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Background: Family history of Parkinson's disease (PD) is a common finding in PD patients. However, a few studies have systematically examined this aspect., Objectives: We investigated the family history of PD patients, comparing demographic and clinical features between familial PD (fPD) and sporadic PD (sPD)., Methods: A cross-sectional study enrolling 2035 PD patients was conducted in 28 Italian centers. Clinical data and family history up to the third degree of kinship were collected., Results: Family history of PD was determined in 21.9% of patients. fPD patients had earlier age at onset than sporadic patients. No relevant differences in the prevalence of motor and nonmotor symptoms were detected. Family history of mood disorders resulted more prevalently in the fPD group., Conclusions: fPD was found to recur more frequently than previously reported. Family history collection beyond the core family is essential to discover disease clusters and identify novel risk factors for PD., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: The main endpoint of the study was to evaluate if a daily intake of whey protein-based dietary supplement causes a worse response to levodopa in people with Parkinson's Disease (PWPD)., Background: In PWPD, the competition between large neutral aminoacids and levodopa at intestinal absorption level may interfere with dopaminergic therapy's (DRT) effect; therefore, protein redistribution dietary regimen has been suggested. Many dietary supplementations are available to help people in balancing the protein intake and overcoming muscle mass loss. However, most of the products contain protein and could potentially affect levodopa action in PWPD., Methods: We performed a randomised single blind monocentric study on PWPD admitted in the rehabilitative unit for a 4-week multidisciplined intensive aerobic rehabilitation treatment. All patients received a standard protein redistribution dietary regimen plus a whey protein-based oral formula ( N  = 26) or Magnesium ( N  = 25) twice daily for 28 days. Neurological assessment and physical evaluation were conducted before (T0) and after (T1) rehabilitative treatment; DRT was recorded T0 and T1 as well. The delta of changes within groups in neurological (UPDRS III) and physical (TUG, 6 MW) evaluation scales was compared between groups., Results: Groups were comparable at baseline in clinical and demographic data; at T1, both groups showed a decrease in UPDRS III, TUG and 6 MWT and no differences between deltas were found. DRT remained stable in both groups., Conclusions: Our results show that whey protein supplementation does not interfere with DRT's efficacy and can be used in PWPD who need a protein supplementation without restrictions in intake hours.

Background and Objectives : Although the growing literature is now focusing on the long-term effects of Deep Brain Stimulation (DBS) in Parkinson's disease (PD), there is still a large gap of knowledge about its long-term implications in rehabilitation. Therefore, this study aimed at investigating the effects of rehabilitation in PD patients years after DBS implantation. Materials and Methods: This retrospective case-control study analyzed records from Moriggia-Pelascini Hospital, Italy from September 2022 to January 2024. Data of PD patients ( n = 47) with (DBS group, n = 22) and without (control group, n = 25) DBS were considered. All study participants underwent a daily rehabilitation program lasting four weeks, including warm-up, aerobic exercises, strength training, postural exercises, and proprioceptive activities. The outcomes assessed were the Unified Parkinson's Disease Rating Scale (UPDRS), Berg Balance Scale (BBS), Timed Up and Go (TUG), 6 Min Walk Test (6MWT), and Self-Assessment Parkinson Disease Scale (SPDDS). Results: DBS group showed significant improvements in terms of all outcome measures after the rehabilitation intervention (UPDRS III: -7.0 (-11.5 to -1.0); p = 0.001; UPDRS I II IV: -12.0 (-19.0 to -4.5); p = 0.001; BBS: 7.0 (3.8 to 10.3); p < 0.001; TUG (s): -2.8 (-5.7 to -1.1); p < 0.001; SPDDS: -8 (-13.0 to -4.0); p < 0.001; 6MWT (m): 81 (37.3 to 132.3); p < 0.001). No differences were reported in the between-group analysis (p: NS). Conclusions : This study emphasizes positive rehabilitation effects on PD patients irrespective of DBS status. Further research is essential to elucidate long-term effects of DBS on rehabilitation outcomes of PD patients.

A key distinguishing factor between mild cognitive impairment (MCI) and dementia in Parkinson's disease (PD) lies in the notable decrease in functioning due to cognitive impairment. The Parkinson's Disease-Cognitive Functional Rating Scale (PD-CRFS) was developed to assess functional limitations caused by cognitive impairment, while reducing the influence of motor impairment. The aim of this multicenter study was to (i) validate the Italian version of the PD-CFRS in PD, (ii) determine optimal cut-off scores for detecting MCI and dementia in PD, (iii) compare its performances with the most established functional assessment tool (IADL). Six hundred and sixty nine PD participants were recruited from 4 Italian Movement Disorders centers (Venice, Milan, Gravedona, and Salerno). They underwent Level-II cognitive evaluation, which resulted in 282 PD-NC, 310 PD-MCI, and 77 PDD. The PD-CFRS's psychometric and clinimetric properties, applicability, and responsiveness were analyzed. The PD-CFRS showed high acceptability. Floor and ceiling effects were acceptable. It also displayed strong internal consistency (Cronbach's α = 0.738), and test-retest reliability (ICC = .854). The PD-CFRS demonstrated higher coefficient of variation to detect dysfunction in PD-MCI patients in comparison to the IADL scale (PD-CFRS 96% vs IADL 22.5%). Convergent validity with the IADL was r = - 0.638 and - 0.527 in males and females, respectively. PD-CFRS total score negatively correlated with global cognition (MoCA corrected score r = - 0.61; p < 0.001). A cut-off score > 6.5 identified PDD with a sensitivity of 90% and specificity of 88% (AUC = .959). A cut-off value of > 1 detected PD-MCI with a sensitivity of 68% and specificity of 69% (AUC = .695). The Italian version of the PD-CFRS demonstrated to be an easy, valid and reliable tool that properly captures functional impairment due to cognitive decline in PD. It also proved to be particularly effective in the advanced stages of PD, and would be a useful support for the diagnosis of PD-MCI and PDD., (© 2024. The Author(s).)

Introduction: Safinamide is a recent antiparkinsonian drug that modulates both dopaminergic and glutamatergic systems with positive effects on motor and nonmotor symptoms of Parkinson's disease (PD). Here, we aimed to describe the efficacy and safety of safinamide in the Italian PD patients in real-life conditions., Methods: We performed a sub-analysis of the Italian cohort of the SYNAPSES study, a multi-country, multi-center, retrospective-prospective cohort observational study, designed to investigate the use of safinamide in routine clinical practice. Patients received for the first time a treatment with safinamide and were followed up for 12 months. The analysis was conducted on the overall population and in subgroups of interest: i) patients > 75 years, ii) patients with relevant comorbidities and iii) patients affected by psychiatric symptoms., Results: Italy enrolled 616/1610 patients in 52 centers, accounting for 38% of the entire SYNAPSES cohort. Of the patients enrolled, 86.0% were evaluable at 12 months, with 23.3% being > 75 years, 42.4% with psychiatric conditions and 67.7% with relevant comorbidities. Safinamide was effective on motor symptoms and fluctuations as measured through the Unified PD rating scale III and IV scores, and on the total score, without safety issues in none of the subgroups considered., Conclusion: The SYNAPSES data related to Italian patients confirms the good safety profile of safinamide even in special groups of patients. Motor fluctuations and motor impairment improved at the follow-up suggesting the significant role of safinamide in managing motor symptoms in PD patients., (© 2023. The Author(s).)

