Parkinson’s Disease The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Outlining a Population “at Risk” of Parkinson’s Disease: Evidence from a Case-Control Study Mon, 29 Aug 2016 11:47:55 +0000 The multifactorial pathogenesis of Parkinson’s Disease (PD) requires a careful identification of populations “at risk” of developing the disease. In this case-control study we analyzed a large Italian population, in an attempt to outline general criteria to define a population “at risk” of PD. We enrolled 300 PD patients and 300 controls, gender and age matched, from the same urban geographical area. All subjects were interviewed on demographics, family history of PD, occupational and environmental toxicants exposure, smoking status, and alcohol consumption. A sample of 65 patients and 65 controls also underwent serum dosing of iron, copper, mercury, and manganese by means of Inductively Coupled-Plasma-Mass-Spectrometry (ICP-MS). Positive family history, toxicants exposure, non-current-smoker, and alcohol nonconsumer status occurred as significant risk factors in our population. The number of concurring risk factors overlapping in the same subject impressively increased the overall risk. No significant differences were measured in the metal serum levels. Our findings indicate that combination of three to four concurrent PD-risk factors defines a condition “at risk” of PD. A simple stratification, based on these questionnaires, might be of help in identifying subjects suitable for neuroprotective strategies. Tommaso Schirinzi, Giuseppina Martella, Alessio D’Elia, Giulia Di Lazzaro, Paola Imbriani, Graziella Madeo, Leonardo Monaco, Marta Maltese, and Antonio Pisani Copyright © 2016 Tommaso Schirinzi et al. All rights reserved. Drosophila Mutant Model of Parkinson’s Disease Revealed an Unexpected Olfactory Performance: Morphofunctional Evidences Sun, 28 Aug 2016 07:40:46 +0000 Parkinson’s disease (PD) is one of the most common neurodegenerative diseases characterized by the clinical triad: tremor, akinesia, and rigidity. Several studies have suggested that PD patients show disturbances in olfaction as one of the earliest, nonspecific nonmotor symptoms of disease onset. We sought to use the fruit fly Drosophila melanogaster as a model organism to explore olfactory function in LRRK loss-of-function mutants, which was previously demonstrated to be a useful model for PD. Surprisingly, our results showed that the LRRK mutant, compared to the wild flies, presents a dramatic increase in the amplitude of the electroantennogram responses and this is coupled with a higher number of olfactory sensilla. In spite of the above reported results, the behavioural response to olfactory stimuli in mutant flies is impaired compared to that obtained in wild type flies. Thus, behaviour modifications and morphofunctional changes in the olfaction of LRRK loss-of-function mutants might be used as an index to explore the progression of parkinsonism in this specific model, also with the aim of studying and developing new treatments. Francescaelena De Rose, Valentina Corda, Paolo Solari, Patrizia Sacchetti, Antonio Belcari, Simone Poddighe, Sanjay Kasture, Paolo Solla, Francesco Marrosu, and Anna Liscia Copyright © 2016 Francescaelena De Rose et al. All rights reserved. The Effect of Hyperhomocysteinemia on Motor Symptoms, Cognitive Status, and Vascular Risk in Patients with Parkinson’s Disease Thu, 25 Aug 2016 16:12:36 +0000 Factors related with hyperhomocysteinemia (HHcy) and the impact of HHcy in Parkinson’s disease (PD) are not well understood. We investigated the factors associated with increased levels of homocysteine (Hcy) and the relationship between HHcy and motor symptoms, cognitive status, and vascular risk in patients with Parkinson’s disease. Among 60 patients (29 males, 48.3%) with PD, the stage of the disease, the severity of clinical symptoms, and the patients’ cognitive status were measured using a modified Hoehn and Yahr Staging Scale (mHY), Unified Parkinson’s Disease Rating Scale (UPDRS) II and III, and Mini-Mental State Examination (MMSE), respectively. Patients were also noted for having dyskinesia and hallucinations. Serum vitamin B12, folic acid, and plasma Hcy ​​levels were measured. Furthermore, the presence of vascular risk factors was recorded. Finally, we investigated carotid artery intima-media thickening and stenosis using colour Doppler ultrasonography as well as the presence of ischemic