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Parkinson Disease: HELP
Articles by Paolo Barone
Based on 148 articles published since 2008
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Between 2008 and 2019, Paolo Barone wrote the following 148 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6
1 Review Quality of Life and Nonmotor Symptoms in Parkinson's Disease. 2017

Barone, Paolo / Erro, Roberto / Picillo, Marina. ·Center for Neurodegenerative Diseases (CEMAND), Neuroscience Section, University of Salerno, Salerno, Italy. Electronic address: pbarone@unisa.it. · Center for Neurodegenerative Diseases (CEMAND), Neuroscience Section, University of Salerno, Salerno, Italy; University College London, Institute of Neurology, London, United Kingdom. · Center for Neurodegenerative Diseases (CEMAND), Neuroscience Section, University of Salerno, Salerno, Italy. ·Int Rev Neurobiol · Pubmed #28802930.

ABSTRACT: Health-related quality of life (HRQoL) is defined as "the perception and evaluation by patients themselves of the impact caused on their lives by the disease and its consequences." HRQoL is conceptualized as a combination of physical, psychological, and social well-being in the context of a particular disease. Following earlier studies revolving on the impact of the classic motor symptoms of Parkinson's disease on HRQoL, mounting evidence have been produced that nonmotor symptoms (NMS) significantly and independently contribute to worse HRQoL. This holds particularly true for such NMS such as neuropsychiatric disturbances, cognitive impairment, and fatigue, the burden of which might well exceed the effects of the motor symptoms. Nonetheless, there is very sparse evidence on how to manage these NMS and whether targeting NMS would in fact lead to an improvement of HRQoL, which calls for the need of future trials with NMS as primary outcomes.

2 Review The relationship between Impulse Control Disorders and cognitive dysfunctions in Parkinson's Disease: A meta-analysis. 2017

Santangelo, Gabriella / Raimo, Simona / Barone, Paolo. ·Department of Psychology, University of Campania Luigi Vanvitelli, Caserta, Italy. Electronic address: gabriella.santangelo@unina2.it. · Department of Psychology, University of Campania Luigi Vanvitelli, Caserta, Italy. · Department of Medicine, Center for Neurodegenerative Diseases (CEMAND), University of Salerno, Italy. ·Neurosci Biobehav Rev · Pubmed #28242338.

ABSTRACT: Impulse Control Disorders (ICD) are associated with impairment in cognitive flexibility and cortical inhibition. In Parkinson's Disease (PD) the relationship between ICD and cognitive dysfunctions is still unclear: some studies found different cognitive profiles between Parkinsonians with and without ICD, whereas others did not. Moreover, findings from studies on ICD in PD are conflicting on which cognitive function is altered. A meta-analysis of 34 studies was performed to shed light on relationship between ICD and cognitive dysfunctions and to reveal the cognitive function compromised in Parkinsonians with ICD. Data were analysed in global cognitive functioning, memory, executive functions, attention/working memory, language, and visuospatial functions. Significant relationship between ICD and dysfunction of abstraction ability/concept formation, set-shifting, visuospatial/constructional abilities and decision-making was found. These findings suggested that people affected by PD with specific frontal dysfunctions are more vulnerable to develop ICD when they take antiparkinsonian drug. Evaluation of specific cognitive functions in routine clinical practice might help to detect those people with PD susceptible to ICD before treating them with antiparkinsonian drugs.

3 Review Walking on four limbs: A systematic review of Nordic Walking in Parkinson disease. 2017

Bombieri, Federica / Schena, Federico / Pellegrini, Barbara / Barone, Paolo / Tinazzi, Michele / Erro, Roberto. ·Department of Neuroscience, Biomedicine and Movement Sciences, Università di Verona, Verona, Italy. · Department of Neuroscience, Biomedicine and Movement Sciences, Università di Verona, Verona, Italy; CeRiSM (Research Centre of Mountain Sport and Health), University of Verona, Rovereto, Italy. · Center for Neurodegenerative Diseases (CEMAND), Department of Medicine and Surgery, Neuroscience Section, University of Salerno, Salerno, Italy. · Department of Neuroscience, Biomedicine and Movement Sciences, Università di Verona, Verona, Italy. Electronic address: michele.tinazzi@univr.it. · Center for Neurodegenerative Diseases (CEMAND), Department of Medicine and Surgery, Neuroscience Section, University of Salerno, Salerno, Italy; Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London, United Kingdom. ·Parkinsonism Relat Disord · Pubmed #28202374.

ABSTRACT: Nordic Walking is a relatively high intensity activity that is becoming increasingly popular. It involves marching using poles adapted from cross-country skiing poles in order to activate upper body muscles that would not be used during normal walking. Several studies have been performed using this technique in Parkinson disease patients with contradictory results. Thus, we reviewed here all studies using this technique in Parkinson disease patients and further performed a meta-analysis of RCTs where Nordic Walking was evaluated against standard medical care or other types of physical exercise. Nine studies including four RCTs were reviewed for a total of 127 patients who were assigned to the Nordic Walking program. The majority of studies reported beneficial effects of Nordic Walking on either motor or non-motor variables, but many limitations were observed that hamper drawing definitive conclusions and it is largely unclear whether the benefits persist over time. It would appear that little baseline disability is the strongest predictor of response. The meta-analysis of the 4 RCTs yielded a statistically significant reduction of the UPDRS-3 score, but its value of less than 1 point does not appear to be clinically meaningful. Well-designed, large RCTs should be performed both against standard medical care and other types of physical exercise to definitively address whether Nordic Walking can be beneficial in PD.

4 Review Personality in Parkinson's disease: Clinical, behavioural and cognitive correlates. 2017

Santangelo, Gabriella / Piscopo, Fausta / Barone, Paolo / Vitale, Carmine. ·Department of Psychology, University of Campania Luigi Vanvitelli, Caserta, Italy; Institute of Diagnosis and Health, Hermitage-Capodimonte, Naples, Italy. · Institute of Diagnosis and Health, Hermitage-Capodimonte, Naples, Italy; Neurodegenerative Diseases Centre, Department of Medicine and Surgery, University of Salerno, Italy. · Institute of Diagnosis and Health, Hermitage-Capodimonte, Naples, Italy; Department of Motor Sciences and Health, University "Parthenope", Naples, Italy. Electronic address: cavit69@hotmail.com. ·J Neurol Sci · Pubmed #28087060.

