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Sökning: WFRF:(Bergquist Filip 1970)

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1.
  • Alt Murphy, Margit, 1970, et al. (författare)
  • An upper body garment with integrated sensors for people with neurological disorders – early development and evaluation
  • 2019
  • Ingår i: BMC Biomedical Engineering. - : Springer Science and Business Media LLC. - 2524-4426. ; 1:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: To develop a novel wearable garment with integrated sensors for continuous monitoring of physiological and movement related variables to evaluate progression, tailor treatments and improve diagnosis in epilepsy, Parkinson’s disease and stroke. Methods: An iterative development process and evaluation of an upper body garment with integrated sensors included: identification of user needs, specification of technical and garment requirements, garment development and production as well as evaluation of garment design, functionality and usability. The project is a multidisciplinary collaboration with experts from medical, engineering, textile, and material science within the wearITmed consortium. The work was organized in regular meetings, task groups and hands-on workshops. User needs were identified using results from a mixed-methods systematic review, a focus group study and expert groups. Usability was evaluated in 19 individuals (13 controls, 6 patients with Parkinson’s disease) using semi-structured interviews and qualitative content analysis. Results: A prototype designed to monitor movements and heart rate was developed. The garment was well accepted by the users regarding design and comfort, although the users were cautious about the technology and suggested improvements. All electronic components passed a washability test. The most robust data was obtained from accelerometer and gyroscope sensors while the electrodes for heart rate registration were sensitive to motion. artefacts. The algorithm development within the wearITmed consortium has shown promising results. Conclusions: The prototype was accepted by the users. Technical improvements are needed, but preliminary data indicate that the garment has potential to be used as a tool for diagnosis and treatment selection and could provide added value for monitoring seizures in epilepsy, fluctuations in PD and activity levels in stroke. Future work aims to improve the prototype further, develop algorithms, and evaluate the functionality and usability in targeted patient groups. The potential of incorporating blood pressure and heart-rate variability monitoring will also be explored.
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2.
  • HØrmann Thomsen, T., et al. (författare)
  • Life with Parkinson's Disease during the COVID-19 Pandemic: The Pressure Is 'OFF'
  • 2021
  • Ingår i: Journal of Parkinson's Disease. - 1877-7171. ; 11:2, s. 491-495
  • Tidskriftsartikel (refereegranskat)abstract
    • People with Parkinson's disease (PwP) have been suggested to be more vulnerable to negative psychological and psycho-social effects of the COVID-19 pandemic. Our aim was to assess the potential impact of the COVID-19 pandemic in PwP. A Danish/Swedish cohort of 67 PwP was analysed. Health-related quality of life (HRQL), depression, anxiety, apathy, sleep and motor symptom-scores were included in the analysis. Additionally, the Danish participants provided free-text descriptions of life during the pandemic. Overall, the participants reported significantly better HRQL during the COVID-19 period compared with before. Reduced social pressure may be part of the explanation. Despite worsened anxiety, night sleep improved. © 2021 - The authors. Published by IOS Press.
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3.
  • Johansson, Dongni, 1988, et al. (författare)
  • Individualization of levodopa treatment using a microtablet dispenser and ambulatory accelerometry
  • 2018
  • Ingår i: CNS Neuroscience & Therapeutics. - : Wiley. - 1755-5930 .- 1755-5949. ; 24:5, s. 439-447
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: This 4-week open-label observational study describes the effect of introducing a microtablet dose dispenser and adjusting doses based on objective free-living motor symptom monitoring in individuals with Parkinson's disease (PD). Methods: Twenty-eight outpatients with PD on stable levodopa treatment with dose intervals of ≤4 hour had their daytime doses of levodopa replaced with levodopa/carbidopa microtablets, 5/1.25 mg (LC-5) delivered from a dose dispenser device with programmable reminders. After 2 weeks, doses were adjusted based on ambulatory accelerometry and clinical monitoring. Results: Twenty-four participants completed the study per protocol. The daily levodopa dose was increased by 15% (112 mg, P < 0.001) from period 1 to 2, and the dose interval was reduced by 12% (22 minutes, P = 0.003). The treatment adherence to LC-5 was high in both periods. The MDS-UPDRS parts II and III, disease-specific quality of life (PDQ-8), wearing-off symptoms (WOQ-19), and nonmotor symptoms (NMS Quest) improved after dose titration, but the generic quality-of-life measure EQ-5D-5L did not. Blinded expert evaluation of accelerometry results demonstrated improvement in 60% of subjects and worsening in 25%. Conclusions: The introduction of a levodopa microtablet dispenser and accelerometry aided dose adjustments improve PD symptoms and quality of life in the short term.
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4.
  • Licheri, Valentina, et al. (författare)
  • Nicotine-induced neuroplasticity in striatum is subregion-specific and reversed by motor training on the rotarod.
  • 2020
  • Ingår i: Addiction biology. - : Wiley. - 1369-1600 .- 1355-6215. ; 25:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Nicotine is recognized as one of the most addictive drugs, which in part could be attributed to progressive neuroadaptations and rewiring of dorsal striatal circuits. Since motor-skill learning produces neuroplasticity in the same circuits, we postulate that rotarod training could be sufficient to block nicotine-induced rewiring and thereby prevent long-lasting impairments of neuronal functioning. To test this hypothesis, Wistar rats were subjected to 15days of treatment with either nicotine (0.36mg/kg) or vehicle. After treatment, a subset of animals was trained on the rotarod. Ex vivo electrophysiology was performed 1week after the nicotine treatment period and after up to 3months of withdrawal to define neurophysiological transformations in circuits of the striatum and amygdala. Our data demonstrate that nicotine alters striatal neurotransmission in a distinct temporal and spatial sequence, where acute transformations are initiated in dorsomedial striatum (DMS) and nucleus accumbens (nAc) core. Following 3months of withdrawal, synaptic plasticity in the form of endocannabinoid-mediated long-term depression (eCB-LTD) is impaired in the dorsolateral striatum (DLS), and neurotransmission is altered in DLS, nAc shell, and the central nucleus of the amygdala (CeA). Training on the rotarod, performed after nicotine treatment, blocks neurophysiological transformations in striatal subregions, and prevents nicotine-induced impairment of eCB-LTD. These datasets suggest that nicotine-induced rewiring of striatal circuits can be extinguished by other behaviors that induce neuroplasticity. It remains to be determined if motor-skill training could be used to prevent escalating patterns of drug use in experienced users or facilitate the recovery from addiction.
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5.
  • Ozanne, Anneli, 1978, et al. (författare)
  • Wearables in epilepsy and Parkinson's disease : A focus group study
  • 2018
  • Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 137:2, s. 188-194
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Wearable sensors that measure movement and physiological variables are attractive for clinical evaluation of neurological diseases such as epilepsy and Parkinson's disease (PD). The aim of this study was to explore perceptions regarding the use of wearable technology in disease monitoring and management as reported by individuals with epilepsy and Parkinson's disease as well as health professionals working with these patient groups.MATERIALS AND METHODS: Six patient groups (n=25) and two groups with health professionals (n=15) participated in this qualitative, descriptive study with focus group interviews. A manifest qualitative content analysis was used.RESULTS: Four categories and nine subcategories emerged from the analysis. Participants saw possible benefits for improved treatment effect and valued this benefit more than possible inconvenience of wearing the sensors. Discrete design and simplicity were considered as facilitators for improved usability. They emphasized the importance of interactive information between patients and health professionals. However, they were concerned about unclear information and inconclusive recordings and some fears about personal integrity were at odds with the expectations on interactivity.CONCLUSIONS: Patients need to feel well informed and find an added value in using wearables. Wearables need to be user-friendly, have an attractive design, and show clinical efficacy in improving disease management. Variations in perceptions regarding integrity, benefits, and effectiveness of monitoring indicate possible conflicts of expectations among participants. The engagement of end users, patients, and health professionals, in the design and implementation process, is crucial for the development of wearable devices that enhance and facilitate neurological rehabilitation practice.
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6.
