A combined pharmacokinetic/pharmacodynamic model of levodopa motor response and dyskinesia in Parkinson's disease patients.

PURPOSE: Levodopa is the reference treatment for Parkinson's disease. However, after several years of treatment, dyskinesia may occur and strategies to overcome this side effect still need to be explored. We identified a unique population pharmacokinetic/pharmacodynamic model in Parkinson's disease to investigate the relationship and dissociability of motor response and dyskinesia. METHODS: Thirty parkinsonian patients (Hoehn and Yahr stages 3-4), treated with levodopa and suffering from peak-dose dyskinesia, were included in a prospective open-label study. They received a single dose of levodopa equal to 150 % of their usual daily dose. Blood samples, motor evaluations (UPDRS III scale) and peak-dose dyskinesia (Goetz scale) were examined after administration. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed using NONMEM software. RESULTS: Pharmacokinetic analysis identified a one-compartment model with the following parameter values [bootstrap 95 % CI]: absorption rate constant (KA) 1.86 1/h [1.08-3.25], clearance 36.6 L/h [31.3-42.8], and volume of distribution 42.9 L [34.3-52.3]. Between-subject variability was 122 % [71-183] and 38 % [26-47] for KA and clearance, respectively. Residual variability was 1120 µg/L [886-1290]. UPDRS III and dyskinesia were best described with an effect compartment and similar KE0 values of 1.37 1/h [1.01-1.77]. For UPDRS III, the E0, EC50, Emax, and Hill coefficient were 31.4 [28.4-35.3], 1410 µg/L [1200-1700], 0.72 [0.71-0.75], and 4.26 [3.20-5.58], respectively. For dyskinesia, the EC50 and Emax were 6280 µg/L [3420-37,900] and 17.9 [12.3-80.8], respectively. Residual variability was 3.15 [2.75-3.53] for UPDRS III and 2.66 [1.94-3.51] for dyskinesia. No covariates influenced the parameters. CONCLUSIONS: In patients treated with levodopa and suffering from dyskinesia, the motor response and dyskinesia have close onsets and duration effects. Maximal motor response tends to be inevitably associated with dyskinesia.

[F0 characteristics in Parkinsonian speech: Contrast between the effect of hypodopaminergy due to Parkinson's disease and that of the therapeutic delivery of L-Dopa]. / Les anomalies de la fréquence fondamentale chez le locuteur Parkinsonien: contraste entre les effets respectifs de l'hypodopaminergie dûe à la maladie de Parkinson et de l'apport thérapeutique par L-Dopa.

Voice and speech impairments are frequent in Parkinson's disease, particularly when the disease is at an advanced stage. These impairments affect spoken communication and may become a serious disability for someone with Parkinson's disease. Many studies based on auditory-perceptual or acoustic methods have been carried out to characterize dysarthria. The heterogeneity of evaluation methods and experimental bias however make results difficult to understand. For instance, in terms of phonatory impairments and with regard to F0, results are contradictory: PD speech may be characterized by either higher F0 or lower F0 compared to control subjects, or there may be no difference at all between the two population. In this study, we aim to provide a conceptual and methodological framework which allows for interpreting the results obtained from 44 speakers (29 PD and 15 control subjects) in relation to physiological (gender, age, PD subjects' pharmacologic state) and linguistic (speech production tasks) constraints. For the present corpus, we did not observe any F0 mean difference between the two groups. Our results however reveal a significant increase in F0 mean in PD subjects under L-dopa. We assume a double and opposite effect on F0 mean during drug withdrawal: low sub-glottal pressure, due to PD, results in a decrease in F0, while laryngeal rigidity leads to an increase in F0. These two effects thus mutually annihilate. Under L-Dopa, however, the drug effect increases sub-glottal pressure, which combined with an increase in F0 due to rigidity, leads to a global increase in F0.

Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers.

