Mg Of Levodopa Research Articles

Intensity-dependent effects of tDCS on motor learning are related to dopamine

Non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), are popular methods for inducing neuroplastic changes to alter cognition and behaviour. One challenge for the field is to optimise stimulation protocols to maximise benefits. For this to happen, we need a better understanding of how stimulation modulates cortical functioning/behaviour. To date, there is increasing evidence for a dose-response relationship between tDCS and brain excitability, however how this relates to behaviour is not well understood. Even less is known about the neurochemical mechanisms which may drive the dose-response relationship between stimulation intensities and behaviour. Here, we examine the effect of three different tDCS stimulation intensities (1 mA, 2 mA, 4 mA anodal motor cortex tDCS) administered during the explicit learning of motor sequences. Further, to assess the role of dopamine in the dose-response relationship between tDCS intensities and behaviour, we examined how pharmacologically increasing dopamine availability, via 100 mg of levodopa, modulated the effect of stimulation on learning. In the absence of levodopa, we found that 4 mA tDCS improved and 1 mA tDCS impaired acquisition of motor sequences relative to sham stimulation. Conversely, levodopa reversed the beneficial effect of 4 mA tDCS. This effect of levodopa was no longer evident at the 48-h follow-up, consistent with previous work characterising the persistence of neuroplastic changes in the motor cortex resulting from combining levodopa with tDCS. These results provide the first direct evidence for a role of dopamine in the intensity-dependent effects of tDCS on behaviour.

Dopamine Increases Accuracy and Lengthens Deliberation Time in Explicit Motor Skill Learning.

Although animal research implicates a central role for dopamine in motor skill learning, a direct causal link has yet to be established in neurotypical humans. Here, we tested if a pharmacological manipulation of dopamine alters motor learning, using a paradigm which engaged explicit, goal-directed strategies. Participants (27 females; 11 males; aged 18-29 years) first consumed either 100 mg of levodopa (n = 19), a dopamine precursor that increases dopamine availability, or placebo (n = 19). Then, during training, participants learnt the explicit strategy of aiming away from presented targets by instructed angles of varying sizes. Targets jumped mid-movement by the instructed aiming angle. Task success was thus contingent upon aiming accuracy and not speed. The effect of the dopamine manipulations on skill learning was assessed during training and after an overnight follow-up. Increasing dopamine availability at training improved aiming accuracy and lengthened reaction times, particularly for larger, more difficult aiming angles, both at training and, importantly, at follow-up, despite prominent session-by-session performance improvements in both accuracy and speed. Exogenous dopamine thus seems to result in a learnt, persistent propensity to better adhere to task goals. Results support the proposal that dopamine is important in engagement of instrumental motivation to optimize adherence to task goals, particularly when learning to execute goal-directed strategies in motor skill learning.

Efficacy and safety of Vicia faba L. extract compared with levodopa in management of Parkinson’s disease and an in‐silico phytomedicine analysis

Background: Parkinson’s disease is a chronic degenerative disease of the central nervous system, presently lacks an effective therapy for its complex pathogenesis. Agents containing Levodopa can alleviate its symptoms. Hypothesis Vicia faba L. (Fava bean) extract may prove a useful antiparkinsonian agent similar to Levodopa. Methods: Thirty patients with Parkinson’s disease, entered into this cross over clinical study. In the first step, each participant received V. faba L. extract containing 106.5 mg of Levodopa. After a wash out period of 7 days, the patients entered the second step during which they received conventional treatment with Levodopa-C tablets. Blood Levodopa were measured 4 hours and 8 hours after each administration. The Movement Disorder Society-Unified Parkinson’s Disease Rating Scale was employed to measure the therapeutic effects in each step. Additionally, a docking analysis was performed to distinguish the chemical constituents of the plant and six key mediators actively involved in Parkinson disease. Results: The fava bean extract significantly alleviate all studied end points except for tremor at rest and freezing. Wilcoxon Signed Ranks Test showed that there was not a significant difference between rigidity, rising chair, gait and bradykinesia. Docking results of the herb components and standard ligands, indicating that the antiparkinsonian activity of V. faba could presumably be related to many phytochemicals. Conclusion: This study showed a beneficial effect of V. faba L. similar to Levodopa-C. and better compliance due to lower adverse events.

Pulmonary function and medication effect in mild-stage subjects with Parkinson's disease.

