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Marrinan, S. L., Otiker, T., Vasist, L. S., Gibson, R. A., Sarai, B. K., Barton, M. E., . . . Burn, D. J. (2018). A randomized, double-blind, placebo-controlled trial of camicinal in Parkinson's disease.. Movement Disorders, 33(2), 329-332
Open this publication in new window or tab >>A randomized, double-blind, placebo-controlled trial of camicinal in Parkinson's disease.
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2018 (English)In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 33, no 2, p. 329-332Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Delayed gastric emptying may impair l-dopa absorption, contributing to motor fluctuations. We evaluated the effect of camicinal (GSK962040), a gastroprokinetic, on the absorption of l-dopa and symptoms of PD.

METHODS: Phase II, double-blind, placebo-controlled trial. Participants were randomized to receive camicinal 50 mg once-daily (n = 38) or placebo (n = 20) for 7 to 9 days.

RESULTS: l-dopa exposure was similar with coadministration of camicinal compared to placebo. Median time to maximum l-dopa concentration was reduced, indicating more rapid absorption of l-dopa. Camicinal resulted in significant reduction in OFF time (-2.31 hours; 95% confidence interval: -3.71, -0.90), significant increase in ON time (+1.88 hours; 95% confidence interval: 0.28, 3.48) per day, and significant decrease in mean total MDS-UPDRS score (-12.5; 95% confidence interval: -19.67, -5.29). Camicinal treatment was generally well tolerated.

CONCLUSIONS: PD symptom improvement with camicinal occurred in parallel with more rapid absorption of l-dopa. This study provides evidence of an improvement of the motor response to l-dopa in people with PD treated with camicinal 50 mg once-daily compared with placebo, which will require further evaluation.

Keywords
Clinical trials Randomized controlled (CONSORT agreement), Parkinson's disease/parkinsonism
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-343107 (URN)10.1002/mds.27259 (DOI)000424815100022 ()29278279 (PubMedID)
Funder
GlaxoSmithKline (GSK)
Available from: 2018-02-25 Created: 2018-02-25 Last updated: 2018-03-26Bibliographically approved
Thomas, I., Westin, J., Alam, M., Bergquist, F., Nyholm, D., Senek, M. & Memedi, M. (2018). A Treatment-Response Index From Wearable Sensors for Quantifying Parkinson's Disease Motor States. IEEE journal of biomedical and health informatics, 22(5), 1341-1349
Open this publication in new window or tab >>A Treatment-Response Index From Wearable Sensors for Quantifying Parkinson's Disease Motor States
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2018 (English)In: IEEE journal of biomedical and health informatics, ISSN 2168-2194, E-ISSN 2168-2208, Vol. 22, no 5, p. 1341-1349Article in journal (Refereed) Published
Abstract [en]

The goal of this study was to develop an algorithm that automatically quantifies motor states (off, on, dyskinesia) in Parkinson's disease (PD), based on accelerometry during a hand pronation-supination test. Clinician's ratings using the Treatment Response Scale (TRS), ranging from -3 (veryOff) to 0 (On) to +3 (very dyskinetic), were used as target. For that purpose, 19 participants with advanced PD and 22 healthy persons were recruited in a single center open label clinical trial in Uppsala, Sweden. The trial consisted of single levodopa dose experiments for the people with PD (PwP), where participants were asked to perform standardized wrist rotation tests, using each hand, before and at prespecified time points after the dose. The participants used wrist sensors containing a three-dimensional accelerometer and gyroscope. Features to quantify the level, variation, and asymmetry of the sensor signals, three-level discrete wavelet transform features, and approximate entropy measures were extracted from the sensors data. At the time of the tests, the PwP were video recorded. Three movement disorder specialists rated the participants' state on the TRS. A Treatment Response Index from Sensors (TRIS) was constructed to quantify the motor states based on the wrist rotation tests. Different machine learning algorithms were evaluated to map the features derived from the sensor data to the ratings provided by the three specialists. Results from cross validation, both in tenfold and a leave-one-individual out setting, showed good predictive power of a support vector machine model and high correlation to the TRS. Values at the end tails of the TRS were under and over predicted due to the lack of observations at those values but the model managed to accurately capture the dose-effect profiles of the patients. In addition, the TRIS had good test-retest reliability on the baseline levels of the PD participants (Intraclass correlation coefficient of 0.83) and reasonable sensitivity to levodopa treatment (0.33 for the TRIS). For a series of test occasions, the proposed algorithms provided dose-effect time profiles for participants with PD, which could be useful during therapy individualization of people suffering from advanced PD.

