Teaching Games for Understanding (TGfU)

Die Diplomarbeit beschäftigt sich im Sinne des Taktik-Spiel-Konzepts mit dem Modell des Teaching Games for Understanding (TGfU), das eine Alternative zu den technikorientieren Sportspielvermittlungsansätzen darstellt, als es das „Warum“ ein Spiel gespielt wird vor das „Wie“ stellt. Nachdem die deutschsprachige Sportspielvermittlungstradition in ihren Grundzügen dargestellt wird und allgemeine methodische Grundphilosophien diskutiert werden, wird im Hauptteil der Arbeit auf das TGfU-Konzept eingegangen. Bei der Analyse der pädagogischen Prinzipien und den zahlreichen Weiterentwicklungen und Abwandlungen des ursprünglichen Modells wird deutlich, dass viele Analogien zwischen den Taktik-Spiel-Modellen im englischsprachigen Raum und den sportspielübergreifenden Ansätzen im deutschsprachigen Raum herrschen, aber das TGfU-Modell auch einige neue Errungenschaften zu bieten hat. Beispiele aus verschiedenen Sportarten, im Speziellen Fußball, sollen die Annahme bekräftigen, dass das Taktik-Spiel-Konzept ein sehr effektiver Weg der schulischen Sportspielvermittlung ist.The diploma thesis deals with a description and analysis of a game centered games teaching approach named Teaching Games for Understanding (TGfU), in which the “why” of game playing is taught before the “how”. Starting with some basic methodological questions and an overview of the games teaching tradition in German-speaking countries, this study mainly describes and analyzes TGfU as the predominating games teaching approach in most English-speaking countries. It can be seen that the approaches share some similarities but also differ in some ways. TGfU also brings some new aspects which haven’t been dealt yet in German-speaking countries so far. Numerous examples, especially those of football lessons, and illustrations from wide-range literature should support the claim that TGfU is a highly efficient way of teaching games at school

Clinical Trial Designs and Measures in Hereditary Spastic Paraplegias

Hereditary spastic paraplegias (HSPs) are a large group of genetically-diverse neurologic disorders characterized clinically by a common feature of lower extremity spasticity and gait difficulties. Current therapies are predominantly symptomatic, and even then usually provide inadequate relief of symptoms. Going forward, HSP therapeutics development requires a systematic analysis of quantifiable measures and tools to assess treatment response. This review summarizes promising therapeutic targets, assessment measures, and previous clinical trials for the HSPs. Oxidative stress, signaling pathways, microtubule dynamics, and gene rescue/replacement have been proposed as potential treatment targets or modalities. Quantitative evaluation of pre-clinical rodent HSP models emphasize rotarod performance, foot base angle, grip strength, stride length, beam walking, critical speed, and body weight. Clinical measures of HSP in humans include 10-m gait velocity, the Spastic Paraplegia Rating Scale (SPRS), Ashworth Spasticity Scale, Fugl-Meyer Scale, timed up-and-go, and the Gillette Functional Assessment Questionnaire. We conducted a broad search for past clinical trials in HSPs and identified trials that investigated pharmacological agents including atorvastatin, gabapentin, L-threonine, botulinum toxin, dalfampridine, methylphenidate, and baclofen. We provide recommendations for future HSP treatment directions based on these prior research experiences as well as regulatory insight

The clinical and electrophysiological investigation of tremor

The various forms of tremor are now classified in two axes: clinical characteristics (axis 1) and etiology (axis 2). Electrophysiology is an extension of the clinical exam. Electrophysiologic tests are diagnostic of physiologic tremor, primary orthostatic tremor, and functional tremor, but they are valuable in the clinical characterization of all forms of tremor. Electrophysiology will likely play an increasing role in axis 1 tremor classification because many features of tremor are not reliably assessed by clinical examination alone. In particular, electrophysiology may be needed to distinguish tremor from tremor mimics, assess tremor frequency, assess tremor rhythmicity or regularity, distinguish mechanical-reflex oscillation from central neurogenic oscillation, determine if tremors in different body parts, muscles, or brain regions are strongly correlated, document tremor suppression or entrainment by voluntary movements of contralateral body parts, and document the effects of voluntary movement on rest tremor. In addition, electrophysiologic brain mapping has been crucial in our understanding of tremor pathophysiology. The electrophysiologic methods of tremor analysis are reviewed in the context of physiologic tremor and pathologic tremors, with a focus on clinical characterization and pathophysiology. Electrophysiology is instrumental in elucidating tremor mechanisms, and the pathophysiology of the different forms of tremor is summarized in this review

Rare Variants in PLXNA4 and Parkinson's Disease.