Parkinson's disease (PD) causes a series of movement disorders, many of them starting in the early stage. To analyze the pulmonary function of mild-stage subjects with PD and to investigate the effects of levodopa on it. We included 21 patients with idiopathic PD and 20 healthy control subjects. The participants were submitted to spirometry and impulse oscillometry assessments. The PD patients were evaluated during the "off" and "on" phases of their anti-PD medication, which was was converted to levodopa in an equivalent daily dose. A statistical analysis was performed with cross-sectional (PD patients "off" medication versus controls) and paired (PD patients "off" medication versus PD patients "on" medication) tests. The effect of levodopa was calculated with partial Eta-squared (η2 ρ). Significance was set at 5%. The PD patients presented normal values in the impulse oscillometry. Regarding spirometry, the results indicated an incipient obstructive ventilatory disorder in the PD group - confirmed by patients' flow-volume curves. The PD patients received a daily dose of 354.7 ± 148.2 mg of levodopa. The paired analyses showed a small effect of anti-PD medication on pulmonary parameters (η2 ρ = 0.197 for spirometry and η2 ρ= 0.043 for impulse oscillometry). Patients with PD in the mild stage of the disease present pulmonary compliance and resistance compatible with normal parameters. The differences regarding the spirometric results indicate an incipient obstructive ventilatory disorder in patients with PD. Levodopa had small effect on pulmonary function in the mild stage of the disease.

Substantial Depletion of Vicine, Levodopa, and Tyramine in a Fava Bean Protein-Based Nutritional Product.

A commercial fava bean protein isolate and a liquid nutritional product formulated with it were tested by validated HPLC methods for the favism-associated pyrimidine glycoside vicine, the dopamine precursor levodopa, and the biogenic amine tyramine. The vicine, levodopa, and tyramine concentrations in the protein isolate—306, 13.3, and <0.5 mg/kg, respectively—when expressed on a protein basis—34, 1.5, and <0.06 mg/100 g protein, respectively—were at least 96% lower than the vicine, levodopa, and tyramine (protein-based) concentrations reported for fava beans (≥900, ~200, and ~4 mg/100 g protein, respectively). This was also true for the vicine (13 mg/kg or 22 mg/100 g protein), levodopa (≤0.17 mg/kg or ≤0.3 mg/100 g protein), and tyramine (0.08 mg/kg or 0.14 mg/100 g protein) concentrations in the nutritional product. On the basis of these data, one serving (11 fl. oz.) of the nutritional product would deliver approximately 5 mg of vicine, <1 mg of levodopa, and <0.1 mg of tyramine.

Effectiveness of Levodopa in Patients with Multiple System Atrophy and Associated Clinicopathological Features.

Objective To determine the clinicopathological features of levodopa or dopamine agonist (DA) responders with multiple system atrophy (MSA), an autopsy-confirmed diagnosis is vital due to concomitant cases of MSA and Parkinson's disease (PD). We therefore aimed to investigate the effectiveness of levodopa and DA in autopsy cases of MSA without PD and thereby clarify the clinical course, magnetic resonance imaging (MRI) findings, and pathological features of levodopa-responsive MSA cases. Methods The medical records (clinical data, MRI findings, and pathological findings) of 12 patients with MSA were obtained, and the patients were pathologically confirmed to not have PD. The clinical diagnoses of the patients were MSA with predominant parkinsonism (MSA-P) (n=7), MSA with predominant cerebellar ataxia (MSA-C) (n=4), and progressive supranuclear palsy (PSP) with a concomitant pathology of MSA (n=1). Results Nine patients received a maximum dose of 300-900 mg of levodopa as treatment, which was effective in two MSA-P patients and mildly effective in another two MSA-P patients. DA was mildly effective in one MSA-C patient. The levodopa responders showed marked autonomic dysfunction relatively late and became bedridden after 10 years. Additionally, they exhibited bilateral hyperintense putaminal rims in MRIs after six and nine years, respectively, after disease onset. One levodopa responder and one DA mild responder showed relatively mild neurodegeneration of the putamen. Conclusion Levodopa responders, despite having MSA-P, may show a relatively slow progression in putaminal neurodegeneration, and might maintain prolonged daily life activities in cases without an early occurrence of autonomic dysfunction.

