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Parkinson Disease: HELP
Articles from Istituti Clinici di Perfezionamento
Based on 106 articles published since 2010
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These are the 106 published articles about Parkinson Disease that originated from Istituti Clinici di Perfezionamento during 2010-2020.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5
1 Review Neuronal microtubules and proteins linked to Parkinson's disease: a relevant interaction? 2019

Calogero, Alessandra M / Mazzetti, Samanta / Pezzoli, Gianni / Cappelletti, Graziella. ·Department of Biosciences, Università degli Studi di Milano, via Celoria 26, I-20133 Milan, Italy. · Fondazione Grigioni per il Morbo di Parkinson, via Zuretti 35, I-20135 Milan, Italy. · Parkinson Institute, ASST "G.Pini-CTO", via Bignami 1, I-20133 Milan, Italy. · Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, via Balzaretti, I-20133 Milan, Italy. ·Biol Chem · Pubmed #31256059.

ABSTRACT: Neuronal microtubules are key determinants of cell morphology, differentiation, migration and polarity, and contribute to intracellular trafficking along axons and dendrites. Microtubules are strictly regulated and alterations in their dynamics can lead to catastrophic effects in the neuron. Indeed, the importance of the microtubule cytoskeleton in many human diseases is emerging. Remarkably, a growing body of evidence indicates that microtubule defects could be linked to Parkinson's disease pathogenesis. Only a few of the causes of the progressive neuronal loss underlying this disorder have been identified. They include gene mutations and toxin exposure, but the trigger leading to neurodegeneration is still unknown. In this scenario, the evidence showing that mutated proteins in Parkinson's disease are involved in the regulation of the microtubule cytoskeleton is intriguing. Here, we focus on α-Synuclein, Parkin and Leucine-rich repeat kinase 2 (LRRK2), the three main proteins linked to the familial forms of the disease. The aim is to dissect their interaction with tubulin and microtubules in both physiological and pathological conditions, in which these proteins are overexpressed, mutated or absent. We highlight the relevance of such an interaction and suggest that these proteins could trigger neurodegeneration via defective regulation of the microtubule cytoskeleton.

2 Review Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine. 2019

Blandini, Fabio / Cilia, Roberto / Cerri, Silvia / Pezzoli, Gianni / Schapira, Anthony H V / Mullin, Stephen / Lanciego, José L. ·Laboratory of Functional Neurochemistry, IRCCS Mondino Foundation, Pavia, Italy. · Parkinson Institute, ASST Gaetano Pini-CTO, Milan, Italy. · Department of Clinical Neurosciences, Institute of Neurology, University College London, Hampstead, UK. · Institute of Translational and Stratified Medicine, Plymouth University Peninsula School of Medicine, Plymouth, UK. · Programa de Neurociencias, Fundación para la Investigación Médica Aplicada (FIMA), Universidad de Navarra, Pamplona, Spain. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CiberNed), Madrid, Spain. · Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. ·Mov Disord · Pubmed #30589955.

ABSTRACT: Glucocerebrosidase is a lysosomal enzyme. The characterization of a direct link between mutations in the gene coding for glucocerebrosidase (GBA1) with the development of Parkinson's disease and dementia with Lewy bodies has heightened interest in this enzyme. Although the mechanisms through which glucocerebrosidase regulates the homeostasis of α-synuclein remains poorly understood, the identification of reduced glucocerebrosidase activity in the brains of patients with PD and dementia with Lewy bodies has paved the way for the development of novel therapeutic strategies directed at enhancing glucocerebrosidase activity and reducing α-synuclein burden, thereby slowing down or even preventing neuronal death. Here we reviewed the current literature relating to the mechanisms underlying the cross talk between glucocerebrosidase and α-synuclein, the GBA1 mutation-associated clinical phenotypes, and ongoing therapeutic approaches targeting glucocerebrosidase. © 2018 International Parkinson and Movement Disorder Society.

3 Review Molecular Imaging of the Cannabinoid System in Idiopathic Parkinson's Disease. 2018

Cilia, Roberto. ·Parkinson Institute, ASST Gaetano Pini-CTO, Milan, Italy. Electronic address: roberto.cilia@gmail.com. ·Int Rev Neurobiol · Pubmed #30314601.

ABSTRACT: The endocannabinoid system is a modulator of neurotransmitter release and is involved in several physiological functions. Hence, it has been increasingly studied as a potential pharmacologic target of Parkinson's disease. Several preclinical and clinical studies evidenced a substantial rearrangement of the endocannabinoid system in the basal ganglia circuit following dopamine depletion. The endocannabinoid system has been additionally implicated in the regulation of neuroinflammation and neuroprotection through the activation of CB2 receptors, suggesting a potential target for disease modifying therapies in Parkinson's disease. In this chapter, current pharmacological and physiological knowledge on the role of the endocannabinoid system will be reviewed, focusing on preclinical studies animal models and clinical studies in patients with idiopathic Parkinson's disease. The main strategies for imaging the brain cannabinoid system will be summarized to finally focus on in vivo imaging of patients with Parkinson's disease.

4 Review Molecular imaging to track Parkinson's disease and atypical parkinsonisms: New imaging frontiers. 2017

Strafella, Antonio P / Bohnen, Nicolaas I / Perlmutter, Joel S / Eidelberg, David / Pavese, Nicola / Van Eimeren, Thilo / Piccini, Paola / Politis, Marios / Thobois, Stephane / Ceravolo, Roberto / Higuchi, Makoto / Kaasinen, Valtteri / Masellis, Mario / Peralta, M Cecilia / Obeso, Ignacio / Pineda-Pardo, Jose Ángel / Cilia, Roberto / Ballanger, Benedicte / Niethammer, Martin / Stoessl, Jon A / Anonymous3450895. ·Morton and Gloria Shulman Movement Disorder Unit & E.J. Safra Parkinson Disease Program, Neurology Div/Dept. Medicine, Toronto Western Hospital, UHN; Krembil Research Institute, UHN; Research Imaging Centre, Campbell Family Mental Health Research Institute, CAMH, University of Toronto, Ontario, Canada. · University of Michigan & Veterans Administration Medical Center, Ann Arbor, Michigan, USA. · Neurology, Radiology, Neuroscience, Physical Therapy & Occupational Therapy, Washington University in St. Louis, St. Louis, Missouri, USA. · Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA. · Newcastle Magnetic Resonance Centre & Positron Emission Tomography Centre, Newcastle University, Campus for Ageing & Vitality, Newcastle upon Tyne, United Kingdom. · Multimodal Neuroimaging Group-Department of Nuclear Medicine Department of Neurology-University of Cologne, Institute of Neuroscience and Medicine, Jülich Research Center, German Center for Neurodegenerative Diseases (DZNE), Germany. · Neurology Imaging Unit, Centre of Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Hammersmith Campus, Imperial College London, United Kingdom. · Neurodegeneration Imaging Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom. · Hospices Civils de Lyon, Hopital Neurologique Pierre Wertheimer, Université Lyon 1; CNRS, Centre de Neurosciences Cognitives, UMR, 5229, Lyon, France. · Department of Clinical and Experimental Medicine, Movement Disorders and Parkinson Center, University of Pisa, Italy. · National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan. · Division of Clinical Neurosciences, Turku University Hospital; Department of Neurology, University of Turku; Turku PET Centre, University of Turku, Turku, Finland. · Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre; Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada. · Movement Disorder and Parkinson's Disease Program, CEMIC University Hospital, Buenos, Aires, Argentina. · Centro Integral de Neurociencias (CINAC), Hospitales Madrid Puerta del Sur & Centro de Investigación Biomédica en Red, Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. · Parkinson Institute, ASST Gaetano Pini-CTO, Milan, Italy. · INSERM, U1028; CNRS, UMR5292; Lyon Neuroscience Research Center, Neuroplasticity & Neuropathology of Olfactory Perception Team, University Lyon, France. · Pacific Parkinson's Research Centre & National Parkinson Foundation Centre of Excellence, University of British Columbia & Vancouver Coastal Health, Vancouver, British, Columbia, Canada. ·Mov Disord · Pubmed #28150432.