Objectives: There is growing evidence that Parkinson's disease and diabetes are partially related diseases; however, the association between the two, and the impact of specific treatments, are still unclear. We evaluated the effect of T2D and antidiabetic treatment on age at PD onset and on all-cause mortality., Research Design and Methods: The standardized rate of T2D was calculated for PD patients using the direct method and compared with subjects with essential tremor (ET) and the general Italian population. Age at onset and survival were also compared between patients without T2D (PD-noT2D), patients who developed T2D before PD onset (PD-preT2D) and patients who developed T2D after PD onset (PD-postT2D)., Results: We designed a retrospective and prospective study. The T2D standardized ratio of PD (N = 8380) and ET (N = 1032) patients was 3.8% and 6.1%, respectively, while in the Italian general population, the overall prevalence was 5.3%. In PD-preT2D patients, on antidiabetic treatment, the onset of PD was associated with a + 6.2 year delay (p < 0.001) while no difference was observed in PD-postT2D. Occurrence of T2D before PD onset negatively affected prognosis (adjusted hazard ratio = 1.64 [95% CI 1.33-2.02]; p < 0.001), while no effect on survival was found in PD-postT2D subjects (hazard ratio = 0.86, [95% CI 0.53-1.39]; p = 0.54)., Conclusions: T2D, treated with any antidiabetic therapy before PD, is associated with a delay in its onset. Duration of diabetes increases mortality in PD-preT2D, but not in PD-postT2D. These findings prompt further studies on antidiabetic drugs as a potential disease-modifying therapy for PD., (© 2022. The Author(s).)

The field related to mood disorders in Parkinson's disease (PD) is fragmented. The aim of this cohort observational study was to evaluate whether the episodes of mood alteration could appear in different disease stages and to verify how nonmotor symptoms were led off into different stages. We enrolled 93 PD outpatients (three groups: drug naive-DN; not exhibiting motor fluctuations-n-MF; and exhibiting motor fluctuations-MF) and 50 healthy controls. Mood state was assessed through the Internal State Scale (ISS) while depressive symptoms were evaluated through the Beck Depression Inventory-II (BDI-II), nonmotor symptoms by means of the Non-Motor Symptoms Scale (NMSS), and the presence of impulse control disorders (ICDs) with the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP). Clinical and pharmacological data have also been recorded. No significant differences in mood state distribution between groups were observed. Nevertheless, as regards the mood state distribution within groups, in n-MF (47.6%) and MF patients (50%), (hypo)mania presence was significantly higher than other symptoms. In DN patients, hypomania showed a prevalence of 38.1% although it was not significant. At least one ICD was reported in 29.3% of n-MF and 50% of MF patients. In the MF group, a moderate positive correlation between ISS ACTivation subscale scores and the presence of ICDs and compulsive medication use emerged. Finally, MF patients reported higher BDI-II total scores than DN. Our results show that mood alterations in PD, considering both depressive symptoms and mood elevation, are related to the advanced stages of the disease as well as the presence of ICDs, and dopaminergic therapy would not always be able to restore a normal mood condition., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Margherita Canesi et al.)

Introduction: Specific pre-existing medical conditions (e.g. hypertension or obesity), advanced age and male sex appear linked to more severe manifestations of SARS Co-V2 infection, thus raising the question of whether Parkinson's disease (PD) poses an increased risk of morbidity and mortality in COVID-19 patients., Methods: In order to describe the outcome of COVID-19 in multi-centre a cohort of PD patients and explore its potential predictors, we gathered the clinical information of 117 community-dwelling patients with COVID-19 followed in 21 tertiary centres in Italy, Iran, Spain, and the UK., Results: Overall mortality was 19.7%, with a significant effect of co-occurrence of dementia, hypertension, and PD duration., Conclusions: The frailty caused by advanced PD poses an increased risk of mortality during COVID-19., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) results in a complex deterioration of motor behavior. Effective pharmacological or surgical treatments addressing the whole spectrum of both motor and cognitive symptoms are lacking. The cumulative functional impairment may have devastating socio-economic consequences on both patients and caregivers. Comprehensive models of care based on multidisciplinary approaches may succeed in better addressing the overall complexity of PD. Neurorehabilitation is a highly promising non-pharmacological intervention for managing PD. The scientific rationale beyond rehabilitation and its practical applicability remain to be established. In the present perspective, we aim to discuss the current evidence supporting integrated motor-cognitive and aerobic rehabilitation approaches for patients with PD while suggesting a practical framework to optimize this intervention in the next future.

Introduction: Caring for a person with Parkinson's disease (PD) is associated with an increased risk of psychiatric morbidity and persistent distress. The objective of this study was to describe the burden and the related factors of caregivers of advanced PD (APD) patients either treated with continuous dopaminergic delivery systems or standard therapy., Methods: This cross-sectional, epidemiologic study conducted in 13 Italian sites enrolled PD patients treated with continuous dopaminergic delivering systems [either levodopa/carbidopa intestinal gel (LCIG) infusion or continuous subcutaneous apomorphine infusion (CSAI)] or continuation of standard of care (SOC) with a caregiver. Patient quality of life (QoL) and caregiver burden were assessed using the Parkinson's Disease Questionnaire (PDQ-8) and Zarit Burden Inventory (ZBI), respectively., Results: 126 patients (mean age 69.3 ± 8 years) and their caregivers (mean age 57.9 ± 12.9) were enrolled. Most caregivers were spouses. Fifty-three patients were treated with LCIG, 19 with CSAI, and 54 with SOC. Mean ZBI scores were 29.6 ± 14.4 for LCIG, 35.8 ± 20.2 for CSAI, and 31.4 ± 16.0 for SOC. Caregivers of LCIG, CSAI, and SOC patients showed no burden or mild/moderate burden in 74, 53, and 63% of the cases, respectively. Mean PDQ-8 scores were 11.25 ± 5.67, 11.26 ± 5.55, and 14.22 ± 6.51 in LCIG, CSAI, and SOC patients. Neurologists considered patients "very much or much improved" in 89, 58, and 13% of the LCIG, CSAI, and SOC groups using the Clinical Global Impression-Global Improvement Scale. Predictors significantly associated with caregiver burden were patients and caregivers' judgment of QoL and caregivers' need to change work., Conclusions: Caregiver burden showed a tendency to be lower when patients are treated with LCIG than with CSAI or SOC.

Background: Both motor and non-motor symptoms could contribute to significant deterioration of psychological well-being in patients with Parkinson's disease (PD). However, its assessment has been only indirectly evaluated using tools based on health-related quality of life (HRQoL), such as the PDQ-39 scale., Objectives: To evaluate psychological well-being in PD using a specific tool of assessment, the Psychological Well-being Scale (PWS), and its clinical correlates., Methods: This article reports data of patients' perception of health state, as measured by means of the PWS, from an epidemiological, cross-sectional study conducted in Italian PD patients (FORTE Study). We tested possible relationship between well-being and clinical characteristics including fatigue, depression, sleep disruption and HRQoL., Results: 272 patients completed the PWS questionnaire. Significant and clinically-relevant correlations were found between PWS total score and Parkinson's Fatigue Scale, Beck Depression Inventory, UPDRS Section I, PD Sleep Scale and PDQ-39 for HRQoL scores. Only clinically negligible correlations were found between PWS and motor scores., Conclusions: Non-motor symptoms have a significant impact on psychological well-being in PD patients.

