Marina Senek

Continuous Drug Delivery in Parkinson’s Disease

Development of motor and non-motor complications during the course of Parkinson’s disease (PD) is a major challenge for therapeutic management. At advanced disease stages, patients frequently fluctuate between PD symptoms–such as bradykinesia–and dyskinesias, in response to fluctuations in drug concentrations. Continuous subcutaneous infusion of the dopamine agonist apomorphine or intestinal infusion of levodopa reduce such fluctuations in both pharmacokinetics and motor function. This is the basis for the concept of continuous drug delivery in PD, and the more theoretical concept of continuous dopaminergic stimulation. These expressions are sometimes used to describe a treatment that is more continuous in its pharmacokinetic profile or that produces more sustained effects, compared with immediate-release levodopa, i.e. not only pump treatments. For example, sustained-release formulations of levodopa or dopamine agonists, transdermal delivery of rotigotine, and addition of catechol-O-methyltransferase inhibitors or monoamine oxidase-B inhibitors have been developed with the aim to provide more continuous drug concentrations, sustained benefits and minimized side effects. Progress has been made, but there are still knowledge gaps regarding how these treatment alternatives can be optimally used. New treatments are currently being developed to provide the continuous drug delivery that is known to successfully alleviate motor and non-motor complications. Hopefully, although not yet proven, these new methods may also prevent or postpone some of the late-stage complications.

Levodopa‐entacapone‐carbidopa intestinal gel in Parkinson's disease: A randomized crossover study

The addition of oral entacapone to levodopa‐carbidopa intestinal gel treatment leads to less conversion of levodopa to 3‐O‐methyldopa, thereby increasing levodopa plasma concentration. The objective of this study was to compare systemic levodopa exposure of the newly developed levodopa‐entacapone‐carbidopa intestinal gel after a 20% dose reduction with levodopa exposure after the usual levodopa‐carbidopa intestinal gel dose in a randomized crossover trial in advanced Parkinsons disease patients.

First clinical experience with levodopa/carbidopa microtablets in Parkinson’s disease

Levodopa is the most effective symptomatic treatment throughout the course of Parkinsons disease, but as the disease progresses, there may be a need for individualized, fine‐tuned treatments.

A Treatment-Response Index From Wearable Sensors for Quantifying Parkinson's Disease Motor States

The goal of this study was to develop an algorithm that automatically quantifies motor states (off, on, dyskinesia) in Parkinsons disease (PD), based on accelerometry during a hand pronation-supination test. Clinicians ratings using the Treatment Response Scale (TRS), ranging from −3 (very Off) 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.

Individualization of levodopa treatment using a microtablet dispenser and ambulatory accelerometry

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 Parkinsons disease (PD).

Using measurements from wearable sensors for automatic scoring of Parkinson’s disease motor states

Objective: The aim of this work is to evaluate clinimetric properties of a method for measuring Parkinson’s disease (PD) upper limb temporal irregularities during spiral drawing tasks.Background: B ...Basic Science Abstracts - Session Title: Parkinsons Disease: Pathophysiology: abstract no. 518

Quantification of upper limb motor symptoms of Parkinson's disease using a smartphone

This free journal suppl. entitled: Supplement: Abstracts of the Twentieth International Congress of Parkinsons Disease and Movement DisordersObjective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype. (Less)Objective: The aim of this study is to develop and evaluate methods for quantifying motor symptoms in Parkinson’s disease (PD) using combined upper limb motor test data collected during tapping and ...20th International Congress of Parkinson’s disease and Movement Disorders, Berlin, Germany, 19-23 June, 2016Upper limb motor tests are related to clinical ratings of motor function in advanced Parkinsons disease

Minimizing levodopa titration period for Parkinson’s disease

This free journal suppl. entitled: Supplement: Abstracts of the Twentieth International Congress of Parkinsons Disease and Movement DisordersObjective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype. (Less)Objective: The aim of this study is to develop and evaluate methods for quantifying motor symptoms in Parkinson’s disease (PD) using combined upper limb motor test data collected during tapping and ...20th International Congress of Parkinson’s disease and Movement Disorders, Berlin, Germany, 19-23 June, 2016Upper limb motor tests are related to clinical ratings of motor function in advanced Parkinsons disease

Upper limb motor tests are related to clinical ratings of motor function in advanced Parkinson's disease

This free journal suppl. entitled: Supplement: Abstracts of the Twentieth International Congress of Parkinsons Disease and Movement DisordersObjective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype. (Less)Objective: The aim of this study is to develop and evaluate methods for quantifying motor symptoms in Parkinson’s disease (PD) using combined upper limb motor test data collected during tapping and ...20th International Congress of Parkinson’s disease and Movement Disorders, Berlin, Germany, 19-23 June, 2016Upper limb motor tests are related to clinical ratings of motor function in advanced Parkinsons disease