TY - JOUR A1 - Ellgring, Johann Heinrich A1 - Oertel, W. H. A1 - Ulm, G. A1 - Gasser, T. A1 - Perleth, B. A1 - Seiler, S. T1 - Partnership and depression in Parkinson's Disease N2 - 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. KW - Depression KW - Parkinson's disease KW - Partnership KW - Psychological distress Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42516 ER - TY - JOUR A1 - Mencacci, Niccoló E. A1 - Isaias, Ioannis U. A1 - Reich, Martin M. A1 - Ganos, Christos A1 - Plagnol, Vincent A1 - Polke, James M. A1 - Bras, Jose A1 - Hersheson, Joshua A1 - Stamelou, Maria A1 - Pittman, Alan M. A1 - Noyce, Alastair J. A1 - Mok, Kin Y. A1 - Opladen, Thomas A1 - Kunstmann, Erdmute A1 - Hodecker, Sybille A1 - Münchau, Alexander A1 - Volkmann, Jens A1 - Samnick, Samuel A1 - Sidle, Katie A1 - Nanji, Tina A1 - Sweeney, Mary G. A1 - Houlden, Henry A1 - Batla, Amit A1 - Zecchinelli, Anna L. A1 - Pezzoli, Gianni A1 - Marotta, Giorgio A1 - Lees, Andrew A1 - Alegria, Paulo A1 - Krack, Paul A1 - Cormier-Dequaire, Florence A1 - Lesage, Suzanne A1 - Brice, Alexis A1 - Heutink, Peter A1 - Gasser, Thomas A1 - Lubbe, Steven J. A1 - Morris, Huw R. A1 - Taba, Pille A1 - Koks, Sulev A1 - Majounie, Elisa A1 - Gibbs, J. Raphael A1 - Singleton, Andrew A1 - Hardy, John A1 - Klebe, Stephan A1 - Bhatia, Kailash P. A1 - Wood, Nicholas W. T1 - Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers JF - Brain N2 - 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. KW - DOPA-responsive-dystonia KW - GCH1 KW - Parkinson's disease KW - dopamine KW - exome sequencing Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121268 VL - 137 IS - 9 ER - TY - JOUR A1 - Giordano, Rosaria A1 - Canesi, Margherita A1 - Isalberti, Maurizio A1 - Isaias, Ioannis Ugo A1 - Montemurro, Tiziana A1 - Viganò, Mariele A1 - Montelatici, Elisa A1 - Boldrin, Valentina A1 - Benti, Riccardo A1 - Cortelezzi, Agostino A1 - Fracchiolla, Nicola A1 - Lazzari, Lorenza A1 - Pezzoli, Gianni T1 - Autologous mesenchymal stem cell therapy for progressive supranuclear palsy: translation into a phase I controlled, randomized clinical study JF - Journal of Translational Medicine N2 - 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 KW - Parkinson's disease KW - cellular therapy KW - deep brain-stimulation KW - bone-marrow KW - transplantation KW - receptor tyrosine kinase KW - Richardson-Olszewski-Syndrome KW - multiple system atrophy KW - advanced therapy medicinal products KW - mesenchymal stem and stromal cells KW - progressive supranuclear palsy KW - treatment options KW - adrenal medulla KW - stromal cells Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117594 VL - 12 IS - 14 ER - TY - JOUR A1 - Gulberti, A. A1 - Moll, C.K.E. A1 - Hamel, W. A1 - Buhmann, C. A1 - Koeppen, J.A. A1 - Boelmans, K. A1 - Zittel, S. A1 - Gerloff, C. A1 - Westphal, M. A1 - Schneider, T.R. A1 - Engel, A.K. T1 - 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 JF - NeuroImage: Clinical N2 - 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. KW - Parkinson's disease KW - interval timing KW - beta oscillations KW - subthalamic nucleus KW - deep brain stimulation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150049 VL - 9 ER - TY - JOUR A1 - Isaias, Ioannis U. A1 - Trujillo, Paula A1 - Summers, Paul A1 - Marotta, Giorgio A1 - Mainardi, Luca A1 - Pezzoli, Gianni A1 - Zecca, Luigi A1 - Costa, Antonella T1 - Neuromelanin Imaging and Dopaminergic Loss in Parkinson's Disease JF - Frontiers in Aging Neuroscience N2 - 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. KW - MRI KW - neuromelanin KW - dopamine KW - Parkinson's disease KW - FP-CIT SPECT Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164046 VL - 8 IS - 196 ER - TY - JOUR A1 - Steigerwald, Frank A1 - Müller, Lorenz A1 - Johannes, Silvia A1 - Matthies, Cordula A1 - Volkmann, Jens T1 - Directional deep brain stimulation of the subthalamic nucleus: a pilot study using a novel neurostimulation device JF - Movement