A multiple motion sensors index for motor state quantification in Parkinson's disease.

AIM: To construct a Treatment Response Index from Multiple Sensors (TRIMS) for quantification of motor state in patients with Parkinson's disease (PD) during a single levodopa dose. Another aim was to compare TRIMS to sensor indexes derived from individual motor tasks. METHOD: Nineteen PD patients performed three motor tests including leg agility, pronation-supination movement of hands, and walking in a clinic while wearing inertial measurement unit sensors on their wrists and ankles. They performed the tests repeatedly before and after taking 150% of their individual oral levodopa-carbidopa equivalent morning dose.Three neurologists blinded to treatment status, viewed patients' videos and rated their motor symptoms, dyskinesia, overall motor state based on selected items of Unified PD Rating Scale (UPDRS) part III, Dyskinesia scale, and Treatment Response Scale (TRS). To build TRIMS, out of initially 178 extracted features from upper- and lower-limbs data, 39 features were selected by stepwise regression method and were used as input to support vector machines to be mapped to mean reference TRS scores using 10-fold cross-validation method. Test-retest reliability, responsiveness to medication, and correlation to TRS as well as other UPDRS items were evaluated for TRIMS. RESULTS: The correlation of TRIMS with TRS was 0.93. TRIMS had good test-retest reliability (ICC = 0.83). Responsiveness of the TRIMS to medication was good compared to TRS indicating its power in capturing the treatment effects. TRIMS was highly correlated to dyskinesia (R = 0.85), bradykinesia (R = 0.84) and gait (R = 0.79) UPDRS items. Correlation of sensor index from the upper-limb to TRS was 0.89. CONCLUSION: Using the fusion of upper- and lower-limbs sensor data to construct TRIMS provided accurate PD motor states estimation and responsive to treatment. In addition, quantification of upper-limb sensor data during walking test provided strong results.

Development of new levodopa treatment strategies in Parkinson's disease-from bedside to bench to bedside.

This review will illustrate the process of moving from an idea through preclinical research and Galenic developments into clinical investigations and finally to approval by regulatory agencies within the European Union. The two new treatment strategies described, levodopa/carbidopa intestinal gel and levodopa/carbidopa microtablets, for advanced Parkinson's disease, have been developed in collaborative research within departments at Uppsala University. With this historical approach, reference priority is given to reports considered to be of special importance for this more than two decades long process 'from bedside to bench to bedside'.

Levodopa/carbidopa microtablets in Parkinson's disease: a study of pharmacokinetics and blinded motor assessment.

BACKGROUND: Motor function assessments with rating scales in relation to the pharmacokinetics of levodopa may increase the understanding of how to individualize and fine-tune treatments. OBJECTIVES: This study aimed to investigate the pharmacokinetic profiles of levodopa-carbidopa and the motor function following a single-dose microtablet administration in Parkinson's disease. METHODS: This was a single-center, open-label, single-dose study in 19 patients experiencing motor fluctuations. Patients received 150% of their individual levodopa equivalent morning dose in levodopa-carbidopa microtablets. Blood samples were collected at pre-specified time points. Patients were video recorded and motor function was assessed with six UPDRS part III motor items, dyskinesia score, and the treatment response scale (TRS), rated by three blinded movement disorder specialists. RESULTS: AUC0-4/dose and C max/dose for levodopa was found to be higher in Parkinson's disease patients compared with healthy subjects from a previous study, (p = 0.0008 and p = 0.026, respectively). The mean time to maximum improvement in sum of six UPDRS items score was 78 min (±59) (n = 16), and the mean time to TRS score maximum effect was 54 min (±51) (n = 15). Mean time to onset of dyskinesia was 41 min (±38) (n = 13). CONCLUSIONS: In the PD population, following levodopa/carbidopa microtablet administration in fasting state, the Cmax and AUC0-4/dose were found to be higher compared with results from a previous study in young, healthy subjects. A large between subject variability in response and duration of effect was observed, highlighting the importance of a continuous and individual assessment of motor function in order to optimize treatment effect.

