Mure H.,Feinstein Institute for Medical Research |
Hirano S.,Feinstein Institute for Medical Research |
Hirano S.,Japan National Institute of Radiological Sciences |
Tang C.C.,Feinstein Institute for Medical Research |
And 10 more authors.
NeuroImage | Year: 2011
The circuit changes that mediate parkinsonian tremor, while likely differing from those underlying akinesia and rigidity, are not precisely known. In this study, to identify a specific metabolic brain network associated with this disease manifestation, we used FDG PET to scan nine tremor dominant Parkinson's disease (PD) patients at baseline and during ventral intermediate (Vim) thalamic nucleus deep brain stimulation (DBS). Ordinal trends canonical variates analysis (OrT/CVA) was performed on the within-subject scan data to detect a significant spatial covariance pattern with consistent changes in subject expression during stimulation-mediated tremor suppression. The metabolic pattern was characterized by covarying increases in the activity of the cerebellum/dentate nucleus and primary motor cortex, and, to a less degree, the caudate/putamen. Vim stimulation resulted in consistent reductions in pattern expression (p< 0.005, permutation test). In the absence of stimulation, pattern expression values (subject scores) correlated significantly (r=0.85, p< 0.02) with concurrent accelerometric measurements of tremor amplitude. To validate this spatial covariance pattern as an objective network biomarker of PD tremor, we prospectively quantified its expression on an individual subject basis in independent PD populations. The resulting subject scores for this PD tremor-related pattern (PDTP) were found to exhibit: (1) excellent test-retest reproducibility (p< 0.0001); (2) significant correlation with independent clinical ratings of tremor (r=0.54, p< 0.001) but not akinesia-rigidity; and (3) significant elevations (p< 0.02) in tremor dominant relative to atremulous PD patients. Following validation, we assessed the natural history of PDTP expression in early stage patients scanned longitudinally with FDG PET over a 4-year interval. Significant increases in PDTP expression (p< 0.01) were evident in this cohort over time; rate of progression, however, was slower than for the PD-related akinesia/rigidity pattern (PDRP). We also determined whether PDTP expression is modulated by interventions specifically directed at parkinsonian tremor. While Vim DBS was associated with changes in PDTP (p< 0.001) but not PDRP expression, subthalamic nucleus (STN) DBS reduced the activity of both networks (p< 0.05). PDTP expression was suppressed more by Vim than by STN stimulation (p< 0.05).These findings suggest that parkinsonian tremor is mediated by a distinct metabolic network involving primarily cerebello-thalamo-cortical pathways. Indeed, effective treatment of this symptom is associated with significant reduction in PDTP expression. Quantification of treatment-mediated changes in both PDTP and PDRP scores can provide an objective means of evaluating the differential effects of novel antiparkinsonian interventions on the different motor features of the disorder. © 2010 Elsevier Inc.
Cilia R.,Parkinson Institute |
Van Eimeren T.,NeuroImage Nord |
Van Eimeren T.,Universitatsklinik Schleswig Holstein
Brain Structure and Function | Year: 2011
The development of an impulse control disorder (ICD) is now recognized as a potential nonmotor adverse effect of dopamine replacement therapy in Parkinson's disease (PD). Here, recent epidemiological, neurophysiological and genetic advances are summarized to outline potential mechanisms involved. It is safe to say that dopaminergic drugs, particularly dopamine agonists, are able to induce ICDs only in a minority of patients, while the majority are somehow protected from this adverse effect. While it seems clear that men with earlyonset PD are more vulnerable, other predisposing factors, such as various current or pre-PD personality traits, are a matter of debate. In terms of neurophysiological advances, one may find striking analogies to the addiction literature suggesting a causal chain beginning with certain predisposing conditions of striatal dopamine synapses, an "unnatural" increase of dopamine stimulation and a characteristic pattern of resulting functional changes in remote networks of appetitive drive and impulse control. Future prospects include potential add-on medications and the possible identification of genetic predispositions at a genome- wide scale. Functional imaging of pharmacogenetic interactions (imaging pharmacogenomics) may be an important tool on that road. © Springer-Verlag 2011.