Place, publisher, year, edition, pages
IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC, 2018
Keywords
Accelerometry, levodopa response, machine learning, parkinson's disease, pattern recognition, signal processing, wearable sensors
National Category
Other Medical Engineering
Identifiers
urn:nbn:se:uu:diva-362487 (URN)10.1109/JBHI.2017.2777926 (DOI)000441795800002 ()29989996 (PubMedID)
Funder
VINNOVAKnowledge Foundation
Available from: 2018-10-10 Created: 2018-10-10 Last updated: 2018-10-10Bibliographically approved
Thomas, I., Alam, M., Nyholm, D., Senek, M. & Westin, J. (2018). Individual dose-response models for levodopa infusion dose optimization. International Journal of Medical Informatics, 112, 137-142
Open this publication in new window or tab >>Individual dose-response models for levodopa infusion dose optimization
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2018 (English)In: International Journal of Medical Informatics, ISSN 1386-5056, E-ISSN 1872-8243, Vol. 112, p. 137-142Article in journal (Refereed) Published
Abstract [en]

Background and objective: To achieve optimal effect with continuous infusion treatment in Parkinson's disease (PD), the individual doses (morning dose and continuous infusion rate) are titrated by trained medical personnel. This study describes an algorithmic method to derive optimized dosing suggestions for infusion treatment of PD, by fitting individual dose-response models. The feasibility of the proposed method was investigated using patient chart data.

Methods: Patient records were collected at Uppsala University hospital which provided dosing information and dose-response evaluations. Mathematical optimization was used to fit individual patient models using the records' information, by minimizing an objective function. The individual models were passed to a dose optimization algorithm, which derived an optimized dosing suggestion for each patient model.

Results: Using data from a single day's admission the algorithm showed great ability to fit appropriate individual patient models and derive optimized doses. The infusion rate dosing suggestions had 0.88 correlation and 10% absolute mean relative error compared to the optimal doses as determined by the hospital's treating team. The morning dose suggestions were consistency lower that the optimal morning doses, which could be attributed to different dosing strategies and/or lack of on-off evaluations in the morning.

Conclusion: The proposed method showed promise and could be applied in clinical practice, to provide the hospital personnel with additional information when making dose adjustment decisions.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2018
Keywords
Levodopa infusion, Algorithmic dosing suggestions, Patient-specific models, Parkinson's disease
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-350278 (URN)10.1016/j.ijmedinf.2018.01.018 (DOI)000426130900018 ()29500011 (PubMedID)
Funder
Knowledge FoundationVINNOVA
Available from: 2018-05-14 Created: 2018-05-14 Last updated: 2018-05-14Bibliographically approved
Johansson, D., Ericsson, A., Johansson, A., Medvedev, A., Nyholm, D., Ohlsson, F., . . . Bergquist, F. (2018). Individualization of levodopa treatment using a microtablet dispenser and ambulatory accelerometry. CNS Neuroscience & Therapeutics, 24(5), 439-447
Open this publication in new window or tab >>Individualization of levodopa treatment using a microtablet dispenser and ambulatory accelerometry
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2018 (English)In: CNS Neuroscience & Therapeutics, ISSN 1755-5930, E-ISSN 1755-5949, Vol. 24, no 5, p. 439-447Article in journal (Refereed) Published
National Category
Neurology Control Engineering
Identifiers
urn:nbn:se:uu:diva-354110 (URN)10.1111/cns.12807 (DOI)000430058800008 ()29652438 (PubMedID)
Available from: 2018-01-25 Created: 2018-06-19 Last updated: 2018-06-20Bibliographically approved
Sahlstrom, T., Eklund, M., Timpka, J., Henriksen, T., Nyholm, D. & Odin, P. (2018). Workforce participation and activities in Parkinson's disease patients receiving device-aided therapy. Acta Neurologica Scandinavica, 138(1), 78-84
Open this publication in new window or tab >>Workforce participation and activities in Parkinson's disease patients receiving device-aided therapy
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2018 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 138, no 1, p. 78-84Article in journal (Refereed) Published
Abstract [en]