ABSTRACT: Molecular imaging has proven to be a powerful tool for investigation of parkinsonian disorders. One current challenge is to identify biomarkers of early changes that may predict the clinical trajectory of parkinsonian disorders. Exciting new tracer developments hold the potential for in vivo markers of underlying pathology. Herein, we provide an overview of molecular imaging advances and how these approaches help us to understand PD and atypical parkinsonisms. © 2016 International Parkinson and Movement Disorder Society.

5 Review Impulse control disorders in Parkinson's disease: seeking a roadmap toward a better understanding. 2011

Cilia, Roberto / van Eimeren, Thilo. ·Parkinson Institute, Istituti Clinici di Perfezionamento, via Bignami 1, 20126 Milan, Italy. roberto.cilia@gmail.com ·Brain Struct Funct · Pubmed #21541715.

ABSTRACT: 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 early-onset 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.

6 Review Low-protein and protein-redistribution diets for Parkinson's disease patients with motor fluctuations: a systematic review. 2010

Cereda, Emanuele / Barichella, Michela / Pedrolli, Carlo / Pezzoli, Gianni. ·Department of Neuroscience, Parkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italy. emanuele.cereda@virgilio.it ·Mov Disord · Pubmed #20669318.

ABSTRACT: 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. Long-term 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).

7 Review Levodopa in Parkinson's disease: from the past to the future. 2010

Pezzoli, Gianni / Zini, Michela. ·Director of Parkinson Institute, Istituti Clinici di Perfezionamento, Via Bignami 1, Milan, Italy. pezzoli@parkinson.it ·Expert Opin Pharmacother · Pubmed #20163273.

ABSTRACT: 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.

8 Clinical Trial None 2017

Cilia, Roberto / Laguna, Janeth / Cassani, Erica / Cereda, Emanuele / Pozzi, Nicolò G / Isaias, Ioannis U / Contin, Manuela / Barichella, Michela / Pezzoli, Gianni. ·From the Parkinson Institute (R.C., E. Cassani, M.B., G.P.), ASST Gaetano Pini-CTO, Milan, Italy · Neurology Clinic (J.L.), Clinica Niño Jesus, Santa Cruz, Bolivia · Nutrition and Dietetics Service (E. Cereda), Fondazione IRCCS Policlinico San Matteo, Pavia · Department of Pathophysiology and Transplantation (N.G.P., I.U.I.), LAMB Pierfranco & Luisa Mariani, University of Milan, Italy · Department of Neurology (N.G.P., I.U.I.), University Hospital Würzburg and Julius-Maximilians-University, Würzburg, Germany · IRCCS-Institute of Neurological Sciences of Bologna (M.C.) · and Department of Biomedical and Neuromotor Sciences (M.C.), University of Bologna, Italy. ·Neurology · Pubmed #28679598.

ABSTRACT: OBJECTIVE: To investigate whether METHODS: We investigated efficacy and safety of single-dose intake of MP powder from roasted seeds obtained without any pharmacologic processing. Eighteen patients with advanced PD received the following treatments, whose sequence was randomized: (1) dispersible levodopa at 3.5 mg/kg combined with the dopa-decarboxylase inhibitor benserazide (LD+DDCI; the reference treatment); (2) high-dose MP (MP-Hd; 17.5 mg/kg); (3) low-dose MP (MP-Ld; 12.5 mg/kg); (4) pharmaceutical preparation of LD without DDCI (LD-DDCI; 17.5 mg/kg); (5) MP plus benserazide (MP+DDCI; 3.5 mg/kg); (6) placebo. Efficacy outcomes were the change in motor response at 90 and 180 minutes and the duration of on state. Safety measures included any adverse event (AE), changes in blood pressure and heart rate, and the severity of dyskinesias. RESULTS: When compared to LD+DDCI, MP-Ld showed similar motor response with fewer dyskinesias and AEs, while MP-Hd induced greater motor improvement at 90 and 180 minutes, longer ON duration, and fewer dyskinesias. MP-Hd induced less AEs than LD+DDCI and LD-DDCI. No differences in cardiovascular response were recorded. CONCLUSION: Single-dose MP intake met all noninferiority efficacy and safety outcome measures in comparison to dispersible levodopa/benserazide. Clinical effects of high-dose MP were similar to levodopa alone at the same dose, with a more favorable tolerability profile. CLINICALTRIALSGOV IDENTIFIER: NCT02680977.

9 Clinical Trial A 5-year prospective assessment of advanced Parkinson disease patients treated with subcutaneous apomorphine infusion or deep brain stimulation. 2011

Antonini, Angelo / Isaias, Ioannis U / Rodolfi, Giorgia / Landi, Andrea / Natuzzi, Francesca / Siri, Chiara / Pezzoli, Gianni. ·Parkinson Institute, Istituti Clinici di Perfezionamento, Via Bignami, 1, 20126, Milan, Italy. ·J Neurol · Pubmed #20972684.

ABSTRACT: Prospective comparative long-term data on the effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and continuous subcutaneous infusion of apomorphine (CSAI) in patients with advanced Parkinson disease (PD) are lacking. We report 5-year follow-up of 25 PD patients treated with either STN-DBS (n = 13) or CSAI (n = 12) who fulfilled CAPSIT-PD criteria. Cohorts were matched for disease duration and severity of motor complications. Baseline clinical and neuropsychological status did not differ among cohorts. Patients were assessed with the UPDRS, MMSE, HAMD-17 and Neuropsychiatric Inventory (NPI).Twelve subjects reached the 5-year follow-up with STN-DBS (one was lost at follow-up) versus two in the CSAI cohort. Drop-outs with CSAI were due to subcutaneous nodules (n = 2), insufficient control of motor fluctuations and dyskinesia (n = 4), death for unrelated reasons (n = 3) and one was lost at follow-up. Average apomorphine dose at last visit was 83.4 ± 19.2 mg/day and average treatment duration was 30 months. At 1-year as well as at last follow-up (intention-to-treat analysis), both therapies decreased daily off-time but only STN-DBS reduced dyskinesia duration and severity. Decrement of medications was greater with STN-DBS. There was a significant worsening of NPI after STN-DBS, primarily because four subjects developed apathy.