Antonini A.,Parkinson Institute |
Odin P.,Central Hospital |
Odin P.,Lund University
Parkinsonism and Related Disorders | Year: 2010
Motor fluctuations and dyskinesia are common in advanced Parkinson's disease and can be poorly managed by current oral medications. Risk factors include the amount of l-dopa administered, gender and patient age. Continuous duodenal l-dopa or subcutaneous apomorphine infusions are helpful strategies because they can control motor complications by providing continuous dopaminergic drug delivery. Apomorphine subcutaneous infusion provides a motor benefit similar to that of dopamine and is relatively easy to use in advanced PD. However, it commonly requires concomitant administration of oral l-dopa and its long-term use is limited by compliance. Continuous administration of l-dopa/carbidopa by infusion in the duodenum/jejunum is a more complex procedure requiring a gastrostomy for the placement of the infusion tube, but it allows replacement of all oral medications and the achievement of a satisfactory therapeutic response paralleled by a reduction of motor complication severity. It should be noted that although these procedures are effective, most evidence relates to small case series and, particularly in the case of apomorphine, despite its long-term availability, there is a complete lack of randomized blinded studies. In addition, unlike deep brain stimulation, it is unclear which patients are the best candidates for these procedures, making any indirect comparison very complex, given the clinical heterogeneity of reported patients. This has consequences in resource allocation and in estimating cost-benefit ratios for these complex therapies in advanced PD. © 2009 Elsevier Ltd. All rights reserved.
Cartelli D.,University of Milan |
Goldwurm S.,Parkinson Institute |
Casagrande F.,University of Milan |
Pezzoli G.,Parkinson Institute |
Cappelletti G.,University of Milan
PLoS ONE | Year: 2012
Data from both toxin-based and gene-based models suggest that dysfunction of the microtubule system contributes to the pathogenesis of Parkinson's disease, even if, at present, no evidence of alterations of microtubules in vivo or in patients is available. Here we analyze cytoskeleton organization in primary fibroblasts deriving from patients with idiopathic or genetic Parkinson's disease, focusing on mutations in parkin and leucine-rich repeat kinase 2. Our analyses reveal that genetic and likely idiopathic pathology affects cytoskeletal organization and stability, without any activation of autophagy or apoptosis. All parkinsonian fibroblasts have a reduced microtubule mass, represented by a higher fraction of unpolymerized tubulin in respect to control cells, and display significant changes in microtubule stability-related signaling pathways. Furthermore, we show that the reduction of microtubule mass is so closely related to the alteration of cell morphology and behavior that both pharmacological treatment with microtubule-targeted drugs, and genetic approaches, by transfecting the wild type parkin or leucine-rich repeat kinase 2, restore the proper microtubule stability and are able to rescue cell architecture. Taken together, our results suggest that microtubule destabilization is a point of convergence of genetic and idiopathic forms of parkinsonism and highlight, for the first time, that microtubule dysfunction occurs in patients and not only in experimental models of Parkinson's disease. Therefore, these data contribute to the knowledge on molecular and cellular events underlying Parkinson's disease and, revealing that correction of microtubule defects restores control phenotype, may offer a new therapeutic target for the management of the disease. © 2012 Cartelli et al.
Pezzoli G.,Parkinson Institute |
Zini M.,Parkinson Institute
Expert Opinion on Pharmacotherapy | Year: 2010
Importance of the field: Levodopa is the mainstay of symptomatic treatment for Parkinson's disease (PD). Although other treatments have been developed in the last 30 years, most patients use levodopa in view of its superior efficacy in controlling PD symptoms. Unfortunately, levodopa is associated with long-term motor complications (motor fluctuations and dyskinesias). The main causes of these undesirable effects are the narrowing of the therapeutic window with the natural progression of the disease, pulsatile dopaminergic stimulation due to the short half-life of the drug and erratic absorption. Several studies suggest that PD control could be enhanced by changing the mode of levodopa delivery so as to ensure continuous and stable supply of the drug to the brain. The objective of this text is to review the ascertained strengths and limitations of levodopa in PD, starting from its history, and propose novel modes of usage designed to cover currently unmet medical needs. Areas covered in this review: Medline literature search (from 1973 to date). What the reader will gain: A perspective on the evolution of PD pharmacological treatment. Take home message: Levodopa still is the best treatment for PD. Truly stable and controlled formulations that ensure clinical response should be developed to reduce the undesirable effects that restrict its efficacy. © 2010 Informa UK Ltd.
