@article{KuzkinaRoessleSegeretal.2023, author = {Kuzkina, A. and R{\"o}ßle, J. and Seger, A. and Panzer, C. and Kohl, A. and Maltese, V. and Musacchio, T. and Blaschke, S. J. and Tamg{\"u}ney, G. and Kaulitz, S. and Rak, K. and Scherzad, A. and Zimmermann, P. H. and Klussmann, J. P. and Hackenberg, S. and Volkmann, J. and Sommer, C. and Sommerauer, M. and Doppler, K.}, title = {Combining skin and olfactory α-synuclein seed amplification assays (SAA)—towards biomarker-driven phenotyping in synucleinopathies}, series = {npj Parkinson's Disease}, volume = {9}, journal = {npj Parkinson's Disease}, issn = {2373-8057}, doi = {10.1038/s41531-023-00519-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357687}, year = {2023}, abstract = {Seed amplification assays (SAA) are becoming commonly used in synucleinopathies to detect α-synuclein aggregates. Studies in Parkinson's disease (PD) and isolated REM-sleep behavior disorder (iRBD) have shown a considerably lower sensitivity in the olfactory epithelium than in CSF or skin. To get an insight into α-synuclein (α-syn) distribution within the nervous system and reasons for low sensitivity, we compared SAA assessment of nasal brushings and skin biopsies in PD (n = 27) and iRBD patients (n = 18) and unaffected controls (n = 30). α-syn misfolding was overall found less commonly in the olfactory epithelium than in the skin, which could be partially explained by the nasal brushing matrix exerting an inhibitory effect on aggregation. Importantly, the α-syn distribution was not uniform: there was a higher deposition of misfolded α-syn across all sampled tissues in the iRBD cohort compared to PD (supporting the notion of RBD as a marker of a more malignant subtype of synucleinopathy) and in a subgroup of PD patients, misfolded α-syn was detectable only in the olfactory epithelium, suggestive of the recently proposed brain-first PD subtype. Assaying α-syn of diverse origins, such as olfactory (part of the central nervous system) and skin (peripheral nervous system), could increase diagnostic accuracy and allow better stratification of patients.}, language = {en} } @article{McFlederMakhotkinaGrohetal.2023, author = {McFleder, Rhonda L. and Makhotkina, Anastasiia and Groh, Janos and Keber, Ursula and Imdahl, Fabian and Pe{\~n}a Mosca, Josefina and Peteranderl, Alina and Wu, Jingjing and Tabuchi, Sawako and Hoffmann, Jan and Karl, Ann-Kathrin and Pagenstecher, Axel and Vogel, J{\"o}rg and Beilhack, Andreas and Koprich, James B. and Brotchie, Jonathan M. and Saliba, Antoine-Emmanuel and Volkmann, Jens and Ip, Chi Wang}, title = {Brain-to-gut trafficking of alpha-synuclein by CD11c\(^+\) cells in a mouse model of Parkinson's disease}, series = {Nature Communications}, volume = {14}, journal = {Nature Communications}, doi = {10.1038/s41467-023-43224-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357696}, year = {2023}, abstract = {Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson's disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, α-synuclein (αSyn). Understanding the mechanism of propagation of αSyn aggregates is essential to developing disease-modifying therapeutics. Using a brain-first mouse model of PD, we demonstrate αSyn trafficking from the brain to the ileum of male mice. Immunohistochemistry revealed that the ileal αSyn aggregations are contained within CD11c+ cells. Using single-cell RNA sequencing, we demonstrate that ileal CD11c\(^+\) cells are microglia-like and the same subtype of cells is activated in the brain and ileum of PD mice. Moreover, by utilizing mice expressing the photo-convertible protein, Dendra2, we show that CD11c\(^+\) cells traffic from the brain to the ileum. Together these data provide a mechanism of αSyn trafficking between the brain and gut.}, language = {en} } @article{BinderLangePozzietal.2023, author = {Binder, Tobias and Lange, Florian and Pozzi, Nicol{\`o} and Musacchio, Thomas and Daniels, Christine and Odorfer, Thorsten and Fricke, Patrick and Matthies, Cordula and Volkmann, Jens and Capetian, Philipp}, title = {Feasibility of local field potential-guided programming for deep brain stimulation in Parkinson's disease: a comparison with clinical and neuro-imaging guided approaches in a randomized, controlled pilot trial}, series = {Brain Stimulation}, volume = {16}, journal = {Brain Stimulation}, number = {5}, doi = {10.1016/j.brs.2023.08.017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350280}, pages = {1243-1251}, year = {2023}, abstract = {Highlights • Beta-Guided programming is an innovative approach that may streamline the programming process for PD patients with STN DBS. • While preliminary findings from our study suggest that Beta Titration may potentially mitigate STN overstimulation and enhance symptom control, • Our results demonstrate that beta-guided programming significantly reduces programming time, suggesting it could be efficiently integrated into routine clinical practice using a commercially available patient programmer. Background Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson's disease (PD). Clinical outcomes after DBS can be limited by poor programming, which remains a clinically driven, lengthy and iterative process. Electrophysiological recordings in PD patients undergoing STN-DBS have shown an association between STN spectral power in the beta frequency band (beta power) and the severity of clinical symptoms. New commercially-available DBS devices now enable the recording of STN beta oscillations in chronically-implanted PD patients, thereby allowing investigation into the use of beta power as a biomarker for DBS programming. Objective To determine the potential advantages of beta-guided DBS programming over clinically and image-guided programming in terms of clinical efficacy and programming time. Methods We conducted a randomized, blinded, three-arm, crossover clinical trial in eight Parkinson's patients with STN-DBS who were evaluated three months after DBS surgery. We compared clinical efficacy and time required for each DBS programming paradigm, as well as DBS parameters and total energy delivered between the three strategies (beta-, clinically- and image-guided). Results All three programming methods showed similar clinical efficacy, but the time needed for programming was significantly shorter for beta- and image-guided programming compared to clinically-guided programming (p < 0.001). Conclusion Beta-guided programming may be a useful and more efficient approach to DBS programming in Parkinson's patients with STN-DBS. It takes significantly less time to program than traditional clinically-based programming, while providing similar symptom control. In addition, it is readily available within the clinical DBS programmer, making it a valuable tool for improving current clinical practice.