Pramipexole combined with levodopa improves motor function but reduces dyskinesia in MPTP‐treated common marmosets

Reduced expression of dyskinesia is observed in levodopa‐primed MPTP‐treated common marmosets when dopamine agonists are used to replace levodopa. We now investigate whether a combination of the D‐2/D‐3 agonist pramipexole and levodopa also reduces dyskinesia intensity while maintaining the reversal of motor disability. Drug naïve, non‐dyskinetic MPTP‐treated common marmosets were treated daily for up to 62 days with levodopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o. BID) or pramipexole (0.04–0.3 mg/kg BID) producing equivalent reversal of motor disability and increases in locomotor activity. Levodopa alone resulted in marked dyskinesia induction but little or no dyskinesia resulted from the administration of pramipexole. From day 36, some animals were treated with a combination of levodopa (3.125–6.25 mg/kg plus carbidopa 12.5 mg/kg p.o. BID) and pramipexole (0.1–0.2 mg/kg p.o. SID). This improved motor disability to a greater extent than occurred with levodopa alone. Importantly, while dyskinesia was greater than that produced by pramipexole alone, the combination resulted in less intense dyskinesia than produced by levodopa alone. These results suggest that pramipexole could be administered with a reduced dose of levodopa to minimize dyskinesia in Parkinson's disease while maintaining therapeutic efficacy. © 2010 Movement Disorder Society     

Disordered respiration as a levodopa-induced dyskinesia in Parkinson's disease.

Symptomatic respiratory disturbance as a consequence of levodopa (L-dopa) therapy for Parkinson's disease (PD) has been described only rarely and may be underrecognized in clinical practice. We report on two patients with PD in whom the introduction or augmentation of L-dopa therapy was associated with the development of irregular and rapid breathing. Analysis of breathing patterns before and after L-dopa demonstrated a striking change in respiratory rate after administration of L-dopa, with the emergence of irregular tachypnea alternating with brief periods of apnea, in a pattern consistent with a central origin. In both cases, the temporal relationship of the respiratory disturbance to the administration of L-dopa suggested a peak-dose drug effect. Previous reports of L-dopa-induced respiratory dyskinesia are reviewed, and the potential mechanisms whereby L-dopa might influence the central control of respiration to produce irregular breathing patterns are discussed.     

The monoamine reuptake blocker brasofensine reverses akinesia without dyskinesia in MPTP-treated and levodopa-primed common marmosets.

The common marmoset develops motor deficits after MPTP treatment and exhibits dyskinesia after chronic levodopa (L-dopa) dosing and subsequent re-challenge with L-dopa and other dopaminergic agents. We report on the actions of the potent monoamine reuptake blocker brasofensine on motor disability, locomotor activity, and dyskinesia in the 1-methyl-4-1, 2,3,6-tetrahydropyridine (MPTP) -treated marmoset model of Parkinson's disease. Oral administration of brasofensine (0.25, 0.5, 1.0, or 2.5 mg/kg) to MPTP-treated marmosets produced a long-lasting, dose-dependent increase in locomotor activity and reduction in disability scores. In addition, coadministration of the lowest dose of brasofensine (0.25 mg/kg orally) with a threshold oral dose of L-dopa (2.5 mg/kg) caused a marked increase in locomotor activity, greater than that produced by either drug alone. In other MPTP-treated marmosets previously primed to exhibit dyskinesia by repeated L-dopa dosing, brasofensine effectively reversed akinesia with a naturalistic and prolonged motor response without the appearance of dyskinesia or stereotypy. This finding contrasts with the severe dyskinesia, stereotypy, and hyperkinesis produced by equivalent doses of L-dopa. The ability of brasofensine to produce a prolonged and naturalistic antiparkinsonian response without eliciting dyskinesia after previous L-dopa priming may relate to actions on D(1) receptor-linked pathways. These findings suggest that monoamine reuptake blockade may be of value in the treatment of Parkinson's disease, both early in the disease course and when L-dopa-induced dyskinesias complicate treatment.     