OBJECTIVE: Glucocerebrosidase (GBA) gene mutations represent a strong risk factor for Parkinson disease (PD). PD penetrance in GBA mutation carriers, which represents a key issue for genetic counseling, especially for relatives of patients with Gaucher disease (GD), is unknown. Our objective was to estimate PD penetrance in a familial study of GBA mutation carriers. METHODS: Probands with familial PD were recruited through the French Parkinson Disease Genetic Study Group. All GBA exons were sequenced in probands and their relatives. To estimate the age-specific cumulative PD risk (i.e., penetrance) in GBA mutation carriers, we used the proband's phenotype exclusion likelihood method and corrected for selection of familial cases by considering the status of one affected relative per family as unknown. RESULTS: Of 525 probands with familial PD, 24 (4.6%) were GBA mutation carriers. Of their 256 relatives, 43 (16.8%) had PD and 26 of 32 affected relatives tested for GBA mutations were mutation carriers; 213 relatives did not have PD and 31 of 71 of unaffected relatives tested for GBA mutations were mutation carriers. Under a dominant model, penetrance was estimated as 7.6%, 13.7%, 21.4%, and 29.7% at 50, 60, 70, and 80 years, respectively. There was no significant difference in penetrance at 70 years between N370S carriers, L444P carriers, and carriers of rarer mutations. CONCLUSION: The relatively high penetrance estimate in GBA carriers obtained in this study should lead to consideration of GBA as a dominant causal gene with reduced penetrance and should be taken into account for genetic counseling in relatives of patients with GD and patients with GBA-associated PD.

[Dysarthria across Parkinson's disease progression. Natural history of its components: dysphonia, dysprosody and dysarthria]. / La dysarthrie au cours de la maladie de Parkinson. Histoire naturelle de ses composantes: dysphonie, dysprosodie et dysarthrie.

Dysarthria refers to a collective name for a group of neurologic motor speech disorders, resulting from central and/or peripheral nervous system abnormalities. Speech alteration in Parkinson's disease, so-called hypokinetic dysarthria, presents with prosodic insufficiency, related to a monotony of pitch and intensity, a reduction of accentuation, variable speech rate and possible phoneme imprecision. In most cases, voice is harsh and breathy. This symptom can affect both voice and speech quality, as well as prosody and intelligibility. As a consequence, many patients complain about speech impairments, which affect their communication in daily living activities. Perceptual and instrumental assessments require different and numerous investigation methods, which use may help to further understand the specific dysarthria pathophysiology. This is of importance in order to adjust treatments for dysarthria; as a matter of fact, dopa-therapy, functional neurosurgery or even behavioural speech therapy have variable effects on voice and speech quality in Parkinson's disease.

[Measurement of intra-oral pressure as a contributor for the understanding of pneumophonic coordination impairment in Parkinsonian dysarthria]. / Contribution de la mesure de la pression intra-orale pour la compréhension des troubles de la coordination pneumophonique dans la dysarthrie parkinsonienne.

INTRODUCTION: Parkinsonian dysarthria can alter oral communication of the patients in the long-term. Subthalamic nucleus (STN) stimulation represents an interesting therapeutic option, although it does not seem to improve axial signs, of which dysarthric speech. The objective of our study was to contribute to the evaluation of STN stimulation effects on speech impairment and in particular on pneumophonic coordination: this latter parameter can be assessed indirectly by evaluating the temporal progression of the intraoral pressure (IOP) during the expiratory phase; thus, IOP represents the transient expression of subglottal pressure (SGP). PATIENTS AND METHOD: Using a dedicated system (EVA2), 20 parkinsonian patients were recorded in ON and OFF STN stimulation conditions in order to evaluate IOP on three measurement points (2nd, 4th and 6th consonants P) during realization of the sentence "Papa ne m'a pas parlé de beau-papa" ("Daddy did not speak to me about daddy-in-law") which corresponds to a breath group. Eleven control subjects were recorded in parallel in order to define reference measurements. RESULTS: STN stimulation improved significantly IOP at the level of the initial measurement points (2nd P and 4th P), with an effect of convergence at the level of the third point (6th P) where the difference between OFF and ON STIM conditions was not significant any more. In addition, the performance of the patients ON STIM remained much lower than that of the control subjects. CONCLUSION: Our results raise the significant concept that IOP measurement can be regarded as a relevant indicator for dysarthria in Parkinson's disease. They also show that the improvement of pneumophonic coordination by STN stimulation is restricted to the initial period of the expiratory phase, confirming again the mitigated and controversial effect of STN stimulation on axial signs.