}, language = {en} } @phdthesis{Badr2023, author = {Badr, Mohammad Mamdouh Abdelwareth Mohammad}, title = {Targeting Regulatory T Cells by CD28 Superagonistic Antibodies Mitigates Neurodegeneration in the A53T-alpha-Synuclein Parkinson's Disease Mouse Model}, doi = {10.25972/OPUS-28954}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-289544}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disease with still no cure available. The prominent feature of PD is the loss of dopaminergic neurons at the Substantia nigra (SN). Genetic and environmental insults affecting the SNCA gene encoding the alpha-Synuclein (alpha-Syn) protein result into an aberrant form of the protein with higher propensity towards oligomerization becoming part of insoluble inclusions called Lewy Bodies (LB). LB impart cytotoxicity leading to neurodegeneration, activate resident microglia and escape to the periphery where they get captured by dendritic cells and presented to na{\"i}ve T cells. Proliferating effector T lymphocytes invade the brain releasing proinflammatory cytokines and performing a cytotoxic effect on neurons. In this study, we examine the hypothesis that the expansion of regulatory T cells (Treg) could exert an anti-inflammatory effect that averts neurodegeneration in the AAV1/2-A53T-alpha-Syn mouse model for PD. Mice brains were transfected by a unilateral stereotaxic injection at the SN region with a chimeric Adeno-Associated Viral vector of serotypes 1 and 2 (AAV1/2) carrying the A53T-mutated human SNCA gene encoding the readily aggregating aberrant alpha-Syn (AAV1/2-A53T-alpha-Syn). One week after injection, mice were treated with the CD28 superagonistic antibody (CD28SA), known to significantly expand the Treg population. Mice were then analyzed by behavioral analysis using the Rotarod performance test and the Cylinder test. The impact of CD28SA on the immune system was examined by flow cytometry. The integrity of the nigrostriatal system was assessed by stereological quantification of Tyrosine hydroxylase (TH)-stained dopaminergic neurons in SN and optical density measurements of TH-stained striatum. The mechanism of action of CD28SA was analyzed by treating PD mice alternatively with a Treg adoptive transfer, while CD28SA effect on levels of neurotrophic factors was quantified by ELISA. We observed an expansion of Treg by FACS analyses three days after CD28SA treatment, demonstrating target engagement. CD28SA treatment of AAV1/2-A53T-alpha-Syn mice provided neuroprotection evident through elevated numbers of dopaminergic neurons in the SN and higher optical density of TH-staining in the striatum, in CD28SA-treated mice compared to PBS-treated control mice, and that was reflected in an enhanced performance in behavioral studies. Additionally, brain infiltration of proinflammatory activated T lymphocytes (CD4+CD69+ and CD8+CD69+ cells), that were obvious in PBS-treated AAV1/2-A53T-alpha-Syn control mice, was augmented in PD mice receiving CD28SA. The alternative treatment with Treg adoptive transfer did replicate the beneficial effects of CD28SA indicating that Treg expansion is the main effector mechanism by which it exerts its neuroprotective effect. CD28SA treatment of PD mice led to an increase of GDNF and BDNF in some brain structures that was not observed in untreated mice. We conclude that in the AAV1/2-A53T-alpha-Syn PD mouse model, CD28SA suppresses proinflammation, reverses behavioral deficits and is neuroprotective on SN dopaminergic cells.}, subject = {Parkinson-Krankheit}, language = {en} } @article{ErbacherVaknineMoshitzkyetal.2022, author = {Erbacher, Christoph and Vaknine, Shani and Moshitzky, Gilli and Lobentanzer, Sebastian and Eisenberg, Lina and Evdokimov, Dimitar and Sommer, Claudia and Greenberg, David S. and Soreq, Hermona and {\"U}{\c{c}}eyler, Nurcan}, title = {Distinct CholinomiR blood cell signature as a potential modulator of the cholinergic system in women with fibromyalgia syndrome}, series = {Cells}, volume = {11}, journal = {Cells}, number = {8}, issn = {2073-4409}, doi = {10.3390/cells11081276}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270686}, year = {2022}, abstract = {Fibromyalgia syndrome (FMS) is a heterogeneous chronic pain syndrome characterized by musculoskeletal pain and other key co-morbidities including fatigue and a depressed mood. FMS involves altered functioning of the central and peripheral nervous system (CNS, PNS) and immune system, but the specific molecular pathophysiology remains unclear. Anti-cholinergic treatment is effective in FMS patient subgroups, and cholinergic signaling is a strong modulator of CNS and PNS immune processes. Therefore, we used whole blood small RNA-sequencing of female FMS patients and healthy controls to profile microRNA regulators of cholinergic transcripts (CholinomiRs). We compared microRNA profiles with those from Parkinson's disease (PD) patients with pain as disease controls. We validated the sequencing results with quantitative real-time PCR (qRT-PCR) and identified cholinergic targets. Further, we measured serum cholinesterase activity in FMS patients and healthy controls. Small RNA-sequencing revealed FMS-specific changes in 19 CholinomiRs compared to healthy controls and PD patients. qRT-PCR validated miR-182-5p upregulation, distinguishing FMS patients from healthy controls. mRNA targets of CholinomiRs bone morphogenic protein receptor 2 and interleukin 6 signal transducer were downregulated. Serum acetylcholinesterase levels and cholinesterase activity in FMS patients were unchanged. Our findings identified an FMS-specific CholinomiR signature in whole blood, modulating immune-related gene expression.