The role of levodopa in improving procedural motor training for patients with chronic stroke

To test the hypothesis that administration of dopamine precursor levodopa improves procedural motor learning (defined as the ability to acquire novel movement patterns gradually through practice) in patients with residual motor deficits in the chronic phase after stroke(> or =1 y after stroke). Neurology department in a Tashkent Medical Academy. Eighteen patients with chronic motor dysfunction because of stroke (33 men, 25 women; age range, 53-78 y; mean time poststroke +/- SD, 3.3+/-2.1 y). Patients received 3 doses of levodopa (100mg of levodopa plus 25mg of carbidopa) or placebo before 1 session of procedural motor learning. Procedural motor learning performed by using the paretic hand assessed by using a modified version of the serial reaction time task with a prbabilistic sequence. The primary outcome measure was the difference in reaction times between random and sequential elements. Levodopa significantly improved our primary outcome measure, procedural motor learning, compared with placebo (P<.05). Reaction times to random elements, analysis of error rates, psychophysical assessments, and performance in a simple motor task were comparable between conditions, indicating that better learning under levodopa was not caused by differences in response styles, arousal, mood, or motor reaction times but that levodopa modulated learning. Our results show that levodopa may improve procedural motor learning in patients with chronic stroke, in line with our hypothesis. These findings suggest that this interventional strategy in combination with customary rehabilitative treatments could significantly improve the outcome of neurorehabilitation in the chronic stage after stroke.

Safety and efficacy of co-careldopa as an add-on therapy to occupational and physical therapy in patients after stroke (DARS): a randomised, double-blind, placebo-controlled trial

SummaryBackgroundDopamine is a key modulator of striatal function and learning and might improve motor recovery after stroke. Previous small trials of dopamine agonists after stroke provide equivocal evidence of effectiveness on improving motor recovery. We aimed to assess the safety and efficacy of co-careldopa plus routine occupational and physical therapy during early rehabilitation after stroke.MethodsThis double-blind, multicentre, randomised controlled trial of co-careldopa versus placebo in addition to routine NHS occupational and physical therapy was done at 51 UK NHS acute inpatient stroke rehabilitation services. We recruited patients with new or recurrent clinically diagnosed ischaemic or haemorrhagic (excluding subarachnoid haemorrhage) stroke 5–42 days before randomisation, who were unable to walk 10 m or more, had a score of less than 7 points on the Rivermead Mobility Index, were expected to need rehabilitation, and were able to access rehabilitation after discharge from hospital. Participants were assigned (1:1) using stratified random blocks to receive 6 weeks of oral co-careldopa or matched placebo in addition to routine NHS physiotherapy and occupational therapy. The initial two doses of co-careldopa were 62·5 mg (50 mg of levodopa and 12·5 mg of carbidopa) and the remaining doses were 125 mg (100 mg of levodopa and 25 mg of carbidopa). Participants were required to take a single oral tablet 45–60 min before physiotherapy or occupational therapy session. The primary outcome was ability to walk independently, defined as a Rivermead Mobility Index score of 7 or more, at 8 weeks. Primary and safety analyses were done in the intention-to-treat population. The trial is registered on the ISRCTN registry, number ISRCTN99643613.FindingsBetween May 30, 2011, and March 28, 2014, of 1574 patients found eligible, 593 (mean age 68·5 years) were randomly assigned to either the co-careldopa group (n=308) or to the placebo group (n=285), on an average 18 days after stroke onset. Primary outcome data were available for all 593 patients. We found no evidence that the ability to walk independently improved with co-careldopa (125 [41%] of 308 patients) compared with placebo (127 [45%] of 285 patients; odds ratio 0·78 [95% CI 0·53–1·15]) at 8 weeks. Mortality at 12 months did not differ between the two groups (22 [7%] vs 17 [6%]). Serious adverse events were largely similar between groups. Vomiting during therapy sessions, after taking the study drug, was the most frequent adverse event and was more frequent in the co-careldopa group than the placebo group (19 [6·2%] vs 9 [3·2%]).InterpretationCo-careldopa in addition to routine occupational and physical therapy does not seem to improve walking after stroke. Further research might identify subgroups of patients with stroke who could benefit from dopaminergic therapy at different doses or times after stroke with more intensive motor therapy.FundingMedical Research Council.

