@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}
}
@article{GiordanoCanesiIsalbertietal.2014,
  author    = {Giordano, Rosaria and Canesi, Margherita and Isalberti, Maurizio and Isaias, Ioannis Ugo and Montemurro, Tiziana and Vigan{\`o}, Mariele and Montelatici, Elisa and Boldrin, Valentina and Benti, Riccardo and Cortelezzi, Agostino and Fracchiolla, Nicola and Lazzari, Lorenza and Pezzoli, Gianni},
  title     = {Autologous mesenchymal stem cell therapy for progressive supranuclear palsy: translation into a phase I controlled, randomized clinical study},
  series = {Journal of Translational Medicine},
  volume    = {12},
  journal   = {Journal of Translational Medicine},
  number    = {14},
  doi       = {10.1186/1479-5876-12-14},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117594},
  year      = {2014},
  abstract  = {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},
  language  = {en}
}
@article{IsaiasBrumbergPozzietal.2020,
  author    = {Isaias, Ioannis U. and Brumberg, Joachim and Pozzi, Nicol{\´o} G. and Palmisano, Chiara and Canessa, Andrea and Marotta, Giogio and Volkmann, Jens and Pezzoli, Gianni},
  title     = {Brain metabolic alterations herald falls in patients with Parkinson's disease},
  series = {Annals of Clinical and Translational Neurology},
  volume    = {7},
  journal   = {Annals of Clinical and Translational Neurology},
  number    = {4},
  doi       = {10.1002/acn3.51013},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235982},
  pages     = {579-583},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{PozziBolzoniBiellaetal.2023,
  author    = {Pozzi, Nicol{\´o} Gabriele and Bolzoni, Francesco and Biella, Gabriele Eliseo Mario and Pezzoli, Gianni and Ip, Chi Wang and Volkmann, Jens and Cavallari, Paolo and Asan, Esther and Isaias, Ioannis Ugo},
  title     = {Brain noradrenergic innervation supports the development of Parkinson's tremor: a study in a reserpinized rat model},
  series = {Cells},
  volume    = {12},
  journal   = {Cells},
  number    = {21},
  issn      = {2073-4409},
  doi       = {10.3390/cells12212529},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357721},
  year      = {2023},
  abstract  = {The pathophysiology of tremor in Parkinson's disease (PD) is evolving towards a complex alteration to monoaminergic innervation, and increasing evidence suggests a key role of the locus coeruleus noradrenergic system (LC-NA). However, the difficulties in imaging LC-NA in patients challenge its direct investigation. To this end, we studied the development of tremor in a reserpinized rat model of PD, with or without a selective lesioning of LC-NA innervation with the neurotoxin DSP-4. Eight male rats (Sprague Dawley) received DSP-4 (50 mg/kg) two weeks prior to reserpine injection (10 mg/kg) (DR-group), while seven male animals received only reserpine treatment (R-group). Tremor, rigidity, hypokinesia, postural flexion and postural immobility were scored before and after 20, 40, 60, 80, 120 and 180 min of reserpine injection. Tremor was assessed visually and with accelerometers. The injection of DSP-4 induced a severe reduction in LC-NA terminal axons (DR-group: 0.024 ± 0.01 vs. R-group: 0.27 ± 0.04 axons/um\(^2\), p < 0.001) and was associated with significantly less tremor, as compared to the R-group (peak tremor score, DR-group: 0.5 ± 0.8 vs. R-group: 1.6 ± 0.5; p < 0.01). Kinematic measurement confirmed the clinical data (tremor consistency (\% of tremor during 180 s recording), DR-group: 37.9 ± 35.8 vs. R-group: 69.3 ± 29.6; p < 0.05). Akinetic-rigid symptoms did not differ between the DR- and R-groups. Our results provide preliminary causal evidence for a critical role of LC-NA innervation in the development of PD tremor and foster the development of targeted therapies for PD patients.},
  language  = {en}
}
@article{BrumbergKuestersAlMomanietal.2017,
  author    = {Brumberg, Joachim and K{\"u}sters, Sebastian and Al-Momani, Ehab and Marotta, Giorgio and Cosgrove, Kelly P. and van Dyck, Christopher H. and Herrmann, Ken and Homola, Gy{\"o}rgy A. and Pezzoli, Gianni and Buck, Andreas K. and Volkmann, Jens and Samnick, Samuel and Isaias, Ioannis U.},
  title     = {Cholinergic activity and levodopa-induced dyskinesia: a multitracer molecular imaging study},
  series = {Annals of Clinical and Translational Neurology},
  volume    = {4},
  journal   = {Annals of Clinical and Translational Neurology},
  number    = {9},
  doi       = {10.1002/acn3.438},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170406},
  pages     = {632-639},
  year      = {2017},
  abstract  = {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.},
  language  = {en}
}
@article{CasarottoTurcoComanduccietal.2019,
  author    = {Casarotto, Silvia and Turco, Francesco and Comanducci, Angela and Perretti, Alessio and Marotta, Giorgio and Pezzoli, Gianni and Rosanova, Mario and Isaias, Ioannis U.},
  title     = {Excitability of the supplementary motor area in Parkinson's disease depends on subcortical damage},
  series = {Brain Stimulation},
  volume    = {12},
  journal   = {Brain Stimulation},
  doi       = {10.1016/j.brs.2018.10.011},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222261},
  pages     = {152-160},
  year      = {2019},
