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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
51

MAPT mutation associated with frontotemporal dementia and parkinsonism (FTDP-17)

Haussmann, Robert, Wysocki, Marek, Brandt, Moritz D., Hermann, Andreas, Donix, Markus 03 June 2020 (has links)
We present a 56-year-old patient suffering from frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The history included a three-generation pedigree and the patient was found to be a mutation carrier. The diagnosis was hindered by late appearance of the hypokinetic movement disorder. For clinicians, it is important to consider rare neurodegenerative disease variants in early-onset familial dementia syndromes with behavioral, cognitive, and motor symptoms
52

Clinical Criteria for the Diagnosis of Parkinson’s Disease

Reichmann, Heinz 05 March 2014 (has links) (PDF)
The diagnosis of Parkinson’s disease (PD) follows the UK Brain Bank Criteria, which demands bradykinesia and one additional symptom, i.e. rigidity, resting tremor or postural instability. The latter is not a useful sign for the early diagnosis of PD, because it does not appear before Hoehn and Yahr stage 3. Early symptoms of PD which precede the onset of motor symptoms are hyposmia, REM sleep behavioral disorder, constipation, and depression. In addition, an increasing number of patients whose PD is related to a genetic defect are being described. Thus, genetic testing may eventually develop into a tool to identify at-risk patients. The clinical diagnosis of PD can be supported by levodopa or apomorphine tests. Imaging studies such as cranial CT or MRI are helpful to distinguish idiopathic PD from atypical or secondary PD. SPECT and PET methods are valuable to distinguish PD tremor from essential tremor if this is clinically not possible. Using all of these methods, we may soon be able to make a premotor diagnosis of PD, which will raise the question whether early treatment is possible and ethically and clinically advisable. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
53

Cutaneous Autonomic Pilomotor Testing to Unveil the Role of Neuropathy Progression in Early Parkinson’s Disease (CAPTURE PD): Protocol for a Multicenter Study

Siepmann, Timo, Pintér, Alexandra, Buchmann, Sylvia J., Stibal, Leonie, Arndt, Martin, Kubasch, Anne Sophie, Kubasch, Marie Luise, Penzlin, Ana Isabel, Frenz, Elka, Zago, Wagner, Horváth, Tamás, Szatmári Jr., Szabolcs, Bereczki, Dániel, Takáts, Annamária, Ziemssen, Tjalf, Lipp, Axel, Freeman, Roy, Reichmann, Heinz, Barlinn, Kristian, Illigens, Ben Min-Woo 10 November 2017 (has links) (PDF)
Background: In Parkinson’s disease (PD), alpha-synuclein accumulation in cutaneous autonomic pilomotor and sudomotor nerve fibers has been linked to autonomic nervous system disturbances even in the early stages of the disease. This study aims to assess the association between alpha-synuclein-mediated structural autonomic nerve fiber damage and function in PD, elucidate the role of neuropathy progression during the early disease stages, and test reproducibility and external validity of pilomotor function assessment using quantitative pilomotor axon-reflex test and sudomotor function via quantitative direct and indirect test of sudomotor function. Methods/design: A prospective controlled study will be conducted at four study sites in Europe and the USA. Fifty-two male and female patients with idiopathic PD (Hoehn and Yahr 1–2) and 52 age- and sex-matched healthy controls will be recruited. Axon-reflex-mediated pilomotor erection will be induced by iontophoresis of phenylephrine on the dorsal forearm. Silicone impressions of the response will be obtained, scanned, and quantified for pilomotor muscle impressions by number, impression size, and area of axon-reflex spread. Axon-reflex-mediated sweating following acetylcholine iontophoresis will be quantified for number and size of droplets and axon-reflex spread. Sympathetic skin responses, autonomic and motor symptoms will be evaluated. Tests will be performed at baseline, after 2 weeks, 1, 2, and 3 years. Skin biopsies will be obtained at baseline and after 3 years and will be analyzed for nerve fiber density and alpha-synuclein accumulation. Discussion: We anticipate that progression of autonomic nerve dysfunction assessed via pilomotor and sudomotor axon-reflex tests is related to progression of autonomic symptom severity and alpha-synuclein deposition. Potential applications of the techniques include interventional studies evaluating disease-modifying approaches and clinical assessment of autonomic dysfunction in patients with PD.
54