Levodopa does not affect expression of reinforcement learning in older adults

Dopamine has been implicated in learning from rewards and punishment, and in the expression of this learning. However, many studies do not fully separate retrieval and decision mechanisms from learning and consolidation. Here, we investigated the effects of levodopa (dopamine precursor) on choice performance (isolated from learning or consolidation). We gave 31 healthy older adults 150 mg of levodopa or placebo (double-blinded, randomised) 1 hour before testing them on stimuli they had learned the value of the previous day. We found that levodopa did not affect the overall accuracy of choices, nor the relative expression of positively or negatively reinforced values. This contradicts several studies and suggests that overall dopamine levels may not play a role in the choice performance for values learned through reinforcement learning in older adults.

Effects of levodopa on stimulus-response learning versus response selection in healthy young adults

Dopaminergic therapy has been shown to worsen some cognitive functions, particularly learning, in Parkinson’s disease (PD). This has been attributed to dopamine overdose of brain regions that are relatively dopamine replete. Dopamine dosages are titrated to the severely depleted dorsal striatum (DS). According to this account, dopaminergic therapy should worsen cognitive functions in healthy young adults who have normal dopamine levels. As a critical test of the dopamine overdose hypothesis, we tested the effect of levodopa on learning stimulus-response associations and on performing stimulus-specific responses once these associations were learned. In a randomized, double-blind, placebo-controlled, between-subjects design, 40 healthy young adults completed a stimulus-response learning task on either levodopa or placebo. Half of the participants received 100mg of levodopa and 25mg of carbidopa whereas the other half received an equal volume of placebo. In Session 1, participants learned to associate abstract images with specific key-press responses through trial and error with outcome feedback. In Session 2, participants performed stimulus-specific selections to abstract images they had previously learned in Session 1. Participants treated with levodopa compared to those on placebo demonstrated unambiguously less efficient acquisition of stimulus-response associations. The groups did not differ in their ability to enact stimulus-specific selections once they were learned, however, even though these responses were not overlearned. This pattern of findings is entirely consistent with the effect of levodopa on cognition in PD. The deleterious effects of levodopa on learning seem independent of PD pathology. These results have important implications for understanding mechanisms of cognitive dysfunction in PD and caution about the potential for cognitive deficits in patients treated with levodopa for other indications.

EP 43. Impulse control disorder (ICD) and dopamine dysregulation syndrome (DDS) in Parkinson’s disease (PD) and deep brain stimulation surgery: A clinical Case

Introduction The treatment of impulse control disorder (ICD) and dopamine dysregulation syndrome (DDS) in Parkinson’s Disease (PD) is complex. It was found in some series, that PD patients undergoing bilateral subthalamic nucleus DBS surgery (stn-DBS) that previously had ICD/DDS significantly improved of that domain after surgery. This fact has prompted a growing interest in the influence that STN-DBS surgery may have in these cases. Clinical case A 52 years-old patient with juvenile PD, onset at 42 years-old, with negative genetic study (parkin/LRRK2 mutations). Six years ago started to develop motor fluctuations, initially controlled with optimization of dopaminergic replacement therapy (DRT), but two years later starts to experience complex motor fluctuations, difficult to control with DRT. Progressively his family started to note some behavioural changes, namely, pathological gambling and hypersexuality, with marked disruption of social, familiar and work life. At this point, he was on 1510 mg equivalents of levodopa (LED), and 260 mg of LED in the form of ropinirole (extended release). The dopamine agonist was gradually suspended with progressive improvement of ICD symptoms. In the last year, he started to develop DDS, reaching to 2000–3000 mg/day of LED ingested through the form of short-acting formulations of levodopa, with disabling peak dose dyskinesia, frequent falls and functional impairment. Additionally, this patient had a motor response to a levodopa challenge of 60% (MDS-UPDRS-III), cognitively presented no significant changes (MoCA: 23; DRS-II; 138), reported no depression (BDI-II: 7) or apathy (AES-C: 27), and moderate ICD (QUIP Q: sexual and DDS domains impaired) and some non-motor symptoms/fluctuations (NMSS-PD: 23; Ardouin Scale: 42). He was then submitted to bilateral stn-DBS surgery. We will present the post-surgical outcome at 8 months. Conclusion Currently, there is not enough evidence in the literature to use stn-DBS surgery as a therapy for ICD/DDS. However, in patients who otherwise meet criteria for stn-DBS this procedure can also be helpful in controlling the symptoms of ICD/DDS, which can have a major impact on social, familiar and professional life as this case demonstrates.

