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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 -