}, language = {en} } @article{RauschenbergerBehnkeGrotemeyeretal.2022, author = {Rauschenberger, Lisa and Behnke, Jennifer and Grotemeyer, Alexander and Knorr, Susanne and Volkmann, Jens and Ip, Chi Wang}, title = {Age-dependent neurodegeneration and neuroinflammation in a genetic A30P/A53T double-mutated α-synuclein mouse model of Parkinson's disease}, series = {Neurobiology of Disease}, volume = {171}, journal = {Neurobiology of Disease}, doi = {10.1016/j.nbd.2022.105798}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300629}, year = {2022}, abstract = {The pathogenesis of Parkinson's disease (PD) is closely interwoven with the process of aging. Moreover, increasing evidence from human postmortem studies and from animal models for PD point towards inflammation as an additional factor in disease development. We here assessed the impact of aging and inflammation on dopaminergic neurodegeneration in the hm\(^{2}\)α-SYN-39 mouse model of PD that carries the human, A30P/A53T double-mutated α-synuclein gene. At 2-3 months of age, no significant differences were observed comparing dopaminergic neuron numbers of the substantia nigra (SN) pars compacta of hm\(^{2}\)α-SYN-39 mice with wildtype controls. At an age of 16-17 months, however, hm\(^{2}\)α-SYN-39 mice revealed a significant loss of dopaminergic SN neurons, of dopaminergic terminals in the striatum as well as a reduction of striatal dopamine levels compared to young, 2-3 months transgenic mice and compared to 16-17 months old wildtype littermates. A significant age-related correlation of infiltrating CD4+ and CD8\(^{+}\) T cell numbers with dopaminergic terminal loss of the striatum was found in hm\(^{2}\)α-SYN-39 mice, but not in wildtype controls. In the striatum of 16-17 months old wildtype mice a slightly elevated CD8\(^{+}\) T cell count and CD11b\(^{+}\) microglia cell count was observed compared to younger aged mice. Additional analyses of neuroinflammation in the nigrostriatal tract of wildtype mice did not yield any significant age-dependent changes of CD4\(^{+}\), CD8\(^{+}\) T cell and B220\(^{+}\) B cell numbers, respectively. In contrast, a significant age-dependent increase of CD8\(^{+}\) T cells, GFAP\(^{+}\) astrocytes as well as a pronounced increase of CD11b+ microglia numbers were observed in the SN of hm\(^{2}\)α-SYN-39 mice pointing towards a neuroinflammatory processes in this genetic mouse model for PD. The findings in the hm\(^{2}\)α-SYN-39 mouse model strengthen the evidence that T cell and glial cell responses are involved in the age-related neurodegeneration in PD. The slow and age-dependent progression of neurodegeneration and neuroinflammation in the hm\(^{2}\)α-SYN-39 PD rodent model underlines its translational value and makes it suitable for studying anti-inflammatory therapies.}, language = {en} } @phdthesis{Yin2023, author = {Yin, Jing}, title = {Progressive alterations of pro- and antidegeneration markers in the nigrostriatal tract of the AAV1/2-A53T-α synuclein rat model of Parkinson's disease}, doi = {10.25972/OPUS-26064}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260645}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Neurodegeneration plays an essential role in Parkinson's disease (PD). Several crucial neuronal pro-and antidegeneration markers were described to be altered in disease models accompanied by neurodegeneration. In the AAV1/2-A53T-aSyn PD rat model progressive time-dependent motor impairment and neurodegeneration in the nigrostriatal tract starting from 2 weeks after PD model induction could be found. Downregulation of Nrf2 in SN and nigrostriatal axon localization, a trend of Tau downregulation in SN and upregulation in axon localization in the AAV1/2-A53T-aSyn PD rat model were observed, indicating potential therapeutic value of these two molecular targets in PD. No alterations of SARM1 and NMNAT2 could be detected, indicating little relevance of these two molecules with our AAV1/2-A53T-aSyn rat model.}, language = {en} } @article{DauerneeJoppeTatenhorstCaldiGomesetal.2021, author = {Dauer n{\´e}e Joppe, Karina and Tatenhorst, Lars and Caldi Gomes, Lucas and Zhang, Shuyu and Parvaz, Mojan and Carboni, Eleonora and Roser, Anna-Elisa and El DeBakey, Hazem and B{\"a}hr, Mathias and Vogel-Mikuš, Katarina and Wang Ip, Chi and Becker, Stefan and Zweckstetter, Markus and Lingor, Paul}, title = {Brain iron enrichment attenuates α-synuclein spreading after injection of preformed fibrils}, series = {Journal of Neurochemistry}, volume = {159}, journal = {Journal of Neurochemistry}, number = {3}, doi = {10.1111/jnc.15461}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262544}, pages = {554 -- 573}, year = {2021}, abstract = {Regional iron accumulation and α-synuclein (α-syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to α-syn, facilitating its aggregation and regulating α-syn expression, it remains unclear if and how iron also modulates α-syn spreading. To elucidate the influence of iron on the propagation of α-syn pathology, we investigated α-syn spreading after stereotactic injection of α-syn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120, or 240 mg/kg carbonyl iron or vehicle between postnatal days 10 and 17. At 12 weeks of age, intrastriatal injections of 5-µg PFFs were performed to induce seeding of α-syn aggregates. At 90 days post-injection, PFFs-injected mice displayed long-term memory deficits, without affection of motor behavior. Interestingly, quantification of α-syn phosphorylated at S129 showed reduced α-syn pathology and attenuated spreading to connectome-specific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a dose-dependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter trans-synaptic α-syn propagation, possibly indicating an involvement of non-neuronal cells in this process. Our study suggests that α-syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of α-syn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via iron-induced alterations of the brain connectome.