Levodopa/DDCI and entacapone is the preferred treatment for Parkinson's disease patients with motor fluctuations in routine practice: a retrospective, observational analysis of a large French cohort.

Levodopa is the gold standard drug for the symptomatic control of Parkinson's disease (PD). However, long-term treatment with conventional formulations [levodopa and a dopa decarboxylase inhibitor (DDCI)], is associated with re-emergence of symptoms because of wearing-off and dyskinesia. Treatment with levodopa/DDCI and entacapone extends the half-life of levodopa, avoiding deep troughs in levodopa plasma levels and providing more continuous delivery of levodopa to the brain. In this open-label, retrospective, observational study we investigated the effects of levodopa/DDCI and entacapone therapy in 800 PD patients with motor fluctuations. Levodopa/DDCI and entacapone treatment was assessed as good/very good in improving motor fluctuations (64%) and activities of daily living (ADL; 62%). The therapeutic utility was considered to be good/very good in 70% of cases. Moreover, there was a reduction in levodopa dose in 20% of patients. Neurologists preferred levodopa/DDCI and entacapone compared with increasing levodopa dosage, dose-fractionation or addition of a dopamine agonist (63%, 29% and 23% of patients respectively). Reasons included achieving more continuous dopaminergic stimulation (40%), reducing motor fluctuations (54%) and improving ADL (41%). This analysis reveals the preference of neurologists for levodopa/DDCI and entacapone over conventional levodopa-modification strategies for the effective treatment of PD motor fluctuations in clinical practice.

Axial rotation in Parkinson's disease.

AIMS: To investigate the ability of patients with Parkinson's disease to perform a rotation around the longitudinal axis of the body. Three questions were raised. Is body rotation impaired in Parkinson's disease? Is there a level of the kinematic chain from the head to the foot at which the impairment is more severe? Is the deficit related to the general slowness of movement in Parkinson's disease? METHODS: Kinematic data were recorded. The temporal organisation of body rotation during gait initiation was analysed in 10 patients with Parkinson's disease, who were all at an advanced stage of the disease and had all experienced falls and freezing during their daily life, and in five controls. The latency of the onset of the rotation of each segment was measured by taking the onset of the postural phase of step initiation as reference value. Locomotor variables were also analysed. RESULTS: Body rotation was found to be impaired in patients with Parkinson's disease, as the delay in the onset of the rotation of each segment is greater than that in controls. Moreover, a specific uncoupling in the onset of shoulder and pelvis segment rotation was seen in patients. This impairment of rotation is not related only to the general slowness of movements. CONCLUSION: Patients with Parkinson's disease were found to have an impairment of posturo-kinetic coordination and impaired capacity to exert appropriate ground reaction forces to orient the pelvis in space.

Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study.

OBJECTIVE: To investigate the efficacy and safety of clozapine in the treatment of levodopa-induced dyskinesias (LID) in patients with severe Parkinson disease (PD). METHODS: Fifty patients were randomized to treatment in this 10-week, double-blind, parallel-group, placebo-controlled, multicenter trial. The principal measure of outcome was the diurnal change in the "on" time with LID assessed using a self-evaluation of the motor performance fluctuations performed every 2 weeks. An acute levodopa challenge was also performed at the beginning and end of the study. RESULTS: A reduction in the duration of "on" periods with LID was noted in favor of the clozapine group at the end of the study (placebo group day 0: 4.54 +/- 0.53 hours, end: 5.28 +/- 0.70 hours; clozapine group day 0: 5.68 +/- 0.66 hours, end: 3.98 +/- 0.57 hours; p = 0.003). The mean clozapine dosage was 39.4 +/- 4.5 (SEM) mg/day. The maximal LID score at rest during the levodopa challenge was significantly decreased under clozapine treatment, with a variation from day 0 to day 70 in the placebo group of +0.15 +/- 1.01 and in the clozapine group of -2.22 +/- 0.52 (p < 0.05). Five patients receiving clozapine and seven receiving placebo discontinued on account of adverse events. Among them, three patients in the clozapine group developed eosinophilia, which rapidly resolved after withdrawal of the drug. CONCLUSION: Clozapine is effective in the treatment of levodopa-induced dyskinesias in severe PD.