Objectives: Many countries have an aging population, and it is thus likely that Parkinson's disease (PD) will become an increasing health problem. It is important to ensure this group can use their resources in the best way possible, including remaining in the work market. This study aimed to investigate workforce participation and daily activities among patients with PD receiving device-aided therapy to provide new knowledge that may be used to inform decisions about these therapy options.

Materials and Methods:This was a retrospective, descriptive quantitative pilot study, including 67 patients with PD from 3 centers in Sweden and Denmark. Included patients were younger than 67years at the time of introduction of device-aided therapy. Eligible patients were identified by the Swedish national Parkinson patient registry or by the treating neurologist. Quantitative interviews were made by telephone.

Results:A majority of the patients could perform the same, or more, amount of activities approximately 5years after the introduction of device-aided therapy. A small number of patients receiving deep brain stimulation (DBS) and levodopa-carbidopa intestinal gel (LCIG) were able to increase their work capacity within 1year of initiating device-aided therapy and a remarkably high share could still work at the end-point of this study, approximately 15years since the diagnosis of PD.

Conclusions:Device-aided therapy may sustain or increase daily activities and workforce participation in patients with PD who have not yet reached retirement age. There is need for prospective studies, both quantitative and qualitative, to confirm these results.

Keywords
activity, device-aided therapy, Parkinson's disease, quality of life, work
National Category
Neurology Occupational Therapy
Identifiers
urn:nbn:se:uu:diva-358378 (URN)10.1111/ane.12929 (DOI)000434633600010 ()29569237 (PubMedID)
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2018-08-31Bibliographically approved
Jonasson, M., Appel, L., Danfors, T., Nyholm, D., Askmark, H., Frick, A., . . . Lubberink, M. (2017). Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction.. American Journal of Nuclear Medicine and Molecular Imaging, 7(6), 263-274
Open this publication in new window or tab >>Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction.
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2017 (English)In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 7, no 6, p. 263-274Article in journal (Refereed) Published
Abstract [en]

[11C]PE2I is a highly selective dopamine transporter PET ligand. Parametric images based on dynamic [11C]PE2I scans, showing dopamine transporter availability (BPND) and relative cerebral blood flow (R1), can be used in differential diagnosis of parkinsonism. This work aimed to investigate a shortened scan duration and automated generation of parametric images which are two prerequisites for routine clinical application. Twelve subjects with parkinsonism and seventeen healthy controls underwent 80 min dynamic [11C]PE2I PET scans. BPND and R1 images were generated using cerebellum reference region defined on a co-registered MRI, as well as a supervised cluster analysis (SVCA)-based reference. Initial 20, 30 and 40 min of the scans were extracted and images of standardized uptake value ratio (SUVR) and R1 were computed using MRI- and SVCA-based reference. Correlation was high between striatal 80 min MRI-based BPND and 40 min SVCA-based SUVR-1 (R2=0.95). High correlation was also found between R1 values in striatal and limbic regions (R2≥0.91) whereas correlation was moderate for cortical regions (R2=0.71). The results indicate that dynamic [11C]PE2I scans can be restricted to 40 min and that SVCA can be used for automatic extraction of a reference region. These outcomes will support routine applications of [11C]PE2I PET in clinical settings.

Keywords
PET, [11C]PE2I, parametric images, parkinsonism, supervised clustering
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-340790 (URN)000419593300003 ()29348981 (PubMedID)
Funder
Swedish Research CouncilSwedish Society for Medical Research (SSMF)
Available from: 2018-02-02 Created: 2018-02-02 Last updated: 2018-02-21Bibliographically approved
Aquilonius, S.-M. & Nyholm, D. (2017). Development of new levodopa treatment strategies in Parkinson’s disease – from bedside to bench to bedside. Upsala Journal of Medical Sciences, 122(2), 71-77
Open this publication in new window or tab >>Development of new levodopa treatment strategies in Parkinson’s disease – from bedside to bench to bedside
2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 2, p. 71-77Article, review/survey (Refereed) Published
Abstract [en]

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'.