ABSTRACT: Affective disorders and personality changes have long been considered pre-motor aspects of Parkinson's disease (PD). Many authors have used the term "premorbid personality" to define distinctive features of PD patients' personality characterized by reduced exploration of new environmental stimuli or potential reward sources ("novelty seeking") and avoidance behaviour ("harm avoidance") present before motor features. The functional correlates underlying the personality changes described in PD, implicate dysfunction of meso-cortico-limbic and striatal circuits. As disease progresses, the imbalance of neurotransmitter systems secondary to degenerative processes, along with dopamine replacement therapy, can produce a reversal of behaviours and an increase in reward seeking, laying the foundations for the emergence of the impulse control disorders. Personality disorders can be interpreted, therefore, as the result of individual susceptibility arising from intrinsic degenerative processes and individual personality features, in combination with extrinsic factors such as lifestyle, PD motor dysfunction and drug treatment. For a better understanding of personality disorders observed in PD and their relationship with the prodromal stage of the disease, prospective clinical studies are needed that correlate different personality profiles with other disease progression markers. Here, we review previous studies investigating the clinical, cognitive and behavioural correlates of personality traits in PD patients.

5 Review The relevance of gender in Parkinson's disease: a review. 2017

Picillo, Marina / Nicoletti, Alessandra / Fetoni, Vincenza / Garavaglia, Barbara / Barone, Paolo / Pellecchia, Maria Teresa. ·Center for Neurodegenerative Diseases (CEMAND), Department of Medicine and Surgery, Neuroscience Section, University of Salerno, Salerno, 84131, Italy. picillo.marina@gmail.com. · Section of Neurosciences, Department GF Ingrassia, University of Catania, Catania, Italy. · Neurologia Fatebenefratelli-ASST Fatebenefratelli Sacco, Milan, Italy. · Molecular Neurogenetics Unit, IRCCS Foundation Neurological Institute "Carlo Besta", Milan, Italy. · Center for Neurodegenerative Diseases (CEMAND), Department of Medicine and Surgery, Neuroscience Section, University of Salerno, Salerno, 84131, Italy. ·J Neurol · Pubmed #28054129.

ABSTRACT: Since the official and systematic inclusion of sex and gender in biomedical research, gender differences have been acknowledged as important determinants of both the susceptibility to develop neurodegenerative diseases in general population and the clinical and therapeutic management of neurodegenerative patients. In this review, we gathered the available evidence on gender differences in Parkinson's disease (PD) regarding clinical phenotype (including motor and non-motor symptoms), biomarkers, genetics and therapeutic management (including pharmacological and surgical treatment). Finally, we will briefly discuss the role of estrogens in determining such differences. Several data demonstrate that PD in women starts with a more benign phenotype, likely due to the effect of estrogens. However, as the disease progresses, women are at higher risk of developing highly disabling treatment-related complications, such as motor and non-motor fluctuations as well as dyskinesia, compared with men. In addition, women have lower chances of receiving effective treatment for PD as deep brain stimulation. Taken together these findings challenge the definition of a more benign phenotype in women. Still, much work needs to be done to better understand the interaction between gender, genetics and environmental factors in determining the PD risk and clinical features. Improving our understanding in this field may result in implementation of strategies to identify prodromal PD and speed efforts to discern new directions for disease tailored treatment and management.

6 Review Toward the premotor diagnosis of Parkinson's disease: Suggestions from a modelling study. 2015

Erro, Roberto / Barone, Paolo. ·Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom. · Dipartimento di Scienze Neurologiche e del Movimento, Università di Verona, Verona, Italy. · University of Salerno Center for Neurodegenerative Disease-CEMAND, Salerno, Italy. ·Mov Disord · Pubmed #26575210.

ABSTRACT: -- No abstract --

7 Review Recruitment strategies and patient selection in clinical trials for Parkinson's disease: Going viral and keeping science and ethics at the highest standards. 2015

Picillo, Marina / Kou, Nancy / Barone, Paolo / Fasano, Alfonso. ·Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital and Division of Neurology, University of Toronto, Toronto, ON, Canada; Centre for Neurodegenerative Diseases (CEMAND), Department of Medicine and Surgery, University of Salerno, Salerno, Italy. · Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital and Division of Neurology, University of Toronto, Toronto, ON, Canada. · Centre for Neurodegenerative Diseases (CEMAND), Department of Medicine and Surgery, University of Salerno, Salerno, Italy. · Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital and Division of Neurology, University of Toronto, Toronto, ON, Canada. Electronic address: alfonso.fasano@gmail.com. ·Parkinsonism Relat Disord · Pubmed #26228079.

ABSTRACT: INTRODUCTION: Enrollment of an adequate number of suitable candidates is a critical component of good quality randomized controlled trials (RCTs). Parkinson's disease (PD) is a highly heterogeneous disease and recruiting a large and homogeneous sample of patients is often challenging. Further, PD patients are often elderly, cognitively impaired and disabled, thus requiring the assistance from their caregivers for participation in RCTs. Only a limited number of studies have explored the effectiveness of recruitment strategies and PD patient selection in clinical trials. We aim to review the four crucial recruitment components of RCTs (i.e. infrastructure, nature of the research, recruiter characteristics and participant characteristics) with particular implications in PD, and to explore strategies to improve recruitment and patient selection in RCTs in PD. CONCLUSION: Movement disorders centers have a key role in managing recruitment and patient selection in RCTs in PD. Key recommendations within the infrastructure component are to improve trust and communication between patient and participant, and to consider the diversity, perceived disadvantages, and health care accessibility of the participants. Further, study designs that involve participant's opinions and considers placebo and lessebo effects are highly recommended for the nature of the research component of RCTs. Finally, a team-based approach with recruiters and participants that establishes relationships between researchers and the community and addresses ethical considerations are encouraged as part of the recruiters and participants components. Finally, we envisage a greater usage of internet-based strategies for clinical trials recruitment in PD with the goal of 'going viral' with the recruitment.

8 Review Cognitive contributions to gait and falls: evidence and implications. 2013

Amboni, Marianna / Barone, Paolo / Hausdorff, Jeffrey M. ·Isituto di Diagnosi e Cura Hermitage-Capodimonte, Naples, Italy; Neurodegenerative Diseases Center, Department of Medicine and Surgery, University of Salerno, Salerno, Italy. ·Mov Disord · Pubmed #24132840.