  • von Below, Daniel, et al. (författare)
  • Validation of the Swedish Patient-Reported Outcomes in Parkinson's Disease Scale in Outpatients
  • 2023
  • Ingår i: Movement Disorders. - 0885-3185. ; 38:9, s. 1668-1678
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundSuccessful treatment of Parkinson's disease (PD) requires symptom monitoring. Patient-Reported Outcomes in Parkinson's Disease (PRO-PD) is a broad scale that covers 35 motor and nonmotor symptoms, but its validation is limited. ObjectiveThe aim was to validate PRO-PD in a random sample of outpatients with PD. MethodsOf 2123 PD patients who visited outpatient clinics in West Sweden over a 12-month period, 25% were randomly selected and invited to participate in a longitudinal observational study. Included patients were assessed at baseline, 1 year, and 3 years, with a subset also assessed at 3 to 6 months. The assessments included PRO-PD, other patient-reported scales, and Clinical Impression of Severity Index for Parkinson's Disease (CISI-PD). ResultsThe study included 286 PD patients. PRO-PD ratings were available from 716 (96%) of 747 study visits. All PRO-PD items exhibited positive skewness without ceiling effects. Internal consistency at baseline was excellent (Cronbach's & alpha;: 0.93). Six-month test-retest reliability was good (intraclass correlation coefficient: 0.87). Convergent validity was good, with correlation coefficients between total PRO-PD and the 8-Item Parkinson's Disease Questionnaire of 0.70, the Non-Motor Symptoms Questionnaire of 0.70, EuroQoL Five-Dimension Five-Level Scale of 0.71, and CISI-PD of 0.69. Median PRO-PD score at baseline was 995 (interquartile range: 613-1399), with a median yearly increase of 71 (interquartile range: -21 to 111). Items representing axial motor symptoms increased most over time. The minimal clinically important change in total score was 119. ConclusionsPRO-PD was found reliable and valid for monitoring symptoms in a representative sample of outpatients with PD.
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7.
  • Aghanavesi, Somayeh, 1981-, et al. (författare)
  • A multiple motion sensors index for motor state quantification in Parkinson's disease
  • 2020
  • Ingår i: Computer Methods and Programs in Biomedicine. - : Elsevier BV. - 0169-2607 .- 1872-7565. ; 189
  • Tidskriftsartikel (refereegranskat)abstract
    • 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. © 2019
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8.
  • Aghanavesi, Somayeh, 1981-, et al. (författare)
  • A smartphone-based system to quantify dexterity in Parkinson's disease patients
  • 2017
  • Ingår i: Informatics in Medicine Unlocked. - : Elsevier BV. - 2352-9148. ; 9, s. 11-17
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives The aim of this paper is to investigate whether a smartphone-based system can be used to quantify dexterity in Parkinson's disease (PD). More specifically, the aim was to develop data-driven methods to quantify and characterize dexterity in PD. Methods Nineteen advanced PD patients and 22 healthy controls participated in a clinical trial in Uppsala, Sweden. The subjects were asked to perform tapping and spiral drawing tests using a smartphone. Patients performed the tests before, and at pre-specified time points after they received 150% of their usual levodopa morning dose. Patients were video recorded and their motor symptoms were assessed by three movement disorder specialists using three Unified PD Rating Scale (UPDRS) motor items from part III, the dyskinesia scoring and the treatment response scale (TRS). The raw tapping and spiral data were processed and analyzed with time series analysis techniques to extract 37 spatiotemporal features. For each of the five scales, separate machine learning models were built and tested by using principal components of the features as predictors and mean ratings of the three specialists as target variables. Results There were weak to moderate correlations between smartphone-based scores and mean ratings of UPDRS item #23 (0.52; finger tapping), UPDRS #25 (0.47; rapid alternating movements of hands), UPDRS #31 (0.57; body bradykinesia and hypokinesia), sum of the three UPDRS items (0.46), dyskinesia (0.64), and TRS (0.59). When assessing the test-retest reliability of the scores it was found that, in general, the clinical scores had better test-retest reliability than the smartphone-based scores. Only the smartphone-based predicted scores on the TRS and dyskinesia scales had good repeatability with intra-class correlation coefficients of 0.51 and 0.84, respectively. Clinician-based scores had higher effect sizes than smartphone-based scores indicating a better responsiveness in detecting changes in relation to treatment interventions. However, the first principal component of the 37 features was able to capture changes throughout the levodopa cycle and had trends similar to the clinical TRS and dyskinesia scales. Smartphone-based scores differed significantly between patients and healthy controls. Conclusions Quantifying PD motor symptoms via instrumented, dexterity tests employed in a smartphone is feasible and data from such tests can also be used for measuring treatment-related changes in patients. © 2017
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9.
  • Aghanavesi, S., et al. (författare)
  • Motion Sensor-Based Assessment of Parkinson's Disease Motor Symptoms During Leg Agility Tests: Results From Levodopa Challenge
  • 2020
  • Ingår i: Ieee Journal of Biomedical and Health Informatics. - : Institute of Electrical and Electronics Engineers (IEEE). - 2168-2194 .- 2168-2208. ; 24:1, s. 111-119
  • Tidskriftsartikel (refereegranskat)abstract
    • Parkinsons disease (PD) is a degenerative, progressive disorder of the central nervous system that mainly affects motor control. The aim of this study was to develop data-driven methods and test their clinimetric properties to detect and quantify PD motor states using motion sensor data from leg agility tests. Nineteen PD patients were recruited in a levodopa single dose challenge study. PD patients performed leg agility tasks while wearing motion sensors on their lower extremities. Clinical evaluation of video recordings was performed by three movement disorder specialists who used four items from the motor section of the unified PD rating scale (UPDRS), the treatment response scale (TRS) and a dyskinesia score. Using the sensor data, spatiotemporal features were calculated and relevant features were selected by feature selection. Machine learning methods like support vector machines (SVM), decision trees, and linear regression, using ten-fold cross validation were trained to predict motor states of the patients. SVM showed the best convergence validity with correlation coefficients of 0.81 to TRS, 0.83 to UPDRS 31 (body bradykinesia and hypokinesia), 0.78 to SUMUPDRS (the sum of the UPDRS items: 26-leg agility, 27-arising from chair, and 29-gait), and 0.67 to dyskinesia. Additionally, the SVM-based scores had similar test-retest reliability in relation to clinical ratings. The SVM-based scores were less responsive to treatment effects than the clinical scores, particularly with regards to dyskinesia. In conclusion, the results from this study indicate that using motion sensors during leg agility tests may lead to valid and reliable objective measures of PD motor symptoms.
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10.
  • Aldred, Jason, et al. (författare)
  • Continuous Subcutaneous Foslevodopa/Foscarbidopa in Parkinson's Disease: Safety and Efficacy Results From a 12-Month, Single-Arm, Open-Label, Phase 3 Study.
  • 2023
  • Ingår i: Neurology and Therapy. - 2193-8253 .- 2193-6536. ; 12:6, s. 1937-1958
  • Tidskriftsartikel (refereegranskat)abstract
    • Foslevodopa/foscarbidopa, a soluble formulation of levodopa/carbidopa (LD/CD) prodrugs for the treatment of Parkinson's disease (PD), is administered as a 24-hour/day continuous subcutaneous infusion (CSCI) with a single infusion site. The efficacy and safety of foslevodopa/foscarbidopa versus oral immediate-release LD/CD was previously demonstrated in patients with PD in a 12-week, randomized, double-blind, phase 3 trial (NCT04380142). We report the results of a separate 52-week, open-label, phase 3 registrational trial (NCT03781167) that evaluated the safety/tolerability and efficacy of 24-hour/day foslevodopa/foscarbidopa CSCI in patients with advanced PD.Male and female patients with levodopa-responsive PD and≥2.5hours of "Off" time/day received 24-hour/day foslevodopa/foscarbidopa CSCI at individually optimized therapeutic doses (approximately 700-4250mg of LD per 24hours) for 52weeks. The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in normalized "Off" and "On" time, percentage of patients reporting morning akinesia, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease Sleep Scale-2 (PDSS-2), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQol 5-dimension questionnaire (EQ-5D-5L).Of 244 enrolled patients, 107 discontinued, and 137 completed treatment. Infusion site events were the most common adverse events (AEs). AEs were mostly nonserious (25.8% of patients reported serious AEs) and mild/moderate in severity. At week 52, "On" time without troublesome dyskinesia and "Off" time were improved from baseline (mean [standard deviation (SD)] change in normalized "On" time without troublesome dyskinesia, 3.8 [3.3] hours; normalized "Off" time, -3.5 [3.1] hours). The percentage of patients experiencing morning akinesia dropped from 77.7% at baseline to 27.8% at week 52. Sleep quality (PDSS-2) and quality of life (PDQ-39 and EQ-5D-5L) also improved.Foslevodopa/foscarbidopa has the potential to provide a safe and efficacious, individualized, 24-hour/day, nonsurgical alternative for patients with PD.ClinicalTrials.gov identifier NCT03781167.
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11.
  • Anderberg, Rozita H, 1976, et al. (författare)
  • Dopamine signaling in the amygdala, increased by food ingestion and GLP-1, regulates feeding behavior.