10 Article Could Mucuna pruriens be the answer to Parkinson's disease management in sub-Saharan Africa and other low-income countries worldwide? 2020

Fothergill-Misbah, Natasha / Maroo, Harshvadan / Cham, Momodou / Pezzoli, Gianni / Walker, Richard / Cilia, Roberto. ·Population Health Sciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom. Electronic address: n.fothergill-misbah@newcastle.ac.uk. · Parkinson's Support Group, P.O. Box, 14542-00800, Nairobi, Kenya. Electronic address: harsh.maroo@gmail.com. · Richard Novati Catholic Hospital, Sogakope, Ghana. Electronic address: modoufa@gmail.com. · Fondazione Grigioni per il Morbo di Parkinson, Milan, Italy; Parkinson Institute, ASST "Gaetano Pini-CTO, Milan, Italy. Electronic address: gianni.pezzoli@gmail.com. · Population Health Sciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom. Electronic address: Richard.walker@nhct.nhs.uk. · Fondazione IRCCS Istituto Neurologico Carlo Besta, Movement Disorders Unit, Milan, Italy. Electronic address: roberto.cilia@istituto-besta.it. ·Parkinsonism Relat Disord · Pubmed #32179240.

ABSTRACT: Parkinson's disease (PD) is a progressive, disabling, neurodegenerative disease that requires long term care and pharmaceutical treatment. Levodopa remains the gold standard treatment for PD globally, although it is largely unavailable and unaffordable for the majority of patients in many sub-Saharan African and other low-income countries (LICs). We suggest the potential for Mucuna pruriens (MP), a leguminous plant, to replace or supplement levodopa-based medicines in countries where levodopa is unaffordable and inaccessible due to its low costs of preparation and high natural availability. MP has been shown to induce a great improvement of motor symptoms with few adverse events in recent studies. However, caution is important until more robust data on the long-term safety of MP are available. We believe that MP could potentially be part of the answer to affordable, symptomatic treatment of PD in LICs worldwide.

11 Article α-Synuclein oligomers in skin biopsy of idiopathic and monozygotic twin patients with Parkinson's disease. 2020

Mazzetti, Samanta / Basellini, Milo J / Ferri, Valentina / Cassani, Erica / Cereda, Emanuele / Paolini, Matilde / Calogero, Alessandra M / Bolliri, Carlotta / De Leonardis, Mara / Sacilotto, Giorgio / Cilia, Roberto / Cappelletti, Graziella / Pezzoli, Gianni. ·Department of Biosciences, Università degli Studi di Milano, Milan, Italy. · Fondazione Grigioni per il Morbo di Parkinson, Milan, Italy. · Parkinson Institute, ASST 'Gaetano Pini-CTO', Milan, Italy. · Clinical Nutrition and Dietetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. · Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy. · Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy. ·Brain · Pubmed #32025699.

ABSTRACT: A variety of cellular processes, including vesicle clustering in the presynaptic compartment, are impaired in Parkinson's disease and have been closely associated with α-synuclein oligomerization. Emerging evidence proves the existence of α-synuclein-related pathology in the peripheral nervous system, even though the presence of α-synuclein oligomers in situ in living patients remains poorly investigated. In this case-control study, we show previously undetected α-synuclein oligomers within synaptic terminals of autonomic fibres in skin biopsies by means of the proximity ligation assay and propose a procedure for their quantification (proximity ligation assay score). Our study revealed a significant increase in α-synuclein oligomers in consecutive patients with Parkinson's disease compared to consecutive healthy controls (P < 0.001). Proximity ligation assay score (threshold value > 96 using receiver operating characteristic) was found to have good sensitivity, specificity and positive predictive value (82%, 86% and 89%, respectively). Furthermore, to disclose the role of putative genetic predisposition in Parkinson's disease aetiology, we evaluated the differential accumulation of oligomers in a unique cohort of 19 monozygotic twins discordant for Parkinson's disease. The significant difference between patients and healthy subjects was confirmed in twins. Intriguingly, although no difference in median values was detected between consecutive healthy controls and healthy twins, the prevalence of healthy subjects positive for proximity ligation assay score was significantly greater in twins than in the consecutive cohort (47% versus 14%, P = 0.019). This suggests that genetic predisposition is important, but not sufficient, in the aetiology of the disease and strengthens the contribution of environmental factors. In conclusion, our data provide evidence that α-synuclein oligomers accumulate within synaptic terminals of autonomic fibres of the skin in Parkinson's disease for the first time. This finding endorses the hypothesis that α-synuclein oligomers could be used as a reliable diagnostic biomarker for Parkinson's disease. It also offers novel insights into the physiological and pathological roles of α-synuclein in the peripheral nervous system.

12 Article Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene. 2019

Chumarina, Margarita / Russ, Kaspar / Azevedo, Carla / Heuer, Andreas / Pihl, Maria / Collin, Anna / Frostner, Eleonor Åsander / Elmer, Eskil / Hyttel, Poul / Cappelletti, Graziella / Zini, Michela / Goldwurm, Stefano / Roybon, Laurent. ·Cell Stem Cell Laboratory for CNS Disease Modeling, Department of Experimental Medical Science, Lund University, 22184, Lund, Sweden. · MultiPark and the Lund Stem Cell Center, Lund University, 22184, Lund, Sweden. · Behavioural Neuroscience Laboratory, Department of Experimental Medical Science, Lund University, 22184, Lund, Sweden. · Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870, Copenhagen, Denmark. · Office for Medical Services/Division of Laboratory Medicine, Department of Clinical Genetics and Pathology, Lund, Sweden. · Department of Clinical Sciences Lund, Mitochondrial Medicine, Lund University, 22184, Lund, Sweden. · Department of Biosciences, Università degli Studi di Milano, via Celoria 26, I-20133, Milan, Italy. · Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, via Balzaretti, I-20133, Milan, Italy. · Parkinson Institute, ASST Pini-CTO, via Bignami 1, 20126, Milan, Italy. · Cell Stem Cell Laboratory for CNS Disease Modeling, Department of Experimental Medical Science, Lund University, 22184, Lund, Sweden. laurent.roybon@med.lu.se. · MultiPark and the Lund Stem Cell Center, Lund University, 22184, Lund, Sweden. laurent.roybon@med.lu.se. ·Acta Neuropathol Commun · Pubmed #31843010.