Keywords
Carbidopa; drug development; intestinal gel; levodopa; microtablets; Parkinson's disease
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-320484 (URN)10.1080/03009734.207.1285374 (DOI)000401756500001 ()28276779 (PubMedID)
Available from: 2017-04-20 Created: 2017-04-20 Last updated: 2017-10-17Bibliographically approved
Sadikov, A., Groznik, V., Mozina, M., Zabkar, J., Nyholm, D., Memedi, M., . . . Georgiev, D. (2017). Feasibility of spirography features for objective assessment of motor function in Parkinson's disease. Paper presented at 15th Conference on Artificial Intelligence in Medicine (AIME), JUN 17-20, 2015, Univ Pavia, Pavia, ITALY. Artificial Intelligence in Medicine, 81(SI), 54-62
Open this publication in new window or tab >>Feasibility of spirography features for objective assessment of motor function in Parkinson's disease
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2017 (English)In: Artificial Intelligence in Medicine, ISSN 0933-3657, E-ISSN 1873-2860, Vol. 81, no SI, p. 54-62Article in journal (Refereed) Published
Abstract [en]

Objective: Parkinson's disease (PD) is currently incurable, however proper treatment can ease the symptoms and significantly improve the quality of life of patients. Since PD is a chronic disease, its efficient monitoring and management is very important. The objective of this paper was to investigate the feasibility of using the features and methodology of a spirography application, originally designed to detect early Parkinson's disease (PD) motoric symptoms, for automatically assessing motor symptoms of advanced PD patients experiencing motor fluctuations. More specifically, the aim was to objectively assess motor symptoms related to bradykinesias (slowness of movements occurring as a result of under-medication) and dyskinesias (involuntary movements occurring as a result of over-medication).

Materials and methods: This work combined spirography data and clinical assessments from a longitudinal clinical study in Sweden with the features and pre-processing methodology of a Slovenian spirography application. The study involved 65 advanced PD patients and over 30,000 spiral-drawing measurements over the course of three years. Machine learning methods were used to learn to predict the "cause" (bradykinesia or dyskinesia) of upper limb motor dysfunctions as assessed by a clinician who observed animated spirals in a web interface. The classification model was also tested for comprehensibility. For this purpose a visualisation technique was used to present visual clues to clinicians as to which parts of the spiral drawing (or its animation) are important for the given classification.

Results: Using the machine learning methods with feature descriptions and pre-processing from the Slovenian application resulted in 86% classification accuracy and over 0.90 AUC. The clinicians also rated the computer's visual explanations of its classifications as at least meaningful if not necessarily helpful in over 90% of the cases.

Conclusions: The relatively high classification accuracy and AUC demonstrates the usefulness of this approach for objective monitoring of PD patients. The positive evaluation of computer's explanations suggests the potential use of this methodology in a decision support setting.

Keywords
Parkinson's disease, Movement disorder, Spirography, Spirography features, Objective monitoring, Visualisation
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-340159 (URN)10.1016/j.artmed.2017.03.011 (DOI)000413608900006 ()28416144 (PubMedID)
Conference
15th Conference on Artificial Intelligence in Medicine (AIME), JUN 17-20, 2015, Univ Pavia, Pavia, ITALY
Funder
VINNOVA
Available from: 2018-02-01 Created: 2018-02-01 Last updated: 2018-02-01Bibliographically approved
Senek, M., Hellström, M., Albo, J., Svenningsson, P. & Nyholm, D. (2017). First clinical experience with levodopa/carbidopa microtablets in Parkinson’s disease. Acta Neurologica Scandinavica, 136(6), 727-731
Open this publication in new window or tab >>First clinical experience with levodopa/carbidopa microtablets in Parkinson’s disease
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2017 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 136, no 6, p. 727-731Article in journal (Refereed) Published
Abstract [en]

Background: Levodopa is the most effective symptomatic treatment throughout thecourse of Parkinson’s disease, but as the disease progresses, there may be a need forindividualized, fine-tunedtreatments.

