@article{IpIsaiasKuscheTekinetal.2016, author = {Ip, Chi Wang and Isaias, Ioannis U. and Kusche-Tekin, Burak B. and Klein, Dennis and Groh, Janos and O´Leary, Aet and Knorr, Susanne and Higuchi, Takahiro and Koprich, James B. and Brotchie, Jonathan M. and Toyka, Klaus V. and Reif, Andreas and Volkmann, Jens}, title = {Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury}, series = {Acta Neuropathologica Communications}, volume = {4}, journal = {Acta Neuropathologica Communications}, number = {108}, doi = {10.1186/s40478-016-0375-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147839}, year = {2016}, abstract = {Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 \% suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 \% torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 \% (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia.}, 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{PasosSteigerwaldReichetal.2019, author = {Pasos, Uri E. Ramirez and Steigerwald, Frank and Reich, Martin M. and Matthies, Cordula and Volkmann, Jens and Reese, Ren{\´e}}, title = {Levodopa modulates functional connectivity in the upper beta band between bubthalamic nucleus and muscle activity in tonic and phasic motor activity patterns in Parkinson's disease}, series = {Frontiers in Human Neuroscience}, volume = {13}, journal = {Frontiers in Human Neuroscience}, number = {223}, doi = {10.3389/fnhum.2019.00223}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201540}, year = {2019}, abstract = {Introduction: Striatal dopamine depletion disrupts basal ganglia function and causes Parkinson's disease (PD). The pathophysiology of the dopamine-dependent relationship between basal ganglia signaling and motor control, however, is not fully understood. We obtained simultaneous recordings of local field potentials (LFPs) from the subthalamic nucleus (STN) and electromyograms (EMGs) in patients with PD to investigate the impact of dopaminergic state and movement on long-range beta functional connectivity between basal ganglia and lower motor neurons. Methods: Eight PD patients were investigated 3 months after implantation of a deep brain stimulation (DBS)-system capable of recording LFPs via chronically-implanted leads (Medtronic, ACTIVA PC+S®). We analyzed STN spectral power and its coherence with EMG in the context of two different movement paradigms (tonic wrist extension vs. alternating wrist extension and flexion) and the effect of levodopa (L-Dopa) intake using an unbiased data-driven approach to determine regions of interest (ROI). Results: Two ROIs capturing prominent coherence within a grand average coherogram were identified. A trend of a dopamine effect was observed for the first ROI (50-150 ms after movement start) with higher STN-EMG coherence in medicated patients. Concerning the second ROI (300-500 ms after movement start), an interaction effect of L-Dopa medication and movement task was observed with higher coherence in the isometric contraction task compared to alternating movements in the medication ON state, a pattern which was reversed in L-Dopa OFF. Discussion: L-Dopa medication may normalize functional connectivity between remote structures of the motor system with increased upper beta coherence reflecting a physiological restriction of the amount of information conveyed between remote structures. This may be necessary to maintain simple movements like isometric contraction. Our study adds dynamic properties to the complex interplay between STN spectral beta power and the nucleus' functional connectivity to remote structures of the motor system as a function of movement and dopaminergic state. This may help to identify markers of neuronal activity relevant for more individualized programming of DBS therapy.}, language = {en} } @article{PalmisanoBrandtVissanietal.2020, author = {Palmisano, Chiara and Brandt, Gregor and Vissani, Matteo and Pozzi, Nicol{\´o} G. and Canessa, Andrea and Brumberg, Joachim and Marotta, Giorgio and Volkmann, Jens and Mazzoni, Alberto and Pezzoli, Gianni and Frigo, Carlo A. and Isaias, Ioannis U.}, title = {Gait Initiation in Parkinson's Disease: Impact of Dopamine Depletion and Initial Stance Condition}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {8}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2020.00137}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200801}, year = {2020}, abstract = {Postural instability, in particular at gait initiation (GI), and resulting falls are a major determinant of poor quality of life in subjects with Parkinson's disease (PD). Still, the contribution of the basal ganglia and dopamine on the feedforward postural control associated with this motor task is poorly known. In addition, the influence of anthropometric measures (AM) and initial stance condition on GI has never been consistently assessed. The biomechanical resultants of anticipatory postural adjustments contributing to GI [imbalance (IMB), unloading (UNL), and stepping phase) were studied in 26 unmedicated subjects with idiopathic PD and in 27 healthy subjects. A subset of 13 patients was analyzed under standardized medication conditions and the striatal dopaminergic innervation was studied in 22 patients using FP-CIT and SPECT. People with PD showed a significant reduction in center of pressure (CoP) displacement and velocity during the IMB phase, reduced first step length and velocity, and decreased velocity and acceleration of the center of mass (CoM) at toe off of the stance foot. All these measurements correlated with the dopaminergic innervation of the putamen and substantially improved with levodopa. These results were not influenced by anthropometric parameters or by the initial stance condition. In contrast, most of the measurements of the UNL phase were influenced by the foot placement and did not correlate with putaminal dopaminergic innervation. Our results suggest a significant role of dopamine and the putamen particularly in the elaboration of the IMB phase of anticipatory postural adjustments and in the execution of the first step. The basal ganglia circuitry may contribute to defining the optimal referent body configuration for a proper initiation of gait and possibly gait adaptation to the environment.}, language = {en} } @article{IsaiasMarzeganPezzolietal.2012, author = {Isaias, Ioannis U. and Marzegan, Alberto and Pezzoli, Gianni and Marotta, Giorgio and Canesi, Margherita and Biella, Gabriele E. M. and Volkmann, Jens and Cavallari, Paolo}, title = {A role for locus coeruleus in Parkinson tremor}, series = {Frontiers in Human Neuroscience}, volume = {5}, journal = {Frontiers in Human Neuroscience}, number = {179}, doi = {10.3389/fnhum.2011.00179}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133955}, year = {2012}, abstract = {We analyzed rest tremor, one of the etiologically most elusive hallmarks of Parkinson disease(PD), in 12 consecutive PD patients during a specific task activating the locus coeruleus (LC) to investigate a putative role of noradrenaline (NA) in tremor generation and suppression. Clinical diagnosis was confirmed in all subjects by reduced dopamine reuptake transporter (DAT) binding values investigated by single photon computed tomography imaging (SPECT) with [\(^{123}\)I] N-\(\omega\)-fluoropropyl-2 \(\beta\)-carbomethoxy-3 \(\beta\)-(4-iodophenyl) tropane (FP-CIT). The intensity of tremor (i.e., the power of Electromyography [EMG] signals), but not its frequency, significantly increased during the task. In six subjects, tremor appeared selectively during the task. In a second part of the study, we retrospectively reviewed SPECT with FP-CIT data and confirmed the lack of correlation between dopaminergic loss and tremor by comparing DAT binding values of 82 PD subjects with bilateral tremor (n = 27), unilateral tremor (n = 22), and no tremor (n = 33). This study suggests a role of the LC in Parkinson tremor.}, language = {en} }