Accurate Detection of Parkinson’s Disease in Tremor Syndromes Using Olfactory Testing

Wolz, Martin, Hähner, Antje, Meixner, Linda, Löhle, Matthias, Reichmann, Heinz, Hummel, Thomas, Storch, Alexander 19 May 2020 (has links)
Background/Aims: The diagnostic value of olfactory testing for the discrimination of tremor-dominant Parkinson’s disease (PD) from other tremor disorders remains enigmatic. We evaluated whether olfactory testing can accurately detect PD in tremor patients. Methods: A retrospective analysis of 299 consecutive subjects referred for the differential diagnosis of a tremor disorder was done. Olfactory testing was performed using ‘Sniffin’ Sticks’, resulting in a composite TDI score of odor threshold (T), discrimination (D), and identification (I). Receiver operating curve (ROC) plots were used to calculate sensitivity/specificity for the detection of PD. Results: Of all subjects, 167 (55.9%) had PD and 85 (28.4%) had essential tremor (ET). The mean TDI score in PD was significantly reduced compared to those in ET and other tremor disorders with no differences between ET and other tremor disorders. ROC analysis revealed strong correlations of TDI scores with PD [area under the curve: 0.85 (95% CI: 0.80–0.89); p < 0.001]. The highest Youden index was observed for a TDI score <25 (Youden index: 0.58). Using this cutoff score and that generated from normative data of healthy controls, the TDI score provided high sensitivity (negative predictive value) and specificity (positive predictive value) of approximately 80% for detecting PD. Conclusion: Olfactory testing is a useful, easily applied and inexpensive diagnostic test which is helpful to detect PD among tremor patients.
55

Prevalence, Duration and Severity of Parkinson’s Disease in Germany: A Combined Meta-Analysis from Literature Data and Outpatient Samples

Enders, Dirk, Balzer-Geldsetzer, Monika, Riedel, Oliver, Dodel, Richard, Wittchen, Hans-Ulrich, Sensken, Sven-Christian, Wolff, Björn, Reese, Jens-Peter 26 May 2020 (has links)
Background: Epidemiological data on the prevalence of Parkinson’s disease (PD) in Germany are limited. The aims of this study were to estimate the age- and gender-specific prevalence of PD in Germany as well as the severity and illness duration. Summary: A systematic literature search was performed in 5 different databases. European studies were included if they reported age- and gender-specific numbers of prevalence rates of PD. Meta-analytic approaches were applied to derive age- and gender-specific pooled prevalence estimates. Data of 4 German outpatient samples were incorporated to calculate the proportion of patients with PD in Germany grouped by Hoehn and Yahr (HY) stages and disease duration. In the German population, 178,169 cases of PD were estimated (prevalence: 217.22/100,000). The estimated relative illness duration was 40% with less than 5 years, 31% with 5–9 years, and 29% with more than 9 years. The proportions for different HY stages were estimated at 13% (I), 30% (II), 35% (III), 17% (IV), and 4% (V), respectively. Key Message: We provide an up-to-date estimation of age and gender-specific as well as severity-based prevalence figures for PD in Germany. Further community studies are needed to estimate population-based severity distributions and distributions of non-motor symptoms in PD.
56

Clinical Criteria for the Diagnosis of Parkinson’s Disease

Reichmann, Heinz January 2010 (has links)
The diagnosis of Parkinson’s disease (PD) follows the UK Brain Bank Criteria, which demands bradykinesia and one additional symptom, i.e. rigidity, resting tremor or postural instability. The latter is not a useful sign for the early diagnosis of PD, because it does not appear before Hoehn and Yahr stage 3. Early symptoms of PD which precede the onset of motor symptoms are hyposmia, REM sleep behavioral disorder, constipation, and depression. In addition, an increasing number of patients whose PD is related to a genetic defect are being described. Thus, genetic testing may eventually develop into a tool to identify at-risk patients. The clinical diagnosis of PD can be supported by levodopa or apomorphine tests. Imaging studies such as cranial CT or MRI are helpful to distinguish idiopathic PD from atypical or secondary PD. SPECT and PET methods are valuable to distinguish PD tremor from essential tremor if this is clinically not possible. Using all of these methods, we may soon be able to make a premotor diagnosis of PD, which will raise the question whether early treatment is possible and ethically and clinically advisable. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
57