EP 58. Corticomuscular coherence during isotonic contractions with DBS and medication in PD patients

Introduction Deep brain stimulation (DBS) effectively alleviates the motor symptoms in Parkinson’s disease (PD) although its effect mechanism is still unclear. Corticomuscular coherence (CMC) is a marker of the functional connectivity between the pyramidal system and the periphery ( Hari and Salenius, 1999 ). CMC has been shown to be reduced in PD patients but restorable with medication ( Salenius et al., 2002 ). DBS, on the other hand, has been shown to variably affect CMC in advanced PD patients ( Airaksinen et al., 2015 ). Objectives We investigated movement related cortical oscillations with primary focus on beta CMC (13–30 Hz). The objective was to discern whether both medication and DBS affect CMC in similar manners in unison with their comparable effects on PD patients’ motor symptoms as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS-III). Patients and methods We recorded magnetoencephalography (MEG) from three PD patients performing hand gripping during DBS ON and medicated (MED ON) conditions and from three age-matched healthy control. For the MED ON condition, patients were administered 200 mg of levodopa with MEG measurements one hour later. Participants performed isotonic contractions with their right hand (hand gripping), and electromyography (EMG) was recorded from the extensor digitorum communis muscle in a belly-tendon montage. We calculated the mean-squared coherence between MEG and the rectified EMG signals. Confidence intervals were set at 99% of the time-shifted MEG-EMG coherence (3 s delay of EMG signal) ( [Halliday et al., 1995] , [Airaksinen et al., 2015] ). For each group and condition, we selected the maximum CMC value in the beta range (13–30 Hz) within the average of an a priori selection of nine left sensorimotor gradiometer pairs in the grand averaged data for each group and condition. Results The grand averaged CMC results are shown in Fig. 1. Medication (MED ON) seemed to normalize beta CMC values in PD patients to comparable levels of the controls whereas DBS led to reduced beta CMC values while both treatments had similar effects on the patients’ motor symptoms (UPDRS-III). Conclusion Although both medication and DBS ameliorate clinical motor performance to similar extents, they seem to have differentiated effects on CMC which may point to differences in the effects mechanisms of the two treatments.

The single intake of levodopa modulates implicit learning in drug naïve, de novo patients with idiopathic Parkinson's disease.

Although dopamine is known to aggravate implicit learning, the exact impact on behaviour when feedback is unavailable remains unclear. Previous studies revealed that non-rewarded learning habits are affected in long-term dopaminergic treated patients with Parkinson's disease (PD). We studied the influence of a onetime levodopa intake on implicit learning in de novo, untreated PD patients. De novo PD patients (n=22) before and after the single intake of levodopa and control subjects (n=23) took part in a Go/NoGo paradigm. One stimulus was defined as target, which was first consistently preceded by one of three non-target stimuli (conditioning). This coupling was dissolved thereafter (deconditioning). In the 'Go version' subjects were asked to respond to the target by pressing a key, whereas in the 'NoGo version' response had to be inhibited. PD patients and controls (n=14/n=19) with an initial learning effect due to the target were included for further statistical analysis. Within the subgroup incorrect responses upon NoGo stimuli increased during the deconditioning phase. In contrast, the same patients failed to show any change after receiving 200mg of levodopa. During the Go version, no change of the overall error rate between conditioning and deconditioning was detectable over all groups. Learning behaviour in untreated PD patients and healthy controls was indistinguishable. In contrast, the same patients varied in their implicit learning after one-time intake of levodopa, when actions had to be inhibited. Hence, the single intake of levodopa appears to modulate implicit learning behaviour in de novo PD patients.

