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Evaluation of spontaneous propulsive movement as a screening tool to detect rescue of Parkinsonism phenotypes in zebrafish models.

ABSTRACT: Zebrafish models of human neuropsychiatric diseases offer opportunities to identify novel therapeutic targets and treatments through phenotype-based genetic or chemical modifier screens. In order to develop an assay to detect rescue of zebrafish models of Parkinsonism, we characterized spontaneous zebrafish larval motor behavior from 3 to 9 days post fertilization in a microtiter plate format suitable for screening, and clarified the role of dopaminergic signaling in its regulation. The proportion of time that larvae spent moving increased progressively between 3 and 9 dpf, whereas their active velocity decreased between 5 and 6 dpf as sporadic burst movements gave way to a more mature beat-and-glide pattern. Spontaneous movement varied between larvae and during the course of recordings as a result of intrinsic larval factors including genetic background. Variability decreased with age, such that small differences between groups of larvae exposed to different experimental conditions could be detected robustly by 6 to 7 dpf. Suppression of endogenous dopaminergic signaling by exposure to MPP(+), haloperidol or chlorpromazine reduced mean velocity by decreasing the frequency with which spontaneous movements were initiated, but did not alter active velocity. The variability of mean velocity assays could be reduced by analyzing groups of larvae for each data point, yielding acceptable screening window coefficients; the sample size required in each group was determined by the magnitude of the motor phenotype in different models. For chlorpromazine exposure, samples of four larvae allowed robust separation of treated and untreated data points (Z=0.42), whereas the milder impairment provoked by MPP(+) necessitated groups of eight larvae in order to provide a useful discovery assay (Z=0.13). Quantification of spontaneous larval movement offers a simple method to determine functional integrity of motor systems, and may be a useful tool to isolate novel molecular modulators of Parkinsonism phenotypes.

SUBMITTER: Farrell TC

PROVIDER: S-EPMC3153634 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Evaluation of spontaneous propulsive movement as a screening tool to detect rescue of Parkinsonism phenotypes in zebrafish models.

Farrell Thomas C TC Cario Clinton L CL Milanese Chiara C Vogt Andreas A Jeong Jong-Hyeon JH Burton Edward A EA

Neurobiology of disease 20110606 1

Zebrafish models of human neuropsychiatric diseases offer opportunities to identify novel therapeutic targets and treatments through phenotype-based genetic or chemical modifier screens. In order to develop an assay to detect rescue of zebrafish models of Parkinsonism, we characterized spontaneous zebrafish larval motor behavior from 3 to 9 days post fertilization in a microtiter plate format suitable for screening, and clarified the role of dopaminergic signaling in its regulation. The proporti ...[more]

PMID: 21669287

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Project description:Background: The prevalence of parkinsonism in developing countries is largely unknown due to difficulty in ascertainment because access to neurologists is often limited. Objective: Develop and validate a parkinsonism screening tool using objective motor task-based tests that can be administered by non-clinicians. Methods: In a cross-sectional population-based sample from South Africa, we evaluated 315 adults, age >40, from an Mn-exposed (smelter) community, using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3), Purdue grooved pegboard, and kinematic-UPDRS3-based motor tasks. In 275 participants (training dataset), we constructed a linear regression model to predict UPDRS3. We selected motor task summary measures independently associated with UPDRS3 (p < 0.05). We validated the model internally in the remaining 40 participants from the manganese-exposed community (test dataset) using the area under the receiver operating characteristic curve (AUC), and externally in another population-based sample of 90 participants from another South African community with only background levels of environmental Mn exposure. Results: The mean UPDRS3 score in participants from the Mn-exposed community was 9.1 in both the training and test datasets (standard deviation = 6.4 and 6.1, respectively). Together, 57 (18.1%) participants in this community had a UPDRS3 ≥ 15, including three with Parkinson's disease. In the non-exposed community, the mean UPDRS3 was 3.9 (standard deviation = 4.3). Three (3.3%) had a UPDRS3 ≥ 15. Grooved pegboard time and mean velocity for hand rotation and finger tapping tasks were strongly associated with UPDRS3. Using these motor task summary measures and age, the UPDRS3 predictive model performed very well. In the test dataset, AUCs were 0.81 (95% CI 0.68, 0.94) and 0.91 (95% CI 0.81, 1.00) for cut points for neurologist-assessed UPDRS3 ≥ 10 and UPDRS3 ≥ 15, respectively. In the external validation dataset, the AUC was 0.85 (95% CI 0.73, 0.97) for UPDRS3 ≥ 10. AUCs were 0.76-0.82 when excluding age. Conclusion: A predictive model based on a series of objective motor tasks performs very well in assessing severity of parkinsonism in both Mn-exposed and non-exposed population-based cohorts.

Project description:ObjectivesNon-traumatic extremity injuries are particularly common in sports, representing a significant economic, academic, and psychosocial burden on athletes. Proposed musculoskeletal risk factors for increased injury and decreased performance in athletes include movement pattern inefficiency, decreased regional stability, decreased mobility, and asymmetrical movement. The Movement System Screening Tool (MSST) is a comprehensive screening tool designed to assess these factors. Thus, the purpose of this study was to describe the development and determine the content and construct validity and inter-rater reliability of the MSST.MethodsA modified Delphi panel of experts determined content validity. 80 athletes (40 with and 40 without a current non-traumatic shoulder injury) completed 21 clinical tests, with exploratory factor analysis and known group analysis performed to determine construct validity. Two independent raters were used to establish individual item and composite score inter-rater reliability.ResultsExploratory factor analysis identified three of the four apriori constructs over 7 factors (14 tests), representing 63% of the variance. Known group analysis revealed a significantly lower composite score in athletes with vs. without a current non-traumatic shoulder injury (56.9±5.8 vs. 62.7±4.5, respectively). A preliminary cut score of 62 was chosen with sensitivity of 85% and specificity of 44%. Composite score inter-rater reliability was excellent ICC (2,1)=0.94, 95% CI (0.91, 0.96) and item reliability ranged from κ=.57 to 1.00.ConclusionsThe MSST possesses constructs representative of injury risk and measurement properties acceptable for use in clinical settings. Comprehensive screens with construct validity and known measurement error are needed not only to identify athletes at risk of injury, but also provide an instrument that can be used in studies that seek to validate training approaches proposed to change movement impairment and injury risk in athletes.

Dataset Information

Evaluation of spontaneous propulsive movement as a screening tool to detect rescue of Parkinsonism phenotypes in zebrafish models.

Publications

Evaluation of spontaneous propulsive movement as a screening tool to detect rescue of Parkinsonism phenotypes in zebrafish models.

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