  abstract  = {Background Cortical dysfunctioning significantly contributes to the pathogenesis of motor symptoms in Parkinson's disease (PD). Objective We aimed at testing whether an acute levodopa administration has measurable and specific cortical effects possibly related to striatal dopaminergic deficit. Methods In thirteen PD patients, we measured the electroencephalographic responses to transcranial magnetic stimulation (TMS/EEG) of the supplementary motor area and superior parietal lobule (n = 8) before and after an acute intake of levodopa. We also performed a single-photon emission computed tomography and [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane to identify the more affected and the less affected brain side in each patient, according to the dopaminergic innervation loss of the putamen. Cortical excitability changes before and after an acute intake of levodopa were computed and compared between the more and the less affected brain side at the single-patient as well as at the group level. Results We found that levodopa intake induces a significant increase (P < 0.01) of cortical excitability nearby the supplementary motor area in the more affected brain side, greater (P < 0.025) than in the less affected brain side. Notably, cortical excitability changes nearby the superior parietal lobule were not statistically significant. Conclusions These results strengthen the idea that dysfunction of specific cortico-subcortical circuits may contribute to pathophysiology of PD symptoms. Most important, they support the use of navigated TMS/EEG as a non-invasive tool to better understand the pathophysiology of PD.},
  language  = {en}
}
@article{CanesiGiordanoLazzarietal.2016,
  author    = {Canesi, Margherita and Giordano, Rosaria and Lazzari, Lorenza and Isalberti, Maurizio and Isaias, Ioannis Ugo and Benti, Riccardo and Rampini, Paolo and Marotta, Giorgio and Colombo, Aurora and Cereda, Emanuele and Dipaola, Mariangela and Montemurro, Tiziana and Vigano, Mariele and Budelli, Silvia and Montelatici, Elisa and Lavazza, Cristiana and Cortelezzi, Agostino and Pezzoli, Gianni},
  title     = {Finding a new therapeutic approach for no-option Parkinsonisms: mesenchymal stromal cells for progressive supranuclear palsy},
  series = {Journal of Translational Medicine},
  volume    = {14},
  journal   = {Journal of Translational Medicine},
  number    = {127},
  doi       = {10.1186/s12967-016-0880-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165725},
  pages     = {1-11},
  year      = {2016},
  abstract  = {Background: The trophic, anti-apoptotic and regenerative effects of bone marrow mesenchymal stromal cells (MSC) may reduce neuronal cell loss in neurodegenerative disorders. Methods: We used MSC as a novel candidate therapeutic tool in a pilot phase-I study for patients affected by progressive supranuclear palsy (PSP), a rare, severe and no-option form of Parkinsonism. Five patients received the cells by infusion into the cerebral arteries. Effects were assessed using the best available motor function rating scales (UPDRS, Hoehn and Yahr, PSP rating scale), as well as neuropsychological assessments, gait analysis and brain imaging before and after cell administration. Results: One year after cell infusion, all treated patients were alive, except one, who died 9 months after the infusion for reasons not related to cell administration or to disease progression (accidental fall). In all treated patients motor function rating scales remained stable for at least six-months during the one-year follow-up. Conclusions: We have demonstrated for the first time that MSC administration is feasible in subjects with PSP. In these patients, in whom deterioration of motor function is invariably rapid, we recorded clinical stabilization for at least 6 months. These encouraging results pave the way to the next randomized, placebo-controlled phase-II study that will definitively provide information on the efficacy of this innovative approach.},
  language  = {en}
}
@article{PalmisanoBeccariaHaufeetal.2022,
  author    = {Palmisano, Chiara and Beccaria, Laura and Haufe, Stefan and Volkmann, Jens and Pezzoli, Gianni and Isaias, Ioannis U.},
  title     = {Gait initiation impairment in patients with Parkinson's disease and freezing of gait},
  series = {Bioengineering},
  volume    = {9},
  journal   = {Bioengineering},
  number    = {11},
  issn      = {2306-5354},
  doi       = {10.3390/bioengineering9110639},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297579},
  year      = {2022},
  abstract  = {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.},
  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{DipaolaPavanCattaneoetal.2016,
  author    = {Dipaola, Mariangela and Pavan, Esteban E. and Cattaneo, Andrea and Frazzitta, Giuseppe and Pezzoli, Gianni and Cavallari, Paolo and Frigo, Carlo A. and Isaias, Ioannis U.},
  title     = {Mechanical Energy Recovery during Walking in Patients with Parkinson Disease},
  series = {PLoS ONE},
  volume    = {11},
  journal   = {PLoS ONE},
  number    = {6},
  doi       = {10.1371/journal.pone.0156420},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179739},
  year      = {2016},
  abstract  = {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.},
  language  = {en}
}