IMPULSIVE-COMPULSIVE DISORDERS IN PARKINSON'S DISEASE. CLINICAL CASES

Objective – a description of clinical cases of impulsive­compulsive disorders in Parkinson , s disease. The first clinical case. Patient N. , 75 years old, suffering for 15 years from Parkinson , s disease, akinetic­rigid form of the disease, stage 4 by Hyun–Yar. Since 2009, he received levodopa/carbidopa 250/25 mg 5 times/day (daily dose of 1250 mg of levodopa); pramipexole 3.5 mg per day (daily dose 3.5 mg), amantadine sulfate 100 mg 5 times/day (daily dose 500 mg). While taking antiparkinsonian drugs the patient developed behavioral disorders such as dopamine disregulatory syndrome combined with punding, hypersexuality and compulsive shopping accompanied by visual hallucinations. The total equivalent dose of levodopa was 1600 mg per day. The second clinical case. Patient R. , 52 years old, suffers from Parkinson , s disease about 5 years, a mixed form. She complained of slowness of movement, tremor in her left hand, sleep disturbances, poor mood. The clinic was appointed piribedil 50 mg 3 times per day. Despite the fact that the patient took only one of dopaminergic drugs in a therapeutic daily dose, she developed impulsive­compulsive disorder as hyper­ sexuality, compulsive shopping and binge eating. Results. In the first clinical case for correction of behavioral disorders in patients with Parkinson , s disease levodopa/carbidopa dose was reduced to 750 mg per day (3/4 Tab. 4 times a day); added to levodopa/benserazide dispersible 100 mg morning and levodopa/benserazide 100 mg before sleep (total dose of levodopa of 950 mg per day). Amantadine sulfate and pramipexole were canceled. It was added to the therapy of atypical neuroleptic clozapine dose 6,25 mg overnight. After 3 months marked improvement, regressed visual hallucina­ tions, improved family relationships, background mood became more stable. The patient continue to sing karaoke, but this hobby has be­ come less intrusive. In the second clinical event correction impulsive­compulsive disorders piribedil was replaced with pramipexole 1.5 mg prolonged form one time a day. At the control examination after 3 months behavioral disorders completely regressed. Conclusion. This article describes two clinical cases of impulsive­compulsive disorders in patients with Parkinson s disease, methods of di­ agnosis and correction capabilities of these disorders.

Liquid melevodopa versus standard levodopa in patients with Parkinson disease and small intestinal bacterial overgrowth.

Patients with Parkinson disease exhibit a highly increased prevalence of small intestinal bacterial overgrowth (SIBO), which has been also associated with the severity of motor fluctuations. Aim of this study was to test the efficacy of liquid levodopa with higher bioavailability in patients with SIBO. Thirty-three patients with Parkinson disease underwent both lactulose and glucose breath tests to assess the presence of SIBO. A urea breath test was performed to assess the presence of a concomitant Helicobacter pylori infection. Patients were challenged with 250 mg of levodopa and 314 mg of levodopa methylester. Drug challenges were performed on different days and at baseline and 1 month after SIBO eradication. During the tests, the motor condition and the plasma levodopa concentrations were evaluated. At baseline, the onset of motor benefit was significantly shorter after melevodopa than after standard levodopa, as confirmed by the latency to motor on condition and t max (time to the on condition, 28.8±11.5 vs 55.5±40.2 minutes; P=0.0004; and t max, 28.2±9.7 vs 50.0±11.0 minutes; P=0.002). The duration of the on time or area under the curve was not significantly different. The underlying gastrointestinal condition did not influence these results. The reduction of the latency to the on condition in the absence of a reduction of the on duration is a promising feature of melevodopa because this effect would increase the total daily on duration. Future studies that evaluate the usefulness of melevodopa beyond the acute challenge (eg, using motor diaries) in patients with gastrointestinal infections are warranted.

P307: Levodopa responsiveness of blink reflex recovery index – an objective method of differentiating Parkinson’s disease from Parkinson plus syndromes

P307: Levodopa responsiveness of blink reflex recovery index – an objective method of differentiating Parkinson’s disease from Parkinson plus syndromes

Cognitive effects of methylphenidate and levodopa in healthy volunteers

Our previous study showed enhanced declarative memory consolidation after acute methylphenidate (MPH) administration. The primary aim of the current study was to investigate the duration of this effect. Secondary, the dopaminergic contribution of MPH effects, the electrophysiological correlates of declarative memory, and the specificity of memory enhancing effects of MPH to declarative memory were assessed. Effects of 40mg of MPH on memory performance were compared to 100mg of levodopa (LEV) in a placebo-controlled crossover study with 30 healthy volunteers. Memory performance testing included a word learning test, the Sternberg memory scanning task, a paired associates learning task, and a spatial working memory task. During the word learning test, event-related brain potentials (ERPs) were measured. MPH failed to enhance retention of words at a 30min delay, but it improved 24h delayed memory recall relative to PLA and LEV. Furthermore, during encoding, the P3b and P600 ERP latencies were prolonged and the P600 amplitude was larger after LEV compared to PLA and MPH. MPH speeded response times on the Sternberg Memory Scanning task and improved performance on the Paired Associates Learning task, relative to LEV, but not PLA. Performance on the Spatial working memory task was not affected by the treatments. These findings suggest that MPH and LEV might have opposite effects on memory