Das dopaminerge System im Gehirn des Menschen: molekulare Grundlagen, Anatomie, Physiologie und Pathologie

Rillich, Jan 02 February 2023 (has links)
Diese Arbeit ist Teil des Toxnetz-Projekts des Fachbereichs Toxikologie an der Universität Leipzig und behandelt Themen rund um den Botenstoff Dopamin. Es wurden hierfür Texte und Essays zu Funktionen, Mechanismen, Hirnarealen und Krankheitsbildern geschrieben, die den Studierenden der Toxikologie als Lernhilfe und Wissensspeicher dienen sollen. Ausführliche Erläuterungen finden sich zu den vier dopaminergen Projektionsbahnen und ihren Interaktionen mit den Basalganglien, dem präfrontalen Cortex, dem Hippocampus und der Amygdala. Die Rolle von Dopamin bei Motivation, Belohnung, Lernen, Gedächtnisbildung und Aufmerksamkeit wird ebenso beleuchtet, wie die bei der Parkinson Krankheit, Schizophrenie, ADHS und Drogensucht.
58

Measuring the Usability of eHealth Solutions for Patients With Parkinson Disease: Observational Study

Bendig, Jonas, Spanz, Anja, Leidig, Jana, Frank, Anika, Stahr, Marcus, Reichmann, Heinz, Loewenbrück, Kai F., Falkenburger, Björn H. 22 February 2024 (has links)
Background: Parkinson disease (PD) is a neurodegenerative disorder with a variety of motor and nonmotor symptoms. Many of these symptoms can be monitored by eHealth solutions, including smartphone apps, wearable sensors, and camera systems. The usability of such systems is a key factor in long-term use, but not much is known about the predictors of successful use and preferable methods to assess usability in patients with PD. Objective: This study tested methods to assess usability and determined prerequisites for successful use in patients with PD. - Methods: We performed comprehensive usability assessments with 18 patients with PD using a mixed methods usability battery containing the System Usability Scale, a rater-based evaluation of device-specific tasks, and qualitative interviews. Each patient performed the usability battery with 2 of 3 randomly assigned devices: a tablet app, wearable sensors, and a camera system. The usability battery was administered at the beginning and at the end of a 4-day testing period. Between usability batteries, the systems were used by the patients during 3 sessions of motor assessments (wearable sensors and camera system) and at the movement disorder ward (tablet app). - Results: In this study, the rater-based evaluation of tasks discriminated the best between the 3 eHealth solutions, whereas subjective modalities such as the System Usability Scale were not able to distinguish between the systems. Successful use was associated with different clinical characteristics for each system: eHealth literacy and cognitive function predicted successful use of the tablet app, and bettermotor function and lower age correlated with the independent use of the camera system. The successful use of the wearable sensors was independent of clinical characteristics. Unfortunately, patients who were not able to use the devices well provided few improvement suggestions in qualitative interviews. Conclusions: eHealth solutions should be developed with a specific set of patients in mind and subsequently tested in this cohort. For a complete picture, usability assessments should include a rater-based evaluation of task performance, and there is a need to develop strategies to circumvent the underrepresentation of poorly performing patients in qualitative usability research.
59

Examining FYCO1 as a modulator of autophagy for alpha-synuclein aggregate clearance in hiPSC derived neurons

