condition and better suited to address therapeutic issues against tardive dyskinesia.

Movement chunking during sequence learning is a dopamine-dependant process: a study conducted in Parkinson's disease.

Chunking of single movements into integrated sequences has been described during motor learning, and we have recently demonstrated that this process involves a dopamine-dependant mechanism in animal (Levesque et al. in Exp Brain Res 182:499-508, 2007; Tremblay et al. in Behav Brain Res 198:231-239, 2009). However, there is no such evidence in human. The aim of the present study was to assess this question in Parkinson's disease (PD), a neurological condition known for its dopamine depletion in the striatum. Eleven PD patients were tested under their usual levodopa medication (ON state), and following a 12-h levodopa withdrawal (OFF state). Patients were compared with 12 healthy participants on a motor learning sequencing task, requiring pressing fourteen buttons in the correct order, which was determined by visual stimuli presented on a computer screen. Learning was assessed from three blocks of 20 trials administered successively. Chunks of movements were intrinsically created by each participant during this learning period. Then, the sequence was shuffled according to the participant's own chunks, generating two new sequences, with either preserved or broken chunks. Those new motor sequences had to be performed separately in a fourth and fifth blocks of 20 trials. Results showed that execution time improved in every group during the learning period (from blocks 1 to 3). However, while motor chunking occurred in healthy controls and ON-PD patients, it did not in OFF-PD patients. In the shuffling conditions, a significant difference was seen between the preserved and the broken chunks conditions for both healthy participants and ON-PD patients, but not for OFF-PD patients. These results suggest that movement chunking during motor sequence learning is a dopamine-dependent process in human.

Can We Predict the Motor Performance of Patients With Parkinson's Disease Based on Their Symptomatology?

Introduction: Parkinson's disease hinders the ability of a person to perform daily activities. However, the varying impact of specific symptoms and their interactions on a person's motor repertoire is not understood. The current study investigates the possibility to predict global motor disabilities based on the patient symptomatology and medication. Methods: A cohort of 115 patients diagnosed with Parkinson's disease (mean age = 67.0 ± 8.7 years old) participated in the study. Participants performed different tasks, including the Timed-Up & Go, eating soup and the Purdue Pegboard test. Performance on these tasks was judged using timing, number of errors committed, and count achieved. K-means method was used to cluster the overall performance and create different motor performance groups. Symptomatology was objectively assessed for each participant from a combination of wearable inertial sensors (bradykinesia, tremor, dyskinesia) and clinical assessment (rigidity, postural instability). A multinomial regression model was derived to predict the performance cluster membership based on the patients' symptomatology, socio-demographics information and medication. Results: Clustering exposed four distinct performance groups: normal behavior, slightly affected in fine motor tasks, affected only in TUG, and affected in all areas. The statistical model revealed that low to moderate level of dyskinesia increased the likelihood of being in the normal group. A rise in postural instability and rest tremor increase the chance to be affected in TUG. Finally, LEDD did not help distinguishing between groups, but the presence of Amantadine as part of the medication regimen appears to decrease the likelihood of being part of the groups affected in TUG. Conclusion: The approach allowed to demonstrate the potential of using clinical symptoms to predict the impact of Parkinson's disease on a person's mobility performance.

Parkinsonian Symptoms, Not Dyskinesia, Negatively Affect Active Life Participation of Dyskinetic Patients with Parkinson's Disease.

Background: The impact of slight-to-moderate levodopa-induced dyskinesia (LID) on the level of participation in active life in patients with Parkinson's disease (PD) has never been objectively determined. Methods: Levels of LID, tremor and bradykinesia were measured during best-ON state in 121 patients diagnosed with PD and having peak-dose LID using inertial sensors positioned on each body limb. Rigidity and postural instability were assessed using clinical evaluations. Cognition and depression were assessed using the MMSE and the GDS-15. Participation in active life was assessed in patients and in 69 healthy controls using the Activity Card Sort (ACS), which measures levels of activity engagement and activities affected by the symptomatology. Outcome measures were compared between patients and controls using ANCOVA, controlling for age or Wilcoxon-Mann-Whitney tests. Spearman correlations and multivariate analyses were then performed between symptomatology and ACS scores. Results: Patients had significantly lower activity engagement than controls and had significantly affected activities. LID was neither associated with activity engagement nor affected activities. Higher levels of tremor, postural instability, cognitive decline and depression were associated with lower activity engagement and higher affected activities. Multivariate analyses revealed that only tremor, postural instability and depression accounted significantly in the variances of these variables. Discussion: Slight-to-moderate LID had little impact compared to other symptoms on the level of participation in active life, suggesting that other symptoms should remain the treatment priority to maintain the level of participation of patients in an active lifestyle.