Approximately 20% of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset familial PD followed by frequency assessment in 975 PD cases and 1014 ethnically-matched controls and linkage analysis to identify potentially causal variants. Based on the predicted penetrance and the frequencies, a variant in PLXNA4 proved to be the best candidate and PLXNA4 was screened for additional variants in 862 PD cases and 940 controls, revealing an excess of rare non-synonymous coding variants in PLXNA4 in individuals with PD. Although we cannot conclude that the variant in PLXNA4 is indeed the causative variant, these findings are interesting in the light of a surfacing role of axonal guidance mechanisms in neurodegenerative disorders but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance

Rare variants in LRRK1 and Parkinson's disease

Approximately 20 % of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset PD to identify 15 potentially causal variants. Segregation analysis and frequency assessment in 862 PD cases and 1,014 ethnically matched controls highlighted variants in EEF1D and LRRK1 as the best candidates. Mutation screening of the coding regions of these genes in 862 cases and 1,014 controls revealed several novel non-synonymous variants in both genes in cases and controls. An in silico multi-model bioinformatics analysis was used to prioritize identified variants in LRRK1 for functional follow- up. However, protein expression, subcellular localization, and cell viability were not affected by the identified variants. Although it has yet to be proven conclusively that variants in LRRK1 are indeed causative of PD, our data strengthen a possible role for LRRK1 in addition to LRRK2 in the genetic underpinnings of PD but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance

Personalised profiling to identify clinically relevant changes in tremor due to multiple sclerosis

Background: There is growing interest in sensor-based assessment of upper limb tremor in multiple sclerosis and other movement disorders. However, previously such assessments have not been found to offer any improvement over conventional clinical observation in identifying clinically relevant changes in an individual's tremor symptoms, due to poor test-retest repeatability. Method: We hypothesised that this barrier could be overcome by constructing a tremor change metric that is customised to each individual's tremor characteristics, such that random variability can be distinguished from clinically relevant changes in symptoms. In a cohort of 24 people with tremor due to multiple sclerosis, the newly proposed metrics were compared against conventional clinical and sensor-based metrics. Each metric was evaluated based on Spearman rank correlation with two reference metrics extracted from the Fahn-Tolosa-Marin Tremor Rating Scale: a task-based measure of functional disability (FTMTRS B) and the subject's self-assessment of the impact of tremor on their activities of daily living (FTMTRS C). Results: Unlike the conventional sensor-based and clinical metrics, the newly proposed ’change in scale’ metrics presented statistically significant correlations with changes in self-assessed impact of tremor (max R2>0.5,p< 0.05 after correction for false discovery rate control). They also outperformed all other metrics in terms of correlations with changes in task-based functional performance (R2=0.25 vs. R2=0.15 for conventional clinical observation, both p< 0.05).Conclusions: The proposed metrics achieve an elusive goal of sensor-based tremor assessment: improving on conventional visual observation in terms of sensitivity to change. Further refinement and evaluation of the proposed techniques is required, but our core findings imply that the main barrier to translational impact for this application can be overcome. Sensor-based tremor assessments may improve personalised treatment selection and the efficiency of clinical trials for new treatments by enabling greater standardisation and sensitivity to clinically relevant changes in symptoms

Knowledge gaps and research recommendations for essential tremor

Essential tremor (ET) is a common cause of significant disability, but its etiologies and pathogenesis are poorly understood. Research has been hampered by the variable definition of ET and by non-standardized research approaches. The National Institute of Neurological Disorders and Stroke (USA) invited experts in ET and related fields to discuss current knowledge, controversies, and gaps in our understanding of ET and to develop recommendations for future research. Discussion focused on phenomenology and phenotypes, therapies and clinical trials, pathophysiology, pathology, and genetics. Across all areas, the need for collaborative and coordinated research on a multinational level was expressed. Standardized data collection using common data elements for genetic, clinical, neurophysiological, and pathological studies was recommended. Large cohorts of patients should be studied prospectively to collect bio-samples, characterize the natural history of the clinical syndrome including patient-oriented outcomes, investigate potential etiologies of various phenotypes, and identify pathophysiological mechanisms. In particular, cellular and system-level mechanisms of tremor oscillations should be elucidated because they may yield effective therapeutic targets and biomarkers. A neuropathology consortium was recommended to standardize postmortem analysis and further characterize neuropathological observations in the cerebellum and elsewhere. Furthermore, genome-wide association studies on large patient cohorts (>10,000 patients) may allow the identification of common genes contributing to risk, and whole exome or genome sequencing may enable the identification of genetic risk and causal mutations in cohorts and well-characterized families

Genetic Etiology of Parkinson Disease Associated with Mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 Genes: A Mutation Update

To date, molecular genetic analyses have identified over 500 distinct DNA variants in five disease genes associated with familial Parkinson disease; α-synuclein (SNCA), parkin (PARK2), PTEN-induced putative kinase 1 (PINK1), DJ-1 (PARK7), and Leucine-rich repeat kinase 2 (LRRK2). These genetic variants include ∼82% simple mutations and ∼18% copy number variations. Some mutation subtypes are likely underestimated because only few studies reported extensive mutation analyses of all five genes, by both exonic sequencing and dosage analyses. Here we present an update of all mutations published to date in the literature, systematically organized in a novel mutation database (http://www.molgen.ua.ac.be/PDmutDB). In addition, we address the biological relevance of putative pathogenic mutations. This review emphasizes the need for comprehensive genetic screening of Parkinson patients followed by an insightful study of the functional relevance of observed genetic variants. Moreover, while capturing existing data from the literature it became apparent that several of the five Parkinson genes were also contributing to the genetic etiology of other Lewy Body Diseases and Parkinson-plus syndromes, indicating that mutation screening is recommendable in these patient groups. Hum Mutat 31:763–780, 2010. © 2010 Wiley-Liss, Inc