The role of the dorsal raphe nucleus in the development,expression, and treatment of L‐dopa‐induced dyskinesia in hemiparkinsonian rats

Convergent evidence indicates that in later stages of Parkinson's disease raphestriatal serotonin neurons compensate for the loss of nigrostriatal dopamine neurons by converting and releasing dopamine derived from exogenous administration of the pharmacotherapeutic L‐3,4‐dihydroxyphenyl‐L ‐alanine (L ‐dopa). Because the serotonin system is not equipped with dopamine autoregulatory mechanisms, it has been postulated that raphe‐mediated striatal dopamine release may fluctuate dramatically. These fluctuations may portend the development of abnormal involuntary movements called L ‐dopa‐induced dyskinesia (LID). As such, it has been hypothesized that reducing the activity of raphestriatal neurons could dampen supraphysiological stimulation of striatal dopamine receptors thereby alleviating LID. To directly address this, the current study employed the rodent model of LID to investigate the contribution of the rostral raphe nuclei (RRN) in the development, expression and treatment of LID. In the first study, dual serotonin/dopamine selective lesions of the RRN and medial forebrain bundle, respectively, verified that the RRN are essential for the development of LID. In a direct investigation into the neuroanatomical specificity of these effects, microinfusions of ±8‐OH‐DPAT into the intact dorsal raphe nucleus dose‐dependently attenuated the expression of LID without affecting the antiparkinsonian efficacy of L ‐dopa. These current findings reveal the integral contribution of the RRN in the development and expression of LID and implicate a prominent role for dorsal raphe 5‐HT1AR in the efficacious properties of 5‐HT1AR agonists. Synapse 63:610–620, 2009. © 2009 Wiley‐Liss, Inc.     

Metric properties of the mini‐mental Parkinson and SCOPA‐COG scales for rating cognitive deterioration in Parkinson's disease

Parkinson's disease (PD) is a chronic neurodegenerative disorder that causes cognitive impairment and dementia in ～30% of patients. Objective: Compare metric qualities of Mini‐Mental Parkinson (MMP) and scales for outcomes in Parkinson's disease‐cognition (SCOPA‐COG) with respect to their relative reliability, validity and ability to predict symptoms (mobility, quality of life, social repercussions, and mood) in PD patients. Outpatients (n=123, 78 males/45 females) diagnosed with PD were included in the study. A multilevel (hierarchical) modeling analysis was performed along with tests of reliability and validity to ascertain which of the two models better predicts symptoms related to PD. Results: The MMP differed significantly between patients with Hoehn and Yahr (H&Y) stages 1, 2 or versus 4/5 (grouped together). The SCOPA‐COG showed differences only between patients in H&Y stages 2 versus 4/5. Both scales were dependent on educational background and age. The SCOPA‐COG had a higher coefficient of variation (0.303) than the MMP (0.184), indicating that it was the more discriminative of the two. Conclusions: The SCOPA‐COG has some advantages over the MMP, the most important being a greater discriminative ability. Multilevel hierarchical analysis clarified the necessity of stratifying the PD population according to educational background, years of illness, and H&Y stage when using these scales. © 2010 Movement Disorder Society     

Fatigue rating scales critique and recommendations by the Movement Disorders Society task force on rating scales for Parkinson's disease