  • 2014
  • Ingår i: Physiology & behavior. - : Elsevier BV. - 1873-507X .- 0031-9384. ; 136, s. 135-144
  • Tidskriftsartikel (refereegranskat)abstract
    • Mesolimbic dopamine plays a critical role in food-related reward processing and learning. The literature focuses primarily on the nucleus accumbens as the key dopaminergic target in which enhanced dopamine signaling is associated with reward. Here, we demonstrate a novel neurobiological mechanism by which dopamine transmission in the amygdala regulates food intake and reward. We show that food intake was associated with increased dopamine turnover in the amygdala. Next, we assess the impact of direct intra-amygdala D1 and D2 receptor activation on food intake and sucrose-driven progressive ratio operant conditioning in rats. Amygdala D2 receptor activation reduced food intake and operant behavior for sucrose, whereas D2 receptor blockade increased food intake but surprisingly reduced operant behavior. In contrast, D1 receptor stimulation or blockade did not alter feeding or operant conditioning for food. The glucagon-like peptide 1 (GLP-1) system, a target for type 2 diabetes treatment, in addition to regulating glucose homeostasis, also reduces food intake. We found that central GLP-1R receptor activation is associated with elevated dopamine turnover in the amygdala, and that part of the anorexic effect of GLP-1 is mediated by D2 receptor signaling in the amygdala. Our findings indicate that amygdala dopamine signaling is activated by both food intake and the anorexic brain-gut peptide GLP-1 and that amygdala D2 receptor activation is necessary and sufficient to change feeding behavior. Collectively these studies indicate a novel mechanism by which the dopamine system affects feeding-oriented behavior at the level of the amygdala.
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12.
  • Anderberg, Rozita H, 1976, et al. (författare)
  • GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality.
  • 2016
  • Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 65, s. 54-66
  • Tidskriftsartikel (refereegranskat)abstract
    • Glucagon-like peptide 1 (GLP-1), produced in the intestine and hindbrain, is known for its glucoregulatory and appetite suppressing effects. GLP-1 agonists are in clinical use for treatment of type 2 diabetes and obesity. GLP-1, however, may also affect brain areas associated with emotionality regulation. Here we aimed to characterize acute and chronic impact of GLP-1 on anxiety and depression-like behavior. Rats were subjected to anxiety and depression behavior tests following acute or chronic intracerebroventricular or intra-dorsal raphe (DR) application of GLP-1 receptor agonists. Serotonin or serotonin-related genes were also measured in the amygdala, DR and the hippocampus. We demonstrate that both GLP-1 and its long lasting analog, Exendin-4, induce anxiety-like behavior in three rodent tests of this behavior: black and white box, elevated plus maze and open field test when acutely administered intraperitoneally, into the lateral ventricle, or directly into the DR. Acute central GLP-1 receptor stimulation also altered serotonin signaling in the amygdala. In contrast, chronic central administration of Exendin-4 did not alter anxiety-like behavior but significantly reduced depression-like behavior in the forced swim test. Importantly, this positive effect of Exendin-4 was not due to significant body weight loss and reduced food intake, since rats pair-fed to Exendin-4 rats did not show altered mood. Collectively we show a striking impact of central GLP-1 on emotionality and the amygdala serotonin signaling that is divergent under acute versus chronic GLP-1 activation conditions. We also find a novel role for the DR GLP-1 receptors in regulation of behavior. These results may have direct relevance to the clinic, and indicate that Exendin-4 may be especially useful for obese patients manifesting with comorbid depression.
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13.
  • Anderberg, Rozita H, 1976, et al. (författare)
  • Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight
  • 2017
  • Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:4, s. 1062-1073
  • Tidskriftsartikel (refereegranskat)abstract
    • Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT2A) and 5-HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT2A, but surprisingly not the 5-HT2C, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin-producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase the electrical activity of the DR serotonin neurons. Finally, our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as a new critical neural substrate for GLP-1 impact on energy homeostasis and expands the current map of brain areas impacted by GLP-1R activation.
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14.
  • Anderberg, Rozita H, 1976, et al. (författare)
  • The Stomach-Derived Hormone Ghrelin Increases Impulsive Behavior.
  • 2016
  • Ingår i: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X. ; 14, s. 1199-1209
  • Tidskriftsartikel (refereegranskat)abstract
    • Impulsivity, defined as impaired decision making, is associated with many psychiatric and behavioral disorders, such as attention-deficit/hyperactivity disorder as well as eating disorders. Recent data indicate that there is a strong positive correlation between food reward behavior and impulsivity, but the mechanisms behind this relationship remain unknown. Here we hypothesize that ghrelin, an orexigenic hormone produced by the stomach and known to increase food reward behavior, also increases impulsivity. In order to assess the impact of ghrelin on impulsivity, rats were trained in three complementary tests of impulsive behavior and choice: differential reinforcement of low rate (DRL), go/no-go, and delay discounting. Ghrelin injection into the lateral ventricle increased impulsive behavior, as indicated by reduced efficiency of performance in the DRL test, and increased lever pressing during the no-go periods of the go/no-go test. Central ghrelin stimulation also increased impulsive choice, as evidenced by the reduced choice for large rewards when delivered with a delay in the delay discounting test. In order to determine whether signaling at the central ghrelin receptors is necessary for maintenance of normal levels of impulsive behavior, DRL performance was assessed following ghrelin receptor blockade with central infusion of a ghrelin receptor antagonist. Central ghrelin receptor blockade reduced impulsive behavior, as reflected by increased efficiency of performance in the DRL task. To further investigate the neurobiological substrate underlying the impulsivity effect of ghrelin, we microinjected ghrelin into the ventral tegmental area, an area harboring dopaminergic cell bodies. Ghrelin receptor stimulation within the VTA was sufficient to increase impulsive behavior. We further evaluated the impact of ghrelin on dopamine-related gene expression and dopamine turnover in brain areas key in impulsive behavior control. This study provides the first demonstration that the stomach-produced hormone ghrelin increases impulsivity and also indicates that ghrelin can change two major components of impulsivity-motor and choice impulsivity.Neuropsychopharmacology advance online publication, 21 October 2015; doi:10.1038/npp.2015.297.
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15.
  • Andersson, Daniel, et al. (författare)
  • Motor activity-induced dopamine release in the substantia nigra is regulated by muscarinic receptors.
  • 2010
  • Ingår i: Experimental neurology. - : Elsevier BV. - 1090-2430 .- 0014-4886. ; 221:1, s. 251-259
  • Tidskriftsartikel (refereegranskat)abstract
    • Nigro-striatal neurons release dopamine not only from their axon terminals in the striatum, but also from somata and dendrites in the substantia nigra. Somatodendritic dopamine release in the substantia nigra can facilitate motor function by mechanisms that may act independently of axon terminal dopamine release in the striatum. The dopamine neurons in the substantia nigra receive a cholinergic input from the pedunculopontine nucleus. Despite recent efforts to introduce this nucleus as a potential target for deep brain stimulation to treat motor symptoms in Parkinson's disease; and the well-known antiparkinsonian effects of anticholinergic drugs; the cholinergic influence on somatodendritic dopamine release is not well understood. The aim of this study was to investigate the possible regulation of locomotor-induced dopamine release in the substantia nigra by endogenous acetylcholine release. In intact and 6-OHDA hemi-lesioned animals alike, the muscarinic antagonist scopolamine, when perfused in the substantia nigra, amplified the locomotor-induced somatodendritic dopamine release to approximately 200% of baseline, compared to 120-130% of baseline in vehicle-treated animals. A functional importance of nigral muscarinic receptor activation was demonstrated in hemi-lesioned animals, where motor performance was significantly improved by scopolamine to 82% of pre-lesion performance, as compared to 56% in vehicle-treated controls. The results indicate that muscarinic activity in the substantia nigra is of functional importance in an animal Parkinson's disease model, and strengthen the notion that nigral dopaminergic regulation of motor activity/performance is independent of striatal dopamine release.
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16.
  • Andersson, Daniel, et al. (författare)
  • Partial depletion of dopamine in substantia nigra impairs motor performance without altering striatal dopamine neurotransmission
  • 2006
  • Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 24:2, s. 617-624
  • Tidskriftsartikel (refereegranskat)abstract
    • Previous data indicate that the release of somatodendritic dopamine in substantia nigra influences motor activity and coordination, but the relative importance of somatodendritic dopamine release vs. terminal striatal dopamine release remains to be determined. We utilized simultaneous measurement of dopamine neurotransmission by microdialysis and motor performance assessment by rotarod test to investigate the effects of local dopamine depletion in rats. The vesicular monoamine transporter inhibitor tetrabenazine (100 µm) was administered locally in substantia nigra as well as in striatum. Nigral tetrabenazine administration decreased nigral dopamine dialysate concentrations to 7% of baseline and whole-tissue dopamine content by 60%. Nigral dopamine depletion was associated with a reduction in motor performance to 73 ± 6% of pretreatment value, but did not alter dialysate dopamine concentrations in the ipsilateral striatum. Striatal tetrabenazine administration decreased striatal dopamine dialysate concentrations to 5% of baseline and doubled the somatodendritic dopamine response to motor activity, but it was not associated with changes in motor performance or dopamine content in striatal tissue. Simultaneous treatment of substantia nigra and striatum reduced motor performance to 58 ± 5% of the pretreatment value. The results of this study indicate that partial depletion of nigral dopamine stores can significantly impair motor functions, and that increased nigral dopamine release can counteract minor impairments of striatal dopamine transmission.