ABSTRACT: Dementia and gait impairments often coexist in older adults and patients with neurodegenerative disease. Both conditions represent independent risk factors for falls. The relationship between cognitive function and gait has recently received increasing attention. Gait is no longer considered merely automated motor activity but rather an activity that requires executive function and attention as well as judgment of external and internal cues. In this review, we intend to: (1) summarize and synthesize the experimental, neuropsychological, and neuroimaging evidence that supports the role played by cognition in the control of gait; and (2) briefly discuss the implications deriving from the interplay between cognition and gait. In recent years, the dual task paradigm has been widely used as an experimental method to explore the interplay between gait and cognition. Several neuropsychological investigations have also demonstrated that walking relies on the use of several cognitive domains, including executive-attentional function, visuospatial abilities, and even memory resources. A number of morphological and functional neuroimaging studies have offered additional evidence supporting the relationship between gait and cognitive resources. Based on the findings from 3 lines of studies, it appears that a growing body of evidence indicates a pivotal role of cognition in gait control and fall prevention. The interplay between higher-order neural function and gait has a number of clinical implications, ranging from integrated assessment tools to possible innovative lines of interventions, including cognitive therapy for falls prevention on one hand and walking program for reducing dementia risk on the other.

9 Review Pathological gambling in Parkinson's disease. A comprehensive review. 2013

Santangelo, Gabriella / Barone, Paolo / Trojano, Luigi / Vitale, Carmine. ·Neuropsychology Laboratory, Department of Psychology, Second University of Naples, Caserta, Italy. gabriella.santangelo@unina2.it ·Parkinsonism Relat Disord · Pubmed #23490464.

ABSTRACT: Pathological gambling (PG) and other Impulse Control Disorders (ICDs), such as hypersexuality, compulsive eating and buying, are often reported in Parkinson's disease (PD). The prevalence of PG is 2.2%-7% in treated PD patients, which is higher than the background population rate. As other non motor symptoms in PD, PG is frequently under-reported by patients and caregivers and may be under-recognized by the treating physicians. Factors associated with PG include male sex, younger age or younger age at PD onset, personal or family history of substance abuse or ICD, a personality profile characterized by impulsiveness, and treatment with dopamine agonists (DA) more than with levodopa (l-dopa). The DA effect seems to be a class effect and not specific for any DA. Neurofunctional studies suggest that medication-induced downregulation of frontostriatal connections and upregulation of striatum might combine to induce impulsive behavior. A dysfunction of fronto-subcortical circuits in PD patients with PG is also supported by neuropsychological findings of impaired executive control and monitoring abilities. Management of ICDs in PD is complex, and until now only discontinuation and/or tapering of DA treatment seem to be an effective management strategy for ICDs in PD. There is no empirical evidence supporting the use of psychiatric drugs for PG such as antipsychotics and antidepressants. Data regarding the effect of deep brain stimulation (DBS), particularly of subthalamic nucleus, on PG and ICDs in PD are still limited and sometimes conflicting since improvement of PG or new onset of PG after surgery have been reported.

10 Review Apathy in Parkinson's disease: diagnosis, neuropsychological correlates, pathophysiology and treatment. 2013

Santangelo, Gabriella / Trojano, Luigi / Barone, Paolo / Errico, Domenico / Grossi, Dario / Vitale, Carmine. ·Department of Psychology, Second University of Naples, Caserta, Italy Istituto di Diagnosi e Cura "Hermitage Capodimonte", Naples, Italy. ·Behav Neurol · Pubmed #23242365.

ABSTRACT: Apathy has been defined as lack of motivation. It has been traditionally considered as a symptom of psychiatric disorders, such as major depression and schizophrenia, but more recently it has been recognized as a specific neuropsychiatric syndrome associated with neurodegenerative such as Parkinson's disease (PD). As a consequence the reported prevalence of apathy in PD ranges from 13.9% to 70%; the mean prevalence is 35%. Prevalence of "pure apathy" (i.e., of apathy without comorbid depression and dementia) seems to be substantially lower, from 3 to 47.9%. High levels of apathy in PD are associated with decreased daily function, specific cognitive deficits and increased stress for families. Although neuroimaging studies do not provide a unique anatomic pattern, several data suggest that the ventromedial prefrontal cortex and the basal ganglia connected through frontal-subcortical circuits, are particularly involved in the genesis of apathy. At present, there are no approved medications for the treatment of apathy in and no proof of efficacy exists for any drug in current use. Further studies and innovative pharmacologic approaches are thus needed to ameliorate our understanding and treatment of apathy in PD.

11 Review Continuous intestinal infusion of levodopa/carbidopa in advanced Parkinson's disease: efficacy, safety and patient selection. 2012

Abbruzzese, Giovanni / Barone, Paolo / Bonuccelli, Ubaldo / Lopiano, Leonardo / Antonini, Angelo. ·Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Italy. ·Funct Neurol · Pubmed #23402675.

ABSTRACT: Long-term oral therapy with levodopa is associated with the development of motor fluctuations and dyskinesia in a large percentage of patients with Parkinson's disease (PD). Motor complications are associated with a number of non-motor symptoms and have a negative impact on disability and quality of life. There are three therapeutic options available for the management of patients at this advanced stage: high frequency deep brain stimulation, continuous subcutaneous infusion of apomorphine, and continuous intestinal infusion of levodopa/carbidopa. On the basis of published data and in consideration of the risk-benefit profile of current therapeutic strategies, we here propose an algorithm to help clinicians select the most suitable treatment option for patients with advanced PD.

12 Review Identifying prodromal Parkinson's disease: pre-motor disorders in Parkinson's disease. 2012

Postuma, Ronald B / Aarsland, Dag / Barone, Paolo / Burn, David J / Hawkes, Christopher H / Oertel, Wolfgang / Ziemssen, Tjalf. ·Department of Neurology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada. ronald.postuma@mcgill.ca ·Mov Disord · Pubmed #22508280.

ABSTRACT: Increasing recognition that Parkinson's disease (PD) may start outside of the substantia nigra has led to a rapidly expanding effort to define prodromal stages of PD, before motor signs permit classical diagnosis. Many of these efforts center around the identification of clinical non-motor symptoms and signs of disease. There is now direct evidence that olfaction, rapid eye movement (REM) sleep behavior disorder (RBD), constipation, and depression can be present in prodromal PD. In addition, there is suggestive evidence that visual changes, other autonomic symptoms, and subtle cognitive changes may also be present at prodromal stages. A critical issue in utility of these prodromal markers will be assessment of sensitivity, specificity, and positive and negative predictive values. Although these have yet to be fully defined, olfactory deficits, some visual changes, and autonomic symptoms occur in the majority of PD patients at diagnosis, suggesting good potential sensitivity. However, with the exception of RBD and perhaps some specific autonomic measures, specificity, and positive predictive value of these markers may be insufficient to be used alone as identifiers of prodromal disease. The evidence for the utility of olfaction, RBD, autonomic markers, visual changes, mood disorders, and cognitive loss as markers of prodromal PD and the potential sensitivity and specificity of these markers are summarized.