Parkinson's disease patients experiencing peak-dose dyskinesia redistribute involuntary movements throughout their body to improve motor control.

INTRODUCTION: In Parkinson's disease (PD), dyskinesia is considered a major side effect of dopamine replacement therapy. Nevertheless, many patients with dyskinesia function adequately. OBJECTIVE: To study objectively dyskinesia phenomenology in order to understand why or how patients with dyskinesia are still able to perform motor tasks. METHODS: Patients with and without dyskinesia, as well as healthy older adults, performed a geostationary task during which they attempted to stabilize a glass of water at eye level. Dyskinesia amplitude displayed by each body segment was extracted from accelerometers, and its distribution among the segments, analyzed. RESULTS: Patients experiencing dyskinesia initially distributed most of their dyskinesia away from the segments directly involved in the task. With time, this distribution shifts back towards the hand. CONCLUSION: Our results suggest that patients developed a strategy of involuntary movement's redistribution to attenuate their functional impact on voluntary movements. However, this strategy can only be maintained for a certain period before "re-emerging" dyskinesia occurs.

Remnants of Cardinal Symptoms of Parkinson's Disease, Not Dyskinesia, Are Problematic for Dyskinetic Patients Performing Activities of Daily Living.

Introduction: The impact of levodopa-induced dyskinesia (LID) on the daily lives of patients with Parkinson's disease (PD) remains to be determined. Furthermore, evidence suggests that cardinal motor symptoms of PD may coexist with LID, but their impact on activities of daily living (ADL) relative to LID is not known. This cross-sectional study aimed at determining the effect of LID and cardinal motor symptoms of PD on ADL in patients who were experiencing peak-dose choreic-type LID. Method: One hundred and twenty-one patients diagnosed with PD known to experience choreic-type LID were recruited for the study. Patients were asked to perform a set of ADL. Levels of LID, tremor, bradykinesia, and freezing of gait (FoG) were measured using 17 inertial sensors design to capture full body movements, while rigidity, and postural instability were assessed using clinical evaluations. Cognition was also assessed using the mini-mental state examination. Success criteria were set for each ADL using the time needed to perform the task and errors measured in 69 age-gender-matched healthy controls. Binary logistic regressions were used to identify symptoms influencing success or failure for each activity. Receiver operating characteristic curves were computed on each significant symptom, and Youden indexes were calculated to determine the critical level of symptomatology at which the performance significantly changed. Results: Results show that 97.7% of patients who presented with LID during the experiment also presented with at least one cardinal motor symptom. On average, patients took more time and did more errors during ADL. Multivariate analyses revealed that for the great majority of ADL, LID were not associated with worsening of performance; however, postural instability, tremor, rigidity, and cognitive decline significantly decreased the odds of success. Conclusions: Residual symptoms of PD, such as tremor, rigidity, and postural instability still present at peak-dose were more problematic than LID in the performance of ADL for patients experiencing slight-to-moderate LID. We also found that cognitive decline was associated with decreased performance in certain tasks. Therefore, a strategy using lower doses of medication to manage LID may be counterproductive since it would not address most of these symptoms already present in patients.

Diffusion-weighted imaging and magnetization transfer imaging of tardive and edentulous orodyskinesia.