Antonini A.,Parkinson Institute |
Bondiolotti G.,University of Milan |
Natuzzi F.,Parkinson Institute |
Bareggi S.R.,University of Milan
European Neuropsychopharmacology | Year: 2010
We studied 19 patients (14 men, 5 women, Hoehn and Yahr (H&Y) ≥ 3) with advanced Parkinson's disease (PD) attending the Parkinson Institute, Milan, whose motor fluctuations and dyskinesia were not controlled by oral medications. After all oral PD medications had been withdrawn, they received a duodenal levodopa infusions (Duodopa, Solvay Pharmaceuticals) for 14. h/day through a transabdominal port; levodopa boluses were administered in the morning and during "off" periods. The patients were evaluated by means of the UPDRS in the morning ("off") and 60-120. min after the infusion ("on") at baseline and for a mean follow-up of 13.5 ± 12.5 months (up to 36. months in 10 patients:). Levodopa (l-DOPA) and its metabolites were determined by HPLC with electrochemical detection. l-DOPA concentrations tended to higher in the afternoon (2008 ± 345 vs 1713 ± 274 ng/mL) and correlated with the daily dose. O-methyldopa (OMD) levels correlated with l-DOPA levels, and the OMD/l-DOPA ratios were stable over the day. There was a relationship between decreasing UPDRS III scores and decreasing OMD/l-DOPA ratios. Dyskinesia (UPDRS IV, items 32-34) showed a clear improvement over time but there was no clear relationship with l-DOPA and OMD levels, or the OMD/ l-DOPA ratio. The l-DOPA/dose ratio was stable over time, whereas OMD levels and the OMD/l-DOPA ratio decreased. It is conceivable that continuous infusion decreases metabolism possibly due to a reduction in methyl donor availability, as demonstrated by the increase in total homocysteine levels. Our results do not support the development of tolerance even after several months of continuous infusion, and indicate that pharmacodynamic factors play a role in afternoon off periods. © 2010 Elsevier B.V. and ECNP.
Pezzoli G.,Parkinson Institute |
Cereda E.,Fondazione IRCCS Policlinico San Matteo
Neurology | Year: 2013
Objective: To investigate the risk of Parkinson disease (PD) associated with exposure to pesticides and solvents using meta-analyses of data from cohort and case-control studies. Methods: Prospective cohort and case-control studies providing risk and precision estimates relating PD to exposure to pesticides or solvents or to proxies of exposure were considered eligible. The heterogeneity in risk estimates associated with objective study quality was also investigated. Results: A total of 104 studies/3,087 citations fulfilled inclusion criteria for meta-analysis. In prospective studies, study quality was not a source of heterogeneity. PD was associated with farming and the association with pesticides was highly significant in the studies in which PD diagnosis was self-reported. In case-control studies, study quality appeared to be a source of heterogeneity in risk estimates for some exposures. Higher study quality was frequently associated with a reduction in heterogeneity. In high-quality case-control studies, PD risk was increased by exposure to any-type pesticides, herbicides, and solvents. Exposure to paraquat or maneb/mancozeb was associated with about a 2-fold increase in risk. In high-quality case-control studies including an appreciable number of cases (>200), heterogeneity remained significantly high (>40%) only for insecticides, organochlorines, organophosphates, and farming; also, the risk associated with rural living was found to be significant. Conclusions: The literature supports the hypothesis that exposure to pesticides or solvents is a risk factor for PD. Further prospective and high-quality case-control studies are required to substantiate a cause-effect relationship. The studies should also focus on specific chemical agents. © 2013 American Academy of Neurology.
Canesi M.,Parkinson Institute |
Rusconi M.L.,University of Bergamo |
Isaias I.U.,Parkinson Institute |
Isaias I.U.,University of Milan |
Pezzoli G.,Parkinson Institute
European Journal of Neurology | Year: 2012
Background and purpose: Creative drive and enhanced artistic-like production may emerge in patients with Parkinson's disease (PD) during dopaminergic therapy. However, it has not been described to date whether this artistic-like production results from dopaminergic drugs triggering innate skills or it could be considered as a repeated behavior possibly associated with impulse control disorders (ICDs). Methods: We investigated creative drive in a cohort of cognitively preserved patients with PD by means of the Torrance Test of Creative Thinking (TTCT). We also investigated a putative association between creative drive and ICDs in 36 PD patients with (PD-c) or without (PD-nc) increased artistic-like production and 36 healthy controls (HC). We considered artistic-like productivity to be enhanced if patients reported working on any form of art more than 2h per day after the introduction of dopaminergic treatment. The TTCT, the Barratt Impulsiveness Scale (BIS-11A), the Minnesota Impulsive Disorders Interview (MIDI), and the Punding Rating Scale were applied. Results: Mean TTCT score of PD-c was found to be similar to HC (169.4±51.6 vs. 170.2±69.7, respectively), and both PD-c and HC had significantly higher TTCT scores than patients with PD-nc (125.4±46.1 P<0.05). TTCT did not correlate with any demographic or clinical data in both PD subgroups. No correlation was found between TTCT, BIS-11A, and MIDI. Conclusions: Our study suggests that newly acquired artistic-like production in patients with PD is not associated with impulsivity or ICDs. Artistic-like production might represent the emerging of innate skills in a subset of predisposed patients with PD on dopaminergic therapy. © 2011 The Author(s). European Journal of Neurology © 2011 EFNS.