ABSTRACT: Variations in the POLG1 gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma, have recently been associated with Parkinson's disease (PD), especially in patients diagnosed with progressive external ophthalmoplegia (PEO). However, the majority of the studies reporting this association mainly focused on the genetic identification of the variation in POLG1 in PD patient primary cells, and determination of mitochondrial DNA copy number, providing little information about the cellular alterations existing in patient brain cells, in particular dopaminergic neurons. Therefore, through the use of induced pluripotent stem cells (iPSCs), we assessed cellular alterations in novel p.Q811R POLG1 (POLG1

13 Article Resting state oscillations suggest a motor component of Parkinson's Impulse Control Disorders. 2019

Spay, Charlotte / Meyer, Garance / Lio, Guillaume / Pezzoli, Gianni / Ballanger, Bénédicte / Cilia, Roberto / Boulinguez, Philippe. ·Université de Lyon, 92 rue Pasteur, 69007 Lyon, France; Université Lyon 1, 43 boulevard du 11 novembre 1918, 69622 Villeurbanne, France; INSERM, U 1028, Lyon Neuroscience Research Center, 95 boulevard Pinel, 69500 Bron, France; CNRS, UMR 5292, Lyon Neuroscience Research Center, 95 boulevard Pinel, 69500 Bron, France. · Centre de Neuroscience Cognitive, UMR 5229, 67 boulevard Pinel, 69675 Bron, France. · Parkinson Institute, ASST Gaetano Pini-CTO, Via bignami 1, 20126 Milan, Italy. · Université de Lyon, 92 rue Pasteur, 69007 Lyon, France; Université Lyon 1, 43 boulevard du 11 novembre 1918, 69622 Villeurbanne, France; INSERM, U 1028, Lyon Neuroscience Research Center, 95 boulevard Pinel, 69500 Bron, France; CNRS, UMR 5292, Lyon Neuroscience Research Center, 95 boulevard Pinel, 69500 Bron, France. Electronic address: philippe.boulinguez@univ-lyon1.fr. ·Clin Neurophysiol · Pubmed #31541984.

ABSTRACT: OBJECTIVES: Impulse control disorders (ICDs) in Parkinson's disease (PD) have been associated with cognitive impulsivity and dopaminergic dysfunction and treatment. The present study tests the neglected hypothesis that the neurofunctional networks involved in motor impulsivity might also be dysfunctional in PD-ICDs. METHODS: We performed blind spectral analyses of resting state electroencephalographic (EEG) data in PD patients with and without ICDs to probe the functional integrity of all cortical networks. Analyses were performed directly at the source level after blind source separation. Discrete differences between groups were tested by comparing patients with and without ICDs. Gradual dysfunctions were assessed by means of correlations between power changes and clinical scores reflecting ICD severity (QUIP score). RESULTS: Spectral signatures of ICDs were found in the medial prefrontal cortex, the dorsal anterior cingulate and the supplementary motor area, in the beta and gamma bands. Beta power changes in the supplementary motor area were found to predict ICDs severity. CONCLUSION: ICDs are associated with abnormal activity within frequency bands and cortical circuits supporting the control of motor response inhibition. SIGNIFICANCE: These results bring to the forefront the need to consider, in addition to the classical interpretation based on aberrant mesocorticolimbic reward processing, the issue of motor impulsivity in PD-ICDs and its potential implications for PD therapy.

14 Article Freezing of gait in Parkinson's disease reflects a sudden derangement of locomotor network dynamics. 2019

Pozzi, Nicoló G / Canessa, Andrea / Palmisano, Chiara / Brumberg, Joachim / Steigerwald, Frank / Reich, Martin M / Minafra, Brigida / Pacchetti, Claudio / Pezzoli, Gianni / Volkmann, Jens / Isaias, Ioannis U. ·Department of Neurology, University Hospital and Julius Maximilian University, Würzburg, Germany. · Fondazione Europea di Ricerca Biomedica (FERB Onlus), Cernusco s/N (Milan), Italy. · Department of Informatics, Bioengineering, Robotics and System Engineering, University of Genoa, Genoa, Italy. · Department of Electronics, Information and Bioengineering, MBMC Lab, Politecnico di Milano, Milan, Italy. · Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany. · Parkinson and Movement Disorder Unit, IRCCS Mondino Foundation, Pavia, Italy. · Centro Parkinson ASST G. Pini-CTO, Milan, Italy. ·Brain · Pubmed #31505548.

ABSTRACT: Freezing of gait is a disabling symptom of Parkinson's disease that causes a paroxysmal inability to generate effective stepping. The underlying pathophysiology has recently migrated towards a dysfunctional supraspinal locomotor network, but the actual network derangements during ongoing gait freezing are unknown. We investigated the communication between the cortex and the subthalamic nucleus, two main nodes of the locomotor network, in seven freely-moving subjects with Parkinson's disease with a novel deep brain stimulation device, which allows on-demand recording of subthalamic neural activity from the chronically-implanted electrodes months after the surgical procedure. Multisite neurophysiological recordings during (effective) walking and ongoing gait freezing were combined with kinematic measurements and individual molecular brain imaging studies. Patients walked in a supervised environment closely resembling everyday life challenges. We found that during (effective) walking, the cortex and subthalamic nucleus were synchronized in a low frequency band (4-13 Hz). In contrast, gait freezing was characterized in every patient by low frequency cortical-subthalamic decoupling in the hemisphere with less striatal dopaminergic innervation. Of relevance, this decoupling was already evident at the transition from normal (effective) walking into gait freezing, was maintained during the freezing episode, and resolved with recovery of the effective walking pattern. This is the first evidence for a decoding of the networked processing of locomotion in Parkinson's disease and suggests that freezing of gait is a 'circuitopathy' related to a dysfunctional cortical-subcortical communication. A successful therapeutic approach for gait freezing in Parkinson's disease should aim at directly targeting derangements of neural network dynamics.

15 Article Muscle-targeted nutritional support for rehabilitation in patients with parkinsonian syndrome. 2019

Barichella, Michela / Cereda, Emanuele / Pinelli, Giovanna / Iorio, Laura / Caroli, Diana / Masiero, Irene / Ferri, Valentina / Cassani, Erica / Bolliri, Carlotta / Caronni, Serena / Maggio, Marcello / Ortelli, Paola / Ferrazzoli, Davide / Maras, Antonios / Riboldazzi, Giulio / Frazzitta, Giuseppe / Pezzoli, Gianni. ·From the Parkinson Institute (M.B., D.C., I.M., V.F., E.C., C.B., S.C., G. Pezzoli), ASST G.Pini-CTO, ex ICP, Milan · Clinical Nutrition and Dietetics Unit (E.C.), Fondazione IRCCS Policlinico San Matteo, Pavia · Dipartimento Riabilitazione Malattia di Parkinson e Disturbi del Movimento (G. Pinelli, P.O., D.F., G.F.), Ospedale Classificato Moriggia Pelascini di Gravedona · U.S. Riabilitazione Parkinson (L.I., A.M., G.R.), Fondazione Gaetano e Piera Borghi di Brebbia · and UOC Clinica Geriatrica (M.M.), Dipartimento Medico-Geriatrico-Riabilitativo, Università-Azienda Ospedaliero-Universitaria di Parma, Italy. ·Neurology · Pubmed #31278117.