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17.
  • Bergquist, Filip, 1970, et al. (författare)
  • Can Objective Measurements Improve Treatment Outcomes in Parkinson’s Disease?
  • 2014
  • Ingår i: European Neurological Review. - 1758-3837. ; 9:1, s. 27-30
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Many examples in medicine show that therapies are most effective when measurement is used to guide their implementation, dose and effects. There are effective symptomatic therapies for the motor symptoms of Parkinson’s disease, which improve quality of life and have a health economic justification for their subsidisation. As measurement should lead to more effective deployment of these therapies, even in a percentage of cases, then costs of therapy would be reduced and by that percentage. We conclude that there is a clear need for continuous objective measures of dyskinesia and bradykinesia while patients go about their normal daily activities. The benefit of measurement would be greatest if these measures were directed at treating fluctuations.
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18.
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19.
  • Bergquist, Filip, 1970, et al. (författare)
  • Effects of local administration of L-, N-, and P/Q-type calcium channel blockers on spontaneous dopamine release in the striatum and the substantia nigra: a microdialysis study in rat.
  • 1998
  • Ingår i: Journal of neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 70:4, s. 1532-40
  • Tidskriftsartikel (refereegranskat)abstract
    • The pivotal role for voltage-sensitive calcium channels in initiating synaptic transmitter release is undisputed, but it is only partly known to what extent the different subtypes contribute in vivo. Their importance for the dendritic release of dopamine has not been investigated in vivo previously. To evaluate comprehensively the relative importance of different voltage-sensitive calcium channel subtypes for striatal dopamine release, and to further investigate the mechanism of dendritic dopamine release in the reticulate part of substantia nigra, dopamine was measured by in vivo microdialysis in the striatum or substantia nigra of awake rats. The calcium channel blockers nimodipine, omega-conotoxin-GVIA, omega-agatoxin-IVA, and neomycin were administered locally through the dialysis probes and compared with calcium-free perfusion. Results indicate that dopamine release in the striatum is mainly dependent on N- and P/Q-type channels, but the dendritic dopamine release in the substantia nigra is mediated mainly by some other calcium-dependent mechanism, for example, calcium mobilization through T-, O-, or R-type calcium channels. A portion of the dendritic release is calcium independent but can be inhibited partially by neomycin, which might suggest a role for inositol 4,5-bisphosphate breakdown products.
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20.
  • Bergquist, Filip, 1970, et al. (författare)
  • Evidence for different exocytosis pathways in dendritic and terminal dopamine release in vivo.
  • 2002
  • Ingår i: Brain research. - 0006-8993. ; 950:1-2, s. 245-53
  • Tidskriftsartikel (refereegranskat)abstract
    • Although dendritic release was first proposed in the 1970s, the mechanism of release is still subject to debate. We have used in vivo microdialysis to study the acute effects of botulinum toxin A, B and tetanus toxin injected in the substantia nigra or striatum of freely moving rats. Spontaneous and evoked dopamine release decreased in both regions after treatment with the SNAP-25 (synaptosome-associated protein of 25 kDa) cleaving protease botulinum toxin A (1000 mouse lethal doses, MLD). Tetanus toxin (4000 MLD) did not significantly change spontaneous or evoked dopamine release in striatum or in the substantia nigra. Another synaptobrevin cleaving protease, botulinum toxin B, inhibited release in the striatum by 55% but did not affect dopamine release when injected in the substantia nigra. The results indicate that both terminal and somatodendritic dopamine release need intact SNAP-25 to occur, but somatodendritic dopamine release in contrast to terminal release depends on a botulinum toxin B resistant pathway.
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21.
  • Bergquist, Filip, 1970, et al. (författare)
  • Influence of R-type (Cav2.3) and t-type (Cav3.1-3.3) antagonists on nigral somatodendritic dopamine release measured by microdialysis.
  • 2003
  • Ingår i: Neuroscience. - 0306-4522. ; 120:3, s. 757-64
  • Tidskriftsartikel (refereegranskat)abstract
    • The release of dopamine from soma and dendrites of dopaminergic neurons in substantia nigra has been reported to be calcium-dependent, but it remains to be determined which calcium channels mediate this effect. We have used in vivo microdialysis in rat substantia nigra and striatum to investigate the effect of Ca(v)3.1-3.3 (T-type) and Ca(v)2.3 (R-type) calcium channel antagonists on somatodendritic and terminal dopamine release. Local reverse dialysis administration of 0.1-10 microM of the Ca(v)2.3 inhibitor SNX-482, or 100 microM of mibefradil, decreased the concentrations of dopamine and its metabolites in dialysate from substantia nigra, whereas 1 microM mibefradil or 40-80 microM nickel(II) induced an increase in nigral dialysate dopamine concentrations. Dopamine concentrations in striatal dialysates were decreased only by 10 microM of SNX-482 or 100 microM of mibefradil. Nickel(II) induced an increase in striatal dialysate dopamine concentration similar to that in substantia nigra. The results indicate a role for Ca(v)2.3 (R-type) voltage sensitive calcium channels in the calcium dependency of somatodendritic dopamine release, but argue against a calcium dependency mediated substantially by Ca(v)3.1-3.3 (T-type) channels.
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22.
  • Bergquist, Filip, 1970, et al. (författare)
  • Motor Efficacy of Subcutaneous DIZ102, Intravenous DIZ101 or Intestinal Levodopa/Carbidopa Infusion
  • 2024
  • Ingår i: MOVEMENT DISORDERS CLINICAL PRACTICE. - 2330-1619.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: It has been suggested that carbidopa at high blood concentrations may counter the therapeutic effect of levodopa in Parkinson's disease by entering the brain and blocking central levodopa conversion to dopamine. We previously demonstrated equivalent plasma levodopa concentration in patients with Parkinson's disease during 16 h of (1) intravenous carbidopa/levodopa (DIZ101) infusion, (2) subcutaneous carbidopa/levodopa (DIZ102) infusion or (3) intestinal carbidopa/levodopa gel infusion. Plasma levels of carbidopa were however approximately four times higher with DIZ101 and DIZ102 than with LCIG, and higher than those usually observed with oral levodopa/carbidopa. Objectives: To investigate if high carbidopa blood concentrations obtained with parenteral levodopa/carbidopa (ratio 8:1) counter the effect of levodopa on motor symptoms. Methods: Eighteen patients with advanced Parkinson's disease were administered DIZ101, DIZ102, and intestinal levodopa/carbidopa gel for 16 h on different days in randomized order. Video recordings of a subset of the motor examination in the Unified Parkinson's Disease Rating Scale (UPDRS) were evaluated by raters blinded for treatment and time. Motor function was also measured using a wrist-worn device monitoring bradykinesia, dyskinesia, and tremor (Parkinson KinetiGraph). Results: There was no tendency for poorer levodopa effect with DIZ101 or DIZ102 as compared to LCIG. Conclusion: Although DIZ101 or DIZ102 causes approximately four times higher plasma carbidopa levels than LCIG, patients responded equally well to all treatments. The results do not indicate that high plasma carbidopa levels hamper the motor efficacy of levodopa.
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23.
  • Bergquist, Filip, 1970, et al. (författare)
  • Neuropeptide release
  • 2008
  • Ingår i: Encyclopedia of Neuroscience. - Oxford : Academic Press. - 9780080450469
  • Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
    • Neuropeptides are by far the largest class of chemical signals used by the central and peripheral nervous system. They are released from large dense core vesicles and here we compare the mechanisms of neuropeptide release with the mechanisms of classical transmitter release from small synaptic vesicles.
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24.