Oral dyskinesias occur in elderly individuals in relation to drug use (tardive dyskinesia, TD) or edentulousness (edentulous orodyskinesia, EOD) but their characterization remains incomplete. Our aim was to investigate whether magnetic resonance techniques such as diffusion-weighted imaging (DWI) and magnetization transfer imaging (MTI) of the brain could be used to differentiate dyskinetic patients from control subjects. Eight drug-treated patients with TD, 12 EOD patients, 8 drug-treated patients without TD, and 10 control subjects were recruited and examined by DWI and MTI. Measurements in the caudate nucleus, putamen, and globus pallidus yielded globally different apparent diffusion coefficient (ADC) values between drug treated patients with TD and control subjects but the magnetization transfer ratios showed no significant variations. The discrimination between dyskinetic patients and control subjects offered by ADC values was however slightly poorer than the discrimination offered by the previously published choline/creatine ratios measured by MR spectroscopy in the basal ganglia. The results are consistent with the pathophysiological hypothesis of damage to cholinergic interneurons.

Pain and denture condition in edentulous orodyskinesia: comparisons with tardive dyskinesia and control subjects.

Edentulous orodyskinesia (ED) is a neglected source of aimless oral movements that may be confused with tardive dyskinesia (TD). We attempted to clarify the clinical features, significance, and orodental factors in relation to ED. Fourteen ED subjects, 13 TD patients, and 15 age-matched controls self-assessed their oral pain perception, condition, and function using a visual analogue scale. Dyskinesias were classified and rated by a neurologist. Perioral thermal and pressure pain threshold studies, and a standardized orodental examination, were conducted blind to subject group. The perceived oral pain level was low in all groups, and those reporting a significant intensity level of pain (>or=50th percentile) were few. The pain thresholds in both dyskinetic groups were comparable to control values. All ED cases wore a complete set of dentures, considered a current source of problems by 85.7% of them. ED cases commonly displayed inadequate dental occlusal relationship (P = 0.014 vs. controls; P = 0.036 vs. TD) and an overclosed vertical dimension (P = 0.006 vs. controls) as well as unstable and unretentive dentures. ED was limited to the oral region, spared the tongue when the mouth is open, and was never severe in our patients. ED has distinct movement characteristics and is often associated with inadequate dentures and biomechanical sources of denture instability. The contribution of the foregoing findings to the expression of oral dyskinesia warrants further studies.

Postural sway and effect of levodopa in early Parkinson's disease.

OBJECTIVE: To characterize postural stability control and levodopa responsiveness in early Parkinson's disease (PD). METHODS: Postural sway was studied during quiet stance in ten patients within six years of PD onset, both before (OFF) and after (ON) regular oral levodopa dosing. Postural sway was recorded using a force platform during 30 sec with eyes open, and six dependent variables were examined. RESULTS: Mild baseline subclinical changes in postural sway were recorded in our patients. Clear benefit was observed in five out of six characteristics (mean sway, transversal sway, sagittal sway, sway intensity, and sway area) in the ON condition. CONCLUSION: Postural control mechanisms are affected early in PD and modulated by dopamine.

Chronic pain and pain processing in Parkinson's disease.

Pain is experienced by the vast majority of patients living with Parkinson's disease. It is most often of nociceptive origin, but may also be ascribed to neuropathic (radicular or central) or miscellaneous sources. The recently validated King's Parkinson's Disease Pain Scale is based on 7 domains including musculoskeletal pain, chronic body pain (central or visceral), fluctuation-related pain, nocturnal pain, oro-facial pain, pain with discolouration/oedema/swelling, and radicular pain. The basal ganglia integrate incoming nociceptive information and contribute to coordinated motor responses in pain avoidance and nocifensive behaviors. In Parkinson's disease, nigral and extra-nigral pathology, involving cortical areas, brainstem nuclei, and spinal cord, may contribute to abnormal central nociceptive processing in patients experiencing pain or not. The dopamine deficit lowers multimodal pain thresholds that are amenable to correction following levodopa dosing. Functional brain imaging with positron emission tomography following administration of H215O revealed abnormalities in the sensory discriminative processing of pain (insula/SII), as well as in the affective motivational processing of pain (anterior cingulate cortex, prefrontal cortex). Pain management is dependent on efforts invested in diagnostic accuracy to distinguish nociceptive from neuropathic pain. Treatment requires an integrated approach including strategies to lessen levodopa-related response fluctuations, in addition to other pharmacological and non-pharmacological options such as deep brain stimulation and rehabilitation.