Cereda E.,Parkinson Institute |
Barichella M.,Parkinson Institute |
Pedrolli C.,Trento Hospital |
Pezzoli G.,Parkinson Institute
Movement Disorders | Year: 2010
The American Academy of Neurology suggests advising the redistribution of daily protein meal content to every Parkinson's disease (PD) patient with motor fluctuations during levodopa treatment. However, no comprehensive evaluation of this complementary therapy has been performed. A systematic review of intervention studies investigating the neurologic outcome of low-protein (<0.8 g/kg of ideal weight/day) and protein-redistribution diets in patients with PD experiencing motor fluctuations during levodopa treatment. All studies (uncontrolled or randomized) investigating a low-protein and/or a protein-redistribution diet (LPD and PRD) and involving patients with PD with motor fluctuations were included, provided that sufficient information on dietary protein content and neurologic outcome measures was available. We identified 16 eligible studies, but they were markedly heterogeneous. There was not enough evidence to support the use of LPD. Response to PRD seemed very good. Acceptability appeared high upon introduction, but it seemed to progressively decrease over time. On average, PRD resulted in improved motor function, but also complications occurred. At the beginning, drop-outs were due to levodopa side effects rather than unsatisfactory benefits. Longterm adherence was more affected by changes in dietary habits than by diet-related side effects. Efficacy and benefits appeared to be higher when the intervention was proposed to subjects in the early stages of PD. PRD can be safely advised to fluctuating patients with PD, but those in whom benefits override the possible inconveniences still need to be identified. The long-term effects of PRD on nutritional status should be evaluated and true effectiveness in clinical practice should be reassessed, given the changes in levodopa formulations and the introduction of several adjuvants (levodopa degradation inhibitors and/or dopamine agonists). © 2010 Movement Disorder Society.
Frazzitta G.,Scientific Institute of Montescano |
Pezzoli G.,Parkinson Institute |
Bertotti G.,Scientific Institute of Montescano |
Maestri R.,Scientific Institute of Montescano
Journal of Neurology | Year: 2013
It has been hypothesized that freezing of gait (FOG) in parkinsonian patients (PD) might be triggered by a breakdown in the normal symmetry of gait. In this study, we evaluated the relationship between asymmetry of gait and FOG and the effects of intensive treadmill treatment on asymmetry. We studied 30 patients with (FOG+) and 30 without (FOG-) freezing in "on" stage. Patients underwent a 4-week rehabilitation treatment using a treadmill with auditory and visual cues and were evaluated at enrolment and at the end of rehabilitation. Outcome measures were gait speed, stride length, asymmetry of gait, Six-minute walking test (6MWT), Unified Parkinson's Disease Rating Scale (UPDRS) II-III, Berg Balance Scale, Timed Up and Go Test, comfortable-fast gait speeds, freezing of gait questionnaire (FOGQ). At enrolment, no differences in gait parameters were observed between the two groups, which differed only in UPDRS-II and BBS. Both FOG+ and FOG- patients spent more time on the left foot (time on left/time on right foot 1.37, p = 0.002, 1.18, p = 0.016, respectively). Rehabilitation determined a homogeneous improvement in both groups of patients for all variables except UPDRS-II and balance, for which a better improvement was observed in FOG+ patients. The improvement in FOGQ in FOG+ patients was significantly correlated to the improvement in asymmetry of gait (Spearman R = 0.46, p = 0.013). Our data support a direct involvement of the asymmetry of gait in the development of FOG in PD. Treadmill training is effective in improving gait and balance in PD FOG+ patients and this might be related to a reduction of asymmetric gait. © 2012 Springer-Verlag.