  • Bergquist, Filip, 1970 (författare)
  • On the mechanisms and physiological function of somatodendritic dopamine release in substantia nigra
  • 2002
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Somatodendritic release of neurotransmitters is a neuronal function that is poorly understood in comparison with the more abundant terminal release. This study aimed at characterising somatodendritic dopamine release in substantia nigra in terms of release mechanisms and possible physiological function in motor control.In vivo microdialysis in conscious rats was used to identify the calcium channels involved in somatodendritic and terminal dopamine release in substantia nigra and striatum, respectively. Microdialysis probes were modified to allow local application of high molecular weight compounds like clostridial toxins, which were used to characterise the SNAP-receptor dependency of somatodendritic and terminal dopamine release. Finally, a novel method with combined dual probe microdialysis and simultaneous motor performance testing on an accelerating rod was developed to investigate the physiological role of somatodendritic dopamine release in motor control.The results indicate that a major portion of somatodendritic dopamine release is calcium dependent. Local treatment with selective and non-selective calcium channel blockers confirmed that N-, and P/Q-type voltage sensitive calcium channels (VSCC) mediate most of the calcium dependency of terminal dopamine release, but revealed that somatodendritic dopamine release is only inhibited by unselective VSCC blockers, or the Cav2.3 (R-type VSCC) blocker SNX-482. Local treatments with clostridial toxins showed that striatal and nigral dopamine release were equally sensitive to SNAP-25 destruction. The VAMP-cleaving botulinum toxin B inhibited striatal, but not nigral, dopamine release. A role for somatodendritic dopamine release in the physiological regulation of motor control was supported by: 1) increases in nigral dopamine release related to physical activity; 2) a modulation of motor performance induced by nigral application of D1-like, or D2-like receptor antagonists; and 3) a partial restoration of motor performance in 6-hydroxydopamine lesioned rats during nigral treatment with the dopamine agonist apomorphine.It is suggested that somatodendritic and terminal dopamine release are mediated by different release mechanisms, in particular different VSCC-types and different vesicle associated membrane protein (VAMP) isoforms. The study also presents evidence for a physiological role of somatodendritic dopamine release in substantia nigra in normal motor control. Nigral dopamine release should therefore be considered in future treatment strategies for Parkinson's disease.
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25.
  • Bergquist, Filip, 1970, et al. (författare)
  • Pharmacokinetics of Intravenously (DIZ101), Subcutaneously (DIZ102), and Intestinally (LCIG) Infused Levodopa in Advanced Parkinson Disease
  • 2022
  • Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Objectives Intestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson disease. The primary objective of this trial was to investigate whether continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady-state plasma concentrations of levodopa that are equivalent in magnitude, and noninferior in variability, to those obtained with LCIG in patients with advanced Parkinson disease. Methods A concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved LCIG in a randomized, 3-period crossover, open-label, multicenter trial. Formulations were infused for 16 hours to patients with Parkinson disease who were using LCIG as their regular treatment. Patients were recruited from several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and noninferior variability of DIZ101 and DIZ102 vs LCIG with respect to levodopa plasma concentrations. Results With dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits compared with LCIG in the 18 participants who received all treatments. Although the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Owing to poor uptake of LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n = 20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient. Discussion It is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa-containing solution.
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26.
  • Bergquist, Filip, 1970, et al. (författare)
  • Role of the commissural inhibitory system in vestibular compensation in the rat.
  • 2008
  • Ingår i: The Journal of physiology. - : Wiley. - 1469-7793 .- 0022-3751. ; 586:Pt 18, s. 4441-52
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated the role of the vestibular commissural inhibitory system in vestibular compensation (VC, the behavioural recovery that follows unilateral vestibular loss), using in vivo microdialysis to measure GABA levels in the bilateral medial vestibular nucleus (MVN) at various times after unilateral labyrinthectomy (UL). Immediately after UL, in close correlation with the appearance of the characteristic oculomotor and postural symptoms, there is a marked increase in GABA release in the ipsi-lesional MVN. This is not prevented by bilateral flocculectomy, indicating that it is due to hyperactivity of vestibular commissural inhibitory neurones. Over the following 96 h, as VC occurs and the behavioural symptoms ameliorate, the ipsi-lesional GABA levels return to near-normal. Contra-lesional GABA levels do not change significantly in the initial stages of VC, but decrease at late stages so that when static symptoms have abated there remains a significant difference between the MVNs of the two sides. We also investigated the role of the commissural inhibition in Bechterew's phenomenon, by reversibly inactivating the intact contra-lesional labyrinth in compensating animals through superfusion of local anaesthetic on the round window. Transient inactivation of the intact labyrinth elicited the lateralized behaviour described by Bechterew, but did not alter the GABA levels in either MVN, suggesting the involvement of distinct cellular mechanisms. These findings indicate that an imbalanced commissural inhibitory system is a root cause of the severe oculomotor and postural symptoms of unilateral vestibular loss, and that re-balancing of commissural inhibition occurs in parallel with the subsequent behavioural recovery during VC.
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27.
  • Bergquist, Filip, 1970, et al. (författare)
  • Somatodendritic dopamine release in rat substantia nigra influences motor performance on the accelerating rod.
  • 2003
  • Ingår i: Brain research. - 0006-8993. ; 973:1, s. 81-91
  • Tidskriftsartikel (refereegranskat)abstract
    • The physiological role of somatodendritic dopamine release in the rat substantia nigra was evaluated with a combination of dual probe microdialysis and simultaneous motor performance tests on an accelerating rod. Three main findings support a modulating influence of somatodendritic dopamine release on motor coordination. (1) The rod performance tests were associated with an increase in extracellular dopamine but not 5-hydroxytryptamine concentrations in substantia nigra and with increases in both dopamine and 5-hydroxytryptamine concentrations in the striatum. (2) Nigral application of dopamine antagonists without intrinsic activity resulted in changed performances on the accelerating rod. The response to nigral perfusion with low concentrations (0.1, 1.0 microM) of the D(2)/D(3)-antagonist raclopride consisted of an impairment in rod performance to 63% of the pre-perfusion performance. Higher concentrations (10, 100 microM), however, were not associated with impaired rod performance, but with increased striatal dopamine concentrations. Perfusion of the substantia nigra with 1, 10 and 100 microM of the D(1)/D(5)-antagonist SCH 23390 dose-dependently impaired rod performance. SCH 23390 consistently increased dopamine and 5-hydroxytryptamine concentrations in substantia nigra but did not change the dialysate in the striatum. (3) In unilaterally 6-hydroxydopamine-lesioned rats, a dose-dependent improvement in rod performance was observed during perfusion of the substantia nigra with the non-selective dopamine agonist apomorphine.
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28.
  • Brederlau, Anke, 1968, et al. (författare)
  • Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson's disease: effect of in vitro differentiation on graft survival and teratoma formation.
  • 2006
  • Ingår i: Stem cells (Dayton, Ohio). - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 24:6, s. 1433-40
  • Tidskriftsartikel (refereegranskat)abstract
    • Human embryonic stem cells (hESCs) have been proposed as a source of dopamine (DA) neurons for transplantation in Parkinson's disease (PD). We have investigated the effect of in vitro predifferentiation on in vivo survival and differentiation of hESCs implanted into the 6-OHDA (6-hydroxydopamine)-lesion rat model of PD. The hESCs were cocultured with PA6 cells for 16, 20, or 23 days, leading to the in vitro differentiation into DA neurons. Grafted hESC-derived cells survived well and expressed neuronal markers. However, very few exhibited a DA neuron phenotype. Reversal of lesion-induced motor deficits was not observed. Rats grafted with hESCs predifferentiated in vitro for 16 days developed severe teratomas, whereas most rats grafted with hESCs predifferentiated for 20 and 23 days remained healthy until the end of the experiment. This indicates that prolonged in vitro differentiation of hESCs is essential for preventing formation of teratomas.
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29.
  • Cedergren Weber, Gustav, et al. (författare)
  • The Impact of COVID-19 on Parkinson's Disease : A Case-Controlled Registry and Questionnaire Study on Clinical Markers and Patients' Perceptions
  • 2023
  • Ingår i: Acta Neurologica Scandinavica. - : John Wiley & Sons. - 0001-6314 .- 1600-0404. ; 2023
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Parkinson's disease (PD) is a neurodegenerative disease with motor and nonmotor symptoms. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Objectives: To explore how COVID-19 affects motor, nonmotor, and general health aspects of PD and to map how PD patients perceive their change in symptoms since falling ill with COVID-19.Method: The study was descriptive, case-controlled, and based on both registry and questionnaire data. At baseline, the controls were matched on age, sex, and disease severity. Information on the severity of the disease, nonmotor symptoms, motor symptoms, and general health was retrieved from the Swedish Registry for PD. Registry data from a COVID-19 group (n=45) and a control group (n=73), as well as questionnaires from a COVID-19 group (n=24) and a control group (n=42), were compared.Results: We did not find that SARS-CoV-2 infection affects any major aspect of nonmotor symptoms, motor symptoms, general health, and perception of change in PD patients' post-COVID-19. Compared to controls, the COVID-19 group reported a more positive subjective experience of pain and quality of life and a perception of change post-COVID-19 regarding general motor function, sleep quality, and mood (all p<0.05).Conclusion: Although SARS-CoV-2 infection does not seem to affect PD symptoms in any major respect, the subjective experience of several aspects of life in PD patients might be slightly improved post-COVID-19 compared to a control group. The findings warrant further investigations due to the small sample size and possible survivorship bias.
