Ilias Thomas

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.

A Pointwise Approach to Dose-Response Meta-Analysis of Aggregated Data

In a two-stage dose-response meta-analysis a common functional relationship is applied to each study and an overall curve is obtained by combining study-specific dose-response coefficients. Possible limitations are: 1) a common dose-response model may have a poor fit in some of the studies; 2) combining dose-response coefficients discard information about study-specific exposure range. A pointwise approach for meta-analysis may overcome those limitations by combining predicted relative risks for a fine grid of exposure values based on potentially different dose-response models. We described how to flexibly model the dose-response association in a single study using fractional polynomials and spline, and how to present the combined results from study-specific analyses. The strategy is illustrated using aggregated data derived from the Surveillance, Epidemiology, and End Results program, with results compared to the corresponding analysis based on individual data. Another example on milk consumption and all-cause mortality is used to show the advantages of the pointwise approach regarding flexibility in the dose-response analyses, limitations of extrapolations, and informativeness in presenting pooled results. Application of the proposed strategy may improve dose-response meta-analysis of observational studies in case of particularly heterogeneous exposure distributions.

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).

The effect of continuous levodopa treatment during the afternoon hours

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

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

Automated dosing schemes for administration of microtablets of levodopa for Parkinson’s disease, using wearable sensors

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

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