Randomized trial of IPX066, carbidopa/levodopa extended release, in early Parkinson's disease

ObjectiveIPX066 is an extended release carbidopa/levodopa formulation designed to rapidly attain and maintain therapeutic plasma concentrations for a prolonged duration, allowing dosing intervals of approximately 6 h. The objective was to assess the efficacy, safety, and impact on quality of life of IPX066 in the treatment of levodopa-naive Parkinson's disease (PD) patients. MethodsThis was a randomized, double-blind, placebo-controlled, 30-week study of 381 levodopa-naïve patients assigned to placebo or IPX066 containing 145, 245 or 390 mg of levodopa administered three times daily (TID). The primary efficacy measure was change from Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living (Part II) + motor scores (Part III), at 30 weeks. Secondary outcome measures included UPDRS total and subscores, patient and clinician global impressions (PGI-I, CGI-I), and the Parkinson's Disease Questionnaire (PDQ-39). ResultsAll IPX066 dosages were superior to placebo throughout the study and at 30 weeks (P < 0.0001). The mean improvement in UPDRS Parts II + III at 30 weeks compared to baseline was 11.7, 12.9, and 14.9 points for the three dosages and 0.6 points for placebo (P < 0.0001, all dosages). PDQ-39 total scores improved with IPX066 (P ≤ 0.034, all dosages). The most commonly reported adverse events with IPX066 included nausea, dizziness, and headache. No unexpected drug-related serious adverse events were reported. ConclusionIPX066 provided significant clinical benefits at the three dosages tested compared to placebo and was well tolerated in levodopa-naive PD patients. Of the dosages tested, IPX066 145 mg TID appeared to provide the best overall balance between efficacy and safety.

Diagnosis and Management of Progressive Supranuclear Palsy

SUMMARY Progressive supranuclear palsy is one of the rare ‘atypical parkinsonian’ disorders. It is distinguished by its disproportionate postural instability and multiple supranuclear gaze defects emphasizing downgaze limitation. Frontal dementia, bradykinesia, greater rigidity in axial compared with limb muscles, dysarthria and dysphagia also produce major disability, with death after an average of 7 years post-onset. Focal midbrain atrophy, basal ganglia gliosis and iron deposition on MRI assist diagnosis, but present formal diagnostic criteria rely on the history and physical examination of the patient. Experimental biomarkers utilizing cerebrospinal fluid, tau and novel imaging techniques are promising but remain unproven. Unlike Parkinson’s disease, supranuclear palsy usually responds poorly to dopaminergic medication. However, a trial of up to 1200 mg of levodopa per day (with carbidopa) is justified in patients with rigidity and bradykinesia. Amantadine and coenzyme Q-10 may also provide minor symptomatic benefits. Physical measures such as gait assistance and alteration of diet or swallowing technique address the two principal causes of morbidity and mortality in PSP.

Dopaminergic modulation of neural correlates of working memory in Parkinson’s Disease

ObjectiveBrain mechanisms underlying performance of working memory (WM) vary according to domain specific requirements of the WM task. In Parkinson’s Disease (PD) domain specific WM tasks can be differentially affected. MethodWe investigated the pattern of brain activation during performance of domain specific working memory tasks in nine patients with early PD before (OFF-state) and after challenge with 200mg of levodopa (ON-state) by functional Magnetic Resonance Imaging (fMRI) using two variants of a phonological and one visual delayed matched to sample task paradigm. Eleven healthy volunteers were studied with the same protocol once. ResultsBehavioural data showed no significant difference of accuracy in performance of the WM tasks between PD and healthy controls. During performance of the verbal WM task fMRI revealed reduced activity within the left middle frontal gyrus, right cerebellum and left posterior inferior temporal gyrus in patients with PD. These abnormalities could be reversed by levodopa. In contrast, reduced activity within the right prefrontal cortex, that was found during visuospatial WM performance remained unchanged after levodopa administration. ConclusionsOur findings demonstrate altered brain activity in PD during verbal and visuospatial WM tasks and show different responses of these disturbed WM networks to levodopa.