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30.
  • Chaudhuri, K. Ray, et al. (författare)
  • Improved Sleep Correlates with Improved Quality of Life and Motor Symptoms with Foslevodopa/Foscarbidopa
  • 2024
  • Ingår i: MOVEMENT DISORDERS CLINICAL PRACTICE. - 2330-1619.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Foslevodopa/foscarbidopa is a subcutaneous infusion of levodopa/carbidopa prodrugs. Objectives: Assess correlations between sleep and efficacy from interim data of a phase 3 trial of foslevodopa/foscarbidopa (NCT03781167). Methods: Pearson correlations between sleep (Parkinson's Disease Sleep Scale-2 [PDSS-2]) and quality of life (QoL; Parkinson's Disease Questionnaire-39), motor experiences of daily living (m-EDL; Movement Disorder Society-Unified Parkinson's Disease Scale Part II), and "Off"/"On" times were calculated for baseline and week 26 improvements. Regression analyses were adjusted for baseline PDSS-2 score. Results: Baseline sleep correlated moderately with QoL (r = 0.44, P < 0.001) and weakly with m-EDL (r = 0.28; P < 0.001). Sleep improvement weakly correlated with improved "Off" time (r = 0.37; P < 0.001) and QoL (r = 0.36; P < 0.001). Regression analyses demonstrated significant positive associations for improved sleep, "Off" time, QoL, and m-EDL. Conclusions: Improved sleep with foslevodopa/foscarbidopa was associated with improved QoL and "Off" time.
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31.
  • Constantinescu, Radu, 1966, et al. (författare)
  • Cerebrospinal fluid markers of neuronal and glial cell damage in patients with autoimmune neurologic syndromes with and without underlying malignancies.
  • 2017
  • Ingår i: Journal of neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 306, s. 25-30
  • Tidskriftsartikel (refereegranskat)abstract
    • Autoimmune neurologic syndromes can be paraneoplastic (associated with malignancies and/or onconeural antibodies), or non-paraneoplastic. Their clinical presentation is often similar. As prognosis is related to malignancy treatment, better biomarkers are needed to identify patients with malignancy. We investigated cerebrospinal fluid (CSF) markers of neuronal (neurofilament light chain, NFL and total tau protein, T-tau) and glial (glial fibrillary acidic protein) damage. CSF-NFL and T-tau were increased in both paraneoplastic and non-paraneoplastic autoimmune syndromes. Patients with manifest malignancies were older, had less epilepsy, more focal central and peripheral neurological signs and symptoms, and worse long-term outcome, than those without malignancy. CSF-NFL-levels predicted long-term outcome but were not diagnostic for malignancy, after age adjustment.
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32.
  • Constantinescu, Radu, 1966, et al. (författare)
  • Cerebrospinal fluid markers of neuronal and glial cell damage to monitor disease activity and predict long-term outcome in patients with autoimmune encephalitis
  • 2016
  • Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101. ; 23:4, s. 796-806
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purposeClinical symptoms and long-term outcome of autoimmune encephalitis are variable. Diagnosis requires multiple investigations, and treatment strategies must be individually tailored. Better biomarkers are needed for diagnosis, to monitor disease activity and to predict long-term outcome. The value of cerebrospinal fluid (CSF) markers of neuronal [neurofilament light chain protein (NFL), and total tau protein (T-tau)] and glial cell [glial fibrillary acidic protein (GFAP)] damage in patients with autoimmune encephalitis was investigated. MethodsDemographic, clinical, magnetic resonance imaging, CSF and antibody-related data of 25 patients hospitalized for autoimmune encephalitis and followed for 1 year were retrospectively collected. Correlations between these data and consecutive CSF levels of NFL, T-tau and GFAP were investigated. Disability, assessed by the modified Rankin scale, was used for evaluation of disease activity and long-term outcome. ResultsThe acute stage of autoimmune encephalitis was accompanied by high CSF levels of NFL and T-tau, whereas normal or significantly lower levels were observed after clinical improvement 1 year later. NFL and T-tau reacted in a similar way but at different speeds, with T-tau reacting faster. CSF levels of GFAP were initially moderately increased but did not change significantly later on. Final outcome (disability at 1 year) directly correlated with CSF-NFL and CSF-GFAP levels at all time-points and with CSF-T-tau at 3 1 months. This correlation remained significant after age adjustment for CSF-NFL and T-tau but not for GFAP. ConclusionIn autoimmune encephalitis, CSF levels of neuronal and glial cell damage markers appear to reflect disease activity and long-term disability.
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33.
  • Constantinescu, Radu, 1966, et al. (författare)
  • Cerebrospinal fluid protein markers in PD patients after DBS-STN surgery—A retrospective analysis of patients that underwent surgery between 1993 and 2001
  • 2018
  • Ingår i: Clinical neurology and neurosurgery. - : Elsevier BV. - 0303-8467. ; 174, s. 174-179
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Cerebrospinal fluid (CSF) markers of neurodegeneration [neurofilament light chain (NFL), total Tau (T-Tau)], tau pathology [phosphorylated tau (p-Tau)], glial cell damage or activation [glial fibrillary acidic protein (GFAP)], and brain amyloidosis [β-amyloid 1-42 (Aβ42)] are useful for diagnosis and prognosis in several neurodegenerative disorders. In this paper we investigate these markers and their relationship to key clinical milestones in patients with advanced Parkinson´s disease (PD) operated at our center with subthalamic nucleus deep brain stimulation (STN-DBS) for at least 15 years ago. Patients and methods Retrospective analysis of available cerebrospinal fluid and clinical data in PD-patients, 15 years or more after they underwent STN-DBS surgery. All PD-patients implanted with STN-DBS at Sahlgrenska University Hospital before January 1, 2001, were regularly assessed until January 10, 2018, or until death, or until lost to follow-up. Results Twenty three PD patients were operated with STN-DBS. Sixteen of these (six females and ten males) underwent at least one lumbar puncture (LP) immediately prior to or after STN-DBS. Their age at the latest available LP was 64 (55–75) years [median (range)], PD duration 20 (11–33) years, and Hoehn & Yahr (H&Y) stage 3 (2–4). Time between DBS operation and the last LP was 4.5 (0.3–10.8) years. Time from the last LP to the last follow up was 6 (0.1–18) years, and for the entire cohort 115 person-years. On January 10, 2018, four PD-patients (25%) were still alive. All preoperative CSF marker levels were normal. Between two days and six months after DBS, NFL and GFAP levels increased sharply but they normalized thereafter in most patients, and were normal up to almost 11 years after neurosurgery. Over time, all patients deteriorated slowly. At the last follow up, H&Y was 5 (3–5) and 12/16 were demented. There was no significant correlation between postoperative (> 6 months) CSF NFL, GFAP, T-Tau, p-Tau, β-amyloid levels and the presence of dementia, psychosis, inability to walk or need for nursing home at the time for LP, nor for presence of dementia at the last follow up or for death as of January 10, 2018. Conclusion CSF protein biomarkers remain normal despite long PD duration, severe disability, and chronic STN-DBS. They cannot be used for PD staging or prognostication but may indicate brain damage caused by other pathological factors.
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34.
  • Constantinescu, Radu, 1966, et al. (författare)
  • Key clinical milestones 15 years and onwards after DBS-STN surgery-A retrospective analysis of patients that underwent surgery between 1993 and 2001
  • 2017
  • Ingår i: Clinical Neurology and Neurosurgery. - : Elsevier BV. - 0303-8467. ; 154, s. 43-48
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for motor fluctuations in Parkinson's disease (PD), but does not halt disease progression. The long-term deterioration of key functions such as cognition, speech, ability to swallow, gait, urinary bladder control, orientation and reality perception is decisive for patients' independency in daily life. In this paper we investigated patients with advanced PD operated at our center with STN-DBS for at least 15 years ago, in respect to key clinical milestones reflecting their overall function in daily living. Patients and methods: Retrospective analysis of clinical data concerning key clinical milestones including death in PD-patients, 15 years or more after they underwent STN-DBS surgery. All PD-patients implanted with STN-DBS at Sahlgrenska Hospital before January 1, 2001, were regularly assessed until death, dropout, or January 11, 2016. Results: Sixteen men and seven women with a median (range) disease duration of 18 (10-28) years were operated with STN-DBS. The median (range) follow-up time post-surgery was 12 (2-18) years and 692 person-years of disease duration were observed. In January 2016, nine PD-patients (39%) were still alive (eight with active STN-DBS). Initially, motor symptoms improved in all patients. Sustained benefit (implying active stimulation at the last follow up) was maintained in 19 of them (83%) but STN-DBS was inactivated in four (17%) due to inefficacy. Over time, all patients deteriorated slowly, and a majority developed severe non-motor and axial symptoms such as dementia, inability to talk, swallow and walk, urinary incontinence, psychosis, and need for nursing home care. At the last follow up, 16/23 (70%) patients were treated with antidepressants. Conclusion: A majority of PD-patients experience sustained motor benefit with continuous STN-DBS. However, over time, non-motor and axial symptoms slowly and severely restrict PD-patients' function in their daily living. (C) 2017 Elsevier B.V. All rights reserved.