Pharmacokinetics of levodopa/carbidopa microtablets versus levodopa/benserazide and levodopa/carbidopa in healthy volunteers.

OBJECTIVES: To compare bioavailability and pharmacokinetics of single doses of 3 different levodopa formulations given orally in healthy volunteers. Two marketed formulations, standard levodopa/carbidopa, 100/25 mg (LC-100), and dispersible levodopa/benserazide, 100/25 mg (LB-100), were used as reference formulations for a newly developed dispersible microtablet formulation of levodopa/carbidopa, 5/1.25 mg (LC-5). The microtablets are intended for individualized dosing of levodopa/carbidopa in Parkinson disease by means of an electronic dose dispenser with a built-in diary for symptom registration. METHODS: A single-dose, open, randomized, 3-way crossover study was performed in 19 healthy subjects. Concentrations of levodopa, carbidopa, and the metabolite 3-O-MD in plasma were determined after intake of 100 mg of levodopa, that is, one tablet of reference formulations and 20 microtablets of the new formulation. RESULTS: The LC-5 microtablets were bioequivalent to the LC-100 tablets in area under the curve (AUC) and maximum concentration in plasma (Cmax) for levodopa, and to the LB-100 tablets in AUC. The dispersible levodopa/benserazide formulation showed earlier time to Cmax and significantly higher Cmax for levodopa in plasma compared to the microtablets. Carbidopa showed larger interindividual variation in AUC and Cmax than levodopa, and the bioequivalence comparison LC-5/LC-100 for this compound did not reach the target. Nevertheless, comparison of 3-O-MD levels for LC-5/LC-100, assuming proportionality to levodopa levels, demonstrated bioequivalence. CONCLUSIONS: The new levodopa/carbidopa microtablets had a pharmacokinetic profile that would allow for a convenient switch of therapy from standard tablets. Frequent dose administration of levodopa/carbidopa microtablets with an electronic dose dispenser might offer an optimal oral drug delivery in Parkinson disease.

Complexity of motor response to different doses of duodenal levodopa infusion in Parkinson disease.

OBJECTIVE: The aim was to elaborately describe individual pharmacokinetic-pharmacodynamic profiles in patients with difficult-to-treat dyskinesias treated with levodopa/carbidopa intestinal gel infusion. METHODS: A nonrandomized, partly blinded, investigator-initiated trial was conducted in 5 patients with idiopathic Parkinson disease who were difficult to keep in "on" state without dyskinesia. Levodopa/carbidopa intestinal gel (Duodopa) doses of 80% to 120% of individually and clinically optimized dosage were infused during five 4-hour periods. Pharmacokinetic profiling, blinded assessment of video recordings, and objective movement analysis were applied every 20 to 30 minutes. RESULTS: Individual correlations between plasma levodopa concentrations and corresponding motor scores 20 to 30 minutes after the sampling time were significant in all patients (P < 0.05 and P < 0.001). Motor scores were generally stable during the 4-hour periods. The objective test revealed that motor performance was faster the more dyskinetic the patients were. Mean individual Treatment Response Scale scores were positive in 24 of the 25 steady-state periods. Dystonia was always combined with choreic dyskinesias. CONCLUSIONS: Motor response from different doses of levodopa/carbidopa intestinal gel is in a broad sense predictable even in dyskinetic patients although major interindividual differences in dose requirement, plasma levels, and motor response are found. That motor performance was faster the more dyskinetic the patients were implies that motor performance may be better with moderate dyskinesia than with mild dyskinesia. This may explain why patients with persistent dyskinesias choose to keep their doses above the dyskinesia threshold. There is no ideal therapeutic window in such patients, but levodopa infusion offers stable motor response.

Manganese-Induced Parkinsonism due to Ephedrone Abuse.

During recent years, a syndrome of hypokinesia, dysarthria, dystonia, and postural impairment, related to intravenous use of a "designer" psychostimulant derived from pseudoephedrine using potassium permanganate as the oxidant, has been observed in drug addicts in several countries in Eastern Europe with some cases also in Western countries. A levodopa unresponsive Parkinsonian syndrome occurs within a few months of abusing the homemade drug mixture containing ephedrone (methcathinone) and manganese. The development of this neurological syndrome has been attributed to toxic effects of manganese, but the role of the psychostimulant ephedrone is unclear. This paper describes the clinical syndrome, results of neuroimaging, and therapeutic attempts.