Fatigue has been shown to be a consistent and common problem in Parkinson's disease (PD) in multiple countries and cultures. It is one of the most disabling of all symptoms, including motor dysfunction, and appears early, often predating the onset of motor symptoms. Several studies of the epidemiology of fatigue have been published, often using different scales, but few on treatment. The Movement Disorder Society (MDS) commissioned a task force to assess available clinical rating scales, critique their psychometric properties, summarize their clinical properties, and evaluate the evidence in support of their use in clinical studies in PD. Six clinical researchers reviewed all studies published in peer reviewed journals of fatigue in PD, evaluated the scales' previous use, performance parameters, and quality of validation data, if available. Scales were rated according to criteria provided by the MDS. A scale was “recommended” if it has been used in clinical studies beyond the group that developed it, has been used in PD and psychometric studies have established that it is a valid, reliable and sensitive to change in people with PD. Requiring a scale to have demonstrated sensitivity to change in PD specifically rather than in other areas in order to attain a rating of “recommended” differs from the use of this term in previous MDS task force scale reviews. “Suggested” scales failed to meet all the criteria of a “recommended” scale, usually the criterion of sensitivity to change in a study of PD. Scales were “listed” if they had been used in PD studies but had little or no psychometric data to assess. Some scales could be used both to screen for fatigue as well as to assess fatigue severity, but some were only used to assess severity. The Fatigue Severity Scale was “recommended” for both screening and severity rating. The Fatigue Assessment Inventory, an expanded version of the Fatigue severity Scale, is “suggested” for both screening and severity. The Functional Assessment of Chronic Illness Therapy‐Fatigue was “recommended” for screening and “suggested” for severity. The Multidimensional Fatigue Inventory was “suggested” for screening and “recommended” for severity. The Parkinson Fatigue Scale was “recommended” for screening and “suggested” for severity rating. The Fatigue Severity Inventory was “listed” for both screening and severity. The Fatigue Impact Scale for Daily Use, an adaptation of the Fatigue Impact Scale was “listed” for screening and “suggested” for severity. Visual Analogue and Global Impression Scales are both “listed” for screening and severity. The committee concluded that current scales are adequate for fatigue studies in PD but that studies on sensitivity and specificity of the scales are still needed. © 2010 Movement Disorder Society     

Striatal delta opioid receptor binding in experimental models of Parkinson's disease and dyskinesia.

Enhanced delta opioid receptor transmission may represent an endogenous compensatory mechanism in parkinsonism to reduce the activity of the indirect striatopallidal pathway following dopamine depletion. Furthermore, increased delta opioid receptor transmission may be causative in the production of dyskinesia following repeated dopaminergic treatment in Parkinson's disease. The present study employed radioligand receptor autoradiography, using [3H]naltrindole, a ligand selective for the delta opioid receptor, to assess delta opioid receptor binding sites in forebrain regions of reserpine-treated rats, and in parkinsonian nondyskinetic, and dyskinetic MPTP-lesioned macaques. In reserpine-treated animals, specific delta opioid binding was increased in premotor cortex (+30%), sensorimotor striatum (+20%), and associative striatum (+17%) rostrally, but was not changed in caudal forebrain. In contrast, delta opioid receptor binding was not significantly altered at any region analyzed, in either nondyskinetic or dyskinetic, MPTP-lesioned macaques, compared to normal. These results suggest that transient changes in delta opioid receptor binding may occur in motor circuits following acute dopamine depletion. However, in the more chronic MPTP-lesioned macaque model, simple changes in delta opioid receptor number or affinity are unlikely to contribute to mechanisms for abnormal opioid transmission in Parkinson's disease and dyskinesia.     

Depression rating scales in Parkinson's disease: critique and recommendations.