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35.
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36.
  • Dickson, Suzanne L., 1966, et al. (författare)
  • The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors.
  • 2012
  • Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 32:14, s. 4812-20
  • Tidskriftsartikel (refereegranskat)abstract
    • The glucagon-like peptide 1 (GLP-1) system is a recently established target for type 2 diabetes treatment. In addition to regulating glucose homeostasis, GLP-1 also reduces food intake. Previous studies demonstrate that the anorexigenic effects of GLP-1 can be mediated through hypothalamic and brainstem circuits which regulate homeostatic feeding. Here, we demonstrate an entirely novel neurobiological mechanism for GLP-1-induced anorexia in rats, involving direct effects of a GLP-1 agonist, Exendin-4 (EX4) on food reward that are exerted at the level of the mesolimbic reward system. We assessed the impact of peripheral, central, and intramesolimbic EX4 on two models of food reward: conditioned place preference (CPP) and progressive ratio operant-conditioning. Food-reward behavior was reduced in the CPP test by EX4, as rats no longer preferred an environment previously paired to chocolate pellets. EX4 also decreased motivated behavior for sucrose in a progressive ratio operant-conditioning paradigm when administered peripherally. We show that this effect is mediated centrally, via GLP-1 receptors (GLP-1Rs). GLP-1Rs are expressed in several key nodes of the mesolimbic reward system; however, their function remains unexplored. Thus we sought to determine the neurobiological substrates underlying the food-reward effect. We found that the EX4-mediated inhibition of food reward could be driven from two key mesolimbic structures-ventral tegmental area and nucleus accumbens-without inducing concurrent malaise or locomotor impairment. The current findings, that activation of central GLP-1Rs strikingly suppresses food reward/motivation by interacting with the mesolimbic system, indicate an entirely novel mechanism by which the GLP-1R stimulation affects feeding-oriented behavior.
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37.
  • Eckernäs, Daniel, 1985, et al. (författare)
  • Acoustic white noise ameliorates reduced regional brain expression of CaMKII and ΔFosB in the spontaneously hypertensive rat model of ADHD
  • 2019
  • Ingår i: IBRO Reports. - : Elsevier BV. - 2451-8301. ; 6, s. 31-39
  • Tidskriftsartikel (refereegranskat)abstract
    • Loud (≥70dBA) acoustic white noise improves cognitive performance in children with ADHD as well as skilled reach and rotarod performance in the spontaneously hypertensive (SH) rat model of ADHD. To investigate how acoustic noise influences the brain activity in the SH rat model of ADHD, immunohistochemical staining of two neuronal activity and plasticity markers, Ca2+/Calmodulin dependent protein kinase II (CaMKII) and ΔFosB, was evaluated in Wistar (n = 24) and SH (n = 16) rats after repeated exposure to acoustic noise or ambient silence. Other SH rats (n = 6) were treated with repeated methylphenidate (MPH). Expression of CaMKII was reduced in the tuberomammillary nucleus (TMN) of the SH rat compared to Wistar but not in the nucleus accumbens (nAc) or the dorsolateral prefrontal cortex (DL-PFC). In the TMN, the expression of CaMKII was increased by noise in both strains. ΔFosB expression was reduced in nAc, DL-PFC and the dorsolateral striatum (DLS) of the SH rat compared to Wistar. Exposure to acoustic white noise significantly increased ΔFosB expression in the nAc and DL-PFC but not in the DLS of SH rats. The results indicate that acoustic noise shifts a reduced neuronal activity in the nAc, TMN and DL-PFC in SH rats toward the normal levels of activity in outbred rats. This may explain why noise has benefit selectively in ADHD. © 2018 The Authors
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38.
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39.
  • Horne, M. K., et al. (författare)
  • An Objective Fluctuation Score for Parkinson's Disease
  • 2015
  • Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction Establishing the presence and severity of fluctuations is important in managing Parkinson's Disease yet there is no reliable, objective means of doing this. In this study we have evaluated a Fluctuation Score derived from variations in dyskinesia and bradykinesia scores produced by an accelerometry based system. Methods The Fluctuation Score was produced by summing the interquartile range of bradykinesia scores and dyskinesia scores produced every 2 minutes between 0900-1800 for at least 6 days by the accelerometry based system and expressing it as an algorithm. This Score could distinguish between fluctuating and non-fluctuating patients with high sensitivity and selectivity and was significant lower following activation of deep brain stimulators. The scores following deep brain stimulation lay in a band just above the score separating fluctuators from non-fluctuators, suggesting a range representing adequate motor control. When compared with control subjects the score of newly diagnosed patients show a loss of fluctuation with onset of PD. The score was calculated in subjects whose duration of disease was known and this showed that newly diagnosed patients soon develop higher scores which either fall under or within the range representing adequate motor control or instead go on to develop more severe fluctuations. The Fluctuation Score described here promises to be a useful tool for identifying patients whose fluctuations are progressing and may require therapeutic changes. It also shows promise as a useful research tool. Further studies are required to more accurately identify therapeutic targets and ranges.
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40.
  • Johansson, Dongni, 1988, et al. (författare)
  • Evaluation of a sensor algorithm for motor state rating in Parkinson's disease
  • 2019
  • Ingår i: Parkinsonism & Related Disorders. - : Elsevier BV. - 1353-8020 .- 1873-5126. ; 64:July, s. 112-117
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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41.
  • Kilinçalp, G., et al. (författare)
  • Predictive Value of Ambulatory Objective Movement Measurement for Outcomes of Levodopa/Carbidopa Intestinal Gel Infusion
  • 2022
  • Ingår i: Journal of Personalized Medicine. - : MDPI AG. - 2075-4426. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients with Parkinson’s disease that may benefit from device-assisted therapy can be identified with guidelines like Navigate PD. The decision to offer advanced treatment and the choice of treatment modality are, however, not straightforward, and some patients respond less favorably to a chosen therapy. Measurements with the Parkinson Kinetigraph (PKG) can detect motor fluctuations and could therefore predict patients that respond better or worse to intestinal levodopa/carbidopa gel infusion (LCIG). In a retrospective analysis of 45 patients that had been selected to start LCIG between 2014 and 2020, the effects of baseline PKG and clinical characteristic on the outcome were determined with ordinal regression. Although all patients had been found to have handicapping medication-related symptom fluctuations, patients without clear objective off fluctuations in the baseline PKG had low odds ratio for success. Lower odds for success were also found with increasing age, whereas gender, medication intensity and baseline PKG summary scores (median bradykinesia and dyskinesia scores, fluctuation dyskinesia score and percent time with tremor) had no significant effect. Absence of easily identified off-periods in the PKG has a negative prognostic value for the effect of LCIG and could prompt noninvasive infusion evaluation before surgery. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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42.
  • Lindgren, H. S., et al. (författare)
  • The effect of additional noradrenergic and serotonergic depletion on a lateralised choice reaction time task in rats with nigral 6-OHDA lesions
  • 2014
  • Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 253, s. 52-62
  • Tidskriftsartikel (refereegranskat)abstract
    • Parkinson's disease (PD) patients often suffer from visuospatial deficits, which have been considered a disruption of the representation of external space. The lateralised choice reaction time (CRT) task is an operant task for rodents in which similar deficits can be assessed. It has been demonstrated that specific parameters in this task is disrupted after unilateral injections of 6-hydroxydopamine (6-OHDA), which have been associated with the dopamine (DA) depletion that inevitably follows this type of lesion. However, studies have demonstrated that this type of lesion also affects the serotonergic (5HT) and noradrenergic (NA) systems. However, the impact of these systems on parameters in the CRT task had not yet been investigated.To this end, rats were pretrained on the CRT task before receiving selective lesions of the DAergic system, either alone or in combination with depletion of the NA or 5HT system. All rats with a 6-OHDA lesion displayed a gradual decline in the selection, initiation and execution of lateralised movements compared to sham-lesion controls on the side contralateral to the lesion. They also displayed a reduced number of useable trials as well as an increased number of procedural errors. Interestingly, the group with an additional noradrenergic lesion was significantly slower in reacting to lateralised stimuli throughout the testing period compared to the other two groups with a 6-OHDA lesion. There was however no difference between the three different lesion groups in the other parameters assessed in the task.These data confirm previous findings demonstrating that the majority of the parameters assessed in the lateralised CRT task are strongly dependent on DA. However, this study has also shown that the NAergic system may play an important role in contributing to the attentive performance influencing the capacity to react to the presented lateralised stimuli. © 2013 Elsevier Inc.