Monoamine oxidase type B (MAO-B) inhibitors, such as selegiline and rasagiline, can be used as monotherapy or adjuvant therapy to levodopa in Parkinson's disease (PD). Data on long-term efficacy of MAO-B inhibitors are limited with no head-to-head comparison available to date. The aim of this case-control retrospective study was to analyze data from patients with PD attending the Parkinson Institute (Milan, Italy) over a 6-year period (2009-2015) and compare the effects of selegiline and rasagiline on levodopa treatment outcomes. Patients with PD treated with either selegiline (n = 85) or rasagiline (n = 85) for 3 years as well as a control group of patients (N = 170) who have never received MAO-B inhibitors, were matched for gender, disease duration (±1 year) and age (±1 year) at baseline assessment (ratio 1:1:2). The Unified PD Rating Scale and the Hoehn-Yahr staging system were used for clinical comparisons. At baseline, mean PD duration was 6.5 years and clinical features were comparable across all three groups. After a mean follow-up of approximately 37 months, no differences in clinical progression of motor and non-motor symptoms were observed between the three groups. However, MAO-B inhibitor use was associated with ~2-fold lower change in daily dose of levodopa (p < 0.001) and lower dyskinesia scores (p = 0.028) than non-users. No intra-class differences were observed between selegiline and rasagiline. Long-term use of MAO-B inhibitors resulted in a significant reduction in levodopa requirements and a lower frequency of dyskinesias in patients with PD. Selegiline and rasagiline had equal efficacy in controlling motor symptoms in PD patients on optimized therapy.

Objective: The objective of this work was to investigate survival, dementia, and genotype-phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene (GBA)., Methods: We included 2,764 unrelated consecutive PD patients: 123 GBA carriers (67 mild-p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group., Results: Multivariable analysis adjusted by sex, age at onset, and disease duration attributed to GBA carriers a greater risk for dementia (hazard ratio [HR] = 3.16; p < 0.001) and death (HR = 1.85; p = 0.002) than noncarriers. When dementia was introduced in the model as a time-dependent covariate, the mortality risk remained greater in carriers (HR = 1.65; p = 0.016), suggesting that other clinical features are likely to contribute to reduced survival. At last examination, GBA carriers had worse motor symptoms, particularly nondopaminergic features. Carriers of severe mutations had greater risk for dementia compared to mild mutations (p < 0.001), but similar mortality risk. Consistent with clinical data, GBA carriers showed reduced posterior parietal and occipital cortical synaptic activity and nigrostriatal function than PD noncarriers. Neuroimaging features of carriers of mild mutations overlapped with PD noncarriers, whereas carriers of severe mutations were closer to DLB., Interpretation: Survival is reduced in GBA carriers compared to noncarriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by type of mutation. In the clinical continuum between PD and DLB, patients with GBA mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. Ann Neurol 2016;80:662-673., (© 2016 American Neurological Association.)

Background: The rates of cognitive decline in patients with Parkinson's disease (PD) are higher than in the general population. Age and disease duration have been associated with increasing rates of dementia in PD. However, the role of other factors including gender has been poorly investigated. We investigated the relationship between dementia and gender along with other established risk factors, such as age and disease duration., Methods: We conducted a cross-sectional retrospective study including all consecutive patients diagnosed with idiopathic PD attending a single out-patient tertiary clinic over an 18-year period (1995-2013). Dementia was diagnosed according to DSM-IV criteria., Results: Prevalence of dementia was 11.5% (95%CI, 10.8-12.3) and 13.5% (95%CI, 12.7-14.5) in the whole population (N = 6599) and in those aged ≥60 years (N = 5373), respectively. Age and disease duration were independently associated with dementia, and the latter was associated with dementia up to 84 years of age. Male gender was an independent risk factor. In addition, while the rate of dementia increased in males over all age strata, we found that in females prevalence began to increase steadily after the age of 65 years, reaching male estimates only after 80 years of age. Higher rates in male gender were observed between 60 and 80 years of age., Conclusion: Age and PD duration are confirmed risk factors for dementia. However, disease duration appeared to be a less important factor in cognitive decline in patients aged ≥85 years. As opposed to gender-specific estimates in the general population, male gender is likely associated with higher rates of dementia in PD patients., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: An increase in artistic-like production in Parkinson's disease (PD) has been associated with compulsive and repetitive behaviours after the introduction of dopaminergic treatment (DT). Recent data suggest that it could be due to the emergence of artistic-like skills triggered by DT., Objective: In order to evaluate whether artistic production and creative thinking are influenced by DT or linked to artistic-like skills, we characterize creativity features in PD and healthy controls (HC) including professional artists., Methods: Three groups of PD out-patients were included consecutively: professional artists (PD-A), patients with (PD-C) and without artistic-like production (PD-NC). Twenty-four gender and age-matched HC were included: professional artists (HC-A) and non-artists (HC-NC). All patients were evaluated by means of a) a battery of neuropsychological tests and a semi-structured interview; b) the Abbreviated Torrance Test for Adults (ATTA) for creative thinking; c) the Minnesota Impulsive Disorders Interview (mMIDI) and a screening for impulse control disorders (ICDs) for compulsive behaviour., Results: ATTA total score was significantly higher in HC-A and PD-A than in the other groups. Although PD-NC showed the lowest ATTA total score the difference vs HC-NC was not significant. ATTA scores were not significantly correlated with DT dosage and duration. mMIDI tests were positive only in PD. There were no differences in ICDs among PD groups., Conclusions: Our results do not support a relationship between DT and the emergence of artistic creativity. We believe that DT may increase the drive to create and that further studies in "on" and "off" medication are needed to clarify this issue.

Objective: To estimate the prevalence of Pisa syndrome (PS) in patients with Parkinson disease (PD) and to assess the association between PS and demographic and clinical variables., Methods: In this multicenter cross-sectional study, consecutive outpatients with PD attending 21 movement disorders Italian tertiary centers were enrolled and underwent standardized clinical evaluation. PS was defined as trunk lateral deviation ≥10°. Patients with PD were compared according to the presence of PS for several demographic and clinical variables., Results: Among 1,631 enrolled patients with PD, PS was detected in 143 patients (8.8%, 95% confidence interval 7.4%-10.3%). Patients with PS were older, had lower body mass index, longer disease duration, higher disease stages, and poorer quality of life. Falls were more frequent in the PS group as well as occurrence of "veering gait" (i.e., the progressive deviation toward one side when patient walked forward and backward with eyes closed). Patients with PS received higher daily levodopa equivalent daily dose and were more likely to be treated with combination of levodopa and dopamine agonists. Osteoporosis and arthrosis were significantly the most frequent associated medical conditions in patients with PS. Multiple explanatory variable logistic regression models confirmed the association of PS with the following variables: Hoehn and Yahr stage, ongoing combined treatment with levodopa and dopamine agonist, associated medical conditions, and presence of veering gait., Conclusions: Our results suggest that PS is a relatively frequent and often disabling complication in PD, especially in the advanced disease stages. The association is dependent on a number of potentially relevant demographic and clinical variables., (© 2015 American Academy of Neurology.)

Background: A very limited number of studies report data on the clinical features of Parkinson's disease (PD) 20 years after onset and beyond., Objective: To characterise PD 20 years after onset, investigating the impact of age at onset and disease duration on the clinical picture and the predictors of outcomes in patients reaching the 20-year time point., Methods: We conducted a retrospective, cross-sectional study and a longitudinal study. All case visits of patients with a disease duration ≥20 years (N=401) were stratified by disease duration (20-22, 23-25, ≥26 years) and by age at onset (cut-off, 50 years). Patients with a disease duration of 20-22 years (N=320) were prospectively followed up for a median of 45 months (IQR 23-89) for the new occurrence of fracture, percutaneous endoscopic gastrostomy, institutionalisation, confinement to a wheelchair or bed and death., Results: Older age at onset and longer disease duration were independently associated with a higher prevalence of major motor and non-motor milestones of disease disability (no interaction observed). In the longitudinal study, the most frequent outcomes were death (N=92), confinement to a wheelchair or bed (N=67) and fracture (N=52). Mortality was associated with the gender: male, older age, dysphagia, orthostatic hypotension, postural instability, fractures and institutionalisation. Fracture was associated with postural instability. Predictors of permanent confinement to a wheelchair or bed were older age, postural instability and institutionalisation. Comorbid dementia at the 20-year examination did not predict any of the outcomes., Conclusions: Age at onset and disease duration are independent determinants of the clinical features of PD beyond 20 years. Non-motor symptoms depend more on age at onset rather than the disease duration itself. Non-levodopa-responsive axial symptoms are the main predictors of all relevant outcomes., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