Beer, Judith 21 February 2024 (has links)
Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide affecting 1 - 2 % of the population older than 65. Patients develop characteristic motoric dysfunctions alongside early-onset non-motor symptoms including sleeping disorders, anxiety or depression and late-stage cognitive deficits such as dementia. To date, dopamine-replacement therapies are the gold standard for treating PD patients, improving motoric disorders by compensating for the loss of dopaminergic neurons in the substantia nigra, however no curative therapies to prevent disease progression are yet available. The pathomechanism underlying PD is complex, and the interplay of factors causing the disease is not entirely understood. The formation of α-synuclein protein aggregates, being one of the hallmarks associated with PD, is regarded as a major contributor to neuronal death and the spreading of PD pathology throughout different brain regions as the disease progresses. In the past, deficits in cellular protein clearance machinery have been affiliated with the accumulation of α-synuclein aggregates in PD. In particular, impairements in the macroautophagy-lysosomal pathway (here referred to as autophagy), which is involved in the degradation of large cytosolic components, were found to promote α-synuclein aggregation. In contrast, autophagic stimulation has been shown to benefit α-synuclein degradation and rescue PD phenotypes in cell and rodent models. In this study, I examined the role of FYCO1 in modulating neuronal autophagic processes for α-synuclein aggregate clearance in hiPSC-derived neurons. FYCO1 is an interaction partner of the central autophagic regulator RAB7 but was mostly unnoticed since it was not found detrimental to cellular homeostasis under basal conditions. Still, previous work of our group has identified FYCO1 to rescue PD phenotypes in model systems such as HEK cells and Drosophila, due to improved α-synuclein clearance following FYCO1 overexpression. Mechanistically, FYCO1 is involved in autophagosome-lysosome fusion events by binding to autophagic vesicles, which is required for autophagosome maturation and final degradation. In addition, FYCO1 affiliates autophagic vesicles with the cellular transport machinery via kinesin motor proteins. While fusion promotion can be assigned to an enhancing effect on autophagic clearance, FYCO1-induced anterograde transport promotion is opposite to the retrograde trafficking route of autophagic vesicles for maturation, which is of special importance in neuronal axons. Here, I illuminated FYCO1 effects on both axonal vesicle transport processes and somal vesicle pools to evaluate its ability to promote autophagy-related degradation in neurons. To this end, I established a lentiviral transduction-based model in hiPSC-derived neurons to express FYCO1 in the presence of either a fluorescently labelled marker for autophagic vesicles (LC3-TFL) or in the presence of α-synuclein. In neuronal axons, FYCO1 overexpression impaired retrograde autophagic transport resulting in less movement, implying an inhibitory effect on axonal autophagy. In contrast, FYCO1 enhanced autophagic processes in neuronal somata by upregulating LC3 levels, promoting the collection of α-synuclein in autophagic vesicle clusters and increasing the colocalisation of autophagosomes with lysosomal markers, pointing to the advance in autophagosome maturation. I could not fully resolve, whether α-synuclein degradation was promoted by this induction, as α-synuclein clearance was not indicated yet in the time course of three weeks. Still, studying mutant forms of FYCO1 revealed deficits in autophagosome maturation, which were not represented with wild-type FYCO1. In particular, the autophagosome-interaction domain was essential for autophagosome-lysosome fusion and additionally seemed to be relevant for autophagosomes entering axonal transport, while mutations in the kinesin binding domain caused autophagosome acidification impairments. The most pronounced effect of FYCO1 overexpression in neurons was the modulation of lysosomal vesicles. Besides increasing lysosomal localisation to autophagic vesicles, FYCO1 promoted retrograde trafficking of axonal lysosomal vesicles, by a so far unresolved mechanism. As increasing transport of lysosomes toward the neuronal soma can be connected to the upregulation of autophagy, I hypothesise FYCO1 to be a mediator in autophagy induction signalling. Nevertheless, such an effect needs to be verified in future studies. Conclusively, with this work, I contributed to the understanding of FYCO1’s role in enhancing neuronal autophagic processes but further studies in more advanced PD models are required to evaluate whether this could contribute to an increased clearance of α-synuclein aggregates.
60

Developing assays to characterize the effects of LRRK2 G2019S on axonal lysosomes