Coordination of axial rotation and step execution: deficits in Parkinson's disease.

To determine why parkinsonian patients (PP) present some difficulties to initiate locomotion, a diagonal step has been investigated in two tasks in five control subjects (CS) and in ten PP. In the first task, the subjects had to perform one diagonal step without change in their orientation (WR); in the second task, they had to perform one diagonal step with a body rotation in the step direction (RO). The defended hypothesis is that the gait initiation deficits in Parkinson disease are a consequence of their difficulties to coordinate al the component of a complex movement. The analysed parameters were the duration of the postural and movement phases, the step length and velocity, and the amplitude of the horizontal ground reaction forces during each phase. Compared to CS, the PP showed a lengthening of the postural phase, a decrease in the step length and velocity and a reduction of the horizontal forces. The comparisons between the performances obtained in the WR versus those obtained the RO show in CS that the performances remained unchanged, whereas in PP the performances were significantly more altered in the RO. It illustrates the specific deficit occurring in PP while performing complex tasks where coordination between several components has to be achieved simultaneously.

Specific functions of the motor cortex in reorganizing coordinations during motor training in animals and humans.

The involvement of the motor cortex in learning movements has recently attracted much attention. One aspect of motor learning is the inhibition of innate synergies which interfere with performance of the acquired movement. Various models of operant responses in dogs have demonstrated the critical role of the motor cortex in the reorganization and inhibition of interfering synergies during learning. The role of the motor cortex and corticospinal influences in the formation of new coordinations in humans was studied here in patients with organic lesions of the cerebral circulation involving the internal capsule, using postural coordination and movements in a bimanual unloading response as an example. Formation of the forearm stabilization response was deeply lesioned on the afflicted side. Some degree of impairment was also seen on the ipsilateral side, but it was no different from the level of learning impairment in patients with lesions not involving the internal capsule or in patients with parkinsonism. The existence of specific contralateral influences of the motor cortex and non-specific descending influences on the process of motor learning is proposed.

[Neuroplasticity and Parkinson's disease] / Neuroplasticité et maladie de Parkinson.

Emerging concept, to date, neuroplasticity becomes a concrete reality in the adult central nervous system (CNS), particularly in a so-called neurodegenerative disease as idiopathic Parkinson's disease (IPD). After a brief survey of some general aspects of plasticity in the CNS, the present tutorial review illustrates with recent data from the literature the modes of plastic changes during the course of IPD, either resulting from dopaminergic denervation (hyperactivity of remaining dopaminergic neurons with increase of their excitatory cholinergic innervation in the substantia nigra, enhancement of the corticostriatal glutamatergic synaptic activity at the striatal level) or due to dopaminergic treatment (change in phosphorylation state of the striatal glutamate receptors, internalization of D1 Dopamine receptors). Neuroplasticity in Parkinson's disease could represent a rational basis for forthcoming therapeutic issues

[Neuroplasticity and Parkinson disease]. / Neuroplasticité et maladie de Parkinson.

Emerging concept, to date, neuroplasticity becomes a concrete reality in the adult central nervous system (CNS), particularly in a so-called neurodegenerative disease as idiopathic Parkinson's disease (IPD). After a brief survey of some general aspects of plasticity in the CNS, the present tutorial review illustrates with recent data from the literature the modes of plastic changes during the course of IPD, either resulting from dopaminergic denervation (hyperactivity of remaining dopaminergic neurons with increase of their excitatory cholinergic innervation in the substantia nigra, enhancement of the corticostriatal glutamatergic synaptic activity at the striatal level) or due to dopaminergic treatment (change in phosphorylation state of the striatal glutamate receptors, internalization of D1 Dopamine receptors). Neuroplasticity in Parkinson's disease could represent a rational basis for forthcoming therapeutic issues.

