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Herman, S., Niemelä, V., Emami Khoonsari, P., Sundblom, J., Burman, J., Landtblom, A.-M., . . . Kultima, K. (2019). Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects. Scientific Reports, 9, Article ID 4129.
Open this publication in new window or tab >>Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4129Article in journal (Refereed) Published
Abstract [en]

Huntington's disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-379886 (URN)10.1038/s41598-019-40186-5 (DOI)000460754600020 ()30858393 (PubMedID)
Funder
Åke Wiberg FoundationEU, Horizon 2020, 654241
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-10-23Bibliographically approved
Johansson, D., Thomas, I., Ericsson, A., Johansson, A., Medvedev, A., Memedi, M., . . . Bergquist, F. (2019). Evaluation of a sensor algorithm for motor state rating in Parkinson's disease. Parkinsonism & Related Disorders, 64, 112-117
Open this publication in new window or tab >>Evaluation of a sensor algorithm for motor state rating in Parkinson's disease
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2019 (English)In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 64, p. 112-117Article in journal (Refereed) Published
Abstract [en]

Introduction: A treatment response objective index (TRIS) was previously developed based on sensor data from pronation-supination tests. This study aimed to examine the performance of TRIS for medication effects in a new population sample with Parkinson's disease (PD) and its usefulness for constructing individual dose-response models.

Methods: Twenty-five patients with PD performed a series of tasks throughout a levodopa challenge while wearing sensors. TRIS was used to determine motor changes in pronation-supination tests following a single levodopa dose, and was compared to clinical ratings including the Treatment Response Scale (TRS) and six sub-items of the UPDRS part III.

Results: As expected, correlations between TRIS and clinical ratings were lower in the new population than in the initial study. TRIS was still significantly correlated to TRS (r(s) = 0.23, P < 0.001) with a root mean square error (RMSE) of 1.33. For the patients (n = 17) with a good levodopa response and clear motor fluctuations, a stronger correlation was found (r(s) = 0.38, RMSE = 1.29, P < 0.001). The mean TRIS increased significantly when patients went from the practically defined off to their best on state (P = 0.024). Individual dose-response models could be fitted for more participants when TRIS was used for modelling than when TRS ratings were used.

Conclusion: The objective sensor index shows promise for constructing individual dose-response models, but further evaluations and retraining of the TRIS algorithm are desirable to improve its performance and to ensure its clinical effectiveness.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2019
Keywords
Levodopa challenge test, Independent evaluation, Wearable sensors, Parkinson's disease, Machine learning algorithms
National Category
Neurology Other Medical Engineering
Identifiers
urn:nbn:se:uu:diva-395925 (URN)10.1016/j.parkreldis.2019.03.022 (DOI)000487567800016 ()30935826 (PubMedID)
Funder
Swedish Foundation for Strategic Research , SBE 13-0086Vinnova, 2014-03727
Available from: 2019-10-30 Created: 2019-10-30 Last updated: 2019-10-30Bibliographically approved
Thomas, I., Alam, M., Bergquist, F., Johansson, D., Memedi, M., Nyholm, D. & Westin, J. (2019). Sensor-based algorithmic dosing suggestions for oral administration of levodopa/carbidopa microtablets for Parkinson's disease: a first experience.. Journal of Neurology, 266(3), 651-658
Open this publication in new window or tab >>Sensor-based algorithmic dosing suggestions for oral administration of levodopa/carbidopa microtablets for Parkinson's disease: a first experience.
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2019 (English)In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 266, no 3, p. 651-658Article in journal (Refereed) Published
Abstract [en]

Objective: Dosing schedules for oral levodopa in advanced stages of Parkinson's disease (PD) require careful tailoring to fit the needs of each patient. This study proposes a dosing algorithm for oral administration of levodopa and evaluates its integration into a sensor-based dosing system (SBDS).

Materials and methods: In collaboration with two movement disorder experts a knowledge-driven, simulation based algorithm was designed and integrated into a SBDS. The SBDS uses data from wearable sensors to fit individual patient models, which are then used as input to the dosing algorithm. To access the feasibility of using the SBDS in clinical practice its performance was evaluated during a clinical experiment where dosing optimization of oral levodopa was explored. The supervising neurologist made dosing adjustments based on data from the Parkinson's KinetiGraph (PKG) that the patients wore for a week in a free living setting. The dosing suggestions of the SBDS were compared with the PKG-guided adjustments.

Results: The SBDS maintenance and morning dosing suggestions had a Pearson's correlation of 0.80 and 0.95 (with mean relative errors of 21% and 12.5%), to the PKG-guided dosing adjustments. Paired t test indicated no statistical differences between the algorithmic suggestions and the clinician's adjustments.

Conclusion: This study shows that it is possible to use algorithmic sensor-based dosing adjustments to optimize treatment with oral medication forPD patients.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-378390 (URN)10.1007/s00415-019-09183-6 (DOI)000459203400013 ()30659356 (PubMedID)
Funder
Knowledge FoundationVinnova
Available from: 2019-03-05 Created: 2019-03-05 Last updated: 2019-06-12Bibliographically approved
Thomas, I., Memedi, M., Westin, J. & Nyholm, D. (2019). The effect of continuous levodopa treatment during the afternoon hours. Acta Neurologica Scandinavica, 139, 70-75
Open this publication in new window or tab >>The effect of continuous levodopa treatment during the afternoon hours
2019 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 139, p. 70-75Article in journal (Refereed) Published
Abstract [en]

Objective: The aim of this retrospective study was to investigate whether patients with Parkinson's disease, who are treated with levodopa‐carbidopa intestinal gel (LCIG), clinically worsen during the afternoon hours and if so, to evaluate whether this occurs in all LCIG‐treated patients or in a subgroup of patients.