ABSTRACT: OBJECTIVE: We evaluated the efficacy of muscle-targeted nutritional support on the functional outcomes of multidisciplinary intensive rehabilitation treatment (MIRT) in patients with Parkinson disease (PD) or parkinsonism. METHODS: We conducted a pragmatic, bicentric, randomized (1:1), assessor-blind controlled trial (Protein, Leucine and Vitamin D Enhancing Rehabilitation [PRO-LEADER]; April 2017 to January 2018) in cognitively intact patients with PD or parkinsonism and undergoing a 30-day MIRT. Patients (n = 150) received a standard hospital diet with or without a whey protein-based nutritional supplement enriched with leucine and vitamin D twice daily. The primary efficacy endpoint was the increase in the distance walked during a 6-minute walking test (6MWT). Secondary endpoints were changes in 4-meter walking speed, Timed Up and Go test (TUG), Berg balance scale, handgrip strength, Self-assessment Parkinson's Disease Disability Scale, body weight, and skeletal muscle mass (SMM). RESULTS: Nutritional support resulted in greater increase in the distance walked during 6MWT (mean 69.6 meters [95% confidence interval (CI) 60.7-78.6]) than no support (51.8 meters [95% CI 37.0-66.7]): center-adjusted mean difference, 18.1 meters (95% CI 0.9-35.3) ( CONCLUSION: The consumption of a whey protein-based nutritional formula enriched with leucine and vitamin D with MIRT improved lower extremity function and preserved muscle mass in patients with PD or parkinsonism.Clinicaltrials.gov IDENTIFIER: NCT03124277. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with parkinsonism undergoing intensive rehabilitation, a whey protein-based nutritional formula enriched with leucine and vitamin D increased distance walked on the 6MWT.

16 Article Sit-to-walk performance in Parkinson's disease: A comparison between faller and non-faller patients. 2019

Palmisano, Chiara / Brandt, Gregor / Pozzi, Nicoló Gabriele / Leporini, Alice / Maltese, Virginia / Canessa, Andrea / Volkmann, Jens / Pezzoli, Gianni / Frigo, Carlo Albino / Isaias, Ioannis Ugo. ·Department of Neurology, University Hospital and Julius-Maximilian-University, Josef-Schneider-Str. 11, 97080 Würzburg, Germany; Department of Electronic, Information and Bioengineering, MBMC Lab, Politecnico di Milano, via Colombo 40, 20133 Milan, Italy. · Department of Neurology, University Hospital and Julius-Maximilian-University, Josef-Schneider-Str. 11, 97080 Würzburg, Germany. · Department of Informatics, Bioengineering, Robotics and System Engineering, University of Genoa, via all'Opera Pia 13a, 16145 Genoa, Italy; Fondazione Europea di Ricerca Biomedica (FERB Onlus), Via Uboldo 18, 20063 Cernusco s/N, Milan, Italy. · Centro Parkinson ASST G. Pini-CTO, via Bignami 1, 20126 Milan, Italy. · Department of Electronic, Information and Bioengineering, MBMC Lab, Politecnico di Milano, via Colombo 40, 20133 Milan, Italy. · Department of Neurology, University Hospital and Julius-Maximilian-University, Josef-Schneider-Str. 11, 97080 Würzburg, Germany; Centro Parkinson ASST G. Pini-CTO, via Bignami 1, 20126 Milan, Italy. Electronic address: Isaias_I@ukw.de. ·Clin Biomech (Bristol, Avon) · Pubmed #30889433.

ABSTRACT: BACKGROUND: Falls are one of the main concerns in people with Parkinson's disease, leading to poor quality of life and increased mortality. The sit-to-walk movement is the most frequent postural transition task during daily life and is highly demanding in terms of balance maintenance and muscular strength. METHODS: With the aim of identifying biomechanical variables of high risk of falling, we investigated the sit-to-walk task performed by 9 Parkinson's disease patients with at least one fall episode in the six months preceding this study, 15 Parkinson's disease patients without previous falls, and 20 healthy controls. Motor performance was evaluated with an optoelectronic system and two dynamometric force plates after overnight suspension of all dopaminergic drugs and one hour after consumption of a standard dose of levodopa/benserazide. FINDINGS: Poor trunk movements critically influenced the execution of the sit-to-walk movement in patients with a history of falling. The peak velocity of the trunk in the anterior-posterior direction discriminated faller from non-faller patients, with high specificity and sensitivity in both the medication-off and -on state. INTERPRETATION: Our results confirm the difficulties in merging consecutive motor tasks in patients with Parkinson's disease. Trunk movements during the sit-to-walk can provide valuable measurements to monitor and possibly predict the risk of falling.

17 Article Generation of an induced pluripotent stem cell line (CSC-46) from a patient with Parkinson's disease carrying a novel p.R301C mutation in the GBA gene. 2019

Gustavsson, Nadja / Marote, Ana / Pomeshchik, Yuriy / Russ, Kaspar / Azevedo, Carla / Chumarina, Margarita / Goldwurm, Stefano / Collin, Anna / Pinto, Luisa / Salgado, António J / Klementieva, Oxana / Roybon, Laurent / Savchenko, Ekaterina. ·Medical Microspectroscopy, Department of Experimental Medical Science, Lund University, Lund, Sweden. · Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal. · Stem Cell Laboratory for CNS Disease Modeling, Department of Experimental Medical Science, BMC D10, Lund University, Lund, Sweden; Strategic Research Area MultiPark, Lund Stem Cell Center, Lund University, Lund, Sweden. · Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy. · Department of Clinical Genetics and Pathology, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden. · Stem Cell Laboratory for CNS Disease Modeling, Department of Experimental Medical Science, BMC D10, Lund University, Lund, Sweden; Strategic Research Area MultiPark, Lund Stem Cell Center, Lund University, Lund, Sweden. Electronic address: Laurent.roybon@med.lu.se. ·Stem Cell Res · Pubmed #30640063.

ABSTRACT: Mutations in the glucocerebrosidase (GBA) gene have been associated with the development of Parkinson's disease (PD). An induced pluripotent stem cell (iPSC) line was generated from a 60-year old patient diagnosed with PD and carrying a new mutation variant p.R301C in GBA. Using non-integrating Sendai virus-based technology, we utilized OCT3/4, SOX2, c-MYC and KLF4 transcription factors to reprogram skin fibroblasts into iPSCs. The generated iPSC line retained the mutation, displayed expression of common pluripotency markers, differentiated into the three germ layers, and exhibited normal karyotype. The iPSC line can be further used for studying PD pathogenesis.