lesions using brain imaging techniques. Plasma Hcy ​​levels were higher with advanced age and in males. In addition, there was an inverse relationship between Hcy ​​and vitamin B12 levels. There was no correlation between HHcy and the stage of the disease, severity of motor symptoms, cognitive status as assessed by the MMSE, vascular risk factors, carotid artery atherosclerotic findings, and ischemic brain lesions. Plasma Hcy levels may rise due to several factors in PD. However, the resulting HHcy has no significant effect on the clinical picture in terms of motor features, cognitive status, and vascular diseases. Bilge Kocer, Hayat Guven, Isik Conkbayir, Selim Selcuk Comoglu, and Sennur Delibas Copyright © 2016 Bilge Kocer et al. All rights reserved. Alpha-Synuclein in Parkinson’s Disease: From Pathogenetic Dysfunction to Potential Clinical Application Wed, 17 Aug 2016 14:18:00 +0000 Parkinson’s disease is a neurodegenerative disease/synucleinopathy that develops slowly; however, there is no efficient method of early diagnosis, nor is there a cure. Progressive dopaminergic neuronal cell loss in the substantia nigra pars compacta and widespread aggregation of the α-synuclein protein (encoded by the SNCA gene) in the form of Lewy bodies and Lewy neurites are the neuropathological hallmarks of Parkinson’s disease. The SNCA gene has undergone gene duplications, triplications, and point mutations. However, the specific mechanism of α-synuclein in Parkinson’s disease remains obscure. Recent research showed that various α-synuclein oligomers, pathological aggregation, and propagation appear to be harmful in certain areas in Parkinson’s disease patients. This review summarizes our current knowledge of the pathogenetic dysfunction of α-synuclein associated with Parkinson’s disease and highlights current approaches that seek to develop this protein as a possible diagnostic biomarker and therapeutic target. Lingjia Xu and Jiali Pu Copyright © 2016 Lingjia Xu and Jiali Pu. All rights reserved. The Cognition of Maximal Reach Distance in Parkinson’s Disease Mon, 15 Aug 2016 09:18:47 +0000 This study aimed to investigate whether the cognition of spatial distance in reaching movements was decreased in patients with Parkinson’s disease (PD) and whether this cognition was associated with various symptoms of PD. Estimated and actual maximal reaching distances were measured in three directions in PD patients and healthy elderly volunteers. Differences between estimated and actual measurements were compared within each group. In the PD patients, the associations between “error in cognition” of reaching distance and “clinical findings” were also examined. The results showed that no differences were observed in any values regardless of dominance of hand and severity of symptoms. The differences between the estimated and actual measurements were negatively deviated in the PD patients, indicating that they tended to underestimate reaching distance. “Error in cognition” of reaching distance correlated with the items of posture in the motor section of the Unified Parkinson’s Disease Rating Scale. This suggests that, in PD patients, postural deviation and postural instability might affect the cognition of the distance from a target object. Satoru Otsuki and Masanori Nagaoka Copyright © 2016 Satoru Otsuki and Masanori Nagaoka. All rights reserved. Mitochondria: Key Organelle in Parkinson’s Disease Sun, 07 Aug 2016 05:58:46 +0000 Rubén Gómez-Sánchez, José M. Bravo-San Pedro, Matthew E. Gegg, Rosa A. González-Polo, and José M. Fuentes Copyright © 2016 Rubén Gómez-Sánchez et al. All rights reserved. 5-HT2A Receptor Binding in the Frontal Cortex of Parkinson’s Disease Patients and Alpha-Synuclein Overexpressing Mice: A Postmortem Study Thu, 04 Aug 2016 07:09:52 +0000 The receptor is highly involved in aspects of cognition and executive function and seen to be affected in neurodegenerative diseases like Alzheimer’s disease and related to the disease pathology. Even though Parkinson’s disease (PD) is primarily a motor disorder, reports of impaired executive function are also steadily being associated with this disease. Not much is known about the pathophysiology behind this. The aim of this study was thereby twofold: (1) to investigate receptor binding levels in Parkinson’s brains and (2) to investigate whether PD associated pathology, alpha-synuclein (AS) overexpression, could be associated with alterations. Binding density