This study investigated cognitive functions in Parkinson's disease (PD) patients with impulse control disorders (ICDs) and aimed to identify possible predictors of behavioral outcome. In this longitudinal cohort study, 40 PD outpatients with ICDs and 40 without, were matched for sex, age at PD onset, age and disease duration at cognitive assessment. All patients had two neuropsychological assessments at least 2 years apart (mean, 3.5 years). Multivariate logistic regression analysis was performed to identify predictors of ICDs remission at follow-up. The PD patients with and without ICDs had overall comparable cognitive performance at baseline. When evaluating changes between baseline and follow-up, we found significant group × time interactions in several frontal lobe-related tests, with the ICDs group showing a less pronounced worsening over time. ICDs remission was associated with better performance at baseline in working memory-related tasks, such as digit span (odds ratio [OR] = 2.69 [95% confidence interval (CI), 1.09-6.66]) and attentive matrices (OR=1.19 [95%CI, 1.03-1.37]). ICDs remitters and non-remitters had no remarkable differences in baseline PD-related features and therapy management strategies (including the extent of dopamine agonist dose reduction). In conclusion, ICDs in PD patients are not related to greater cognitive impairment or executive dysfunction, but rather show relatively lower cognitive decline over time. The impaired top-down inhibitory control characterizing ICDs is likely attributable to a drug-induced overstimulation of relatively preserved prefrontal cognitive functions. Full behavioral remission in the long term was predicted by better working memory abilities. © 2015 International Parkinson and Movement Disorder Society., (© 2015 International Parkinson and Movement Disorder Society.)

Importance: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of genetic Parkinson disease (PD) known to date. The clinical features of manifesting LRRK2 mutation carriers are generally indistinguishable from those of patients with sporadic PD. However, some PD cases associated with LRRK2 mutations lack Lewy bodies (LBs), a neuropathological hallmark of PD. We investigated whether the presence or absence of LBs correlates with different clinical features in LRRK2-related PD., Observations: We describe genetic, clinical, and neuropathological findings of 37 cases of LRRK2-related PD including 33 published and 4 unpublished cases through October 2013. Among the different mutations, the LRRK2 p.G2019S mutation was most frequently associated with LB pathology. Nonmotor features of cognitive impairment/dementia, anxiety, and orthostatic hypotension were correlated with the presence of LBs. In contrast, a primarily motor phenotype was associated with a lack of LBs., Conclusions and Relevance: To our knowledge, this is the first report of clinicopathological correlations in a series of LRRK2-related PD cases. Findings from this selected group of patients with PD demonstrated that parkinsonian motor features can occur in the absence of LBs. However, LB pathology in LRRK2-related PD may be a marker for a broader parkinsonian symptom complex including cognitive impairment.

Background: Swallowing disturbances are an important issue in Parkinson's disease (PD) as several studies have shown that they are associated with increased risk of aspiration pneumonia and mortality. Information about factors related to swallowing disturbances, such as disease duration, age at assessment and concomitant dementia, is limited and would be useful for their management., Methods: All consecutive PD out-patients evaluated at a movement disorders clinic over a 7-year period (2007-2014), were included in the present retrospective study. Presence of symptomatic swallowing disturbances was assessed using the specific item of the Non Motor Symptom Questionnaire., Results: In the whole PD population (N = 6462), prevalence of symptomatic swallowing disturbances was 11.7% (95%CI, 10.9-12.5). Multivariable logistic regression analysis (adjusted for education) disclosed a significant interaction between disease duration and gender (P = 0.009). In both gender strata, swallowing disturbances were significantly associated with longer disease duration and dementia (P < 0.001 for all). A significant effect for age at assessment was also found in male patients. In non-demented patients, swallowing disturbances were associated with male gender, age and disease duration (P < 0.02 for all). In demented patients an association was found only with male gender (P = 0.018) and disease duration (P < 0.001)., Conclusions: Gender, age, disease duration and dementia all seem to contribute to the occurrence of swallowing disturbances independently. However, the role played by these factors in sub-groups of patients stratified by gender and concomitant dementia suggests that swallowing disturbances are likely related to different neuro-degenerative patterns within the brain. The underlying mechanisms deserve further investigation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Age is considered an important risk factor for Parkinson's disease (PD). However, although life-expectancy has increased considerably, incidence rates of PD appeared to be stable over the last two decades. Accordingly, an increase in mean age at onset over time could be expected. We investigated the changes in age at onset in PD over the last two decades., Methods: All consecutive PD patients assessed over a 18-year period (1995-2013) in a single tertiary outpatient clinic were included in the present retrospective cohort study., Results: After adjusting for several confounders (gender, positive family history for PD, education, smoking at onset and past exposure to environmental/occupational pollutants), 5-year cohorts of year of disease onset were associated with increasing age at onset in both prevalent (N = 6996) and incident (N = 4172) cases (for trend, P < 0.001). From 1995-2000 to 2010-2013 there was an increase in predicted age of 4.1 years (95% CI, 3.0-5.2) and 3.9 years (95% CI, 2.7-5.1) in prevalent and incident cases, respectively. However, the change in predicted age at PD onset, across cohorts of year at onset, showed a steeper increase than the corresponding sex and cohort-matched mean age from the official Italian statistics., Conclusions: Over the last two decades, age at onset of PD appeared to shift progressively towards more advanced age. However, sequential, high-quality population-based incidence studies are required. To establish whether there is a trend towards increase in age at onset over and above general population ageing and to assess whether the increase is associated with improved medical and socio-economic conditions., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: To assess in a noninterventional setting the prevalence and severity of fatigue in patients with Parkinson disease (PD)., Methods: This was a cross-sectional study conducted in Italian patients with PD. Objectives included the evaluation of the current prevalence and severity of fatigue in patients with PD measured using the 16-item Parkinson Fatigue Scale (PFS-16), distressing fatigue (defined as a PFS-16 mean score ≥3.3), and assessment of its clinical correlates., Results: A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean (±SD) score of 2.87 ± 0.99. Of these, 136 patients (33.8%) reported distressing fatigue (PFS-16 mean score ≥3.3). Patients with distressing fatigue were older (p = 0.044) and had a longer duration of PD (p < 0.0001) than those without distressing fatigue. The presence of distressing fatigue was associated with higher total Unified Parkinson's Disease Rating Scale (UPDRS) scores, poorer quality of life (39-item Parkinson's Disease Questionnaire [PDQ-39]), worse social and psychological behaviors, a higher severity of depressive symptoms, and a higher prevalence of sleep disorders (all p < 0.001). Logistic regression analyses revealed that higher total UPDRS scores, female sex, depression, sleep disorders, as well as higher UPDRS activities of daily living scores and PDQ-39 mobility scores increase the likelihood of distressing fatigue in patients with PD., Conclusions: Approximately one-third of patients with PD have distressing fatigue, which is significantly associated with depression and sleep disorders. The fact that the presence of fatigue worsens patient quality of life supports the need to better diagnose and treat this debilitating symptom., (© 2014 American Academy of Neurology.)