}, language = {en} } @article{PlumEggersHellingetal.2020, author = {Plum, Sarah and Eggers, Britta and Helling, Stefan and Stepath, Markus and Theiss, Carsten and Leite, Renata E. P. and Molina, Mariana and Grinberg, Lea T. and Riederer, Peter and Gerlach, Manfred and May, Caroline and Marcus, Katrin}, title = {Proteomic characterization of synaptosomes from human substantia nigra indicates altered mitochondrial translation in Parkinson's disease}, series = {Cells}, volume = {9}, journal = {Cells}, number = {12}, issn = {2073-4409}, doi = {10.3390/cells9122580}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219978}, year = {2020}, abstract = {The pathological hallmark of Parkinson's disease (PD) is the loss of neuromelanin-containing dopaminergic neurons within the substantia nigra pars compacta (SNpc). Additionally, numerous studies indicate an altered synaptic function during disease progression. To gain new insights into the molecular processes underlying the alteration of synaptic function in PD, a proteomic study was performed. Therefore, synaptosomes were isolated by density gradient centrifugation from SNpc tissue of individuals at advanced PD stages (N = 5) as well as control subjects free of pathology (N = 5) followed by mass spectrometry-based analysis. In total, 362 proteins were identified and assigned to the synaptosomal core proteome. This core proteome comprised all proteins expressed within the synapses without regard to data analysis software, gender, age, or disease. The differential analysis between control subjects and PD cases revealed that CD9 antigen was overrepresented and fourteen proteins, among them Thymidine kinase 2 (TK2), mitochondrial, 39S ribosomal protein L37, neurolysin, and Methionine-tRNA ligase (MARS2) were underrepresented in PD suggesting an alteration in mitochondrial translation within synaptosomes.}, language = {en} } @article{SianHulsmannRiederer2021, author = {Sian-Hulsmann, Jeswinder and Riederer, Peter}, title = {The nigral coup in Parkinson's Disease by α-synuclein and its associated rebels}, series = {Cells}, volume = {10}, journal = {Cells}, number = {3}, issn = {2073-4409}, doi = {10.3390/cells10030598}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234073}, year = {2021}, abstract = {The risk of Parkinson's disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson's disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder.}, language = {en} } @phdthesis{Karikari2022, author = {Karikari, Akua Afriyie}, title = {Alpha Synuclein Specific T Lymphocytes Promote Neurodegeneration in the A53T-α-synuclein Parkinson's Disease Mouse Model}, doi = {10.25972/OPUS-18308}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-183080}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Parkinson's disease (PD), which is the most common motor neurodegenerative disorder has attracted a tremendous amount of research advancement amid the challenges of the lack of an appropriate model that summate all the features of the human disease. Nevertheless, an aspect of the disease that is yet to be fully elucidated is the role of the immune system particularly the adaptive arm in the pathogenesis of PD. The focus of this study therefore was to characterize the contribution of lymphocytes in PD using the AAV1/2-A53T-α-synuclein mouse model of the disease that encodes for human mutated A53T-α-synuclein. This model was suitable for this research because it reflects more faithfully the molecular pathology underlying the human disease by exhibition of insoluble α-synuclein containing Lewy-like protein aggregates as compared to the more classical toxin models used in PD research. The outcome of this study showed that stereotaxic delivery of pathogenic α-synuclein via a viral vector into the substantia nigra engender the invasion of activated CD4+ and CD8+ T lymphocytes in the brain. The invasion of activated T cells in the brain especially in the substantia nigra then results in enhanced microglial activation and the disintegration of dopaminergic neurons. In addition, it was also discovered that CD4+ T cells augmented dopaminergic cell death to a greater extent than CD8+ T cells although; axonal degeneration occurred relatively independent from T cells contribution. The ex vivo and in vitro, experiments also indicated that the T cells were not only activated but they were specific to the mutated human α-synuclein antigen. As a result, they demonstrated selectivity in inducing more cell death to primary hippocampal neurons transduced with AAV1/2-A53T-α-synuclein vector than neurons with empty viral vector infection. The mechanism of T cell induced neuronal cell loss could not be attributed to the presence of cytokines neither was it mediated through MHC I and II. On the whole, this research has established that the presence of pathogenic α-synuclein in the substantia nigra has the potential to trigger immune responses that involve the transmigration of adaptive immune cells into the brain. The infiltration of the T cells consequently has a detrimental effect on the survival of dopaminergic neurons and the progression of the disease}, subject = {Parkinson-Krankheit}, language = {en} } @article{KuzkinaBargarSchmittetal.2021, author = {Kuzkina, Anastasia and Bargar, Connor and Schmitt, Daniela and R{\"o}ßle, Jonas and Wang, Wen and Schubert, Anna-Lena and Tatsuoka, Curtis and Gunzler, Steven A. and Zou, Wen-Quan and Volkmann, Jens and Sommer, Claudia and Doppler, Kathrin and Chen, Shu G.}, title = {Diagnostic value of skin RT-QuIC in Parkinson's disease: a two-laboratory study}, series = {NPJ Parkinson's Disease}, volume = {7}, journal = {NPJ Parkinson's Disease}, number = {1}, doi = {10.1038/s41531-021-00242-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260451}, year = {2021}, abstract = {Skin alpha-synuclein deposition is considered a potential biomarker for Parkinson's disease (PD). Real-time quaking-induced conversion (RT-QuIC) is a novel, ultrasensitive, and efficient seeding assay that enables the detection of minute amounts of alpha-synuclein aggregates. We aimed to determine the diagnostic accuracy, reliability, and reproducibility of alpha-synuclein RT-QuIC assay of skin biopsy for diagnosing PD and to explore its correlation with clinical markers of PD in a two-center inter-laboratory comparison study. Patients with clinically diagnosed PD (n = 34), as well as control subjects (n = 30), underwent skin punch biopsy at multiple sites (neck, lower back, thigh, and lower leg). The skin biopsy samples (198 in total) were divided in half to be analyzed by RT-QuIC assay in two independent laboratories. The a-synuclein RT-QuIC assay of multiple skin biopsies supported the clinical diagnosis of PD with a diagnostic accuracy of 88.9\% and showed a high degree of inter-rater agreement between the two laboratories (92.2\%). Higher alpha-synuclein seeding activity in RT-QuIC was shown in patients with longer disease duration and more advanced disease stage and correlated with the presence of REM sleep behavior disorder, cognitive impairment, and constipation. The alpha-synuclein RT-QuIC assay of minimally invasive skin punch biopsy is a reliable and reproducible biomarker for Parkinson's disease. Moreover, alpha-synuclein RT-QuIC seeding activity in the skin may serve as a potential indicator of progression as it correlates with the disease stage and certain non-motor symptoms.