TY - JOUR A1 - Del Vecchio, Jasmin A1 - Hanafi, Ibrahem A1 - Pozzi, Nicoló Gabriele A1 - Capetian, Philipp A1 - Isaias, Ioannis U. A1 - Haufe, Stefan A1 - Palmisano, Chiara T1 - Pallidal recordings in chronically implanted dystonic patients: mitigation of tremor-related artifacts JF - Bioengineering N2 - Low-frequency oscillatory patterns of pallidal local field potentials (LFPs) have been proposed as a physiomarker for dystonia and hold the promise for personalized adaptive deep brain stimulation. Head tremor, a low-frequency involuntary rhythmic movement typical of cervical dystonia, may cause movement artifacts in LFP signals, compromising the reliability of low-frequency oscillations as biomarkers for adaptive neurostimulation. We investigated chronic pallidal LFPs with the Percept\(^{TM}\) PC (Medtronic PLC) device in eight subjects with dystonia (five with head tremors). We applied a multiple regression approach to pallidal LFPs in patients with head tremors using kinematic information measured with an inertial measurement unit (IMU) and an electromyographic signal (EMG). With IMU regression, we found tremor contamination in all subjects, whereas EMG regression identified it in only three out of five. IMU regression was also superior to EMG regression in removing tremor-related artifacts and resulted in a significant power reduction, especially in the theta-alpha band. Pallido-muscular coherence was affected by a head tremor and disappeared after IMU regression. Our results show that the Percept PC can record low-frequency oscillations but also reveal spectral contamination due to movement artifacts. IMU regression can identify such artifact contamination and be a suitable tool for its removal. KW - dystonia KW - tremor KW - local field potentials KW - globus pallidus KW - deep brain stimulation Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313498 SN - 2306-5354 VL - 10 IS - 4 ER - TY - JOUR A1 - Haufe, Stefan A1 - Isaias, Ioannis U. A1 - Pellegrini, Franziska A1 - Palmisano, Chiara T1 - Gait event prediction using surface electromyography in parkinsonian patients JF - Bioengineering N2 - Gait disturbances are common manifestations of Parkinson’s disease (PD), with unmet therapeutic needs. Inertial measurement units (IMUs) are capable of monitoring gait, but they lack neurophysiological information that may be crucial for studying gait disturbances in these patients. Here, we present a machine learning approach to approximate IMU angular velocity profiles and subsequently gait events using electromyographic (EMG) channels during overground walking in patients with PD. We recorded six parkinsonian patients while they walked for at least three minutes. Patient-agnostic regression models were trained on temporally embedded EMG time series of different combinations of up to five leg muscles bilaterally (i.e., tibialis anterior, soleus, gastrocnemius medialis, gastrocnemius lateralis, and vastus lateralis). Gait events could be detected with high temporal precision (median displacement of <50 ms), low numbers of missed events (<2%), and next to no false-positive event detections (<0.1%). Swing and stance phases could thus be determined with high fidelity (median F1-score of ~0.9). Interestingly, the best performance was obtained using as few as two EMG probes placed on the left and right vastus lateralis. Our results demonstrate the practical utility of the proposed EMG-based system for gait event prediction, which allows the simultaneous acquisition of an electromyographic signal to be performed. This gait analysis approach has the potential to make additional measurement devices such as IMUs and force plates less essential, thereby reducing financial and preparation overheads and discomfort factors in gait studies. KW - electromyography KW - inertial measurement units KW - gait-phase prediction KW - machine learning KW - Parkinson’s disease Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304380 SN - 2306-5354 VL - 10 IS - 2 ER - TY - JOUR A1 - Palmisano, Chiara A1 - Beccaria, Laura A1 - Haufe, Stefan A1 - Volkmann, Jens A1 - Pezzoli, Gianni A1 - Isaias, Ioannis U. T1 - Gait initiation impairment in patients with Parkinson’s disease and freezing of gait JF - Bioengineering N2 - Freezing of gait (FOG) is a sudden episodic inability to produce effective stepping despite the intention to walk. It typically occurs during gait initiation (GI) or modulation and may lead to falls. We studied the anticipatory postural adjustments (imbalance, unloading, and stepping phase) at GI in 23 patients with Parkinson’s disease (PD) and FOG (PDF), 20 patients with PD and no previous history of FOG (PDNF), and 23 healthy controls (HCs). Patients performed the task when off dopaminergic medications. The center of pressure (CoP) displacement and velocity during imbalance showed significant impairment in both PDNF and PDF, more prominent in the latter patients. Several measurements were specifically impaired in PDF patients, especially the