TY  - JOUR
A1  - Palmisano, Chiara
A1  - Brandt, Gregor
A1  - Vissani, Matteo
A1  - Pozzi, Nicoló G.
A1  - Canessa, Andrea
A1  - Brumberg, Joachim
A1  - Marotta, Giorgio
A1  - Volkmann, Jens
A1  - Mazzoni, Alberto
A1  - Pezzoli, Gianni
A1  - Frigo, Carlo A.
A1  - Isaias, Ioannis U.
T1  - Gait Initiation in Parkinson’s Disease: Impact of Dopamine Depletion and Initial Stance Condition
JF  - Frontiers in Bioengineering and Biotechnology
N2  - 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.
KW  - gait initiation
KW  - Parkinson’s disease
KW  - basal ganglia
KW  - dopamine
KW  - base of support
KW  - anthropometric measurements
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200801
SN  - 2296-4185
VL  - 8
ER  - 
TY  - JOUR
A1  - Ip, Chi Wang
A1  - Isaias, Ioannis U.
A1  - Kusche-Tekin, Burak B.
A1  - Klein, Dennis
A1  - Groh, Janos
A1  - O´Leary, Aet
A1  - Knorr, Susanne
A1  - Higuchi, Takahiro
A1  - Koprich, James B.
A1  - Brotchie, Jonathan M.
A1  - Toyka, Klaus V.
A1  - Reif, Andreas
A1  - Volkmann, Jens
T1  - Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury
JF  - Acta Neuropathologica Communications
N2  - 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.
KW  - Dystonia
KW  - DYT1
KW  - dopamine
KW  - peripheral injury
KW  - second hit
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147839
VL  - 4
IS  - 108
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  -