}, language = {en} } @article{BrumbergKuzkinaLapaetal.2021, author = {Brumberg, Joachim and Kuzkina, Anastasia and Lapa, Constantin and Mammadova, Sona and Buck, Andreas and Volkmann, Jens and Sommer, Claudia and Isaias, Ioannis U. and Doppler, Kathrin}, title = {Dermal and cardiac autonomic fiber involvement in Parkinson's disease and multiple system atrophy}, series = {Neurobiology of Disease}, volume = {153}, journal = {Neurobiology of Disease}, doi = {10.1016/j.nbd.2021.105332}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260061}, pages = {105332}, year = {2021}, abstract = {Pathological aggregates of alpha-synuclein in peripheral dermal nerve fibers can be detected in patients with idiopathic Parkinson's disease and multiple system atrophy. This study combines skin biopsy staining for p-alpha-synuclein depositions and radionuclide imaging of the heart with [\(^{123}\)I]-metaiodobenzylguanidine to explore peripheral denervation in both diseases. To this purpose, 42 patients with a clinical diagnosis of Parkinson's disease or multiple system atrophy were enrolled. All patients underwent a standardized clinical workup including neurological evaluation, neurography, and blood samples. Skin biopsies were obtained from the distal and proximal leg, back, and neck for immunofluorescence double labeling with anti-p-alpha-synuclein and anti-PGP9.5. All patients underwent myocardial [\(^{123}\)I]-metaiodobenzylguanidine scintigraphy. Dermal p-alpha-synuclein was observed in 47.6\% of Parkinson's disease patients and was mainly found in autonomic structures. 81.0\% of multiple system atrophy patients had deposits with most of cases in somatosensory fibers. The [\(^{123}\)I]-metaiodobenzylguanidine heart-to-mediastinum ratio was lower in Parkinson's disease than in multiple system atrophy patients (1.94 +/- 0.63 vs. 2.91 +/- 0.96; p < 0.0001). Irrespective of the diagnosis, uptake was lower in patients with than without p-alpha-synuclein in autonomic structures (1.42 +/- 0.51 vs. 2.74 +/- 0.83; p < 0.0001). Rare cases of Parkinson's disease with p-alpha-synuclein in somatosensory fibers and multiple system atrophy patients with deposits in autonomic structures or both fiber types presented with clinically overlapping features. In conclusion, this study suggests that alpha-synuclein contributes to peripheral neurodegeneration and mediates the impairment of cardiac sympathetic neurons in patients with synucleinopathies. Furthermore, it indicates that Parkinson's disease and multiple system atrophy share pathophysiologic mechanisms of peripheral nervous system dysfunction with a clinical overlap.}, language = {en} } @article{PuetzKramRauhetal.2021, author = {P{\"u}tz, Stephanie M. and Kram, Jette and Rauh, Elisa and Kaiser, Sophie and Toews, Romy and Lueningschroer-Wang, Yi and Rieger, Dirk and Raabe, Thomas}, title = {Loss of p21-activated kinase Mbt/PAK4 causes Parkinson-like symptoms in Drosophila}, series = {Disease Models \& Mechanisms}, volume = {14}, journal = {Disease Models \& Mechanisms}, number = {6}, doi = {10.1242/dmm.047811}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259222}, pages = {dmm047811}, year = {2021}, abstract = {Parkinson's disease (PD) provokes bradykinesia, resting tremor, rigidity and postural instability, and also non-motor symptoms such as depression, anxiety, sleep and cognitive impairments. Similar phenotypes can be induced in Drosophila melanogaster through modification of PD-relevant genes or the administration of PD inducing toxins. Recent studies correlated deregulation of human p21-activated kinase 4 (PAK4) with PD, leaving open the question of a causative relationship of mutations in this gene for manifestation of PD symptoms. To determine whether flies lacking the PAK4 homolog Mushroom bodies tiny (Mbt) show PD-like phenotypes, we tested for a variety of PD criteria. Here, we demonstrate that mbt mutant flies show PD-like phenotypes including age-dependent movement deficits, reduced life expectancy and fragmented sleep. They also react to a stressful situation with higher immobility, indicating an influence of Mbt on emotional behavior. Loss of Mbt function has a negative effect on the number of dopaminergic protocerebral anterior medial (PAM) neurons, most likely caused by a proliferation defect of neural progenitors. The age-dependent movement deficits are not accompanied by a corresponding further loss of PAM neurons. Previous studies highlighted the importance of a small PAM subgroup for age-dependent PD motor impairments. We show that impaired motor skills are caused by a lack of Mbt in this PAM subgroup. In addition, a broader re-expression of Mbt in PAM neurons improves life expectancy. Conversely, selective Mbt knockout in the same cells shortens lifespan. We conclude that mutations in Mbt/PAK4 can play a causative role in the development of PD phenotypes.}, language = {en} } @article{LangeSteigerwaldMalzacheretal.2021, author = {Lange, Florian and Steigerwald, Frank and Malzacher, Tobias and Brandt, Gregor Alexander and Odorfer, Thorsten Michael and Roothans, Jonas and Reich, Martin M. and Fricke, Patrick and Volkmann, Jens and Matthies, Cordula and Capetian, Philipp D.