18 Article Unraveling gut microbiota in Parkinson's disease and atypical parkinsonism. 2019

Barichella, Michela / Severgnini, Marco / Cilia, Roberto / Cassani, Erica / Bolliri, Carlotta / Caronni, Serena / Ferri, Valentina / Cancello, Raffaella / Ceccarani, Camilla / Faierman, Samanta / Pinelli, Giovanna / De Bellis, Gianluca / Zecca, Luigi / Cereda, Emanuele / Consolandi, Clarissa / Pezzoli, Gianni. ·Parkinson Institute, Azienda Socio Sanitaria Territoriale (ASST) Gaetano Pini-CTO, Milan, Italy. · Institute of Biomedical Technologies (IBT), Italian National Research Council (CNR), Milan, Italy. · IRCCS Istituto Auxologico Italiano, Obesity Research Laboratory, Milan, Italy. · Department of Health Sciences, San Paolo Hospital Medical School, University of Milan, Milan, Italy. · Department of Parkinson Disease Rehabilitation, Moriggia-Pelascini Hospital, Gravedona ed Uniti, Fondazione Europea Ricerca Biomedica (FERB), Gravedona, Italy. · Department of Psychiatry, Columbia University Medical Center, New York State Psychiatric Institute, New York, NY USA. · Clinical Nutrition and Dietetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. ·Mov Disord · Pubmed #30576008.

ABSTRACT: BACKGROUND: Although several studies have suggested that abnormalities in gut microbiota may play a critical role in the pathogenesis of PD, data are still extremely heterogeneous. METHODS: 16S gene ribosomal RNA sequencing was performed on fecal samples of 350 individuals, subdivided into idiopathic PD (n = 193, of whom 39 were drug naïve) stratified by disease duration, PSP (n = 22), MSA (n = 22), and healthy controls (HC; n = 113). Several confounders were taken into account, including dietary habits. RESULTS: Despite the fact that unadjusted comparison of PD and HC showed several differences in relative taxa abundances, the significant results were greatly reduced after adjusting for confounders. Although most of these differences were associated with disease duration, lower abundance in Lachnospiraceae was the only difference between de novo PD and HC (remaining lower across almost all PD duration strata). Decreased Lachnospiraceae and increased Lactobacillaceae and Christensenellaceae were associated with a worse clinical profile, including higher frequencies of cognitive impairment, gait disturbances, and postural instability. When compared with HC, MSA and PSP patients shared the changes in PD, with a few exceptions: in MSA, Lachnospiraceae were not lower, and Prevotellaceae were reduced; in PSP, Lactobacillaceae were similar, and Streptococcaceae were reduced. CONCLUSIONS: Gut microbiota may be an environmental modulator of the pathogenesis of PD and contribute to the interindividual variability of clinical features. Data are influenced by PD duration and several confounders that need to be taken into account in future studies. Prospective studies in de novo PD patients are needed to elucidate the net effect of dysbiosis on the progression of the disease. © 2018 International Parkinson and Movement Disorder Society.

19 Article Excitability of the supplementary motor area in Parkinson's disease depends on subcortical damage. 2019

Casarotto, Silvia / Turco, Francesco / Comanducci, Angela / Perretti, Alessio / Marotta, Giorgio / Pezzoli, Gianni / Rosanova, Mario / Isaias, Ioannis U. ·Department of Biomedical and Clinical Sciences "L. Sacco", LASEB Laboratory, University of Milan, via GB Grassi 74, 20157, Milan, Italy. Electronic address: silvia.casarotto@unimi.it. · Fondazione Europea di Ricerca Biomedica (FERB Onlus), via Ambrogio Uboldo 21, 20063, Cernusco sul Naviglio, Milan, Italy; Department of Neurology, University Hospital and Julius-Maximilian-University, Josef-Schneider-Str. 11, 97080, Würzburg, Germany. Electronic address: francesco.turco1989@gmail.com. · Department of Biomedical and Clinical Sciences "L. Sacco", LASEB Laboratory, University of Milan, via GB Grassi 74, 20157, Milan, Italy. Electronic address: angela.comanducci@unimi.it. · Fondazione Europea di Ricerca Biomedica (FERB Onlus), via Ambrogio Uboldo 21, 20063, Cernusco sul Naviglio, Milan, Italy. Electronic address: paramiauxparkinson@gmail.com. · Department of Nuclear Medicine, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, via Francesco Sforza 28, 20122, Milan, Italy. Electronic address: marottag@policlinico.mi.it. · Parkinson Institute ASST G. Pini-CTO, via Bignami 1, 20126, Milan, Italy. Electronic address: gianni.pezzoli@gmail.com. · Department of Biomedical and Clinical Sciences "L. Sacco", LASEB Laboratory, University of Milan, via GB Grassi 74, 20157, Milan, Italy; Fondazione Europea di Ricerca Biomedica (FERB Onlus), via Ambrogio Uboldo 21, 20063, Cernusco sul Naviglio, Milan, Italy. Electronic address: mario.rosanova@unimi.it. · Fondazione Europea di Ricerca Biomedica (FERB Onlus), via Ambrogio Uboldo 21, 20063, Cernusco sul Naviglio, Milan, Italy; Department of Neurology, University Hospital and Julius-Maximilian-University, Josef-Schneider-Str. 11, 97080, Würzburg, Germany; Parkinson Institute ASST G. Pini-CTO, via Bignami 1, 20126, Milan, Italy. Electronic address: Isaias_I@ukw.de. ·Brain Stimul · Pubmed #30416036.

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 [ 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.

20 Article The prevalence of psychological distress in Parkinson's disease patients: The brief symptom inventory (BSI-18) versus the Hopkins symptom checklist (SCL-90-R). 2019

Carrozzino, Danilo / Siri, Chiara / Bech, Per. ·Psychiatric Research Unit, Psychiatric Centre North Zealand, Copenhagen University Hospital, Hillerød, Denmark; Department of Psychological, Health, and Territorial Sciences, University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy. Electronic address: danilo.carrozzino@unich.it. · Parkinson Institute, ASST G. Pini-CTO, ex ICP, Milan, Italy. · Psychiatric Research Unit, Psychiatric Centre North Zealand, Copenhagen University Hospital, Hillerød, Denmark. ·Prog Neuropsychopharmacol Biol Psychiatry · Pubmed #30017779.