Depression is a common comorbid condition in Parkinson's disease (PD) and a major contributor to poor quality of life and disability. However, depression can be difficult to assess in patients with PD due to overlapping symptoms and difficulties in the assessment of depression in cognitively impaired patients. As several rating scales have been used to assess depression in PD (dPD), the Movement Disorder Society commissioned a task force to assess their clinimetric properties and make clinical recommendations regarding their use. A systematic literature review was conducted to explore the use of depression scales in PD and determine which scales should be selected for this review. The scales reviewed were the Beck Depression Inventory (BDI), Hamilton Depression Scale (Ham-D), Hospital Anxiety and Depression Scale (HADS), Zung Self-Rating Depression Scale (SDS), Geriatric Depression Scale (GDS), Montgomery-Asberg Depression Rating Scale (MADRS), Unified Parkinson's Disease Rating Scale (UPDRS) Part I, Cornell Scale for the Assessment of Depression in Dementia (CSDD), and the Center for Epidemiologic Studies Depression Scale (CES-D). Seven clinical researchers with clinical and research experience in the assessment of dPD were assigned to review the scales using a structured format. The most appropriate scale is dependent on the clinical or research goal. However, observer-rated scales are preferred if the study or clinical situation permits. For screening purposes, the HAM-D, BDI, HADS, MADRS, and GDS are valid in dPD. The CES-D and CSDD are alternative instruments that need validation in dPD. For measurement of severity of depressive symptoms, the Ham-D, MADRS, BDI, and SDS scales are recommended. Further studies are needed to validate the CSDD, which could be particularly useful for the assessment of severity of dPD in patients with comorbid dementia. To account for overlapping motor and nonmotor symptoms of depression, adjusted instrument cutoff scores may be needed for dPD, and scales to assess severity of motor symptoms (e.g., UPDRS) should also be included to help adjust for confounding factors. The HADS and the GDS include limited motor symptom assessment and may, therefore, be most useful in rating depression severity across a range of PD severity; however, these scales appear insensitive in severe depression. The complex and time-consuming task of developing a new scale to measure depression specifically for patients with PD is currently not warranted.     

Ceftriaxone reduces L‐dopa–induced dyskinesia severity in 6‐hydroxydopamine parkinson's disease model

Background: Increased extracellular glutamate may contribute to l ‐dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l ‐dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT‐1 expression in a rat 6‐hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l ‐dopa, could reduce l ‐dopa–induced dyskinesia in an established dyskinesia model. Methods: Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post‐6‐hydroxydopamine lesion (days 7‐13) and continued every other week (days 21‐27, 35‐39) until the end of the study (day 39 postlesion, 20 days of l ‐dopa). Results: Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l ‐dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l ‐dopa was unaffected by ceftriaxone. The ceftriaxone‐treated l ‐dopa group had significantly increased striatal GLT‐1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l ‐dopa alone group. Conclusions: Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l ‐dopa, may reduce dyskinesia severity without affecting l ‐dopa efficacy or the reduction of striatal tyrosine hydroxylase loss. © 2017 International Parkinson and Movement Disorder Society     

Parkinson's disease‐cognitive rating scale: Psychometrics for mild cognitive impairment

Lack of validated data on cutoff scores for mild cognitive impairment (MCI) and sensitivity to change in predementia stages of Parkinson's disease (PD) limit the utility of instruments measuring global cognition as screening and outcome measures in therapeutic trials. Investigators who were blinded to PD‐Cognitive Rating Scale (PD‐CRS) scores classified a cohort of prospectively recruited, nondemented patients into a PD with normal cognition (PD‐NC) group and a PD with MCI (PD‐MCI) group using Clinical Dementia Rating (CDR) and the Mattis Dementia Rating Scale‐2 (MDRS‐2). The discriminative power of the PD‐CRS for PD‐MCI was examined in a representative sample of 234 patients (145 in the PD‐NC group; 89 in the PD‐MCI group) and in a control group of 98 healthy individuals. Sensitivity to change in the PD‐CRS score (the minimal clinically important difference was examined with the Clinical Global Impression of Change scale and was calculated with a combination of distribution‐based and anchor‐based approaches) was explored in a 6‐month observational multicenter trial involving a subset of 120 patients (PD‐NC, 63; PD‐MCI, 57). Regression analysis demonstrated that PD‐CRS total scores (P < 0.001) and age (P = 0.01) independently differentiated PD‐NC from PD‐MCI. Area under the receiver operating characteristic curve (AUC) analysis (AUC, 0.85; 95% confidence interval, 0.80–0.90) indicated that a score ≤81 of 134 was the optimal cutoff point on the total score for the PD‐CRS (sensitivity, 79%; specificity, 80%; positive predictive value, 59%; negative predictive value, 91%). A range of change from 10 to 13 points on the PD‐CRS total score was indicative of clinically significant change. These findings suggest that the PD‐CRS is a useful tool to identify PD‐MCI and to track cognitive changes in nondemented patients with PD. © 2013 International Parkinson and Movement Disorder Society     