}, title = {Reduced Programming Time and Strong Symptom Control Even in Chronic Course Through Imaging-Based DBS Programming}, series = {Frontiers in Neurology}, volume = {12}, journal = {Frontiers in Neurology}, issn = {1664-2295}, doi = {10.3389/fneur.2021.785529}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-249634}, year = {2021}, abstract = {Objectives: Deep brain stimulation (DBS) programming is based on clinical response testing. Our clinical pilot trial assessed the feasibility of image-guided programing using software depicting the lead location in a patient-specific anatomical model. Methods: Parkinson's disease patients with subthalamic nucleus-DBS were randomly assigned to standard clinical-based programming (CBP) or anatomical-based (imaging-guided) programming (ABP) in an 8-week crossover trial. Programming characteristics and clinical outcomes were evaluated. Results: In 10 patients, both programs led to similar motor symptom control (MDS-UPDRS III) after 4 weeks (medicationOFF/stimulationON; CPB: 18.27 ± 9.23; ABP: 18.37 ± 6.66). Stimulation settings were not significantly different, apart from higher frequency in the baseline program than CBP (p = 0.01) or ABP (p = 0.003). Time spent in a program was not significantly different (CBP: 86.1 ± 29.82\%, ABP: 88.6 ± 29.0\%). Programing time was significantly shorter (p = 0.039) with ABP (19.78 ± 5.86 min) than CBP (45.22 ± 18.32). Conclusion: Image-guided DBS programming in PD patients drastically reduces programming time without compromising symptom control and patient satisfaction in this small feasibility trial.}, language = {en} } @phdthesis{Andreska2021, author = {Andreska, Thomas}, title = {Effects of dopamine on BDNF / TrkB mediated signaling and plasticity on cortico-striatal synapses}, doi = {10.25972/OPUS-17431}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-174317}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Progressive loss of voluntary movement control is the central symptom of Parkinson's disease (PD). Even today, we are not yet able to cure PD. This is mainly due to a lack of understanding the mechanisms of movement control, network activity and plasticity in motor circuits, in particular between the cerebral cortex and the striatum. Brain-derived neurotrophic factor (BDNF) has emerged as one of the most important factors for the development and survival of neurons, as well as for synaptic plasticity. It is thus an important target for the development of new therapeutic strategies against neurodegenerative diseases. Together with its receptor, the Tropomyosin receptor kinase B (TrkB), it is critically involved in development and function of the striatum. Nevertheless, little is known about the localization of BDNF within presynaptic terminals in the striatum, as well as the types of neurons that produce BDNF in the cerebral cortex. Furthermore, the influence of midbrain derived dopamine on the control of BDNF / TrkB interaction in striatal medium spiny neurons (MSNs) remains elusive so far. Dopamine, however, appears to play an important role, as its absence leads to drastic changes in striatal synaptic plasticity. This suggests that dopamine could regulate synaptic activity in the striatum via modulation of BDNF / TrkB function. To answer these questions, we have developed a sensitive and reliable protocol for the immunohistochemical detection of endogenous BDNF. We find that the majority of striatal BDNF is provided by glutamatergic, cortex derived afferents and not dopaminergic inputs from the midbrain. In fact, we found BDNF in cell bodies of neurons in layers II-III and V of the primary and secondary motor cortex as well as layer V of the somatosensory cortex. These are the brain areas that send dense projections to the dorsolateral striatum for control of voluntary movement. Furthermore, we could show that these projection neurons significantly downregulate the expression of BDNF during the juvenile development of mice between 3 and 12 weeks. In parallel, we found a modulatory effect of dopamine on the translocation of TrkB to the cell surface in postsynaptic striatal Medium Spiny Neurons (MSNs). In MSNs of the direct pathway (dMSNs), which express dopamine receptor 1 (DRD1), we observed the formation of TrkB aggregates in the 6-hydroxydopamine (6-OHDA) model of PD. This suggests that DRD1 activity controls TrkB surface expression in these neurons. In contrast, we found that DRD2 activation has opposite effects in MSNs of the indirect pathway (iMSNs). Activation of DRD2 promotes a rapid decrease in TrkB surface expression which was reversible and depended on cAMP. In parallel, stimulation of DRD2 led to induction of phospho-TrkB (pTrkB). This effect was significantly slower than the effect on TrkB surface expression and indicates that TrkB is transactivated by DRD2. Together, our data provide evidence that dopamine triggers dual modes of plasticity on striatal MSNs by acting on TrkB surface expression in DRD1 and DRD2 expressing MSNs. This surface expression of the receptor is crucial for the binding of BDNF, which is released from corticostriatal afferents. This leads to the induction of TrkB-mediated downstream signal transduction cascades and long-term potentiation (LTP). Therefore, the dopamine-mediated translocation of TrkB could be a mediator that modulates the balance between dopaminergic and glutamatergic signaling to allow synaptic plasticity in a spatiotemporal manner. This information and the fact that TrkB is segregated to persistent aggregates in PD could help to improve our understanding of voluntary movement control and to develop new therapeutic strategies beyond those focusing on dopaminergic supply.}, subject = {Brain-derived neurotrophic factor}, language = {en} } @article{SteigerwaldMuellerJohannesetal.2016, author = {Steigerwald, Frank and M{\"u}ller, Lorenz and Johannes, Silvia and Matthies, Cordula and Volkmann, Jens}, title = {Directional deep brain stimulation of the subthalamic nucleus: a pilot study using a novel neurostimulation device}, series = {Movement Disorders}, volume = {31}, journal = {Movement Disorders}, number = {8}, doi = {10.1002/mds.26669}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187683}, pages = {1240-1243}, year = {2016}, abstract = {Introduction A novel neurostimulation system allows steering current in horizontal directions by combining segmented leads and multiple independent current control. The aim of this study was to evaluate directional DBS effects on parkinsonian motor features and adverse effects of subthalamic neurostimulation. Methods Seven PD patients implanted with the novel directional DBS system for bilateral subthalamic DBS underwent an extended monopolar review session during the first postoperative week, in which current thresholds were determined for rigidity control and stimulation-induced adverse effects using either directional or ring-mode settings. Results Effect or adverse effect thresholds were modified by directional settings for each of the 14 STN leads. Magnitude of change varied markedly between leads, as did orientation of optimal horizontal current steering. Conclusion Directional current steering through chronically implanted segmented electrodes is feasible, alters adverse effect and efficacy thresholds in a highly individual manner, and expands the therapeutic window in a monopolar review as compared to ring-mode DBS.