13 Review Cognitive impairment in nondemented Parkinson's disease. 2011

Barone, Paolo / Aarsland, Dag / Burn, David / Emre, Murat / Kulisevsky, Jaime / Weintraub, Daniel. ·Department of Neurological Sciences, University Federico II-ICD Hermitage, Capodimonte, Naples, Italy. barone@unina.it ·Mov Disord · Pubmed #22170275.

ABSTRACT: A substantial percentage of patients with newly diagnosed Parkinson's disease without dementia are reported to be affected by cognitive impairment (CI). In practice, however, CI is underrecognized, as the signs may not be apparent in early-stage disease and many routine assessment tools lack the sensitivity to detect subtle cognitive dysfunction. Patients with PD and mild CI (MCI) may have a higher risk of developing dementia than cognitively intact PD patients; however, it is not currently known which patients with CI are at increased risk of developing dementia. This review summarizes current knowledge about CI in nondemented PD; it discusses the structural and functional changes associated with CI and addresses areas of unmet needs. We focus on questions that should be addressed in future studies to achieve consensus on its characteristics and definition, pathophysiology, epidemiology, diagnosis and assessment, and treatment and management.

14 Review Effects of cholinesterase inhibitors in Parkinson's disease dementia: a review of clinical data. 2011

van Laar, Teus / De Deyn, Peter Paul / Aarsland, Dag / Barone, Paolo / Galvin, James E. ·Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. t.van.laar@neuro.umcg.n ·CNS Neurosci Ther · Pubmed #21951368.

ABSTRACT: AIMS: Cognitive impairment and dementia are common features of Parkinson's disease (PD). Patients with Parkinson's disease dementia (PDD) often have significant cholinergic defects, which may be treated with cholinesterase inhibitors (ChEIs). The objective of this review was to consider available efficacy, tolerability, and safety data from studies of ChEIs in PDD. DISCUSSIONS: A literature search resulted in the identification of 20 relevant publications. Of these, the treatment of PD patients with rivastigmine, donepezil, or galantamine was the focus of six, eleven, and two studies respectively, while one study reported use of both tacrine and donepezil. The majority of studies were small (<40 patients), with the exception of two large randomized controlled trials (RCTs) that are the main focus of this review. In the smaller studies, treatment benefits were reported on a range of outcome measures, though results were extremely variable. While the full results of a large RCT of donepezil in patients with PDD are not yet available, significant treatment differences were reported on the CIBIC-plus at the highest treatment dose. A trend toward improvement was also observed in treated patients on the ADAS-cog. The second large RCT found significant improvements in rivastigmine-treated patients compared with placebo on both the ADAS-cog (P < 0.001) and the ADCS-CGIC (P < 0.007), as well as on all secondary efficacy outcomes. Consequently, rivastigmine is now widely approved for the symptomatic treatment of mild to moderate PDD. CONCLUSIONS: Taken together, these studies suggest that ChEIs are efficacious in the treatment of PDD.

15 Review Role of pramipexole in the management of Parkinson's disease. 2010

Antonini, Angelo / Barone, Paolo / Ceravolo, Roberto / Fabbrini, Giovanni / Tinazzi, Michele / Abbruzzese, Giovanni. ·Department for Parkinson Disease, IRCCS San Camillo, Venice, Italy. angelo3000@yahoo.com ·CNS Drugs · Pubmed #20839895.

ABSTRACT: The non-ergot dopamine agonist pramipexole is currently indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease and for the treatment of moderate-to-severe primary restless legs syndrome. A new extended-release formulation of pramipexole has now also been launched in Europe and the US to improve ease of use, compliance and provide a more continuous therapeutic effect over 24 hours. Before initiating any treatment, the benefit-risk ratio to the individual patient must be considered. For pramipexole in the treatment of Parkinson's disease, this means taking into account the available evidence regarding its symptomatic efficacy, effect on delaying long-term levodopa-related motor complications, beneficial effect on non-motor symptoms such as depression, and its safety and tolerability profile. Studies have shown that pramipexole is effective as monotherapy in early Parkinson's disease and as adjunctive therapy in advanced disease. Trials further suggest that the benefits of pramipexole may extend beyond the relief of motor symptoms (akinesia, rigidity and tremor at rest) to the amelioration of depressive symptoms in Parkinson's disease. Pramipexole is generally well tolerated; however, compared with levodopa treatment, pramipexole is associated with a higher rate of some dopaminergic adverse effects.

16 Review Dopamine receptor agonists and depression in Parkinson's disease. 2009

Picillo, Marina / Rocco, Mariangela / Barone, Paolo. ·Department of Neurological Sciences, University of Naples Federico II, Naples, Italy. ·Parkinsonism Relat Disord · Pubmed #20123564.

ABSTRACT: Depression is one of the most common non-motor symptoms in Parkinson's disease (PD). It is associated with a more rapid progression of physical symptoms, greater decline in cognitive skills, and a poorer quality of life. Despite the high prevalence of depression and antidepressant use in PD, validated guidelines for the treatment of PD-associated depression (dPD) are lacking. Several methodological limitations have been recognized in the available studies examining the treatment of dPD. Some studies support a relevant role of the catecholaminergic systems in the pathogenesis of dPD. In open-label studies, the dopamine receptor agonists pramipexole and pergolide have shown antidepressant effects in PD patients. A placebo-controlled study of pramipexole in dPD is ongoing. The combined results of data from animal models and evidence in human studies support the strategy of dopaminergic stimulation as a treatment of depression. Treatment strategies for depressive symptoms in PD should include optimization of dopaminergic treatment prior to the addition of classic antidepressant drugs, thus reducing the risk of side-effects associated with multi-drug therapies.

17 Review Dopamine agonist-based strategies in the treatment of Parkinson's disease. 2008

Antonini, Angelo / Barone, Paolo. ·Istituti Clinici di Perfezionamento, Parkinson Institute, Via Bignami 1, Milan, Italy. angelo3000@yahoo.com ·Neurol Sci · Pubmed #19381765.