CoP displacement along the anteroposterior axis during unloading. The pattern of segmental center of mass (SCoM) movements did not show differences between groups. The standing postural profile preceding GI did not correlate with outcome measurements. We have shown impaired motor programming at GI in Parkinsonian patients. The more prominent deterioration of unloading in PDF patients might suggest impaired processing and integration of somatosensory information subserving GI. The unaltered temporal movement sequencing of SCoM might indicate some compensatory cerebellar mechanisms triggering time-locked models of body mechanics in PD. KW - freezing of gait KW - gait initiation KW - Parkinson’s disease KW - posture KW - segmental centers of mass KW - anthropometric measurement KW - base of support Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297579 SN - 2306-5354 VL - 9 IS - 11 ER - TY - JOUR A1 - Pozzi, Nicoló G. A1 - Palmisano, Chiara A1 - Reich, Martin M. A1 - Capetian, Philip A1 - Pacchetti, Claudio A1 - Volkmann, Jens A1 - Isaias, Ioannis U. T1 - Troubleshooting gait disturbances in Parkinson’s disease with deep brain stimulation JF - Frontiers in Human Neuroscience N2 - Deep brain stimulation (DBS) of the subthalamic nucleus or the globus pallidus is an established treatment for Parkinson’s disease (PD) that yields a marked and lasting improvement of motor symptoms. Yet, DBS benefit on gait disturbances in PD is still debated and can be a source of dissatisfaction and poor quality of life. Gait disturbances in PD encompass a variety of clinical manifestations and rely on different pathophysiological bases. While gait disturbances arising years after DBS surgery can be related to disease progression, early impairment of gait may be secondary to treatable causes and benefits from DBS reprogramming. In this review, we tackle the issue of gait disturbances in PD patients with DBS by discussing their neurophysiological basis, providing a detailed clinical characterization, and proposing a pragmatic programming approach to support their management. KW - Parkinson’s disease KW - freezing of gait (FOG) KW - deep brain stimulation (DBS) KW - subthalamic nucleus (STN) KW - globus pallidus pars interna (GPi) KW - pedunculopontine nucleus (PPN) Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-274007 SN - 1662-5161 VL - 16 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 - Isaias, Ioannis U. A1 - Brumberg, Joachim A1 - Pozzi, Nicoló G. A1 - Palmisano, Chiara A1 - Canessa, Andrea A1 - Marotta, Giogio A1 - Volkmann, Jens A1 - Pezzoli, Gianni T1 - Brain metabolic alterations herald falls in patients with Parkinson's disease JF - Annals of Clinical and Translational Neurology N2 - Pathophysiological understanding of gait and balance disorders in Parkinson’s disease is insufficient and late recognition of fall risk limits efficacious followup to prevent or delay falls. We show a distinctive reduction of glucose metabolism in the left posterior parietal cortex, with increased metabolic activity in the cerebellum, in parkinsonian patients 6–8 months before their first fall episode. Falls in Parkinson’s disease may arise from altered cortical processing of body spatial orientation, possibly predicted by abnormal cortical metabolism. KW - Parkionson's disease KW - brain metabolic alterations Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235982 VL - 7 IS - 4 ER - TY - JOUR A1 - Brumberg, Joachim A1 - Schröter, Nils A1 - Blazhenets, Ganna A1 - Frings, Lars A1 - Volkmann, Jens A1 - Lapa, Constantin A1 - Jost, Wolfgang H. A1 - Isaias, Ioannis U. A1 - Meyer, Philipp T. T1 - Differential diagnosis of parkinsonism: a head-to-head comparison of FDG PET and MIBG scintigraphy JF - NPJ Parkinsons Disease N2 - [\(^{18}\)F]fluorodeoxyglucose (FDG) PET and [\(^{123}\)I]metaiodobenzylguanidine (MIBG) scintigraphy may contribute to the differential diagnosis of neurodegenerative parkinsonism. To identify the superior method, we retrospectively evaluated 54 patients with suspected neurodegenerative parkinsonism, who were referred for FDG PET and MIBG scintigraphy. Two investigators visually assessed FDG PET scans using an ordinal 6-step score for disease-specific patterns of Lewy body diseases (LBD) or atypical parkinsonism (APS) and assigned the latter to the subgroups multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal syndrome. Regions-of-interest analysis on anterior planar MIBG images served to calculate the heart-to-mediastinum ratio. Movement disorder specialists blinded to imaging results established clinical follow-up diagnosis by means of guideline-derived case vignettes. Clinical follow-up (1.7 +/- 2.3 years) revealed the following diagnoses: n = 19 LBD (n = 17 Parkinson's disease [PD], n = 1 PD dementia, and n = 1 dementia with Lewy bodies), n = 31 APS (n = 28 MSA, n = 3 PSP), n = 3 non-neurodegenerative parkinsonism; n = 1 patient could not be diagnosed and was excluded. Receiver operating characteristic analyses for