Beginning-of-dose and rebound worsening in MPTP-treated common marmosets treated with levodopa.

A wide range of motor fluctuations develop in Parkinson's disease (PD) patients after prolonged levodopa (L-dopa) treatment, but few experimental models exist in which these can be investigated. We report on motor fluctuations occurring in MPTP-treated common marmosets (Callithrix jacchus) treated repeatedly with L-dopa. All animals showed an improvement in motor function in response to L-dopa, and rapidly developed peak-dose dyskinesia. During the period of L-dopa action, brief periods of immobility were occasionally observed. After acute L-dopa challenge, animals exhibited a worsening of motor function before improvement, and after the beneficial response to L-dopa declined, motor performance showed rebound worsening to below-baseline values. Before L-dopa challenge and during wearing-off and rebound worsening, leg dystonias were observed. Although these findings cannot necessarily be generalized to all MPTP-treated nonhuman primates, they demonstrate that MPTP-treated marmosets show a range of different motor fluctuations analogous to those seen in PD patients chronically treated with L-dopa. Therefore, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates can provide a model in which the pathophysiology of treatment complications can be investigated.     

Stimulation of cannabinoid receptors reduces levodopa-induced dyskinesia in the MPTP-lesioned nonhuman primate model of Parkinson's disease.

Long-term treatment with levodopa in Parkinson's disease results in the development of motor fluctuations, including reduced duration of antiparkinsonian action and involuntary movements, i.e., levodopa-induced dyskinesia. Cannabinoid receptors are concentrated in the basal ganglia, and stimulation of cannabinoid receptors can increase gamma-aminobutyric acid transmission in the lateral segment of globus pallidus and reduce glutamate release in the striatum. We thus tested the hypothesis that the cannabinoid receptor agonist nabilone (0.01, 0.03, and 0.10 mg/kg) would alleviate levodopa-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -lesioned marmoset model of Parkinson's disease. Coadministration of nabilone (0.1 mg/kg) with levodopa was associated with significantly less total dyskinesia (dyskinesia score, 12; range, 6-17; primate dyskinesia rating scale) than levodopa alone (22; range, 14-23; P < 0.05). This effect was more marked during the onset period (0-20 minutes post levodopa). There was no reduction in the antiparkinsonian action of levodopa. Furthermore, the intermediate dose of nabilone used (0.03 mg/kg) increased the duration of antiparkinsonian action of levodopa by 76%. Thus, cannabinoid receptor agonists may be useful in the treatment of motor complications in Parkinson's disease.     

Calibration of unified Parkinson's disease rating scale scores to Movement Disorder Society‐unified Parkinson's disease rating scale scores