ABSTRACT: The prevalence of psychological distress in Parkinson's disease (PD) patients has been evaluated by many different assessment instruments and with diverse control groups. The most frequently used distress symptom scale has been the Hopkins Symptom Checklist (SCL-90-R), although it contains many symptoms with problematic validity clinically. The 18-item subscale of the SCL-90-R, the Brief Symptom Inventory (BSI-18) has recently been shown to have a sufficient validity to screen for the prevalence of psychological distress (somatization) in PD patients. We have performed a clinimetric analysis by comparing the BSI-18 with SCL-90-R relevant subscales in PD patients. Our micro-analysis has focused on the Mokken model to test the scalability of the subscales. The macro-analysis has focused both on effect size statistics and the normative level of psychological distress with reference to the Italian general population data using T-score metric. The Mokken analysis indicated acceptable scalability for all the subscales of BSI-18. The effect size statistics identified somatization in both BSI-18 and SCL-90-R as the most prevalent and intense symptom of psychological distress. The T-score metric identified the phobic anxiety subscale of SCL-90-R to be clinically much more important than the BSI-18 anxiety subscale in the PD patients. We have found the SCL-90-R subscale of phobic anxiety and the BSI-18 somatization subscale most clinically valid when measuring psychological distress in PD patients.

21 Article Pathological Gambling in Parkinson's disease: Autonomic measures supporting impaired decision-making. 2019

Angioletti, Laura / Siri, Chiara / Meucci, Nicoletta / Pezzoli, Gianni / Balconi, Michela. ·Department of Psychology, Catholic University of the Sacred Heart, Milan, Italy. · Research Unit in Affective and Social Neuroscience, Catholic University of the Sacred Heart, Milan, Italy. · Parkinson Institute, ASST G. Pini-CTO, ex ICP, Milan, Italy. ·Eur J Neurosci · Pubmed #29888425.

ABSTRACT: According to the somatic marker hypothesis, autonomic measures and arousal modulation can reveal a difference in subgroups of patients developing impaired decision-making because of addictions. Previously, pathological gambling (PG) and Parkinson's disease (PD) have been associated with differential arousal levels during gambling behavior. However, no research considered the specific autonomic responses of Parkinson's disease patients with pathological gambling and with a previous history of gambling. Thus, this study investigated skin conductance responses (SCRs), skin conductance level (SCL) and heart rate (HR) during the Iowa Gambling Task (IGT) in two groups of PD patients with gambling disorder, active (PD Gamblers; n = 14) or remitted (PD Non-Gamblers; n = 13) and a control group of patients with Parkinson's disease only (n = 13). Anticipatory autonomic responses to disadvantageous decks and advantageous decks during the Iowa Gambling Task were measured for each participant. The PD Gamblers group performed worse than the PD Non-Gamblers and the control groups at the IGT task and exhibited lower SCRs, SCL, and HR during the decision-making processing of cards belonging to disadvantageous decks. The role of autonomic and behavioral measures was considered.

22 Article Multiparametric MR imaging of Parkinsonisms at 3 tesla: Its role in the differentiation of idiopathic Parkinson's disease versus atypical Parkinsonian disorders. 2018

Calloni, S F / Conte, G / Sbaraini, S / Cilia, R / Contarino, V E / Avignone, S / Sacilotto, G / Pezzoli, G / Triulzi, F M / Scola, E. ·Post-graduation School in Radiodiagnostics, University of Milan, Milan, Italy. Electronic address: calloni.sonia@gmail.com. · Neuroradiology Unit, Ospedale Maggiore Policlinico IRCCS Ca' Granda, Milan, Italy. · Post-graduation School in Radiodiagnostics, University of Milan, Milan, Italy. · Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy. ·Eur J Radiol · Pubmed #30527319.

ABSTRACT: OBJECTIVES: The Nigrosome-1 and putaminal hypointensity depicted on susceptibility-weighted imaging (SWI), and midbrain atrophy assessed on T1-weighted are some of the most common radiological parameters to diagnose Parkinsonism at Magnetic Resonance (MR) imaging. Our aim is to assess the feasibility of these signs in the differentiation of Idiopathic Parkinson's disease (IPD) patients versus disease (DC) and healthy controls (HC) and in the assessment of the Atypical Progressive Parkinsonisms (APPs). METHODS: Presence or loss of the Nigrosome-1 was assessed retrospectively on multiple-echo SWI obtained on a 3 T scan by two neuroradiologists. Results were compared with the 123I-FP-CIT SPECT images. Morphologic diagnostic features suggestive of APPs such as midbrain atrophy and putaminal hypointensity were evaluated by qualitative scores. The midbrain and putaminal scores were summed (combined score) and then added to the Nigrosome-1 score (global score). RESULTS: The study included 126 patients with IPD (n = 56), APPs patients (n = 30; 18 PSP, 3 MSA-C, 9 MSA-P), 16 DC and 24 HC. Sensitivity and specificity of the Nigrosome-1 in discriminating IPD from controls were 96,43% and 85.00%, APPs from controls were 100% and 85%, IPD from APPs were 96,43% and 0% respectively. Combined score for midbrain atrophy and putaminal hypointensity resulted in the most accurate for distinguishing APPs from IPD with a value of ≥ 2 (AUC = 0.98). CONCLUSION: Nigrosome-1 is a valid tool to differentiate IPD-APPs from controls. The combined score of midbrain atrophy and putaminal hypointensity represents a valid diagnostic pointer in the differential diagnosis of APPs from IPD.

23 Article Cortical response to levodopa in Parkinson's disease patients with dyskinesias. 2018

Turco, Francesco / Canessa, Andrea / Olivieri, Chiara / Pozzi, Nicoló G / Palmisano, Chiara / Arnulfo, Gabriele / Marotta, Giorgio / Volkmann, Jens / Pezzoli, Gianni / Isaias, Ioannis U. ·Fondazione Europea di Ricerca Biomedica (FERB Onlus), Milan, Italy. · Department of Informatics, Bioengineering, Robotics and System Engineering, University of Genoa, Genoa, Italy. · Department of Neurology, University Hospital Wuerzburg and Julius-Maximillian-University, Wuerzburg, Germany. · Department of Electronics, Information and Bioengineering, MBMC Lab, Politecnico di Milano, Milan, Italy. · Department of Nuclear Medicine, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy. · Parkinson Institute ASST G. Pini-CTO, Milan, Italy. ·Eur J Neurosci · Pubmed #30117212.