}, language = {en} } @article{GulbertiMollHameletal.2015, author = {Gulberti, A. and Moll, C.K.E. and Hamel, W. and Buhmann, C. and Koeppen, J.A. and Boelmans, K. and Zittel, S. and Gerloff, C. and Westphal, M. and Schneider, T.R. and Engel, A.K.}, title = {Predictive timing functions of cortical beta oscillations are impaired in Parkinson's disease and influenced by L-DOPA and deep brain stimulation of the subthalamic nucleus Impaired beta-band timing functions in PD}, series = {NeuroImage: Clinical}, volume = {9}, journal = {NeuroImage: Clinical}, doi = {10.1016/j.nicl.2015.09.013}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150049}, pages = {436-449}, year = {2015}, abstract = {Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory-motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing.}, language = {en} } @article{IsaiasTrujilloSummersetal.2016, author = {Isaias, Ioannis U. and Trujillo, Paula and Summers, Paul and Marotta, Giorgio and Mainardi, Luca and Pezzoli, Gianni and Zecca, Luigi and Costa, Antonella}, title = {Neuromelanin Imaging and Dopaminergic Loss in Parkinson's Disease}, series = {Frontiers in Aging Neuroscience}, volume = {8}, journal = {Frontiers in Aging Neuroscience}, number = {196}, doi = {10.3389/fnagi.2016.00196}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164046}, year = {2016}, abstract = {Parkinson's disease (PD) is a progressive neurodegenerative disorder in which the major pathologic substrate is a loss of dopaminergic neurons from the substantia nigra. Our main objective was to determine the correspondence between changes in the substantia nigra, evident in neuromelanin and iron sensitive magnetic resonance imaging (MRI), and dopaminergic striatal innervation loss in patients with PD. Eighteen patients and 18 healthy control subjects were included in the study. Using neuromelanin-MRI, we measured the volume of the substantia nigra and the contrast-to-noise-ratio between substantia nigra and a background region. The apparent transverse relaxation rate and magnetic susceptibility of the substantia nigra were calculated from dual-echo MRI. Striatal dopaminergic innervation was measured as density of dopamine transporter (DAT) by means of single-photon emission computed tomography and [123I] N-ω-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) tropane. Patients showed a reduced volume of the substantia nigra and contrast-to-noise-ratio and both positively correlated with the corresponding striatal DAT density. The apparent transverse relaxation rate and magnetic susceptibility values of the substantia nigra did not differ between patients and healthy controls. The best predictor of DAT reduction was the volume of the substantia nigra. Clinical and imaging correlations were also investigated for the locus coeruleus. Our results suggest that neuromelanin-MRI can be used for quantifying substantia nigra pathology in PD where it closely correlates with dopaminergic striatal innervation loss. Longitudinal studies should further explore the role of Neuromelanin-MRI as an imaging biomarker of PD, especially for subjects at risk of developing the disease.}, language = {en} } @article{MencacciIsaiasReichetal.2014, author = {Mencacci, Niccol{\´o} E. and Isaias, Ioannis U. and Reich, Martin M. and Ganos, Christos and Plagnol, Vincent and Polke, James M. and Bras, Jose and Hersheson, Joshua and Stamelou, Maria and Pittman, Alan M. and Noyce, Alastair J. and Mok, Kin Y. and Opladen, Thomas and Kunstmann, Erdmute and Hodecker, Sybille and M{\"u}nchau, Alexander and Volkmann, Jens and Samnick, Samuel and Sidle, Katie and Nanji, Tina and Sweeney, Mary G. and Houlden, Henry and Batla, Amit and Zecchinelli, Anna L. and Pezzoli, Gianni and Marotta, Giorgio and Lees, Andrew and Alegria, Paulo and Krack, Paul and Cormier-Dequaire, Florence and Lesage, Suzanne and Brice, Alexis and Heutink, Peter and Gasser, Thomas and Lubbe, Steven J. and Morris, Huw R. and Taba, Pille and Koks, Sulev and Majounie, Elisa and Gibbs, J. Raphael and Singleton, Andrew and Hardy, John and Klebe, Stephan and Bhatia, Kailash P. and Wood, Nicholas W.}, title = {Parkinson's disease in GTP cyclohydrolase 1 mutation carriers}, series = {Brain}, volume = {137}, journal = {Brain}, number = {9}, doi = {10.1093/brain/awu179}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121268}, pages = {2480-92}, year = {2014}, abstract = {GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75\%) than in controls (6/5935 = 0.1\%; odds ratio 7.5; 95\% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.}, language = {en} } @article{GiordanoCanesiIsalbertietal.2014, author = {Giordano, Rosaria and Canesi, Margherita and Isalberti, Maurizio and Isaias, Ioannis Ugo and Montemurro, Tiziana and Vigan{\`o}, Mariele and Montelatici, Elisa and Boldrin, Valentina and Benti, Riccardo and Cortelezzi, Agostino and Fracchiolla, Nicola and Lazzari, Lorenza and Pezzoli, Gianni}, title = {Autologous mesenchymal stem cell therapy for progressive supranuclear palsy: translation into a phase I controlled, randomized clinical study}, series = {Journal of Translational Medicine}, volume = {12}, journal = {Journal of Translational Medicine}, number = {14}, doi = {10.1186/1479-5876-12-14}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117594}, year = {2014}, abstract = {Background: Progressive Supranuclear Palsy (PSP) is a sporadic and progressive neurodegenerative disease which belongs to the family of tauopathies and involves both cortical and subcortical structures. No effective therapy is to date available. Methods/design: Autologous bone marrow (BM) mesenchymal stem cells (MSC) from patients affected by different type of parkinsonisms have shown their ability to improve the dopaminergic function in preclinical and clinical models. It