The aim of this study was to develop formulas to convert the UPDRS to Movement Disorder Society (MDS)‐UPDRS scores. The MDS‐UPDRS is a revision of the UPDRS with sound clinimetric properties. Reliable formulas to recalculate UPDRS scores into MDS‐UPDRS equivalents are pivotal to the practical transition and definitive adoption of the MDS‐UPDRS. UPDRS and MDS‐UPDRS scores were collected on 875 PD patients. A developmental sample was used to regress UPDRS scores on corresponding MDS‐UPDRS scores based on three H & Y groupings (I/II, III, and IV/V). Regression weighting factors and intercept terms provided formulas for UPDRS conversions to be tested in a validation sample. Concordance between the true MDS‐UPDRS Part scores and those derived from the formulas was compared using Bland‐Altman's plots and Lin's concordance coefficient (LCC). Significant concordance between UPDRS‐estimated MDS‐UPDRS scores was achieved for Parts II (Motor Experiences of Daily Living) (LCC = 0.93) and III (Motor Examination) (LCC = 0.97). The formulas resulted in mean differences between the true MDS‐UPDRS and estimated MDS‐UPDRS scores of less than 1 point for both Parts II and III. Concordance was not achieved for Parts I and IV (Non‐motor Experiences of Daily Living and Complications of Therapy). Formulas allow archival UPDRS Parts II and III individual patient data to be accurately transferred to MDS‐UPDRS scores. Because Part I collects data on much more extensive information than the UPDRS, and because Part IV is structured differently in the two versions, old ratings for these parts cannot be converted. © 2012 Movement Disorder Society     

Animal models of l‐dopa‐induced dyskinesia in Parkinson's disease

Understanding the biological mechanisms of l ‐dopa‐induced motor complications is dependent on our ability to investigate these phenomena in animal models of Parkinson's disease. The most common motor complications consist in wearing‐off fluctuations and abnormal involuntary movements appearing when plasma levels of l ‐dopa are high, commonly referred to as peak‐dose l ‐dopa‐induced dyskinesia. Parkinsonian models exhibiting these features have been well‐characterized in both rodent and nonhuman primate species. The first animal models of peak‐dose l ‐dopa‐induced dyskinesia were produced in monkeys lesioned with N‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and treated chronically with l ‐dopa to elicit choreic movements and dystonic postures. Seminal studies were performed in these models using both metabolic mapping and electrophysiological techniques, providing fundamental pathophysiological insights that have stood the test of time. A decade later, it was shown possible to reproduce peak‐dose l ‐dopa‐induced dyskinesia in rats and mice rendered parkinsonian with nigrostriatal 6‐hydroxydopamine lesions. When treated with l ‐dopa, these animals exhibit abnormal involuntary movements having both hyperkinetic and dystonic components. These models have enabled molecular‐ and cellular‐level investigations into the mechanisms of l ‐dopa‐induced dyskinesia. A flourishing literature using genetically engineered mice is now unraveling the role of specific genes and neural circuits in the development of l ‐dopa‐induced motor complications. Both non‐human primate and rodent models of peak‐dose l ‐dopa‐induced dyskinesia have excellent construct validity and provide valuable tools for discovering therapeutic targets and evaluating potential treatments. © 2018 International Parkinson and Movement Disorder Society     

A follow‐up study on 6‐[18F]fluoro‐L‐dopa uptake in early Parkinson's disease shows nonlinear progression in the putamen

Sixteen subjects with de novo Parkinson's disease (PD) underwent three 6‐[18F]fluoro‐L‐dopa (Fdopa) positron emission tomography (PET) scans during a follow‐up time of 5 years (mean ± SD 5.5 ± 0.4 years) to study the progression of striatal dopaminergic hypofunction. Throughout the study, the smallest Fdopa uptake values were found in the dorso‐caudal part of the putamen contralateral to the side with dominant motor symptoms. The rate of decline in Fdopa uptake in the contralateral putamen was faster in the beginning of the disease and slowed down as the disease progressed. The annual decline in Fdopa influx constant (Ki, unit × 10^?3 min^?1) was on average 0.5 during the first 2 years and 0.2 during the subsequent 3 years (P = 0.002) in the contralateral putamen. In caudate, the rate of decline in Fdopa values was slower than in the putamen and did not change significantly during the follow‐up time, annual decline in the contralateral caudate being 0.1 between baseline and 2 years and 0.3 between 2 and 5 years (P = 0.4). These results suggest that progression of putaminal dopaminergic hypofuncion in PD follows a nonlinear pattern at least in the contralateral side being faster in the beginning of the disease. © 2009 Movement Disorder Society