[Spatial orienting of attention: a study of reaction time during pointing movement]. / Orientation spatiale de l'attention: étude des temps de réaction lors du mouvement de pointage.

AIM: The aim of this study was to investigate how advance information both explicit and implicit provided prior to movement may affect the spatial orientation and the internal attention control processes in normal adult subjects. The originality of this work compared to the test of Posner, lies essentially in the methodology used to study the attentional systems. The use of three procedures of reaction time (RT) allowed us to study the setting concerned of the specific and non-specific components of the attention in the motor preparation. By associating of these three procedures of RT, we have evaluated the effects of the explicit and implicit components of advance information on motor preparation. The use of advance information to the movement requires the implication of the attentional systems. MATERIAL AND METHODS: Experiments were carried out using a simple reaction time (RT) procedure involving the use of an orientation cue and two choice reaction time situations: one with a neutral preparatory cue and one with a priming cue giving the likelihood of the preparatory stimulus (S1) being compatible with the imperative stimulus (S2). The mechanisms underlying the subjects' vigilance and the orientation of their attention were studied by assessing the effects on their reaction times of the preparatory signal and those of the cue giving the likelihood of S1 and S2 being compatible. The preparatory signal was designed to explicitly attract the subjects' attention towards the position of the forthcoming pointing target, whereas the cue giving the compatibility between S1 and S2 was intended to mobilize the subject's attention more implicitly. Prior to performing the pointing movement towards a visual target, the subjects' attention was therefore mobilized by the advance information containing two components: the explicit information about the position of S1 and the implicit information about the probability of S1 and S2 being compatible. RESULTS AND CONCLUSION: The results obtained here on 17 normal adult subjects show that the subjects significantly improved their RTs by using the explicit component of the information provided. The implicit information available was also used in the choice reaction situations: a priming effect was found to occur, which resulted in the shortening of the primed "compatible cue" reaction times in comparison with the "neutral cue" reaction times, and in the correlation which was found to exist between the reaction time performances and the degree of compatibility between the preparatory signal and the imperative signal. These results suggest that various components of the attentional system may participate in processing the advance information provided prior to the movement in reaction time tasks of the kind used here. The explicit information provided prior to the movement may mobilize the subject's vigilance and spatially orients his attention; whereas the implicit information available may rather subserve the internal control of the subject's attention.

[A specific function of the motor cortex in the reorganization of coordination in motor learning in animals and humans]. / Spetsificheskaia funktsiia motornoi kory v reorganizatsii koordinatsii pri dvigatel'nom obuchenii u zhivotnykh i cheloveka.

The findings suggest that a particular function of MCx in motor learning involves suppression of synergies and co-ordination which interferes with acquisition of new motor patterns. Experimental animal models based on inhibition of certain natural synergies or reflexes in the process of learning new co-ordination have been developed where the MCx is responsible for inhibition of natural motor patterns. Following the MCx lesion the natural synergies dominate again and the learned movement cannot be adequately performed. Similar disturbances occur after combined lesions of the premotor and parietal associative cortex or after lesions of the cerebellar nuclei. However, after the associative cortex or cerebellar lesions the recovery of learned co-ordinations is possible. This suggests the inhibition of inappropriate synergies or co-ordination during motor learning is a specific function of the MCx, the latter taking part in organisation of new co-ordination between posture and movement in humans as well.

[Tremor and abnormal movement in multiple sclerosis: symptomatic therapeutic indications]. / Les tremblements et les mouvements anormaux au cours de la sclérose en plaques: indications thérapeutiques à visée symptomatique.