We tested the hypothesis that causality analysis, applied to the spontaneous beat-to-beat variability of heart period (HP) and systolic arterial pressure (SAP), can identify the improvement of autonomic control linked to plantar mechanical stimulation in patients with Parkinson's disease (PD). A causality index, measuring the strength of the association from SAP to HP variability, and derived according to the Granger paradigm (i.e. SAP causes HP if the inclusion of SAP into the set of signals utilized to describe cardiovascular interactions improves the prediction of HP series), was calculated using both linear model-based (MB) and nonlinear model-free (MF) approaches. Univariate HP and SAP variability indices in time and frequency domains, and bivariate descriptors of the HP-SAP variability interactions were computed as well. We studied ten PD patients (age range: 57-78 years; Hoehn-Yahr scale: 2-3; six males, four females) without orthostatic hypotension or symptoms of orthostatic intolerance and 'on-time' according to their habitual pharmacological treatment. PD patients underwent recordings at rest in a supine position and during a head-up tilt before, and 24 h after, mechanical stimulation was applied to the plantar surface of both feet. The MF causality analysis indicated a greater involvement of baroreflex in regulating HP-SAP variability interactions after mechanical stimulation. Remarkably, MB causality and more traditional univariate or bivariate techniques could not detect changes in cardiovascular regulation after mechanical stimulation, thus stressing the importance of accounting for nonlinear dynamics in PD patients. Due to the higher statistical power of MF causality we suggest its exploitation to monitor the baroreflex control improvement in PD patients, and we encourage the clinical application of the Granger causality approach to evaluate the modification of the autonomic control in relation to the application of a pharmacological treatment, a rehabilitation procedure or external intervention.

Objective: Dopamine dysregulation syndrome (DDS) refers to a compulsive pattern of dopaminergic drug misuse complicating Parkinson's disease (PD). To date, few data are available on DDS risk factors, cognitive profile and long-term outcome., Methods: In this retrospective case-control study, consecutive PD outpatients fulfilling criteria for DDS were assessed over a 6-year period (2005-2011). They were compared with 70 PD cases matched for age at onset, gender and disease duration, and with 1281 subjects with motor fluctuations and dyskinesias. DDS patients and matched controls underwent extensive neuropsychological assessment. Strategies for DDS patients management and the outcome at the last follow-up visit were recorded., Results: Thirty-five patients with DDS were identified, reporting history of depression, family history of PD and drug abuse, greater difference between 'Off' versus 'On' motor symptoms compared to age-matched controls. They had younger age at onset (but not any gender difference) compared to general PD population. Cognitive profile of DDS did not show major abnormalities, including executive functions. DDS patients have been followed up for 3.2±2.1 years and remission was recorded in 40% of cases. Negative DDS outcome was significantly associated with poor caregiver supervision. Sustained remission occurred more commonly on clozapine and on duodenal levodopa infusion and subthalamic nucleus deep brain stimulation (STN-DBS) than on apomorphine pump treatment., Conclusions: Clinicians should be aware of risk factors predisposing to DDS. Duodenal levodopa infusion and, less consistently, STN-DBS were more commonly associated with DDS remission. Effective caregiving plays a key role in long-term behavioural outcome.

Motor impairment in Parkinson's disease (PD) is partly due to defective central processing of lower limb afferents. Concomitant alterations in cardiovascular autonomic control leading to orthostatic hypotension may worsen motor ability. We evaluated whether mechanical activation of feet sensory afferents could improve gait and modify the response of cardiovascular autonomic control to stressors in 16 patients (age 66 ± 2 yr) with idiopathic PD (Hoehn & Yhar scale 2-3) on their usual therapy. Eight subjects (group A) were randomized to undergo skin pressure (0.58 ± 0.04 kg/mm(2)) stimulation at the hallux tip and first metatarsal joint (effective stimulation; ES) of both feet. Eight remaining patients (group B) underwent sham stimulation (SS) followed by ES. Three-dimensional movement analysis provided quantitative indexes of movement disability before (baseline) and 24 h after ES and SS. Spectral analysis of heart rate and blood pressure variability provided markers of cardiac sympatho-vagal (LF/HF) and vascular sympathetic (LFSAP) modulations. Markers were measured at rest and during 75° head-up tilt, before and 24 h after ES and SS. After ES, step length and gait velocity increased, upright rotation velocity was enhanced, and step number was decreased. After ES, LFSAP declined. The increase in LF/HF and LFSAP induced by tilt was greater than before feet stimulation. No changes in gait and autonomic parameters were observed after SS. Twenty-four hours after ES, patients with PD showed improved gait and increased cardiac and vascular sympathetic modulation during upright position compared with baseline. Conversely, SS was ineffective on both movement and autonomic parameters, indicating a site specificity effect of the stimulation.

The Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has been available in English since 2008. As part of this process, the MDS-UPDRS organizing team developed guidelines for development of official non-English translations. We present here the formal process for completing officially approved non-English versions of the MDS-UPDRS and specifically focus on the first of these versions in Italian. The MDS-UPDRS was translated into Italian and tested in 377 native-Italian speaking PD patients. Confirmatory and exploratory factor analyses determined whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Italian translation. To be designated an 'Official MDS translation,' the Comparative Fit Index (CFI) had to be ≥0.90 relative to the English-language version. For all four parts of the Italian MDS-UPDRS, the CFI, in comparison with the English-language data, was ≥0.94. Exploratory factor analyses revealed some differences between the two datasets, however these differences were considered to be within an acceptable range. The Italian version of the MDS-UPDRS reaches the criterion to be designated as an Official Translation and is now available for use. This protocol will serve as outline for further validation of this in multiple languages.

Entropy-based approaches are frequently used to quantify complexity of short-term cardiovascular control from spontaneous beat-to-beat variability of heart period (HP) and systolic arterial pressure (SAP). Among these tools the ones optimizing a critical parameter such as the pattern length are receiving more and more attention. This study compares two entropy-based techniques for the quantification of complexity making use of completely different strategies to optimize the pattern length. Comparison was carried out over HP and SAP variability series recorded from 12 Parkinson's disease (PD) patients without orthostatic hypotension or symptoms of orthostatic intolerance and 12 age-matched healthy control (HC) subjects. Regardless of the method, complexity of cardiovascular control increased in PD group, thus suggesting the early impairment of cardiovascular function.

Background: Significant efforts have been focused on investigating the contribution of common variants to Parkinson disease (PD) risk. Several independent GWAS and metanalysis studies have shown a genome-wide significant association of single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) regions. Here we investigated the role of SNCA and MAPT as PD susceptibility genes in a large Italian population of 904 patients and 891 controls. An evaluation of gene-gene and gene-environment interactions in association with PD was also attempted., Methods: The SNCA Rep1 microsatellite was genotyped by a fluorescent PCR assay, whereas the SNPlex genotyping system was used to genotype 12 additional markers across the SNCA gene, and 2 SNPs tagging the risk MAPT H1 haplotype., Results: Single-marker analysis demonstrated nominal evidence of association for: i) the 261-bp-long allele of Rep1; ii) 7 SNPs in the SNCA region (top SNP: rs356186, P = 3.08 × 10(-04), intron 4); iii) both SNPs identifying the MAPT H1 haplotype (P = 4.63 × 10(-04) and P = 4.23 × 10(-04) for rs1800547 and rs9468, respectively). Moreover, we found a highly significant protective haplotype spanning ∼83 kb from intron 4 to the 3' end of SNCA (P = 1.29 × 10(-05))., Conclusions: Our findings strongly confirm SNCA and MAPT as major PD susceptibility genes for idiopathic PD in the Italian population. Interaction analyses did not evidence either epistatic effects between the two loci or gene-environment interactions., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background and Purpose: Creative drive and enhanced artistic-like production may emerge in patients with Parkinson's disease (PD) during dopaminergic therapy. However, it has not been described to date whether this artistic-like production results from dopaminergic drugs triggering innate skills or it could be considered as a repeated behavior possibly associated with impulse control disorders (ICDs)., Methods: We investigated creative drive in a cohort of cognitively preserved patients with PD by means of the Torrance Test of Creative Thinking (TTCT). We also investigated a putative association between creative drive and ICDs in 36 PD patients with (PD-c) or without (PD-nc) increased artistic-like production and 36 healthy controls (HC). We considered artistic-like productivity to be enhanced if patients reported working on any form of art more than 2h per day after the introduction of dopaminergic treatment. The TTCT, the Barratt Impulsiveness Scale (BIS-11A), the Minnesota Impulsive Disorders Interview (MIDI), and the Punding Rating Scale were applied., Results: Mean TTCT score of PD-c was found to be similar to HC (169.4±51.6 vs. 170.2±69.7, respectively), and both PD-c and HC had significantly higher TTCT scores than patients with PD-nc (125.4±46.1 P<0.05). TTCT did not correlate with any demographic or clinical data in both PD subgroups. No correlation was found between TTCT, BIS-11A, and MIDI., Conclusions: Our study suggests that newly acquired artistic-like production in patients with PD is not associated with impulsivity or ICDs. Artistic-like production might represent the emerging of innate skills in a subset of predisposed patients with PD on dopaminergic therapy., (© 2011 The Author(s). European Journal of Neurology © 2011 EFNS.)