Peripheral blood RNA expression profiling in illicit methcathinone users reveals effect on immune system.

Methcathinone (ephedrone) is relatively easily accessible for abuse. Its users develop an extrapyramidal syndrome and it is not known if this is caused by methcathinone itself, by side-ingredients (manganese), or both. In the present study we aimed to clarify molecular mechanisms underlying this condition. We used microarrays to analyze whole-genome gene expression patterns of peripheral blood from 20 methcathinone users and 20 matched controls. Gene expression profile data were analyzed by Bayesian modeling and functional annotation. Of 28,869 genes on the microarrays, 326 showed statistically significant differential expression with FDR adjusted p-values below 0.05. Quantitative real-time PCR confirmed differential expression for the most of the genes selected for validation. Functional annotation and network analysis indicated activation of a gene network that included immunological disease, cellular movement, and cardiovascular disease functions (enrichment score 42). As HIV and HCV infections were confounding factors, we performed additional stratification of subjects. A similar functional activation of the "immunological disease" category was evident when we compared subjects according to injection status (past versus current users, balanced for HIV and HCV infection). However, this difference was not large therefore the major effect was related to the HIV status of the subjects. Mn-methcathinone abusers have blood RNA expression patterns that mostly reflect their HIV and HCV infections.

Circadian rhythmicity in levodopa pharmacokinetics in patients with Parkinson disease.

OBJECTIVES: The purpose of this study was to compare daytime and nighttime plasma pharmacokinetics (PK) of levodopa in patients with Parkinson disease. METHODS: Four-hour plasma profiles of levodopa were captured in 8 patients with Parkinson disease after the second daily levodopa dose and after the identical dose at bedtime. Patients were fasting 2 hours before and 2 hours after dose intakes, except standardized amounts of tap water. Body position was upright during daytime testing and supine during nighttime testing. Four patients were additionally tested at daytime in supine position. RESULTS: The absorption rate was significantly delayed at nighttime dosing. The time at which the maximum peaks occurred was delayed from 25 (15-240) to 105 (20-240) minutes, respectively. Maximum concentrations were significantly lower at night, but the plasma exposure (area under the curve, 0-4 hours) was unaffected. Supine daytime plasma PK was in between day and night results. CONCLUSIONS: There is a slower absorption rate of levodopa during nighttime, probably related to delayed gastric emptying. However, the extent of absorption and bioavailability were unaffected. As the effect of posture on plasma PK was less than the effect of nighttime, this study suggests that the circadian rhythm has a pronounced effect on gastric emptying and absorption rate. Nevertheless, body position may also be an important factor, and it can be recommended that levodopa tablets be taken in upright position that probably should be sustained for at least 30 minutes.

Physiotherapy in cervical dystonia: six experimental single-case studies.

The aim of the study was to explore the outcome of a physiotherapy program targeted to improve the quality of life of people with cervical dystonia (CD) by reducing pain, improving awareness of postural orientation, increasing muscle strength, and reducing the effort of moving the head and neck. In six single case studies, the primary outcome measure for each case was the Cervical Dystonia Questionnaire (CDQ) to measure the impact of the program on the individuals' quality of life. Secondary outcome measures were identified for the different components of the physiotherapy program: Visual Analogue Scale (pain); Postural Orientation Index (postural orientation awareness); and Movement Energy Index (effort of moving head and neck). Each of the cases had the severity of their problems scored on the Toronto Western Spasmodic Torticollis Scale. The study period was 26 weeks: 2 weeks' baseline period, 4 weeks' treatment period, and 20 weeks' follow-up. All measures except the Movement Energy Index (MEI) and CDQ-24 were taken three times per week for the first 6 weeks of the study and then once at 3 and 6 months. The MEI was taken once a week during the pretreatment and the treatment periods and during the first 2 weeks of follow-up and also after 3 and 6 months of follow-up. The CDQ-24 was taken once in the pretreatment period, once after completion of treatment, once 2 weeks after treatment, and once at 3 and 6 months of follow-up. Five of the six case studies reported an increase in quality of life at 6-month follow-up, as measured on the CDQ-24. Three of the six cases reported a reduction in pain and severity of the dystonia and had improved scores on the postural orientation measure at 6-month follow-up. All six patients had a reduction in the movement energy scores, but this was not significant. The outcomes of the six case studies would suggest that further investigation is required to show the effectiveness of physiotherapy programs in the management of CD.