Tremor and movement disorders in multiple sclerosis (MS) patients cause a severe functional impairment. The different types of tremor observed in MS are: cerebellor tremor with a dominant intention component, Holmes tremor characterized by the addition of rest and postural components and palatal tremor. When no medication can improve the functional status, it is acceptable to discuss the deep brain stimulation in the VIM thalamus, thus making possible a partial attenuation of the rest and postural component, mainly affecting the proximal part of the affected limb. Among the movement disorders, paroxysmal dyskinesias are not rare and a good therapeutic response is obtained with carbamazepine: dystonia and parkinsonism are usually coincidental features during MS.

Lateral leg raising in patients with Parkinson's disease: influence of equilibrium constraint.

Patients with Parkinson's disease often have difficulty maintaining postural stability. This impairment is attributed to postural adjustment deficits. We studied the postural adjustments associated with the performance of two complex tasks which differed only in the final equilibrium constraints. Ten patients with Parkinson's disease and six age-matched control subjects were asked to raise one leg laterally to an abduction angle of approximately 45 degrees as fast as possible to the right or left in random order. In the first series of tests, the subjects were instructed to maintain the leg at 45 degrees, whereas in the second series they were instructed to place their foot back on the ground. Recordings included ground reaction forces and kinematics. In the patients with Parkinson's disease the final posture for the first task was never maintained. The strategy used to shift the body weight was different for the two groups. In control subjects, it was initiated by a whole body rotation around the ankle followed by a trunk inclination around the hip. Conversely, in patients with Parkinson's disease, the shift of the body weight was initiated by a trunk inclination around the hip and then by a whole body rotation around the ankle. The amplitude of the trunk inclination toward the supporting side was smaller than in the control subjects. The second task with less severe equilibrium constraints was, on the whole, better performed by the patients even though the same postural adjustment deficits were present.

[Diagnostic criteria for idiopathic Parkinson's disease]. / Criteres de diagnostic de la maladie de Parkinson idiopathique.

Clinical diagnosis of parkinsonian syndrome is reasonably easy, but the distinction between idiopathic Parkinson's disease (IPD) and other parkinsonian syndromes (Secondary parkinsonisms and "Parkinsons plus") may be very difficult particularly in early cases. A correct diagnosis is not only important for counselling and management of patients but also in conducting pharmacological and epidemiological studies. A critical analysis of the diagnosis criteria of IPD, based on the pathological verification, is discussed from recent data of literature. Without any validated and available criteria from functional imaging or molecular biology, the most effective diagnostic criteria remain on the clinical range; the five most effective criteria are resting tremor, rigidity, bradykinesia, asymmetry at onset and marked levoDOPA responsiveness. The diagnosis of IPD should be periodically reassessed along the course of its natural history.

Forward versus backward oriented stepping movements in Parkinsonian patients.

The primary purpose of this paper was to compare the effect of reversing the direction of step initiation in Parkinson's disease. Forward (FDS) and backward (BDS) oriented stepping initiation analyses were conducted on combined kinematic and kinetic data recorded on Parkinsonian patients (PD) and healthy age-matched subjects. Two successive phases were examined: a postural phase from T1 (onset of the center of pressure [CP] displacement) to T2 (onset of the malleolus displacement), which was followed by a stepping phase from T2 to T3 (end of the malleolus displacement; i.e., the end of the step). In healthy subjects, the duration of the postural phase remained unchanged regardless of the direction in which the step was initiated. The stepping phase duration and the first step length were reduced in BDS in comparison with FDS. In both tasks, the absolute value of the horizontal force in sagittal plane (Fx) remained unchanged. The maximal velocity of the iliac crest marker (estimated whole body center of gravity [CG]) in the sagittal plane (Vmax CG) remained within the same range regardless of direction of stepping. In Parkinsonian patients, the duration of the postural phase was markedly prolonged in both tasks in comparison with healthy subjects. The mean duration of stepping phase was approximately the same as in normal subjects, but the first step length was considerably reduced, as were horizontal force (Fx) and Vmax CG. This impairment, which was due to a decrease in the propulsive forces, was significantly more pronounced in BDS that in FDS.