ABSTRACT: More therapeutic options have become available for Parkinson's disease (PD) in recent years, leading to significant improvements in motor control both at early and advanced disease stages. More importantly, the need to expand disease management beyond motor symptom control has been recently highlighted and contribution of non-motor features to quality of life is now relevant. Dopamine agonists represent a valid therapeutic option in PD and their effect on non-motor domains like mood or cognition is now acknowledged as a key factor in fully addressing patients' needs. Pramipexole is a well established dopamine agonist that is currently being investigated for its potential disease-modifying effect and action on mood in PD. In this review we will examine factors contributing to treatment decision-making and discuss how a proper balance between motor and non-motor features should be aimed for in approaching PD therapy.

18 Clinical Trial Effects of Safinamide on Pain in Fluctuating Parkinson's Disease Patients: A Post-Hoc Analysis. 2017

Cattaneo, Carlo / Barone, Paolo / Bonizzoni, Erminio / Sardina, Marco. ·Medical Department, Zambon SpA, Bresso (MI), Italy. · Centre for Neurodegenerative Diseases (CEMAND), Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy. · Department of Clinical Science and Community, Section of Medical Statistics and Biometry "GA Maccacaro", University of Milan, Milan, Italy. · R&D Department, Zambon SpA, Bresso (MI), Italy. ·J Parkinsons Dis · Pubmed #27802242.

ABSTRACT: BACKGROUND: Pain, a frequent non-motor symptom in Parkinson's Disease (PD), significantly impacts on quality of life. Safinamide is a new drug with dopaminergic and non-dopaminergic properties, approved in Europe as adjunct therapy to levodopa for the treatment of fluctuating PD patients. Results from two 24-month, double-blind, placebo-controlled studies demonstrated that safinamide has positive effects on both motor functions and quality of life in PD patients. OBJECTIVE: To investigate the effects of safinamide on pain management in PD patients with motor fluctuations using pooled data from studies 016 and SETTLE. METHODS: This post-hoc analysis evaluated the reduction of concomitant pain treatments and the changes in the scores of the items related to pain of the Parkinson's Disease Quality of Life Questionnaire (PDQ-39). A path analysis was performed in order to examine direct and indirect associations between safinamide and PDQ-39 pain-related items assessed after 6-months of treatment. RESULTS: The percentage of patients with no pain treatments at the end of the trials was significantly lower in the safinamide group compared to the placebo group. Safinamide 100 mg/day significantly reduced on average the individual use of pain treatments by ≈24% and significantly improved two out of three PDQ-39 pain-related items of the "Bodily discomfort" domain.Path analysis showed that the direct effect of safinamide on pain accounted for about 80% of the total effect. CONCLUSIONS: These results suggest that safinamide may have a positive effect on pain, one of the most underestimated non-motor symptoms. Prospective studies are warranted to investigate this potential benefit.

19 Clinical Trial Efficacy, safety, and tolerability of overnight switching from immediate- to once daily extended-release pramipexole in early Parkinson's disease. 2010

Rascol, Olivier / Barone, Paolo / Hauser, Robert A / Mizuno, Yoshikuni / Poewe, Werner / Schapira, Anthony H V / Salin, Laurence / Sohr, Mandy / Debieuvre, Catherine / Anonymous5680666. ·Departments of Clinical Pharmacology and Neurosciences, Toulouse University Hospital, INSERM CIC9302-UMR825 Toulouse, France. rascol@cict.fr ·Mov Disord · Pubmed #20669265.

ABSTRACT: The aim of this article is to test the feasibility, in early Parkinson's disease (PD), of an overnight switch from immediate-release (IR) pramipexole to a new once-daily extended-release (ER) formulation. Nonfluctuating patients on pramipexole IR three-times daily, alone or with levodopa, for early PD were randomly switched overnight to double-blind IR three-times daily (N = 52) or ER once-daily (N = 104) at initially unchanged daily dosage. Successful switching (defined as no worsening >15% of baseline UPDRS II+III score and no drug-related adverse event withdrawal) was assessed at 9 weeks, after optional dosage adjustments (primary endpoint), and at 4 weeks, before adjustment. Other secondary endpoints included adjusted mean changes from baseline in UPDRS scores and proportion of responders based on Clinical or Patient Global Impression (CGI/PGI). Absolute difference between percentage of successful switch to ER versus IR was tested for ER noninferiority, defined as a 95% confidence-interval lower bound not exceeding -15%. At 9 weeks, 84.5% of the ER group had been successfully switched, versus 94.2% for IR. Noninferiority was not demonstrated, with a difference of -9.76% (95% CI: [-18.81%, +1.66%]). At 4 weeks, 81.6% of the ER group had been successfully switched, versus 92.3% for IR, a difference of -10.75% (95% CI: [-20.51%, +1.48%]). UPDRS changes and CGI/PGI analyses showed no differences between the groups. Both formulations were safe and well tolerated. Pramipexole ER was not equivalent to IR, but the difference was marginal. The fact that >80% of the patients successfully switched overnight at unchanged dosage shows that this practice was feasible in most patients.

20 Clinical Trial Rivastigmine versus placebo in hyperhomocysteinemic Parkinson's disease dementia patients. 2008

Barone, Paolo / Burn, David J / van Laar, Teus / Hsu, Chuanchieh / Poewe, Werner / Lane, Roger M. ·Dipartimento di Scienze Neurologiche, Università Federico II di Napoli, Naples, Italy. barone@unina.it ·Mov Disord · Pubmed #18581467.

ABSTRACT: The effects of rivastigmine versus placebo in Parkinson's disease dementia (PDD) patients with elevated or normal/low plasma homocysteine were determined. In this prospective analysis of a 24-week, randomly assigned, placebo-controlled study of rivastigmine in PDD, subpopulations comprised patients with plasma homocysteine >or=14 micromol/L (elevated) or <14 micromol/L (normal/low). Coprimary outcomes were the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Alzheimer Disease Cooperative Society-Clinical Global Impression of Change (ADCS-CGIC). Secondary outcomes included additional measures of cognition, including attention and executive function, daily function, and neuropsychiatric symptoms. Adverse events (AEs) were monitored. In total, 342 of 541 patients provided samples for analysis, from which 72% had elevated plasma homocysteine. Hyperhomocysteinemic patients showed treatment differences (rivastigmine vs. placebo) of 4.0 on ADAS-cog and 0.7 on ADCS-CGIC (both P < 0.01), and significant treatment differences on secondary outcomes. Rivastigmine- and placebo-treated hyperhomocysteinemic patients (16.5% and 14.6%) discontinued the study because of AEs. Patients with normal/low homocysteine showed no treatment differences on primary or secondary outcomes (1.4 on the ADAS-cog and 0.1 on ADCS-CGIC, both P = ns); 16.7% and 10.3% rivastigmine- and placebo-treated patients discontinued because of AEs. Elevated homocysteine was associated with greater rivastigmine treatment differences than normal/low homocysteine.