Aim: To evaluate individualized levodopa/carbidopa dosing using microtablets dispensedwith a dose dispenser, with respect to efficacy and usability as perceived bypatients.

Methods: Patient records and dose dispenser reports from patients previously or currentlytreated with microtablets and a dose dispenser were reviewed, and a patientquestionnaire concerning effect and usability was sent to patients.

Results: Eleven patient records, four dose dispenser reports and nine survey responseswere obtained. The treatment effect was considered to be improved by six of ninepatients. One-thirdfound their bradykinesia to be improved, and the non-troublesomedyskinesia was unchanged according to a majority of patients; however, some experiencedthe duration and magnitude of troublesome dyskinesia to be worse. The usabilitywas generally rated as good. The four dose dispenser reports obtained showed97(±5)% total adherence.

Conclusions: The experienced effect of treatment can, for some patients, be improvedby the use of microtablets, and the dose dispenser was considered user-friendly.Further studies with a larger study population and prospective design are needed toconfirm the results.

Keywords
carbidopa, dose dispenser, levodopa, microtablets, Parkinson’s disease, pharmacotherapy
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-339874 (URN)10.1111/ane.12756 (DOI)000414488000021 ()
Available from: 2018-01-23 Created: 2018-01-23 Last updated: 2018-03-21Bibliographically approved
Willows, T., Dizdar, N., Nyholm, D., Widner, H., Grenholm, P., Schmiauke, U., . . . Kjellander, S. (2017). Initiation of Levodopa-Carbidopa Intestinal Gel Infusion Using Telemedicine (Video Communication System) Facilitates Efficient and Well-Accepted Home Titration in Patients with Advanced Parkinson's Disease. Journal of Parkinson's Disease, 7(4), 719-728
Open this publication in new window or tab >>Initiation of Levodopa-Carbidopa Intestinal Gel Infusion Using Telemedicine (Video Communication System) Facilitates Efficient and Well-Accepted Home Titration in Patients with Advanced Parkinson's Disease
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2017 (English)In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 7, no 4, p. 719-728Article in journal (Refereed) Published
Abstract [en]

Background: Levodopa-carbidopa intestinal gel (LCIG; Duodopa r) is used for continuous infusion in advanced Parkinson's disease. To achieve optimal effect, the LCIG dose is individually titrated, traditionally conducted during hospitalization in Sweden. However, dose adjustment depends on surrounding conditions, physical activity, and emotional stress, which is why titration at home could be beneficial. Telemedicine (TM) using a video communication system offers alternative titration procedures, allowing LCIG initiation at home. Objective: Study objectives were to show the feasibility of TM for LCIG home titration, evaluate resource use, and assess patient, neurologist, and nurse satisfaction. Methods: Four clinics enrolled 15 patients to observe efficiency and feasibility of TM-based monitoring. Results: Patient median (range) age was 67 (52-73) years and time since diagnosis was 10 (7-23) years. Median time between LCIG initiation and end of TM-assisted titration was 2.8 (2.0-13.8) days. Median time required for home titration by neurologists, nurses, and patients was (hours: minutes) 1 : 14 (0 : 29-1 : 52), 5 : 49 (2 : 46-10 : 3), and 8 : 53 (4 : 11-14 : 11), respectively. Neurologists and nurses considered this to be less time than required for hospital titration. TM allowed patients 92% free time from start to end of titration. Technical problems associated with TM contacts were rare, mostly related to digital link, and quickly resolved. Patients, neurologists, and nurses were satisfied using TM. No serious adverse events were reported; there was one device complaint (tube occlusion). Conclusions: In this study, TM-assisted LCIG titration at home was resource-efficient, technically feasible, well-accepted and was deemed satisfactory by patients, neurologists, and nurses.

Keywords
Advanced Parkinson's disease, levodopa-carbidopa intestinal gel, LCIG, duodenal levodopa-carbidopa infusion, Duodopa, telemedicine, video communication system, home titration, routine patient care, healthcare resource utilization
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-343148 (URN)10.3233/JPD-161048 (DOI)000416092100018 ()28984615 (PubMedID)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-9776-7715

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