Background: Abnormal repetitive behaviors have been reported in Parkinson's disease (PD) during dopamine replacement therapy (DRT) and associated with individual predisposing features, including impulsivity. However, impulsivity and compulsive symptoms have never been explored in PD patients before initiation of DRT. We previously reported a 20% of impulse control disorders (ICD) in an Italian cohort., Methods: 103 consecutive newly diagnosed drug-naïve PD patients (means: age = 60.5 ± 9.2 years; duration = 15.4 ± 15.3 months) were screened for compulsive sexual behavior, compulsive buying, intermittent explosive disorder (Minnesota Impulsive Disorders Interview, MIDI), and pathological gambling (South Oaks Gambling Screen, SOGS). Barratt Impulsiveness Scale (BIS-11) and Maudsley Obsessional-Compulsive Questionnaire (MOCQ/R) assessed impulsivity, obsessive-compulsive symptoms, respectively. Depression (GDS-15) and general cognitive status were additionally assessed. We also compared ICDs frequency with our healthy controls., Results: 17.5% of PD patients screened positive for at least one ICD at MIDI (17/103) and SOGS (1/103), though none had a disorder based on DSM-IV criteria. These frequencies were similar to healthy controls. There was a trend toward higher scores in BIS-11 attentive-impulsivity subscale (15.2 ± 4.8 vs. 18.7 ± 4.9; P = 0.007) and in MOCQ/R-Doubting subscale (0.67 ± 1.1 vs. 1.5 ± 1.2; P = 0.007) in PD with ICD. We also observed a positive correlation between GDS-15 and BIS-11., Conclusions: Similar to our healthy control population, we found a significant proportion of early PD patients positive for ICDs before starting treatment. We also found a relationship between impulsivity and depression. A detailed behavioral assessment before starting dopaminergic therapy is recommended., (Copyright © 2011 Movement Disorder Society.)

Background: Sleep disorders are common in multiple system atrophy (MSA), but the prevalence of excessive daytime sleepiness (EDS) is not well known., Objective: To assess the frequency and associations of EDS in MSA., Design: Survey of EDS in consecutive patients with MSA and comparison with patients with Parkinson disease (PD) and individuals without known neurologic disease., Setting: Twelve tertiary referral centers., Participants: Eighty-six consecutive patients with MSA; 86 patients with PD matched for age, sex, and Hoehn and Yahr stage; and 86 healthy subject individuals matched for age and sex., Main Outcome Measures: Epworth Sleepiness Scale (ESS), modified ESS, Sudden Onset of Sleep Scale, Tandberg Sleepiness Scale, Pittsburgh Sleep Quality Index, disease severity, dopaminergic treatment amount, and presence of restless legs syndrome., Results: Mean (SD) ESS scores were comparable in MSA (7.72 [5.05]) and PD (8.23 [4.62]) but were higher than in healthy subjects (4.52 [2.98]) (P < .001). Excessive daytime sleepiness (ESS score >10) was present in 28% of patients with MSA, 29% of patients with PD, and 2% of healthy subjects (P < .001). In MSA, in contrast to PD, the amount of dopaminergic treatment was not correlated with EDS. Disease severity was weakly correlated with EDS in MSA and PD. Restless legs syndrome occurred in 28% of patients with MSA, 14% of patients with PD, and 7% of healthy subjects (P < .001). Multiple regression analysis (with 95% confidence intervals obtained using nonparametric bootstrapping) showed that sleep-disordered breathing and sleep efficiency predicted EDS in MSA and amount of dopaminergic treatment and presence of restless legs syndrome in PD., Conclusions: More than one-quarter of patients with MSA experience EDS, a frequency similar to that encountered in PD. In these 2 conditions, EDS seems to be associated with different causes.

Transdermal rotigotine was used in six patients with advanced Parkinson's disease and sleep disorders (UPDRS part II item 12 score ≥ 2) receiving oral levodopa and diurnal apomorphine infusions. Transdermal rotigotine (2-4 mg/24h) was used at night for four months. Sleep disorders improved, the total Parkinson's Disease Sleep Scale score falling by an average of 45%; significant improvements emerged in the items quality of sleep and difficulty in remaining asleep (p<0.05). No undesirable dopaminergic effects were reported. This preliminary open-label study suggests that transdermal rotigotine may be a well tolerated and effective treatment in patients with advanced Parkinson's disease, reducing nocturnal disability and ameliorating sleep disorders without inducing undesirable dopaminergic effects.

The cognitive status of patients with Parkinson's disease (PD) who developed pathological gambling (PG) during dopamine replacement therapy has been poorly explored. We compared clinical and cognitive features of 21 consecutive PD patients with active PG (PD-PG) versus 42 PD controls of similar disease duration without any impulse control disorder. All patients underwent full neuropsychological testing to evaluate executive and other frontal lobe-related functions, attention, learning and memory, language, visuospatial abilities and neuropsychiatric status [using Geriatric Depression Scale (GDS) and Neuropsychiatric Inventory (NPI)] as well as the South Oaks Gambling Screen Scale (SOGS). PD-PG were younger (60.4 vs. 64.9, p = 0.01) and more frequently of male gender (85 vs. 57%, p = 0.02). The two groups did not differ in medication dosages and kind of dopamine agonist. PD-PG had higher MMSE (29.1 vs. 27.4, p = 0.02) and performed better at Rey Auditory Verbal learning Test (45.9 vs. 40.4, p = 0.04), verbal phonemic fluencies (38.7 vs. 31.8, p = 0.02), verbal semantic fluencies (44.9 vs. 37.4, p = 0.01) and attentive matrices (47.6 vs. 43.5, p = 0.05) while the remaining cognitive performances were comparable to controls. Moreover, based on the NPI, PD-PG had higher aggressiveness, irritability, disinhibition and eating disorders than controls. In conclusion the occurrence of PG in our cohort of patients with PD was associated with preserved executive functions.