21 Article Comparative cognitive and neuropsychiatric profiles between Parkinson's disease, multiple system atrophy and progressive supranuclear palsy. 2018

Santangelo, Gabriella / Cuoco, Sofia / Pellecchia, Maria Teresa / Erro, Roberto / Barone, Paolo / Picillo, Marina. ·Department of Psychology, University of Campania "Luigi Vanvitelli", Caserta, Italy. gabriella.santangelo@unicampania.it. · Center for Neurodegenerative Diseases (CEMAND), Department of Medicine and Surgery, Neuroscience Section, University of Salerno, Fisciano, Italy. ·J Neurol · Pubmed #30178175.

ABSTRACT: BACKGROUND: Parkinsonian syndromes are characterized by a wide spectrum of non-motor symptoms. A few studies explored cognitive deficits and neuropsychiatric symptoms in atypical parkinsonism compared to Parkinson's disease (PD). The study was performed to identify cognitive and neuropsychiatric differences between PD, multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) and to evaluate the influence of clinical features, depressive symptomatology and apathy on cognitive performances in the three groups. METHODS: Fifty-five PD, 44 MSA and 42 PSP patients underwent cognitive tests assessing attention, language, memory, visuospatial and executive functions as well as scales assessing depression and apathy. Out of these patients, 20 PD, 20 MSA and 20 PSP patients were selected to be matched for age, education and global cognitive status. Within each whole patients group, correlational analysis was performed between clinical, behavioural and cognitive parameters. RESULTS: The main difference among the groups matched was on cognitive tests exploring verbal learning, executive and linguistic functions. The PSP group was more impaired than the PD and MSA groups on cognitive tests assessing executive functions. On the other hand, MSA group obtained similar cognitive performance to the PD group. As to behavioural symptoms, in whole PSP and MSA groups, apathy and depression were more severe than in PD group, while apathy (but not depression) were more severe in the PSP group as compared to the MSA group. CONCLUSIONS: The present study underlined the pervasiveness of cognitive deficits, apathy and depressive symptoms in PSP, whereas little cognitive differences were found between PD and MSA. The findings indirectly supported a dysfunction of prefronto-subcortical circuitries (i.e., dorsolateral prefrontal and limbic circuits) in PSP and PD. Cognitive similarities between MSA and PD reinforced the pivotal role of altered basal ganglia and corresponding frontal deafferentation in the occurrence of the cognitive deficits.

22 Article Cognition among individuals along a spectrum of increased risk for Parkinson's disease. 2018

Chahine, Lana M / Urbe, Liz / Caspell-Garcia, Chelsea / Aarsland, Dag / Alcalay, Roy / Barone, Paolo / Burn, David / Espay, Alberto J / Hamilton, Jamie L / Hawkins, Keith A / Lasch, Shirley / Leverenz, James B / Litvan, Irene / Richard, Irene / Siderowf, Andrew / Coffey, Christopher S / Simuni, Tanya / Weintraub, Daniel / Anonymous1301056. ·University of Pittsburgh, Pittsburgh, PA, United States of America. · The University of Iowa, Iowa City, Iowa, United States of America. · Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, England. · Columbia University Medical Center, Department of Neurology, New York, NY, United States of America. · Department of Medicine and Surgery, Center for Neurodegenerative Diseases, University of Salerno, Fisciano, Italy. · Institute for Ageing and Health, Newcastle University, Newcastle, United Kingdom. · Department of Neurology, University of Cincinnati Academic Health Center, Cincinnati, OH, United States of America. · The Michael J. Fox Foundation for Parkinson's Research, New York, NY, United States of America. · Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States of America. · Institute for Neurodegenerative Disorders, New Haven, CT, United States of America. · Cleveland Clinic, Cleveland, OH, United States of America. · UCSD Movement Disorder Center, Department of Neurosciences, University of California San Diego, San Diego, CA, United States of America. · Departments of Neurology and Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States of America. · Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States of America. · Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America. · Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, United States of America. · Parkinson's Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC), Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, United States of America. ·PLoS One · Pubmed #30125297.

ABSTRACT: INTRODUCTION: Several characteristics associated with increased risk for Parkinson's disease (PD) have been identified, including specific genotypes and various non-motor symptoms. Characterizing non-motor features, such as cognitive abilities, among individuals considered at-risk for PD is essential to improving prediction of future neurodegeneration. METHODS: Participants belonging to the following cohorts of the Parkinson Progression Markers Initiative (PPMI) study were included: de novo PD with dopamine transporter binding deficit (n = 423), idiopathic REM sleep behavior disorder (RBD, n = 39), hyposmia (n = 26) and non-PD mutation carrier (NMC; Leucine-rich repeat kinase 2 (LRRK2) G2019S (n = 88) and glucocerebrosidase (GBA) gene (n = 38) mutations)). Inclusion criteria enriched the RBD and hyposmia cohorts, but not the NMC cohort, with individuals with dopamine transporter binding deficit. Baseline neuropsychological performance was compared, and analyses were adjusted for age, sex, education, and depression. RESULTS: The RBD cohort performed significantly worse than the hyposmia and NMC cohorts on Symbol Digit Modality Test (mean (SD) 32.4 (9.16) vs. 41.8 (9.98), p = 0.002 and vs. 45.2 (10.9), p<0.001) and Judgment of Line Orientation (11.3 (2.36) vs.12.9 (1.87), p = 0.004 and vs. 12.9 (1.87), p<0.001). The RBD cohort also performed worse than the hyposmia cohort on the Montreal Cognitive Assessment (25.5 (4.13) vs. 27.3 (1.71), p = 0.02). Hyposmics did not differ from PD or NMC cohorts on any cognitive test score. CONCLUSION: Among individuals across a spectrum of risk for PD, cognitive function is worse among those with the characteristic most strongly associated with future risk of PD or dementia with Lewy bodies, namely RBD.