Disorders N2 - 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. KW - deep brain stimulation KW - Parkinson's disease Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187683 VL - 31 IS - 8 ER - TY - JOUR A1 - Plum, Sarah A1 - Eggers, Britta A1 - Helling, Stefan A1 - Stepath, Markus A1 - Theiss, Carsten A1 - Leite, Renata E. P. A1 - Molina, Mariana A1 - Grinberg, Lea T. A1 - Riederer, Peter A1 - Gerlach, Manfred A1 - May, Caroline A1 - Marcus, Katrin T1 - Proteomic characterization of synaptosomes from human substantia nigra indicates altered mitochondrial translation in Parkinson's disease JF - Cells N2 - 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. KW - synaptosomes KW - proteomics KW - Parkinson's disease KW - substantia nigra pars compacta KW - mitochondrial pathology KW - mitochondrial translation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219978 SN - 2073-4409 VL - 9 IS - 12 ER - TY - JOUR A1 - Kuzkina, Anastasia A1 - Bargar, Connor A1 - Schmitt, Daniela A1 - Rößle, Jonas A1 - Wang, Wen A1 - Schubert, Anna-Lena A1 - Tatsuoka, Curtis A1 - Gunzler, Steven A. A1 - Zou, Wen-Quan A1 - Volkmann, Jens A1 - Sommer, Claudia A1 - Doppler, Kathrin A1 - Chen, Shu G. T1 - Diagnostic value of skin RT-QuIC in Parkinson's disease: a two-laboratory study JF - NPJ Parkinson's Disease N2 - 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. KW - diagnostic markers KW - Parkinson's disease Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260451 VL - 7 IS - 1 ER - TY - JOUR A1 - Dauer née Joppe, Karina A1 - Tatenhorst, Lars A1 - Caldi Gomes, Lucas A1 - Zhang, Shuyu A1 - Parvaz, Mojan A1 - Carboni, Eleonora A1 - Roser, Anna‐Elisa A1 - El DeBakey, Hazem A1 - Bähr, Mathias A1 - Vogel‐Mikuš, Katarina A1 - Wang Ip, Chi A1 - Becker, Stefan A1 - Zweckstetter, Markus A1 - Lingor, Paul T1 - Brain iron enrichment attenuates α‐synuclein spreading after injection of preformed fibrils JF - Journal of Neurochemistry N2 - 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. KW - alpha‐synuclein KW - alpha‐synuclein propagation KW - alpha‐synuclein seeding KW - iron dyshomeostasis KW - Parkinson's disease Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262544 VL - 159 IS - 3 SP - 554 EP - 573 ER - TY - JOUR A1 - Pütz, Stephanie M. A1 - Kram, Jette A1 - Rauh, Elisa A1 - Kaiser, Sophie A1 - Toews, Romy A1 - Lueningschroer-Wang, Yi A1 - Rieger, Dirk A1 - Raabe, Thomas T1 - Loss of p21-activated kinase Mbt/PAK4 causes Parkinson-like symptoms in Drosophila JF - Disease Models & Mechanisms N2 - 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. KW - Sleep fragmentation KW - Life expectancy KW - Emotional behavior KW - Dopaminergic PAM cluster neurons KW - Drosophila KW - Parkinson's disease KW - Mbt KW - PAK4 KW - Negative geotaxis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259222 VL - 14 IS - 6 ER - TY - JOUR A1 - Lange, Florian A1 - Steigerwald, Frank A1 - Malzacher, Tobias A1 - Brandt, Gregor Alexander A1 - Odorfer, Thorsten Michael A1 - Roothans, Jonas A1 - Reich, Martin M. A1 - Fricke, Patrick A1 - Volkmann, Jens A1 - Matthies, Cordula A1 - Capetian, Philipp D. T1 - Reduced Programming Time and Strong Symptom Control Even in Chronic Course Through Imaging-Based DBS Programming JF - Frontiers in Neurology N2 - 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. KW - directional deep brain stimulation KW - image-guided programming KW - subthalamic nucleus KW - chronic stimulation KW - randomized controlled double-blind study KW - Parkinson's disease Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-249634 SN - 1664-2295 VL - 12 ER - TY - JOUR A1 - Sian-Hulsmann, Jeswinder A1 - Riederer, Peter T1 - The nigral coup in Parkinson's Disease by α-synuclein and its associated rebels JF - Cells N2 - 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. KW - Parkinson's disease KW - substantia nigra KW - alpha-synuclein KW - genetics KW - iron KW - neuroinflammation KW - viruses KW - immunology