Bhatia, Priyanka 20 February 2024 (has links)
A striking feature of Parkinson's disease (PD) is that the distal axonal terminals of neurons degenerate prior to the soma, a process referred to as 'dying-back'. Another hallmark of the disease is the pathological accumulation of abnormal protein aggregates in soma and axons. Lysosomes, a critical component of the protein quality control machinery, have thus been thought to be altered in PD. LRRK2 G2019S, a gain-of-kinase-function mutation, is one of PD's most common known causative mutations, and LRRK2-specific small molecule inhibitors have been developed as possible therapeutics. However, LRRK2 G2019S is incompletely penetrant, and its role in axonal degeneration is unclear. LRRK2 phosphorylates a subset of Rab GTPases, including Rab10. Since Rab GTPases are mediators of organelle trafficking, we speculated that LRRK2 G2019S affects the transport of organelles, such as lysosomes, thereby contributing to early PD pathogenesis. Using neural progenitor cell-derived neurons from two LRRK2 G2019S-PD patients; we developed a model of axonal trafficking of lysosomes to characterize the impact of mutant LRRK2 on lysosomal trafficking. In comparison to their isogenic gene-corrected controls, we observed a subtle reduction in mutant axonal lysosomal speed, which could indicate that mutant LRRK2 mildly disrupts retrograde lysosomal transport. We also observed that this trafficking phenotype was only partially rescued by LRRK2 kinase inhibitors, which could indicate the importance of other factors regulating axonal transport. Consistent with this idea, we found that mutant LRRK2 was associated with increased co-localization of phosphorylated Rab10 on a small subset of distal axonal lysosomes. Furthermore, the over-expression of Rab10 only mildly affected lysosomal trafficking in axons. Interestingly, damaging the lysosomal membrane increased LRRK2-dependent Rab10 phosphorylation, leading us to speculate that membrane damage in the axon might induce LRRK2 activity. Since lysosomes have been shown to mediate plasma membrane repair, we speculated that membrane damage might exacerbate LRRK2-dependent phenotypes in distal axons. Axotomy was used to test this idea, and we observed an inconsistent delay in the regrowth of mutant axons after axotomy. Moreover, we identified an association between mutant LRRK2 and the transient increase in lysosomes at the injury site, indicating that LRRK2 G2019S might potentially affect damage-prone distal axons. Since the LRRK2 G2019S-associated phenotypes observed in our assays were relatively mild in one isogenic pair, we were curious about the clinical and genetic phenotypes of the patients from whom the somatic cells for neural progenitor cell generation were sourced. Interestingly, we observed that clinical features of PD, including age-of-onset, motor symptoms, cognitive impairment, and the level of cerebrospinal fluid biomarkers, were heterogeneous between the two patients. Additionally, genetic analysis of specific PD risk-associated loci in MAPT and SNCA revealed that one patient was more at risk of developing PD than the other, indicating influence from genetic factors in addition to LRRK2 G2019S. These factors might affect the axonal phenotypes observed in our assays. Overall, we have developed assays to investigate the effects of LRRK2 G2019S on axonal lysosomes. These assays can potentially be a useful tool to better understand early pathogenesis in heterogeneous PD patients and test targeted therapeutics that can be successful over an eclectic cohort of PD patients, all of whom are diagnosed based on deteriorating motor symptoms.:TABLE OF CONTENTS I