23 Article Step length predicts executive dysfunction in Parkinson's disease: a 3-year prospective study. 2018

Amboni, Marianna / Iuppariello, Luigi / Iavarone, Alessandro / Fasano, Alfonso / Palladino, Raffaele / Rucco, Rosaria / Picillo, Marina / Lista, Ilaria / Varriale, Pasquale / Vitale, Carmine / Cesarelli, Mario / Sorrentino, Giuseppe / Barone, Paolo. ·Department of Medicine and Surgery "Scuola Medica Salernitana", Center for Neurodegenerative Diseases, University of Salerno, Via S. Allende, 1, 84081, Baronissi, SA, Italy. marianna.amboni@gmail.com. · Istituto di Diagnosi e Cura Hermitage-Capodimonte, Via Cupa delle Tozzole, 2, 80131, Naples, Italy. marianna.amboni@gmail.com. · DIETI, University of Naples, "Federico II", Naples, Italy. · Department of Pediatric Rehabilitation, Santobono-Pausilipon Children's Hospital, Naples, Italy. · Neurological and Stroke Unit, Centro Traumatologico Ortopedico Hospital AORN "Ospedali dei Colli", Naples, Italy. · Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson's Disease, Division of Neurology, Toronto Western Hospital, UHN, University of Toronto, Toronto, ON, Canada. · Krembil Research Institute, Toronto, ON, Canada. · Department of Primary Care and Public Health, Imperial College, London, UK. · Department of Public Health, University of Naples, "Federico II", Naples, Italy. · Istituto di Diagnosi e Cura Hermitage-Capodimonte, Via Cupa delle Tozzole, 2, 80131, Naples, Italy. · Department of Motor Sciences and Wellness, University of Naples Parthenope, Naples, Italy. · Department of Medicine and Surgery "Scuola Medica Salernitana", Center for Neurodegenerative Diseases, University of Salerno, Via S. Allende, 1, 84081, Baronissi, SA, Italy. ·J Neurol · Pubmed #30014240.

ABSTRACT: Cognition and gait appear to be closely related. The chronological interplay between cognitive decline and gait dysfunction is not fully understood. The aim of the present prospective study is investigating whether the dysfunction of specific gait parameters, during specific task and medication conditions, may predict subsequent cognitive impairment in Parkinson's disease (PD). We evaluated cognition and gait in 39 Parkinsonian patients at an initial assessment and after 3 years. Cognitive performance was evaluated with a neuropsychological battery designed to assess memory, executive/attention, and visuospatial domains. Gait was investigated using a gait analysis system during both the off and on states in the following conditions: (1) normal gait; (2) motor dual task; and (3) cognitive dual task. We used regression models to determine whether gait predicts subsequent cognitive dysfunction. Overall, the cognitive test scores were stable over time with the exception of the executive/attention scores, whereas all gait parameters declined. The step length during the cognitive dual task during the on state at the initial evaluation was the only significant predictor of executive/attention domain dysfunction at follow up. The results were confirmed when executive/attention dysfunction at the initial assessment evaluation was included in the regression model as a covariate. Our longitudinal study offers additional insight into the progression of gait dysfunction, and its chronological relationship with cognitive dysfunction in PD patients. In particular, the present study indicates that step length during a cognitive task when on medication is an independent predictor of future executive/attention decline.

24 Article LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study. 2018

Quadri, Marialuisa / Mandemakers, Wim / Grochowska, Martyna M / Masius, Roy / Geut, Hanneke / Fabrizio, Edito / Breedveld, Guido J / Kuipers, Demy / Minneboo, Michelle / Vergouw, Leonie J M / Carreras Mascaro, Ana / Yonova-Doing, Ekaterina / Simons, Erik / Zhao, Tianna / Di Fonzo, Alessio B / Chang, Hsiu-Chen / Parchi, Piero / Melis, Marta / Correia Guedes, Leonor / Criscuolo, Chiara / Thomas, Astrid / Brouwer, Rutger W W / Heijsman, Daphne / Ingrassia, Angela M T / Calandra Buonaura, Giovanna / Rood, Janneke P / Capellari, Sabina / Rozemuller, Annemieke J / Sarchioto, Marianna / Fen Chien, Hsin / Vanacore, Nicola / Olgiati, Simone / Wu-Chou, Yah-Huei / Yeh, Tu-Hsueh / Boon, Agnita J W / Hoogers, Susanne E / Ghazvini, Mehrnaz / IJpma, Arne S / van IJcken, Wilfred F J / Onofrj, Marco / Barone, Paolo / Nicholl, David J / Puschmann, Andreas / De Mari, Michele / Kievit, Anneke J / Barbosa, Egberto / De Michele, Giuseppe / Majoor-Krakauer, Danielle / van Swieten, John C / de Jong, Frank J / Ferreira, Joaquim J / Cossu, Giovanni / Lu, Chin-Song / Meco, Giuseppe / Cortelli, Pietro / van de Berg, Wilma D J / Bonifati, Vincenzo / Anonymous851112. ·Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands. · Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy AO2|M, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands; Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, Netherlands. · Department of Neurological Sciences, "Sapienza" Università degli Studi di Roma, Rome, Italy. · Department of Neurology and Alzheimer Center, Erasmus Medical Center, Rotterdam, Netherlands. · Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands; Medical Research Council/British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands; Avans Hogeschool, Breda, Netherlands. · Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands; Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. · Neuroscience Research Centre, Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan. · Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Institute of Neurological Sciences of Bologna (ISBN), Bologna, Italy; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy. · Neurology Service and Stroke Unit, Brotzu General Hospital, Cagliari, Italy. · Department of Neurosciences and Mental Health, Neurology, Santa Maria Hospital, Centro Hospitalar Lisboa Norte (CHLN), Lisbon, Portugal; Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Portugal. · Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University Naples, Naples, Italy. · Department of Neuroscience, Imaging, and Medical Sciences, Gabriele d'Annunzio University, Chieti-Pescara, Italy; Aging Research Centre, Centro di Scienze dell'invecchiamento, Gabriele d'Annunzio University Foundation, Chieti, Italy. · Center for Biomics, Erasmus Medical Center, Rotterdam, Netherlands. · Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy AO2|M, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands. · Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Institute of Neurological Sciences of Bologna (ISBN), Bologna, Italy; Dipartimento di Scienze Biomediche e NeuroMotorie (DIBINEM), Alma Mater Studiorum-University of Bologna, Bologna, Italy. · Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands. · Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Institute of Neurological Sciences of Bologna (ISBN), Bologna, Italy; UOC Clinica Neurologica, Dipartimento di Scienze Biomediche e Neuromotorie, University of Bologna, Bologna, Italy. · Department of Neurology, University of São Paulo, São Paulo, Brazil. · National Centre for Disease Prevention and Health Promotion, National Institute of Health, Rome, Italy. · Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands; Bluebee, Rijswijk, Netherlands. · Human Molecular Genetics Laboratory, Department of Medical Research, Chang Gung Memorial Hospital and Chang Gung University, Kweishan, Taoyuan, Taiwan. · Department of Neurology, Taipei Medical University Hospital, and School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. · Department of Developmental Biology, iPS Core Facility, Erasmus Medical Center, Rotterdam, Netherlands. · Centre for Neurodegenerative Diseases (CEMAND), Neuroscience Section, University of Salerno, Salerno, Italy. · Department of Neurology, City Hospital, Birmingham, UK. · Lund University, Skane University Hospital, Department of Clinical Sciences Lund, Neurology, Lund, Sweden. · Department of Neurology, "Bonomo" Hospital, Andria, Italy. · Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Portugal. · Department of Neurology and Psychiatry, Research Centre for Social Diseases (CIMS), "Sapienza" Università degli Studi di Roma, Rome, Italy; Neurological Centre of Latium [Gruppo NEUROMED]) Centro Studi Clinici Malattia di Parkinson, Rome, Italy. · Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands. Electronic address: v.bonifati@erasmusmc.nl. ·Lancet Neurol · Pubmed #29887161.