Enteral levodopa/carbidopa infusion in advanced Parkinson disease: long-term exposure.

OBJECTIVES: In patients with advanced Parkinson disease, levodopa/carbidopa formulated as a gel suspension (Duodopa) permits continuous delivery into the small intestine using a portable pump, resulting in less variability in levodopa concentrations and fewer motor fluctuations and dyskinesias than with oral levodopa administration. This is a retrospective analysis of the long-term clinical experience with this agent. METHODS: All but 1 of the patients who had received enteral levodopa infusion treatment between January 1, 1991, and June 30, 2002, consented to a review of their hospital charts. RESULTS: Of the 65 patients with initial testing of the treatment, 86% opted for continued treatment via percutaneous endoscopic gastrostomy or gastrojejunostomy. Total exposure to levodopa infusion was 216 patient-years (mean, 3.7 years). Maximum treatment duration was 10.7 years. Fifty-two patients were treated for 1 year or longer. The adverse effect profile of levodopa/carbidopa infusion was similar to that observed with oral administration of levodopa. Seven deaths occurred, all considered unrelated to the treatment. Intestinal tube problems, including dislocation of the intestinal tube to the stomach, were the most common technical problem, occurring in 69% of the patients during the first year. The optimal daily dose of levodopa decreased by an average of 5% during follow-up. CONCLUSIONS: The safety of enteral infusion of levodopa/carbidopa formulated as a gel suspension was found acceptable. For most patients, the technical challenges posed by the enteral infusion system were offset by the improvement in motor fluctuations and dyskinesias offered by this technique.

Evidence for astrocytosis in ALS demonstrated by [11C](L)-deprenyl-D2 PET.

OBJECTIVE: To use deuterium-substituted [11C](L)-deprenyl PET to depict astrocytosis in vivo in patients with amyotrophic lateral sclerosis (ALS). BACKGROUND: In human brain, the enzyme MAO-B is primarily located in astrocytes. L-deprenyl binds to MAO-B and autoradiography with 3H-L-deprenyl has been used to map astrocytosis in vitro. Motor neuron loss in ALS is accompanied by astrocytosis and astrocytes may play an active role in the neurodegenerative process. Deuterium-substituted [11C](L)-deprenyl PET provides an opportunity to localize astrocytosis in vivo in the brain of patients with ALS. METHODS: Deuterium-substituted [11C](L)-deprenyl PET was performed in seven patients with ALS and seven healthy control subjects. RESULTS: Increased uptake rate of [11C](L)-deprenyl was demonstrated in ALS in pons and white matter. CONCLUSION: This study provides evidence that astrocytosis may be detected in vivo in ALS by the use of deuterium-substituted [11C](L)-deprenyl PET though further studies are needed to determine whether deuterium-substituted [11C](L)-deprenyl binding tracks disease progression and reflects astrocytosis.

Focused proteomics in post-mortem human spinal cord.

With a highly sensitive electrospray ionization-Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR MS) system, proteins were identified in minimal amounts of spinal cord from patients with the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and compared to proteins in spinal cord from control subjects. The results show 18 versus 16 significantly identified (p < 0.05) proteins, respectively, all known to be found in the central nervous system. The most abundant protein in both groups was the glial fibrillary acidic protein, GFAP. Other proteins were, for example, hemoglobin alpha- and beta chain, myelin basic protein, thioredoxin, alpha enolase, and choline acetyltransferase. This study also includes the technique of laser microdissection in combination with pressure catapulting (LMPC) for the dissection of samples and specific neurons. Furthermore, complementary experiments with nanoLC-matrix assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF-TOF MS) confirmed the results of the ESI-FTICR MS screening and provided additional results of further identified proteins.