Methods: Three published studies were identified and included in the analysis. All studies provided individual response data assessed on the treatment response scale (TRS), and patients were treated with continuous LCIG. Ninety‐eight patients from the three studies fulfilled the criteria. t tests were performed to find differences on the TRS values between the morning and the afternoon hours, linear mixed effect models were fitted on the afternoon hours' evaluations to find trends of wearing‐off, and patients were classified into three TRS categories (meaningful increase in TRS, meaningful decrease in TRS, non‐meaningful increase or decrease).

Results: In all three studies, significant statistical differences were found between the morning TRS values and the afternoon TRS values (P‐value <=0.001 in all studies). The linear mixed effect models had significant negative coefficients for time in two studies, and 48 out of 98 patients (49%) showed a meaningful decrease in TRS during the afternoon hours.

Conclusion: The results from all studies were consistent, both in the proportion of patients in the three groups and in the value of TRS decrease in the afternoon hours. Based on these findings, there seems to be a group of patients with predictable "off" behavior in the later parts of the day.

Keywords
diurnal motor fluctuation, infusion pumps, levodopa, Parkinson disease
National Category
Neurology Other Social Sciences
Identifiers
urn:nbn:se:uu:diva-368653 (URN)10.1111/ane.13020 (DOI)000452067700007 ()30180267 (PubMedID)
Available from: 2018-12-06 Created: 2018-12-06 Last updated: 2019-01-21Bibliographically approved
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
Lubberink, M., Widström, C., Jonasson, M., Appel, L., Fällmar, D., Nyholm, D., . . . Danfors, T. (2018). Differential diagnosis of patients with parkinsonian syndrome using multilinear regression to disease-specific C-11-PE2I-PET templates and classification tree learning. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45, S409-S409
Open this publication in new window or tab >>Differential diagnosis of patients with parkinsonian syndrome using multilinear regression to disease-specific C-11-PE2I-PET templates and classification tree learning
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S409-S409Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372967 (URN)000449266204001 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2019-01-10Bibliographically approved
Sousa, J. M., Appel, L., Engström, M., Papadimitriou, S., Nyholm, D., Larsson, E.-M., . . . Lubberink, M. (2018). Evaluation of zero-echo-time attenuation correction for integrated PET/MR brain imaging-comparison to head atlas and 68Ge-transmission-based attenuation correction. EJNMMI Physics, 5(20)
Open this publication in new window or tab >>Evaluation of zero-echo-time attenuation correction for integrated PET/MR brain imaging-comparison to head atlas and 68Ge-transmission-based attenuation correction
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2018 (English)In: EJNMMI Physics, ISSN 2197-7364, E-ISSN 2191-219X, Vol. 5, no 20Article in journal (Refereed) Published
Abstract [en]

Background: MRI does not offer a direct method to obtain attenuation correction maps as its predecessors (stand-alone PET and PET/CT), and bone visualisation is particularly challenging. Recently, zero-echo-time (ZTE) was suggested for MR-based attenuation correction (AC). The aim of this work was to evaluate ZTE- and atlas-AC by comparison to 68Ge-transmission scan-based AC.

Nine patients underwent brain PET/MR and stand-alone PET scanning using the dopamine transporter ligand 11C-PE2I. For each of them, two AC maps were obtained from the MR images: an atlas-based, obtained from T1-weighted LAVA-FLEX imaging with cortical bone inserted using a CT-based atlas, and an AC map generated from proton-density-weighted ZTE images. Stand-alone PET 68Ge-transmission AC map was used as gold standard. PET images were reconstructed using the three AC methods and standardised uptake value (SUV) values for the striatal, limbic and cortical regions, as well as the cerebellum (VOIs) were compared. SUV ratio (SUVR) values normalised for the cerebellum were also assessed. Bias, precision and agreement were calculated; statistical significance was evaluated using Wilcoxon matched-pairs signed-rank test.

Results: Both ZTE- and atlas-AC showed a similar bias of 6–8% in SUV values across the regions. Correlation coefficients with 68Ge-AC were consistently high for ZTE-AC (r 0.99 for all regions), whereas they were lower for atlas-AC, varying from 0.99 in the striatum to 0.88 in the posterior cortical regions. SUVR showed an overall bias of 2.9 and 0.5% for atlas-AC and ZTE-AC, respectively. Correlations with 68Ge-AC were higher for ZTE-AC, varying from 0.99 in the striatum to 0.96 in the limbic regions, compared to atlas-AC (0.99 striatum to 0.77 posterior cortex).

Conclusions: Absolute SUV values showed less variability for ZTE-AC than for atlas-AC when compared to 68Ge-AC, but bias was similar for both methods. This bias is largely caused by higher linear attenuation coefficients in atlas- and ZTE-AC image compared to 68Ge-images. For SUVR, bias was lower when using ZTE-AC than for atlas-AC. ZTE-AC shows to be a more robust technique than atlas-AC in terms of both intra- and inter-patient variability.

Keywords
Atlas-AC, Attenuation correction, PET/MR, Static imaging, ZTE-AC
National Category
Medical Image Processing Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-364358 (URN)10.1186/s40658-018-0220-0 (DOI)000447946100001 ()30345471 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2019-01-14Bibliographically 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
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-9776-7715

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