discriminating LBD vs. non-LBD revealed a larger area under the curve for FDG PET than for MIBG scintigraphy at statistical trend level for consensus rating (0.82 vs. 0.69, p = 0.06; significant for investigator #1: 0.83 vs. 0.69, p = 0.04). The analysis of PD vs. MSA showed a similar difference (0.82 vs. 0.69, p = 0.11; rater #1: 0.83 vs. 0.69, p = 0.07). Albeit the notable differences in diagnostic performance did not attain statistical significance, the authors consider this finding clinically relevant and suggest that FDG PET, which also allows for subgrouping of APS, should be preferred. KW - clinical diagnosis KW - F-18-FDG PET KW - disease KW - dementia KW - accuracy KW - stimulation KW - guidelines KW - criteria KW - brain KW - risk Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230675 VL - 6 ER - 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 - Dipaola, Mariangela A1 - Pavan, Esteban E. A1 - Cattaneo, Andrea A1 - Frazzitta, Giuseppe A1 - Pezzoli, Gianni A1 - Cavallari, Paolo A1 - Frigo, Carlo A. A1 - Isaias, Ioannis U. T1 - Mechanical Energy Recovery during Walking in Patients with Parkinson Disease JF - PLoS ONE N2 - The mechanisms of mechanical energy recovery during gait have been thoroughly investigated in healthy subjects, but never described in patients with Parkinson disease (PD). The aim of this study was to investigate whether such mechanisms are preserved in PD patients despite an altered pattern of locomotion. We consecutively enrolled 23 PD patients (mean age 64±9 years) with bilateral symptoms (H&Y ≥II) if able to walk unassisted in medication-off condition (overnight suspension of all dopaminergic drugs). Ten healthy subjects (mean age 62±3 years) walked both at their ‘preferred’ and ‘slow’ speeds, to match the whole range of PD velocities. Kinematic data were recorded by means of an optoelectronic motion analyzer. For each stride we computed spatio-temporal parameters, time-course and range of motion (ROM) of hip, knee and ankle joint angles. We also measured kinetic (Wk), potential (W\(_{p}\)), total (W\(_{totCM}\)) energy variations and the energy recovery index (ER). Along with PD progression, we found a significant correlation of W\(_{totCM}\) and W\(_{p}\) with knee ROM and in particular with knee extension in terminal stance phase. W\(_{k}\) and ER were instead mainly related to gait velocity. In PD subjects, the reduction of knee ROM significantly diminished both W\(_{p}\) and W\(_{totCM}\). Rehabilitation treatments should possibly integrate passive and active mobilization of knee to prevent a reduction of gait-related energetic components. KW - Parkinson disease KW - mechanical energy KW - kinematics KW - velocity KW - hip KW - gait analysis KW - walking KW - knees Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179739 VL - 11 IS - 6 ER - TY - JOUR A1 - Brumberg, Joachim A1 - Küsters, Sebastian A1 - Al-Momani, Ehab A1 - Marotta, Giorgio A1 - Cosgrove, Kelly P. A1 - van Dyck, Christopher H. A1 - Herrmann, Ken A1 - Homola, György A. A1 - Pezzoli, Gianni A1 - Buck, Andreas K. A1 - Volkmann, Jens A1 - Samnick, Samuel A1 - Isaias, Ioannis U. T1 - Cholinergic activity and levodopa-induced dyskinesia: a multitracer molecular imaging study JF - Annals of Clinical and Translational Neurology N2 - Objective: To investigate the association between levodopa‐induced dyskinesias and striatal cholinergic activity in patients with Parkinson's disease. Methods: This study included 13 Parkinson's disease patients with peak‐of‐dose levodopa‐induced dyskinesias, 12 nondyskinetic patients, and 12 healthy controls. Participants underwent 5‐[\(^{123}\)I]iodo‐3‐[2(S)‐2‐azetidinylmethoxy]pyridine single‐photon emission computed tomography, a marker of nicotinic acetylcholine receptors, [\(^{123}\)I]N‐ω‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)nortropane single‐photon emission computed tomography, to measure dopamine reuptake transporter density and 2‐[\(^{18}\)F]fluoro‐2‐deoxyglucose positron emission tomography to assess regional cerebral metabolic activity. Striatal binding potentials, uptake values at basal ganglia structures, and correlations with clinical variables were analyzed. Results: Density of nicotinic acetylcholine receptors in the caudate nucleus of dyskinetic subjects was similar to that of healthy controls and significantly higher to that of nondyskinetic patients, in particular, contralaterally to the clinically most affected side. Interpretation: Our findings support the hypothesis that the expression of dyskinesia may be related to cholinergic neuronal excitability in a dopaminergic‐depleted striatum. Cholinergic signaling would play a role in maintaining striatal dopaminergic responsiveness, possibly defining disease phenotype and progression. KW - levodopa-induced dyskinesia KW - cholinergic activity KW - Parkinson’s disease Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170406 VL - 4 IS - 9 ER - TY - JOUR A1 - Canessa, Andrea A1 - Pozzi, Nicolò G. A1 - Arnulfo, Gabriele A1 - Brumberg, Joachim A1 - Reich, Martin M. A1 - Pezzoli, Gianni A1 - Ghilardi, Maria F. A1 - Matthies, Cordula A1 - Steigerwald, Frank A1 - Volkmann, Jens A1 - Isaias, Ioannis U. T1 - Striatal Dopaminergic Innervation Regulates Subthalamic Beta-Oscillations and Cortical-Subcortical Coupling during Movements: Preliminary Evidence in Subjects with Parkinson's Disease JF - Frontiers in Human Neuroscience N2 - Activation of the basal ganglia has been shown during the preparation and execution of movement. However, the functional interaction of cortical and subcortical brain areas during movement and the relative contribution of dopaminergic striatal innervation remains unclear. We recorded local field potential (LFP) activity from the subthalamic nucleus (STN) and high-density electroencephalography (EEG) signals in four patients with Parkinson’s disease (PD) off dopaminergic medication during a multi-joint motor task performed with their dominant and non-dominant hand. Recordings were performed by means of a fully-implantable deep brain stimulation (DBS) device at 4 months after surgery. Three patients also performed a single-photon computed tomography (SPECT) with [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT) to assess striatal dopaminergic innervation. Unilateral movement execution led to event-related desynchronization (ERD) followed by a rebound after movement termination event-related synchronization (ERS) of oscillatory beta activity in the STN and primary sensorimotor cortex of both hemispheres. Dopamine deficiency directly influenced movement-related beta-modulation, with greater beta-suppression in the most dopamine-depleted hemisphere for both ipsi- and contralateral hand movements. Cortical-subcortical, but not interhemispheric subcortical coherencies were modulated by movement and influenced by striatal dopaminergic innervation, being stronger in the most dopamine-depleted hemisphere. The data are consistent with a role of dopamine in shielding subcortical structures from an excessive cortical entrapment and cross-hemispheric coupling, thus allowing fine-tuning of movement. KW - beta oscillations KW - Parkinson’s disease KW - motor control KW - movement disorders KW - imaging KW - subthalamic nucleus KW - coherence analysis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164061 VL - 10 IS - 611 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 - 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 - Isaias, Ioannis U. A1 - Volkmann, Jens A1 - Marzegan, Alberto A1 - Marotta, Giorgio A1 - Cavallari, Paolo A1 - Pezzoli, Gianni T1 - The Influence of Dopaminergic Striatal Innervation on Upper Limb Locomotor Synergies JF - PLoS One N2 - To determine the role of striatal dopaminergic innervation on upper limb synergies during walking, we measured arm kinematics in 13 subjects with Parkinson disease. Patients were recruited according to several inclusion criteria to represent the best possible in vivo model of dopaminergic denervation. Of relevance, we included only subjects with normal spatio-temporal parameters of the stride and gait speed to avoid an impairment of upper limbs locomotor synergies as a consequence of gait impairment per se. Dopaminergic innervation of the striatum was measured by FP-CIT and SPECT. All patients showed a reduction of gait-associated arms movement. No linear correlation was found between arm ROM reduction and contralateral dopaminergic putaminal innervation loss. Still, a partition analysis revealed a 80% chance of reduced arm ROM when putaminal dopamine content loss was >47%. A significant correlation was described between the asymmetry indices of the swinging of the two arms and dopaminergic striatal innervation. When arm ROM was reduced, we found a positive correlation between upper-lower limb phase shift modulation ( at different gait velocities) and striatal dopaminergic innervation. These findings are preliminary evidence that dopaminergic striatal tone plays a modulatory role in upper-limb locomotor synergies and upper-lower limb coupling while walking at different velocities. KW - pet KW - Parkinsons disease KW - basal ganglia KW - spinal-cord KW - walking KW - gait KW - arm KW - coordination KW - movements Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133976 VL - 7 IS - 12 ER - TY - JOUR A1 - Isaias, Ioannis U. A1 - Marzegan, Alberto A1 - Pezzoli, Gianni A1 - Marotta, Giorgio A1 - Canesi, Margherita A1 - Biella, Gabriele E. M. A1 - Volkmann, Jens A1 - Cavallari, Paolo T1 - A role for locus coeruleus in Parkinson tremor JF - Frontiers in Human Neuroscience N2 - 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. KW - locus coeruleus KW - disease KW - basal ganglia KW - resting tremor KW - functional neuroanatomy KW - dopamine KW - norepinephrine KW - progression KW - binding KW - rat KW - noradrenalin KW - parkinson disease KW - tremor Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133955 VL - 5 IS - 179 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 -