[Conformationally altered proteins cause neurodegenerative diseases]. / Konformationsförändrade proteiner orsakar neurodegenerativa sjukdomar.

Brain aggregates of conformationally altered proteins are key features of neurodegeneration and are believed to directly cause or contribute to disease development. Mechanisms underlying the dysregulation of proteins in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other neurodegenerative disorders are now being characterized, due to the discovery of genes causing rare disease forms. As of today, only symptomatic pharmacotherapies are available, but new insights into the underlying molecular mechanisms are providing strategies to prevent or even cure these devastating disorders.

Levodopa infusion therapy in Parkinson disease: state of the art in 2004.

Orally administered levodopa, in combination with a decarboxylase inhibitor, is the gold standard therapy for Parkinson disease (PD). The problems in management of motor fluctuations in the advanced stages of the disorder are due to the close relationship between plasma levodopa levels and availability of dopamine at striatal receptor sites. The fluctuating levodopa concentrations are mainly explained by the fact that levodopa absorption only occurs in the proximal small intestine. The patient's motor function thus depends on gastric emptying, which is erratic and may even be delayed in PD. Oral therapy with sustained-release formulations and COMT inhibitors have not solved the problems satisfactorily. Therefore, infusions of levodopa by intravenous and enteral (duodenal/jejunal) routes of administration have been studied. In this review of the literature on clinically relevant levodopa infusion studies, it is shown that improvements regarding fluctuations in both plasma levodopa levels and motor performance have been repeatedly reported. The results acquired so far suggest that levodopa infusion is a safe and efficacious therapy. Recent drug delivery development and long-term studies have shown that infusion is a clinically feasible alternative to treat advanced PD.

Cerebrospinal fluid protein patterns in neurodegenerative disease revealed by liquid chromatography-Fourier transform ion cyclotron resonance mass spectrometry.

This study demonstrates the power of a novel proteomic approach developed for the detection and identification of biological markers in body fluids. The goal was to observe alterations in the protein patterns of cerebrospinal fluid (CSF) related to amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder with unknown etiology. In the experiments, tryptic digests of CSF from patients and healthy controls were analyzed by on-line capillary liquid chromatography-Fourier transform ion cyclotron resonance mass spectrometry. (FT-ICR MS) Typically, around 4000 peptides were detected in one such experiment, and a pattern recognition program was constructed for the data analysis to distinguish mass chromatograms from patients and controls. This strategy was evaluated comparing the peptide patterns of CSF spiked in vitro with a biomarker, with control CSF. The patterns were clearly separated and the tryptic peptides of the biomarker were successfully selected as characteristic peaks. Hence, the method was applied to compare mass chromatograms of CSF from 12 ALS-patients and 10 matched healthy controls. While no biomarker alone could be identified from the characteristic peaks, we were able to assign 4 out of 5 unknown samples correctly (i.e., 80% correctly diagnosed, 20% false-negative), and it would be 100% if we reject a possible outlier believed to be caused by an occlusion in the spinal CSF compartment. These findings are very promising, although the clinical relevance is not fully established due to the low number of unknown samples analyzed. In addition to the diagnostic potential, these results may be important steps towards understanding the neurodegenerative process.

[A national curriculum in neurology for medical education]. / Nationellt core curriculum i neurologi för läkarutbildningen.

The knowledge within medicine is growing rapidly. It has become more and more difficult to decide what knowledge that has to be taught to medical students during their University Medical Degree (MD) education and what has to be omitted from their study plans. As help for teachers and students, a core curriculum of the education defines what is of importance for all students. However, there is a risk of "curriculum overload" with too much information being put into a short time interval. To avoid this and to define what is really the "core" of a course, a national consensus decision may be useful. As an example of this approach, we here report a new joint Swedish core curriculum in neurology for medical students. Teachers responsible for neurological education at all six universities giving University MD education in Sweden have in January 2003 agreed upon the core curriculum that we present. It is our hope that this method can be useful also for other clinical specialities.