Switching from oral medications to continuous infusion of levodopa/carbidopa gel reduces motor complications in advanced Parkinson's disease (PD), but effects on nonmotor symptoms (NMSs) are unknown. In this prospective open-label observational study, we report the effects of intrajejunal levodopa/carbidopa gel infusion on NMS in PD based on standard assessments utilizing the nonmotor symptoms scale (NMSS) along with the unified Parkinson's disease rating scale (UPDRS 3 motor and 4 complications) and quality of life (QoL) using the Parkinson's disease questionnaire (PDQ-8). Twenty-two advanced PD patients (mean age 58.6 years, duration of disease 15.3 years) were followed for 6 months. A statistically significant beneficial effect was shown in six of the nine domains of the NMSS: cardiovascular, sleep/fatigue, attention/memory, gastrointestinal, urinary, and miscellaneous (including pain and dribbling) and for the total score of this scale (NMSST) paralleling improvement of motor symptoms (UPDRS 3 motor and 4 complications in "best on" state) and dyskinesias/motor fluctuations. In addition, significant improvements were found using the Parkinson's disease sleep scale (PDSS) and the PDQ-8 (QoL). The improvement in PDQ-8 scores correlated highly significantly with the changes in NMSST, whereas a moderately strong correlation was observed with UPDRS changes. This is the first demonstration that a levodopa-based continuous dopaminergic stimulation is beneficial for NMS and health-related quality of life in PD in addition to the reduction of motor fluctuations and dyskinesias., (Copyright 2009 Movement Disorder Society.)

Dementia is a frequent non-motor feature of Parkinson's disease (PD). Elevated plasma homocysteine (Hcy) levels have been associated with both cognitive impairment and dementia. Increased Hcy levels have been observed in levodopa-treated patients with PD. The objective of our study was to evaluate the association between plasma Hcy levels and dementia in PD. We performed a multicenter cross-sectional study on patients with PD with (PDD) and without (PDnD) dementia and age- and sex-matched healthy controls. We compared Hcy levels in patients with PDD and PDnD and healthy controls, and we performed logistic regression analysis to search for an association between the presence of dementia and increased Hcy levels in PD. Patients with PD (121), PDD (42), and PDnD (79), and age- and sex-matched controls (154) were enrolled. Hcy levels were higher in patients with PD compared to controls (17.5 micromol/L +/- 10.2 vs. 11 +/- 4.1; P < 0.00001). Among patients with PD, Hcy levels were higher in the PDD group compared to the PDnD group (20.7 micromol/L +/- 12.1 vs. 15.8 +/- 8.5; P = 0.002). In a multivariate logistic regression model, higher Hcy levels [Odds ratios comparing the top (>18.9 micromol/L) with the bottom tertile (<12.4 micromol/L): 3.68; 95% CI: 1.14-11.83] were significantly associated with dementia. These data support the association between elevated Hcy levels and the presence of dementia in PD., ((c) 2009 Movement Disorder Society.)

Two small studies reported suboptimal therapy adherence in Parkinson's disease. We conducted a larger multicenter European study to assess medicine-taking behavior. Parkinson's disease patients taking dopaminergic therapy were enrolled in 8 centers in 5 countries, and disease severity and demographics recorded. Antiparkinson drug adherence was measured for 4 weeks using electronic monitoring bottles which record the date and time of cap opening (Aardex, Switzerland). One hundred twelve patients, mean age 65 years (standard deviation (SD) 10), with Parkinson's disease for 7.7 (SD 8.2) years completed the study. Total median adherence (doses taken/doses prescribed) was 97.7% (interquartile range [IQ] 90.6-100), days adherence (correct dose days) was 86.2% (IQ 61.1-96.2) and timing adherence (doses taken at correct time intervals) was 24.4% (IQ 5.3-56.5). Fourteen patients (12.5%) took less than 80% of prescribed doses, which was defined as suboptimal adherence. Patients with satisfactory adherence took a median of 8 mg/day (IQ 0-33) less than their prescribed dose of levodopa (P = NS), while suboptimal adherence patients took a median of 481 mg/day (IQ 205-670) less than their prescribed dose (P = 0.0006). The Parkinson motor score was significantly higher in patients with suboptimal adherence at 29 (IQ 20-40), versus those with satisfactory adherence at 19 (IQ 13-26), P = 0.005. Once daily drugs had significantly better adherence when compared with drugs prescribed more frequently (P < 0.0001). Suboptimal therapy adherence is associated with significant deviation from prescribed levodopa doses, despite greater Parkinson's motor severity. Optimizing oral medication intake has a potential role in maximizing the therapy response in Parkinson's disease., ((c) 2009 Movement Disorder Society.)

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive, late-onset neurodegenerative disease that affects older carriers of premutation (CGG) repeat expansions of the fragile X mental retardation 1 (FMR1) gene. Clinical features include intention tremor, gait ataxia, memory loss, peripheral neuropathy, autonomic dysfunction, and parkinsonism. The presence of parkinsonism in FXTAS raises the possibility that some individuals who have Parkinson disease are actually carriers of a premutation FMR1 allele., Objective: To screen DNA samples from a large cohort of females with Parkinson disease for an excess of expanded alleles of the FMR1 gene., Design and Patients: We screened a cohort of 595 women with parkinsonism, the largest screening of a parkinsonism-associated group to date, for the presence of an FMR1 premutation allele (55-200 CGG repeats). The screening protocol uses an enhanced polymerase chain reaction method capable of flagging any FMR1 expanded CGG repeat in women as well as in men., Setting: Diagnostic assessments were performed at an outpatient tertiary clinic (Parkinson Institute, Milan). Genotyping was conducted at the University of California, Davis., Main Outcome Measures: CGG repeat number and clinical/neuroimaging assessments of patients with Parkinson disease were conducted. Two premutation carriers were identified., Results: Two individuals possessed an FMR1 allele in the premutation range (CGG repeats: 30 and 75; 30 and 115). This carrier frequency (2 of 595 [0.34%]) is not significantly different from estimates of the allele frequency among women in the general population (0.4%-0.8%). Clinical and radiologic features of these 2 patients were similar to those of the general Parkinson disease population; however, 1 patient (115 CGG repeats) had a family history of 2 sons with the fragile X syndrome., Conclusion: Screening of women within the parkinsonism clinical spectrum is unlikely to be productive in the absence of additional medical or family history suggestive of involvement of the FMR1 gene.

We are reporting our clinical experience in 66 patients with advanced Parkinson's disease (PD) who were switched to tolcapone because of persisting off periods despite treatment with entacapone (according to the European Agency for the Evaluation of Medicinal products: EMEA). We used UPDRS II-III-IV in "on" state to monitor tolcapone effectiveness at 6 and 12 months. We found significant reductions in mean off-time duration (UPDRS item 39) and levodopa dose at follow up. Eleven patients dropped out (17%) during the first month of treatment, 2 (3%) because liver enzymes exceeded normal limit. Amongst patients who continued tolcapone, 30/55 (54%) reported "off-time" reduction > or =25% (UPDRS-39 decrement > or =1 point). Our findings indicate that tolcapone widens the levodopa therapeutic window, even in patients who have not benefited from entacapone. We suggest that tolcapone is indicated before patients are referred for more invasive procedures.

Background: Pathological gambling (PG) may develop in patients with Parkinson disease (PD) during dopamine replacement therapy, but the underlying neural correlates are still unclear., Objective: To investigate resting state brain perfusion in PD patients with active PG compared with matched PD controls and healthy controls., Design: Case-control study., Setting: Outpatient tertiary clinic., Participants: Eleven right-handed PD patients with active PG according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) criteria, 40 matched PD controls, and 29 age-matched healthy controls., Intervention: All the participants underwent resting state brain perfusion single-photon emission computed tomography using technetium TC 99m ethylcysteinate dimer bicisate. All PD subjects were taking dopaminergic medication., Main Outcome Measure: Statistical Parametric Mapping was used for data analysis (P<.005, false discovery rate corrected)., Results: PD patients with PG showed resting state overactivity in a right hemisphere network that included the orbitofrontal cortex, the hippocampus, the amygdala, the insula, and the ventral pallidum. No areas of perfusion reduction were detected., Conclusions: We found that PD patients with PG have abnormal resting state dysfunction of the mesocorticolimbic network possibly associated with a drug-induced overstimulation of relatively preserved reward-related neuronal systems. These findings support the concept that PG is a "behavioral" addictive disorder.