KW - aging and cell death Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234073 SN - 2073-4409 VL - 10 IS - 3 ER - TY - JOUR A1 - Brumberg, Joachim A1 - Kuzkina, Anastasia A1 - Lapa, Constantin A1 - Mammadova, Sona A1 - Buck, Andreas A1 - Volkmann, Jens A1 - Sommer, Claudia A1 - Isaias, Ioannis U. A1 - Doppler, Kathrin T1 - Dermal and cardiac autonomic fiber involvement in Parkinson's disease and multiple system atrophy JF - Neurobiology of Disease N2 - 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. KW - peripheral nervous system KW - Parkinson's disease KW - skin biopsy KW - MIBG scintigraphy KW - multiple system atrophy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260061 VL - 153 ER - TY - JOUR A1 - Rauschenberger, Lisa A1 - Behnke, Jennifer A1 - Grotemeyer, Alexander A1 - Knorr, Susanne A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - Age-dependent neurodegeneration and neuroinflammation in a genetic A30P/A53T double-mutated α-synuclein mouse model of Parkinson’s disease JF - Neurobiology of Disease N2 - 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. KW - Parkinson's disease KW - neuroinflammation KW - neurodegeneration Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300629 VL - 171 ER - TY - JOUR A1 - Erbacher, Christoph A1 - Vaknine, Shani A1 - Moshitzky, Gilli A1 - Lobentanzer, Sebastian A1 - Eisenberg, Lina A1 - Evdokimov, Dimitar A1 - Sommer, Claudia A1 - Greenberg, David S. A1 - Soreq, Hermona A1 - Üçeyler, Nurcan T1 - Distinct CholinomiR blood cell signature as a potential modulator of the cholinergic system in women with fibromyalgia syndrome JF - Cells N2 - 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. KW - fibromyalgia syndrome KW - cholinergic system KW - CholinomiRs KW - microRNA KW - miR-182-5p KW - Parkinson's disease Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270686 SN - 2073-4409 VL - 11 IS - 8 ER - TY - JOUR A1 - McFleder, Rhonda L. A1 - Makhotkina, Anastasiia A1 - Groh, Janos A1 - Keber, Ursula A1 - Imdahl, Fabian A1 - Peña Mosca, Josefina A1 - Peteranderl, Alina A1 - Wu, Jingjing A1 - Tabuchi, Sawako A1 - Hoffmann, Jan A1 - Karl, Ann-Kathrin A1 - Pagenstecher, Axel A1 - Vogel, Jörg A1 - Beilhack, Andreas A1 - Koprich, James B. A1 - Brotchie, Jonathan M. A1 - Saliba, Antoine-Emmanuel A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - Brain-to-gut trafficking of alpha-synuclein by CD11c\(^+\) cells in a mouse model of Parkinson’s disease JF - Nature Communications N2 - 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. KW - antigen-presenting cells KW - neuroimmunology KW - Parkinson's disease Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357696 VL - 14 ER - TY - JOUR A1 - Kuzkina, A. A1 - Rößle, J. A1 - Seger, A. A1 - Panzer, C. A1 - Kohl, A. A1 - Maltese, V. A1 - Musacchio, T. A1 - Blaschke, S. J. A1 - Tamgüney, G. A1 - Kaulitz, S. A1 - Rak, K. A1 - Scherzad, A. A1 - Zimmermann, P. H. A1 - Klussmann, J. P. A1 - Hackenberg, S. A1 - Volkmann, J. A1 - Sommer, C. A1 - Sommerauer, M. A1 - Doppler, K. T1 - Combining skin and olfactory α-synuclein seed amplification assays (SAA)—towards biomarker-driven phenotyping in synucleinopathies JF - npj Parkinson’s Disease N2 - 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. KW - diagnostic markers KW - Parkinson's disease Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357687 SN - 2373-8057 VL - 9 ER - TY - JOUR A1 - Binder, Tobias A1 - Lange, Florian A1 - Pozzi, Nicolò A1 - Musacchio, Thomas A1 - Daniels, Christine A1 - Odorfer, Thorsten A1 - Fricke, Patrick A1 - Matthies, Cordula A1 - Volkmann, Jens A1 - Capetian, Philipp T1 - 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 JF - Brain Stimulation N2 - 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. KW - beta power KW - deep brain stimulation KW - local field potentials KW - Parkinson's disease KW - DBS programming KW - DBS biomarkers Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350280 VL - 16 IS - 5 ER -