is also possible to isolate and expand MSC from the BM of PSP patients with the same proliferation rate and immuphenotypic profile as MSC from healthy donors. BM MSC can be efficiently delivered to the affected brain regions of PSP patients where they can exert their beneficial effects through different mechanisms including the secretion of neurotrophic factors. Here we propose a randomized, placebo-controlled, double-blind phase I clinical trial in patients affected by PSP with MSC delivered via intra-arterial injection. Discussion: To our knowledge, this is the first clinical trial to be applied in a no-option parkinsonism that aims to test the safety and to exploit the properties of autologous mesenchymal stem cells in reducing disease progression. The study has been designed to test the safety of this " first-in-man" approach and to preliminarily explore its efficacy by excluding the placebo effect. Trial registration: NCT01824121}, language = {en} } @article{EllgringOertelUlmetal.1992, author = {Ellgring, Johann Heinrich and Oertel, W. H. and Ulm, G. and Gasser, T. and Perleth, B. and Seiler, S.}, title = {Partnership and depression in Parkinson's Disease}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-42516}, year = {1992}, abstract = {In this study, the influence of partnership on depression and coping with Parkinson's disease has been investigated. Twentythree single female patients, 46 married patients (23 female, 23 male) with unimpaired partnership and 42 patients (21 female, 21 male) whose partnership had worsened since the onset of disease, were compared with regard to depression and self reported extent of psychosocial distress. Single female patients tended to have higher depression scores than patients in a stable partnership, especially in items concerning personal worthlessness and senselessness of life. Patients differed in the extent of distress concerning social behavior, psychological problems/anxiety and efficiency. Within the group of single female patients two subgroups emerged: (1) patients with low extent of distress in all aspects; (2) patients who were highly distressed by psychological problems and physical disability but weakly distressed from social interaction. Male and female patients living in a stable partnership reported only a generally low to moderate extent of distress. More than half of the male and female patients who reported an impairment of their relationship also had scores of moderate to severe depression. These patients also had the h~ghest extent of distress in each ofthe aspects assessed. The results are dicussed with regard to possible interactive effects ofthe disease, quality of the partnership and availability of coping strategies.}, language = {en} } @phdthesis{Muenchbach2001, author = {M{\"u}nchbach, Miriam Birgit}, title = {Untersuchungen zur endogenen Bildung, Cytotoxizit{\"a}t und DNA-sch{\"a}digenden Wirkung des dopaminergen Neurotoxins TaClo}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-385}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2001}, abstract = {Die kausalen Ursachen, die zur Ausl{\"o}sung der neurodegenerativen Erkrankung Morbus Parkinson f{\"u}hren, sind noch immer unklar. Man nimmt heute an, daß das Absterben dopaminerger Neurone im Mittelhirn von Parkinsonpatienten multifaktoriell ausgel{\"o}st wird. Genetische Pr{\"a}disposition sowie endogene und exogene Umweltgifte wie etwa Substanzen, die strukturelle {\"A}hnlichkeit mit dem bekanntesten dopaminergen Neurotoxin MPTP (1-Methyl-4-phenyl-1,2,3,5-tetrahydropyridin) besitzen, werden als Hauptursachen f{\"u}r die Entstehung des Parkinsonsyndroms diskutiert. Diese Arbeit besch{\"a}ftigt sich mit einer neuen Klasse von neurotoxisch wirksamen Tetrahydro-b-carbolinen, die sich von Trichloracetaldehyd (Chloral) ableiten. Die wohl prominenteste Verbindung in dieser Reihe ist TaClo (1-Trichlormethyl-1,2,3,4-tetrahydro-b-carbolin), das im menschlichen K{\"o}rper nach Aufnahme des Schlafmittels Chloralhydrat durch Pictet-Spengler-Kondensation mit dem endogen vorhandenen Tryptamin gebildet wird. Zus{\"a}tzlich scheint die Bildung von TaClo aus dem Industriel{\"o}sungsmittel TRI (Trichlorethylen), das im Organismus zu Chloral metabolisiert wird, m{\"o}glich. Die {\"u}ber Chloral eingef{\"u}hrte große CCl3-Gruppe erh{\"o}ht die Lipophilie von TaClo, die Passage der Blut-Hirn-Schranke ist erleichtert. In der Tat haben zahlreiche Untersuchungen in vitro und in vivo gezeigt, daß TaClo toxische Prozesse in dopaminergen und serotonergen Systemen zu induzieren vermag. Ein wesentliches Ziel dieser Arbeit bestand darin, die in-vivo-Entstehung und Metabolisierung von TaClo im Menschen sowie den Einfluß dieses Neurotoxins auf die DNA herauszuarbeiten und n{\"a}her zu untersuchen. Im einzelnen wurden folgende Ergebnisse erzielt: TaClo sch{\"a}digt die DNA, wie Versuche an zellfreier DNA und in-vitro-Experimente an PC12-Zellen belegen. Die endogene Bildung von TaClo in Chloralhydrat-behandelten Patienten und die in-vitro-Entstehung von TaClo aus Trichlorethylen wurde mittels HPLC-ESI-MS-MS-Analytik eindeutig bewiesen. Außerdem wurden erste Hinweise auf eine Anreicherung des Neurotoxins im menschlichen K{\"o}rper erhalten. Stereostrukturelle Aspekte der Bildung und Verstoffwechslung von TaClo wurden aufgekl{\"a}rt und TaClo-Metabolite in in-vitro- und in-vivo-Proben identifiziert. Das Tetrahydro-b-carbolin entsteht in racemischer Form, wird also nicht enzymatisch sondern spontan durch Pictet-Spengler-Reaktion gebildet. Zus{\"a}tzlich wurden Hinweise auf eine enzymatische Metabolisierung von TaClo gefunden. Außerdem gelang es, eine etablierte Methode des oxidativen Abbaus zur Aufkl{\"a}rung der absoluten Konfiguration von Tetrahydropyridin-Heterocyclen [z.B. Eleagnin] auf Substanzen mit benzylischer Hydroxy- oder Metylether-Gruppe zu erweitern. Geringe Mengen (1-2 mg) an Substanzen, die in benzylischer Position eine chirale Sauerstoffunktion besitzen, wurden durch Ruthenium-katalysierte Oxidation zu GC-g{\"a}ngigen S{\"a}uren abgebaut, deren absolute Konfiguration nach Trennung an chiraler Phase durch Vergleich mit enantiomerenreinem Referenzmaterial bestimmt wurde. Diese Zuordnung erlaubte den R{\"u}ckschluß auf die absolute Konfiguration einer Reihe Ausgangsverbindungen.}, subject = {Parkinson-Krankheit}, language = {de} }