Objective: To determine whether pain is more frequent among people with Parkinson disease (PD) than among age-matched controls., Design: Case-control study., Patients and Methods: Logistic regression models taking into account type of pain, time between pain and PD onset, and possible confounders were used to compare 402 PD patients with 317 age-matched healthy control subjects., Results: The overall frequency of pain was significantly greater in PD patients than in controls (281 [69.9%] vs 199 [62.8%]; P = .04), mainly because the healthy control group lacked dystonic pain. Conversely, the frequency of nondystonic pain was similar among PD patients and controls (267 [66.4%] vs 199 [62.8%]; P = .28). Nevertheless, we observed a significant association between PD and nondystonic pain, beginning after the onset of parkinsonian symptoms (odds ratio, 2.1; 95% confidence interval, 1.4-2.9). Cramping and central neuropathic pain were more frequent among PD patients than controls. About one-quarter of patients who experienced pain reported pain onset before starting antiparkinsonian therapy., Conclusion: These data support the hypothesis that pain begins at clinical onset of PD or thereafter as a nonmotor feature of PD.

Background and Methods: We used (123)I-Ioflupane SPECT to study 32 unrelated patients with essential tremor (16 with positive familial history), 47 sporadic tremor dominant patients with Parkinson's disease and 31 healthy control subjects. Discriminant analysis was used to categorize healthy subjects and patients with Parkinson's disease or essential tremor., Results: Patients with essential tremor had higher uptake values (50% putamen and 21% caudate, P<0.001) compared to those with Parkinson's disease but lower than healthy subjects (15% putamen and 21% caudate, P<0.05). Discriminant analysis classified seven essential tremor patients in the healthy subjects cohort (22%) and two as Parkinson's disease (6%)., Conclusions: Our results show that some essential tremor patients may present mild abnormalities of striatal dopamine transporters and a typical Parkinson's disease-like pattern of uptake loss. These findings suggest a link between the two disorders.

Background: A significant percentage of patients with Parkinson's disease (PD) continue to experience motor fluctuations and dyskinesias despite the association of dopamine agonists and levodopa with COMT or MAO-B inhibitors. The use of apomorphine infusion is limited by compliance while deep brain stimulation is feasible only for a small number of patients mostly because of age constraints., Objective: To assess prospectively the effectiveness of duodenal levodopa infusion on quality of life as well as motor features in patients with advanced PD. In all but 1 case levodopa infusion was stopped at nighttime., Methods: We report the outcome of 22 PD patients, followed for up to 2 years, who were on continuous duodenal levodopa/carbidopa infusion through percutaneous endoscopic gastrostomy., Results: We found a significant reduction in 'off' period duration as well as dyskinesia severity (Unified Parkinson's Disease Rating Scale part IV, items 33 and 39). There was significant improvement in the 39-item Parkinson's Disease Quality of Life Questionnaire as well as in the Unified Parkinson's Disease Rating Scale part II up to the 2-year follow-up. Five patients withdrew: 2 for poor compliance and 3 for adverse events (1 was related to percutaneous endoscopic gastrostomy)., Conclusions: These results demonstrate significant clinical improvements in quality of life and activities of daily living consistent with the occurrence of a satisfactory therapeutic response and a reduction in dyskinesia severity., (2008 S. Karger AG, Basel)

We analysed the parkin gene in a large consecutive series (146) of unrelated early onset Parkinson's disease (onset ?40 years of age) patients. Twelve cases (8.2%) had homozygous or compound heterozygous point mutations and/or exon rearrangements, while a single mutation was found in four subjects (2.7%). We identified eight exon rearrangements and nine point mutations, two of which were novel: c.735delT (p.C212/X224) and c.815C>G (p.C238W). Genotype-phenotype correlation revealed that parkin carriers had features similar to those of non-carrier early onset Parkinson disease patients.

We performed [123I]FP-CIT/SPECT in 20 drug-naive Parkinson's disease (PD) patients, 10 with unilateral akinesia/rigidity at onset (arPD) and 10 with additional tremor-at-rest (tPD), to evaluate whether resting tremor at onset is associated with differences in striatal dopamine transporter binding. Patients of the two cohorts were matched for age, disease duration (<3 years) and severity of non-tremor motor symptoms; 31 healthy participants served as controls. Mean striatal dopamine transporter binding reduction in PD patients vs. controls was 42% for arPD and 50% for tPD; mean ipsilateral striatum and caudate nucleus uptake values were lower by 12 and 24%, respectively, in tPD than arPD. We conclude that widespread degeneration of the nigrostriatal dopaminergic pathway might be necessary for the development of parkinsonian tremor-at-rest.

Background: Individuals with fragile X-associated tremor/ataxia syndrome frequently have associated features of parkinsonism, often leading to an initial diagnosis of Parkinson disease or other parkinsonism spectrum disorders. Parkinson disease populations may thus include individuals who harbor premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene., Objective: To screen DNA samples (male) from an Italian Parkinson disease clinic for an excess of premutation expansions of the FMR1 gene., Design: DNA samples obtained from 903 unrelated males through consecutive clinic visits were analyzed by an enhanced polymerase chain reaction method for detecting expanded CGG repeats., Setting: Diagnostic assessments were performed at the Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy. Genotyping was conducted at the University of California Davis School of Medicine., Participants: A cohort of unrelated males with clinical features of parkinsonism. All but 12 males were of Italian origin, and all reported Caucasian ethnicity., Main Outcome Measure: CGG repeat number., Results: Three premutation carriers (61, 69, and 80 CGG repeats) were identified (0.33%), which is not significantly higher than the frequency of premutation alleles in the general population. The outcome of the current study, the largest screen of individuals with parkinsonism to date, supports previous screens of smaller parkinsonism cohorts., Conclusion: Broad screening for premutation alleles in Parkinson disease populations is unlikely to be productive in the absence of additional clinical or family history data that suggest involvement of the FMR1 gene.

We assessed prospectively clinical and quality of life changes in 9 patients with Parkinson's disease (PD; H&Y > or = 3) with severe motor fluctuations and dyskinesia who started continuous daily levodopa duodenal infusion through percutaneous endoscopic gastrostomy. Seven patients completed the follow-up period. Duration of "off" periods and time with disabling dyskinesia shortened significantly in all patients (P < 0.01). Total daily dose of levodopa infused did not differ from baseline equivalents. There were significant improvements in UPDRS-II (activities of daily living) and -IV (motor complications) in the "on" condition (P < 0.02), and in four PDQ-39 domains (mobility, activities of daily living, stigma, bodily discomfort; P < 0.05). Two patients withdrew for adverse events. Our results demonstrate that a satisfactory therapeutic window can be achieved and maintained for several months in advanced PD patients.

We used 123I-Ioflupane SPECT to study striatal dopamine transporter (DAT) binding in 36 Parkinson's disease (PD) patients with history of severe occupational exposure to hydrocarbons. Data were compared with 38 PD patients without exposure history as well as healthy controls. Both PD cohorts showed significant striatal uptake decrements compared with controls. We found significantly lower values in the whole striatum of exposed compared with non-exposed patients (0.83 +/- 0.25 vs. 1.05 +/- 0.39; P = 0.004), more pronounced in the putamen (0.61 +/- 0.24 vs. 0.85 +/- 0.42; P = 0.004). We conclude that severe occupational exposure to hydrocarbons may modify disease course and ultimately accelerate nigro-striatal denervation.