ABSTRACT: Levodopa-induced dyskinesias are a common and disabling side effect of dopaminergic therapy in Parkinson's disease, but their neural mechanisms in vivo are still poorly understood. Besides striatal pathology, the importance of cortical dysfunction has been increasingly recognized. The supplementary motor area in particular, may have a relevant role in dyskinesias onset given its involvement in endogenously generated actions. The aim of the present study was to investigate the levodopa-related cortical excitability changes along with the emergence of levodopa-induced peak-of-dose dyskinesias in subjects with Parkinson's disease. Thirteen patients without dyskinesias and ten with dyskinesias received 200/50 mg fast-acting oral levodopa/benserazide following overnight withdrawal (12 hr) from their dopaminergic medication. We targeted transcranial magnetic stimulation to the supplementary motor area, ipsilateral to the most dopamine-depleted striatum defined with single-photon emission computed tomography with [

24 Article Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease. 2018

Blauwendraat, Cornelis / Reed, Xylena / Kia, Demis A / Gan-Or, Ziv / Lesage, Suzanne / Pihlstrøm, Lasse / Guerreiro, Rita / Gibbs, J Raphael / Sabir, Marya / Ahmed, Sarah / Ding, Jinhui / Alcalay, Roy N / Hassin-Baer, Sharon / Pittman, Alan M / Brooks, Janet / Edsall, Connor / Hernandez, Dena G / Chung, Sun Ju / Goldwurm, Stefano / Toft, Mathias / Schulte, Claudia / Bras, Jose / Wood, Nicholas W / Brice, Alexis / Morris, Huw R / Scholz, Sonja W / Nalls, Mike A / Singleton, Andrew B / Cookson, Mark R / Anonymous7931112. ·Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland. · Department of Molecular Neurosciences, Institute of Neurology, University College London (UCL), London, United Kingdom. · Department of Human Genetics, McGill University, Montréal, Quebec, Canada. · Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada. · Institut National de la Santé et de la Recherche Medicale U1127, Centre National de la Recherche Scientifique-Unité Mixte de Recherché (UMR) 7225, Sorbonne Universités, Université Pierre-et-Marie-Curie, University of Paris 06, UMR S1127, Institut du Cerveau et de la Moelle Épinière, Paris, France. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Dementia Research Institute, UCL, London, United Kingdom. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom. · Department of Medical Sciences and Institute for Research in Biomedicine, University of Aveiro, Aveiro, Portugal. · Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York. · Movement Disorders Institute, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. · Parkinson Institute of Milan, Azienda Socio Sanitaria Territoriale Gaetano Pini/CTO, Milano, Italy. · Department of Neuroscience, Rita Levi Montalcini, University of Turin, Turin, Italy. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · Department of Clinical Neuroscience, UCL Institute of Neurology, London, United Kingdom. · Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland. · Data Tecnica International, Glen Echo, Maryland. ·JAMA Neurol · Pubmed #30039155.

ABSTRACT: Importance: Pathogenic variants in LRRK2 are a relatively common genetic cause of Parkinson disease (PD). Currently, the molecular mechanism underlying disease is unknown, and gain and loss of function (LOF) models of pathogenesis have been postulated. LRRK2 variants are reported to result in enhanced phosphorylation of substrates and increased cell death. However, the double knockout of Lrrk2 and its homologue Lrrk1 results in neurodegeneration in a mouse model, suggesting that disease may occur by LOF. Because LRRK2 inhibitors are currently in development as potential disease-modifying treatments in PD, it is critical to determine whether LOF variants in LRRK2 increase or decrease the risk of PD. Objective: To determine whether LRRK1 and LRRK2 LOF variants contribute to the risk of developing PD. Design, Setting, and Participants: To determine the prevailing mechanism of LRRK2-mediated disease in human populations, next-generation sequencing data from a large case-control cohort (>23 000 individuals) was analyzed for LOF variants in LRRK1 and LRRK2. Data were generated at 5 different sites and 5 different data sets, including cases with clinically diagnosed PD and neurologically normal control individuals. Data were collected from 2012 through 2017. Main Outcomes and Measures: Frequencies of LRRK1 and LRRK2 LOF variants present in the general population and compared between cases and controls. Results: Among 11 095 cases with PD and 12 615 controls, LRRK1 LOF variants were identified in 0.205% of cases and 0.139% of controls (odds ratio, 1.48; SE, 0.571; 95% CI, 0.45-4.44; P = .49) and LRRK2 LOF variants were found in 0.117% of cases and 0.087% of controls (odds ratio, 1.48; SE, 0.431; 95% CI, 0.63-3.50; P = .36). All association tests suggested lack of association between LRRK1 or LRRK2 variants and PD. Further analysis of lymphoblastoid cell lines from several heterozygous LOF variant carriers found that, as expected, LRRK2 protein levels are reduced by approximately half compared with wild-type alleles. Conclusions and Relevance: Together these findings indicate that haploinsufficiency of LRRK1 or LRRK2 is neither a cause of nor protective against PD. Furthermore, these results suggest that kinase inhibition or allele-specific targeting of mutant LRRK2 remain viable therapeutic strategies in PD.

25 Article Beyond 35 years of Parkinson's disease: a comprehensive clinical and instrumental assessment. 2018

Romagnolo, Alberto / Fabbri, Margherita / Merola, Aristide / Montanaro, Elisa / Palermo, Sara / Martone, Tiziana / Seresini, Agostino / Goldwurm, Stefano / Rizzone, Mario Giorgio / Lopiano, Leonardo. ·Department of Neuroscience "Rita Levi Montalcini", University of Turin, Via Cherasco 15, 10124, Turin, Italy. al.romagnolo@gmail.com. · Department of Neuroscience "Rita Levi Montalcini", University of Turin, Via Cherasco 15, 10124, Turin, Italy. · Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisbon, Portugal. · Department of Neurology, Gardner Family Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, Cincinnati, OH, USA. · Department of Psychology, University of Turin, Via Verdi 10, 10124, Turin, Italy. · Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. · Parkinson Institute, ASST "G.Pini-CTO", Via Bignami 1, Milan, 20133, Italy. ·J Neurol · Pubmed #29943201.

ABSTRACT: BACKGROUND: We sought to characterize the clinical, neuropsychological, electrophysiological, and neuroimaging features of Parkinson's disease (PD) after over 35 years since the onset of motor symptoms. METHODS: Five consecutively consenting PD patients treated with subthalamic nucleus deep brain stimulation (STN-DBS) were recruited in a cross-sectional study of motor (Unified PD Rating Scale section-III), non-motor (Non-Motor Symptoms Scale), autonomic (Scale for Outcome in PD-Autonomic), and neuropsychological features associated with the very advanced phase of PD. In addition, patients underwent neurophysiological (autonomic tests and nerve conduction studies) and neuroimaging (brain MRI, RESULTS: There was a sustained motor response to L-dopa (range 14.4-35.6%), STN-DBS (23.3-38.4%), and L-dopa plus STN-DBS (37.8-63.0%). There were mild-to-moderate non-motor symptoms (range 19-83 on a scale of 0 to 360) and autonomic dysfunction (8-28 on a scale of 0-69). Two patients were demented, one had mild cognitive impairment, and two were cognitively preserved. Three patients had a sensory-axonal peripheral neuropathy and two a moderate-to-severe autonomic neuropathy. All cases showed a complete nigro-striatal dopaminergic denervation and a severe cardiovascular noradrenergic denervation. The brain MRI revealed only moderate frontal atrophy. The genetic tests were unremarkable. CONCLUSIONS: Even after more than 35 years of disease, L-dopa  and STN-DBS remain effective on PD cardinal symptoms. Although axial, autonomic, and neuropsychological features may become key determinants of disability, some patients maintain a satisfactory quality of life, without significant motor and non-motor impairment.

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