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43.
  • Matić, Teodora, et al. (författare)
  • Unsupervised Learning from Motion Sensor Data to Assess the Condition of Patients with Parkinson’s Disease
  • 2019
  • Ingår i: AIME 2019. - Cham : Springer. - 9783030216429 - 9783030216412 ; , s. 420-424
  • Konferensbidrag (refereegranskat)abstract
    • Parkinson’s disease (PD) is a chronic neurodegenerative disorder that predominantly affects the patient’s motor system, resulting in muscle rigidity, bradykinesia, tremor, and postural instability. As the disease slowly progresses, the symptoms worsen, and regular monitoring is required to adjust the treatment accordingly. The objective evaluation of the patient’s condition is sometimes rather difficult and automated systems based on various sensors could be helpful to the physicians. The data in this paper come from a clinical study of 19 advanced PD patients with motor fluctuations. The measurements used come from the motion sensors the patients wore during the study. The paper presents an unsupervised learning approach applied on this data with the aim of checking whether sensor data alone can indicate the patient’s motor state. The rationale for the unsupervised approach is that there was significant inter-physician disagreement on the patient’s condition (target value for supervised machine learning). The input to clustering came from sensor data alone. The resulting clusters were matched against the physicians’ estimates showing relatively good agreement.
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44.
  • Memedi, Mevludin, 1983-, et al. (författare)
  • Automatic Spiral Analysis for Objective Assessment of Motor Symptoms in Parkinson's Disease
  • 2015
  • Ingår i: Sensors. - : MDPI AG. - 1424-8220. ; 15:9, s. 23727-23744
  • Tidskriftsartikel (refereegranskat)abstract
    • A challenge for the clinical management of advanced Parkinson's disease (PD) patients is the emergence of fluctuations in motor performance, which represents a significant source of disability during activities of daily living of the patients. There is a lack of objective measurement of treatment effects for in-clinic and at-home use that can provide an overview of the treatment response. The objective of this paper was to develop a method for objective quantification of advanced PD motor symptoms related to off episodes and peak dose dyskinesia, using spiral data gathered by a touch screen telemetry device. More specifically, the aim was to objectively characterize motor symptoms (bradykinesia and dyskinesia), to help in automating the process of visual interpretation of movement anomalies in spirals as rated by movement disorder specialists. Digitized upper limb movement data of 65 advanced PD patients and 10 healthy (HE) subjects were recorded as they performed spiral drawing tasks on a touch screen device in their home environment settings. Several spatiotemporal features were extracted from the time series and used as inputs to machine learning methods. The methods were validated against ratings on animated spirals scored by four movement disorder specialists who visually assessed a set of kinematic features and the motor symptom. The ability of the method to discriminate between PD patients and HE subjects and the test-retest reliability of the computed scores were also evaluated. Computed scores correlated well with mean visual ratings of individual kinematic features. The best performing classifier (Multilayer Perceptron) classified the motor symptom (bradykinesia or dyskinesia) with an accuracy of 84% and area under the receiver operating characteristics curve of 0.86 in relation to visual classifications of the raters. In addition, the method provided high discriminating power when distinguishing between PD patients and HE subjects as well as had good test-retest reliability. This study demonstrated the potential of using digital spiral analysis for objective quantification of PD-specific and/or treatment-induced motor symptoms.
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45.
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46.
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47.
  • Mitra, Reinika, et al. (författare)
  • Local Change in Urinary Bladder Contractility Following CNS Dopamine Denervation in the 6-OHDA Rat Model of Parkinson's Disease
  • 2015
  • Ingår i: Journal of Parkinsons Disease. - : IOS Press. - 1877-7171 .- 1877-718X. ; 5:2, s. 301-311
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Urinary problems, including urinary frequency, urgency, and nocturia are some of the non-motor symptoms that correlate most with poor quality of life in Parkinson's disease. However, the mechanism behind these symptoms is poorly understood, in particular regarding peripheral bladder pathophysiology following dopamine degeneration. Objective: In this study, we compared the contractile responsiveness of urinary bladder from the 6-OHDA unilateral rat model of Parkinson's disease with that of normal untreated animals. Methods: The contractility of the urinary detrusor muscle was evaluated in bladder strip preparations using electrical field stimulation, and muscarinic and purinoceptor stimulations in an vitro organ bath setup. Results: Our data show that the overall contractile response following electrical field stimulation was significantly higher (43% at maximum contraction by 20-40 Hz stimulation) in the 6-OHDA-lesioned rats as compared to control animals. This increase was associated with a significant increase in the cholinergic contractile response, where the muscarinic agonist methacholine produced a 44% (at 10(-4) Mconcentration) higher response in the 6-OHDA-treated rats as compared to controls with a significant left-shift of the dose response. This indicates an altered sensitivity of the muscarinic receptor system following the specific central 6-OHDA-induced dopamine depletion. In addition a 36% larger contraction of strips from the 6-OHDA animals was also observed with purinoceptor activation using the agonist ATP (5x10(-3) M) during atropine treatment. Conclusions: Our data shows that it is not only the central dopamine control of the micturition reflex that is altered in Parkinson's disease, but also the local contractile function of the urinary bladder. The current study draws attention to a mechanism of urinary dysfunction in Parkinson's disease that has previously not been described.
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48.
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49.
  • Niazi Shahabi, Haydeh, 1966, et al. (författare)
  • An investigation of dopaminergic metabolites in the striatum and in the substantia nigra in vivo utilising radiolabelled L-DOPA and high performance liquid chromatography: a new approach in the search for transmitter metabolites.
  • 2003
  • Ingår i: Neuroscience. - 0306-4522. ; 120:2, s. 425-33
  • Tidskriftsartikel (refereegranskat)abstract
    • Although the major routes of dopamine metabolism seem to be established, at least in terminal regions such as the striatum, it is important to search for previously unknown metabolites and to investigate the relevance of previously suggested minor alternative pathways. An urgent issue is to verify and quantify the transformation of dopamine to putative toxic species, another is to further explore metabolism of dopamine located in cell bodies/dendrites, e.g. in the substantia nigra. We have developed a new method in order to widen the search for alternative metabolites of dopamine. The method is based on systemic injection of tritiated L-DOPA to rats in vivo. Brain tissue was homogenised and centrifuged and the resulting supernatant fractioned following passage through a liquid chromatography system. The radioactivity of each fraction was measured using a scintillation system. By identifying fractions containing major catecholamines and metabolites, according to a standard solution, novel metabolites can be searched for in the remaining fractions. It was possible to obtain sufficient radioactivity in separate fractions of supernatant of homogenised tissue, even from such a small brain nucleus as substantia nigra. Radioactivity was obtained in those fractions that contained the major catecholamines and their metabolites, as well as in other fractions where it may represent previously unknown metabolites of L-DOPA/dopamine. The method was used to evaluate the possibility that cytochrome P450 2E1 is involved in the metabolism of dopamine in the substantia nigra. Significant changes in the radioactivity pattern were induced by inhibition of the enzyme but conclusions about whether cytochrome P450 2E1 is involved in the metabolism of dopamine or not requires further studies. The method can be used to study the metabolism of dopamine and can be extended, by using other radiolabelled precursors, also to evaluate metabolism of other transmitters, e.g. serotonin.
  •  
50.
  • Odin, Per, et al. (författare)
  • Viewpoint and practical recommendations from a movement disorder specialist panel on objective measurement in the clinical management of Parkinson's disease
  • 2018
  • Ingår i: Npj Parkinson's Disease. - : Springer Science and Business Media LLC. - 2373-8057. ; 4
  • Tidskriftsartikel (refereegranskat)abstract
    • Motor aspects of Parkinson's disease, such as fluctuations and dyskinesia, can be reliably evaluated using a variety of "wearable" technologies, but practical guidance on objective measurement (OM) and the optimum use of these devices is lacking. Therefore, as a first step, a panel of movement disorder specialists met to provide guidance on how OM could be assessed and incorporated into clinical guidelines. A key aspect of the incorporation of OM into the management of Parkinson's disease (PD) is defining cutoff values that separate "controlled" from "uncontrolled" symptoms that can be modified by therapy and that relate to an outcome that is relevant to the person with PD (such as quality of life). Defining cutoffs by consensus, which can be subsequently tested and refined, is the first step to optimizing OM in the management of PD. OM should be used by all clinicians that treat people with PD but the least experienced may find the most value, but this requires guidance from experts to allow non-experts to apply guidelines. While evidence is gained for devices that produce OM, expert opinion is needed to supplement the evidence base.
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