ABSTRACT: BACKGROUND: Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies do not carry mutations in known disease-causing genes. The aim of this study was to identify a novel gene implicated in the development of these disorders. METHODS: Our study was done in three stages. First, we did genome-wide linkage analysis of an Italian family with dominantly inherited Parkinson's disease to identify the disease locus. Second, we sequenced the candidate gene in an international multicentre series of unrelated probands who were diagnosed either clinically or pathologically with Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies. As a control, we used gene sequencing data from individuals with abdominal aortic aneurysms (who were not examined neurologically). Third, we enrolled an independent series of patients diagnosed clinically with Parkinson's disease and controls with no signs or family history of Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies from centres in Portugal, Sardinia, and Taiwan, and screened them for specific variants. We also did mRNA and brain pathology studies in three patients from the international multicentre series carrying disease-associated variants, and we did functional protein studies in in-vitro models, including neurons from induced pluripotent stem-like cells. FINDINGS: Molecular studies were done between Jan 1, 2008, and Dec 31, 2017. In the initial kindred of ten affected Italian individuals (mean age of disease onset 59·8 years [SD 8·7]), we detected significant linkage of Parkinson's disease to chromosome 14 and nominated LRP10 as the disease-causing gene. Among the international series of 660 probands, we identified eight individuals (four with Parkinson's disease, two with Parkinson's disease dementia, and two with dementia with Lewy bodies) who carried different, rare, potentially pathogenic LRP10 variants; one carrier was found among 645 controls with abdominal aortic aneurysms. In the independent series, two of these eight variants were detected in three additional Parkinson's disease probands (two from Sardinia and one from Taiwan) but in none of the controls. Of the 11 probands from the international and independent cohorts with LRP10 variants, ten had a positive family history of disease and DNA was available from ten affected relatives (in seven of these families). The LRP10 variants were present in nine of these ten relatives, providing independent-albeit limited-evidence of co-segregation with disease. Post-mortem studies in three patients carrying distinct LRP10 variants showed severe Lewy body pathology. Of nine variants identified in total (one in the initial family and eight in stage 2), three severely affected LRP10 expression and mRNA stability (1424+5delG, 1424+5G→A, and Ala212Serfs*17, shown by cDNA analysis), four affected protein stability (Tyr307Asn, Gly603Arg, Arg235Cys, and Pro699Ser, shown by cycloheximide-chase experiments), and two affected protein localisation (Asn517del and Arg533Leu; shown by immunocytochemistry), pointing to loss of LRP10 function as a common pathogenic mechanism. INTERPRETATION: Our findings implicate LRP10 gene defects in the development of inherited forms of α-synucleinopathies. Future elucidation of the function of the LRP10 protein and pathways could offer novel insights into mechanisms, biomarkers, and therapeutic targets. FUNDING: Stichting ParkinsonFonds, Dorpmans-Wigmans Stichting, Erasmus Medical Center, ZonMw-Memorabel programme, EU Joint Programme Neurodegenerative Disease Research (JPND), Parkinson's UK, Avtal om Läkarutbildning och Forskning (ALF) and Parkinsonfonden (Sweden), Lijf and Leven foundation, and cross-border grant of Alzheimer Netherlands-Ligue Européene Contre la Maladie d'Alzheimer (LECMA).

25 Article Serum IGF-1 is associated with cognitive functions in early, drug-naïve Parkinson's disease. 2017

Picillo, Marina / Pivonello, Rosario / Santangelo, Gabriella / Pivonello, Claudia / Savastano, Riccardo / Auriemma, Renata / Amboni, Marianna / Scannapieco, Sara / Pierro, Angela / Colao, Annamaria / Barone, Paolo / Pellecchia, Maria Teresa. ·Center for Neurodegenerative Diseases (CEMAND), Department of Medicine and Surgery, Neuroscience Section, University of Salerno, Salerno, Italy. · Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy. · Neuropsychology Laboratory, Department of Psychology, Second University of Naples, Caserta, Italy. · IOS and Coleman Medicina Futura Medical Center, Naples, Italy. · IDC Hermitage-Capodimonte, Naples, Italy. ·PLoS One · Pubmed #29065116.

ABSTRACT: OBJECTIVE: Cognitive deficits are common in Parkinson's disease (PD) since the early stages and many patients eventually develop dementia. Yet, occurrence of dementia in PD is unpredictable. Evidence supports the hypothesis that insulin-like growth factor-1 (IGF-1) is involved in cognitive deficits. Our aim was to evaluate the relationship between serum IGF-1 levels and neuropsychological scores in a large cohort of drug-naïve PD patients during the earliest stages of the disease. METHODS: Serum IGF-1 levels were determined in 405 early, drug-naïve PD patients and 191 healthy controls (HC) enrolled in the Parkinson's Progression Markers Initiative (PPMI). The association between serum IGF-1 levels and neuropsychological scores was evaluated with linear regression analysis. RESULTS: IGF-1 levels were similar in PD and HC. In PD patients the lowest IGF-1 quartile was a predictor of lower performances at the Semantic Fluency task (β = -3.46, 95%CI: -5.87 to -1.01, p = 0.005), the Symbol Digit Modalities Score (β = -2.09, 95%CI: -4.02 to -0.15, p = 0.034), and Hopkins Verbal Learning Test Retention (β = -0.05, 95%CI: -0.09 to -0.009, p = 0.019). CONCLUSIONS: Lower serum IGF-1 levels are associated to poor performances in cognitive tasks assessing executive function, attention and verbal memory in a large cohort of early PD patients. Follow-up studies are warranted to assess if IGF-1 is related to the development of dementia in PD.

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