LIST OF FIGURES IV LIST OF TABLES VI ABBREVIATIONS VII 1 INTRODUCTION 1 1.1 Neurodegenerative diseases 1 1.2 Parkinson’s disease 2 1.2.1 General Features 2 1.2.2 Phenomenon of “dying back” in PD 6 1.2.3 Contribution of axonal architecture and function to “dying back” 7 1.2.4 Etiology of PD 10 1.2.4.1 Environmental factors 10 1.2.4.2 Genetic factors linked to axonal function 11 1.3 Lysosomes 12 1.3.1 Composition and biogenesis of lysosomes 13 1.3.2 Lysosomes as digestive centers 15 1.3.3 Lysosomes as secretory organelles 18 1.3.4 Lysosomes in PD 20 1.3.4.1 Genetic PD factors linked to lysosomal function 21 1.4 Leucine-rich repeat kinase 2 (LRRK2) 22 1.4.1 LRRK2 domain organization and function 22 1.4.2 Clinical features of PD patients with LRRK2 mutations (LRRK2-PD) 24 1.4.3 LRRK2 animal models 24 1.4.4 LRRK2 induced pluripotent stem cell (iPSC)-based models 25 1.4.5 Animal and iPSC-based models demonstrate a role for LRRK2 in the endo-lysosomal system 27 1.4.6 LRRK2 kinase inhibitors 30 2 AIMS OF THE THESIS 32 3 MATERIALS AND METHODS 33 3.1 Materials 33 3.1.1 Chemicals 33 3.1.2 Purchased kits 34 3.1.3 Plasmids 34 3.1.4 Antibodies 35 3.1.5 Dyes 36 3.1.6 Primers and oligonucleotides 36 3.1.7 Cell culture media and reagents 37 3.1.8 Small molecules 38 3.1.9 Compounds 38 3.1.10 Cell culture media 39 3.1.11 Human Neural Progenitor Cell (NPC) lines 40 3.2 Methods 41 3.2.1 Ethics statement 41 3.2.2 Licenses 41 3.2.3 Information about iPSC and NPC line generation 41 3.2.4 Preparation of cell culture coated plates 41 3.2.5 Maintenance of NPCs 42 3.2.6 Differentiation of NPCs to neurons 42 3.2.7 Preparation of microfluidic chambers 43 3.2.8 Seeding neurons as single cells 44 3.2.9 HEK293T cell culture 45 3.2.10 Treatment of neurons with compounds 45 3.2.11 Genomic DNA isolation 46 3.2.12 Polymerase-Chain Reaction (PCR) 46 3.2.13 Agarose gel electrophoresis 46 3.2.14 Plasmid DNA isolation 46 3.2.15 Lentiviral vector production 47 3.2.16 Lentiviral infection of human neurons 48 3.2.17 Protein isolation and quantification 48 3.2.18 Capillary electrophoresis 49 3.2.19 Axotomy 49 3.2.20 Immunostaining 50 3.2.21 Live cell imaging 51 3.2.22 Quantification of axonal trafficking using kymographs 52 3.2.23 Quantification of axonal trafficking using an object based method 53 3.2.24 Apotome imaging and quantification 54 3.2.25 Confocal imaging and quantification 54 3.2.26 Clinical and biomarker data collection 55 4 RESULTS 57 4.1 Establishing an axonal lysosomal trafficking assay 57 4.1.1 NPCs from LRRK2 G2019S patients and their respective isogenic controls differentiate into neurons 57 4.1.2 Axons can be spatially separated from soma and dendrites 60 4.1.3 Setting up the axonal trafficking assay 62 4.2 Axonal lysosomal trafficking assay detects LRRK2 G2019S associated changes in lysosome movement 65 4.3 Axonal lysosomal trafficking assay detects partial rescue by a small molecule LRRK2 inhibitor 71 4.4 LRRK2 G2019S is associated with an increase in the proportion of lysosomes co-localizing with phosphorylated Rab10 76 4.5 Rab10 over-expression mildly affects lysosomal trafficking in axons 78 4.6 Lysosomal membrane damage increases LRRK2-mediated Rab10 phosphorylation 81 4.7 LRRK2 G2019S is not associated with consistent effects on long-term axonal regrowth after axotomy 82 4.8 LRRK2 G2019S is associated with transient accumulation of lysosomes at the injury site after axotomy 86 4.9 Assessment of clinical, biomarker and genetic data from the LRRK2 G2019S patient donors 88 5 DISCUSSION 92 6 APPENDIX 101 7 SUMMARY 104 8 ZUSSAMENFASSUNG 106 9 BIBLIOGRAPHY 108 10 ACKNOWLEDGEMENTS 136 11 DECLARATIONS 138

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