for the -specific radioligand [3H]-MDL 100.907 was measured in membrane suspensions of frontal cortex tissue from PD patients. Protein levels of AS were further measured using western blotting. Results showed higher AS levels accompanied by increased receptor binding in PD brains. In a separate study, we looked for changes in receptors in the prefrontal cortex in 52-week-old transgenic mice overexpressing human AS. We performed region-specific receptor binding measurements followed by gene expression analysis. The transgenic mice showed lower binding in the frontal association cortex that was not accompanied by changes in gene expression levels. This study is one of the first to look at differences in serotonin receptor levels in PD and in relation to AS overexpression. Nadja Bredo Rasmussen, Mikkel Vestergaard Olesen, Tomasz Brudek, Per Plenge, Anders Bue Klein, Jenny E. Westin, Karina Fog, Gitta Wörtwein, and Susana Aznar Copyright © 2016 Nadja Bredo Rasmussen et al. All rights reserved. Comparison of Test Your Memory and Montreal Cognitive Assessment Measures in Parkinson’s Disease Tue, 05 Jul 2016 11:52:31 +0000 Background. MoCA is widely used in Parkinson’s disease (PD) to assess cognition. The Test Your Memory (TYM) test is a cognitive screening tool that is self-administered. Objectives. We sought to determine (a) the optimal value of TYM to discriminate between PD patients with and without cognitive deficits on MoCA testing, (b) equivalent MoCA and TYM scores, and (c) interrater reliability in TYM testing. Methods. We assessed the discriminant ability of TYM and the equivalence between TYM and MoCA scores and measured the interrater reliability between three raters. Results. Of the 135 subjects that completed both tests, 55% had cognitive impairment according to MoCA. A MoCA score of 25 was equivalent to a TYM score of 43-44. The area under the receiver operator characteristic (ROC) curve for TYM to differentiate between PD-normal and PD-cognitive impairment was 0.82 (95% CI 0.75 to 0.89). The optimal cutoff to distinguish PD-cognitive impairment from PD-normal was ≤45 (sensitivity 90.5%, specificity 59%) thereby correctly classifying 76.3% of patients with PD-cognitive impairment. Interrater agreement was high (0.97) and TYM was completed in under 7 minutes (interquartile range 5.33 to 8.52 minutes). Conclusions. The TYM test is a useful and less resource intensive screening test for cognitive deficits in PD. Emily J. Henderson, Howard Chu, Daisy M. Gaunt, Alan L. Whone, Yoav Ben-Shlomo, and Veronica Lyell Copyright © 2016 Emily J. Henderson et al. All rights reserved. Parkinson’s Disease: New Insights into Pathophysiology and Rehabilitative Approaches Thu, 30 Jun 2016 14:46:59 +0000 Vincenza Frisardi, Andrea Santamato, and Binith Cheeran Copyright © 2016 Vincenza Frisardi et al. All rights reserved. Goal Setting for Cognitive Rehabilitation in Mild to Moderate Parkinson’s Disease Dementia and Dementia with Lewy Bodies Wed, 29 Jun 2016 15:11:30 +0000 Alongside the physical symptoms associated with Parkinson’s disease dementia and dementia with Lewy bodies, health services must also address the cognitive impairments that accompany these conditions. There is growing interest in the use of nonpharmacological approaches to managing the consequences of cognitive disorder. Cognitive rehabilitation is a goal-orientated behavioural intervention which aims to enhance functional independence through the use of strategies specific to the individual’s needs and abilities. Fundamental to this therapy is a person’s capacity to set goals for rehabilitation. To date, no studies have assessed goal setting in early-stage Parkinson’s disease dementia or dementia with Lewy bodies. Semistructured interviews were carried out with 29 participants from an ongoing trial of cognitive rehabilitation for people with these conditions. Here, we examined the goal statements provided by these participants using qualitative content analysis, exploring the types and nature of the goals set. Participants’ goals reflected their motivations to learn new skills or improve performance in areas such as technology-use, self-management and orientation, medication management, and social and leisure activities. These results suggest that goal setting is achievable for these participants, provide insight into the everyday cognitive difficulties that they experience, and highlight possible domains as targets for intervention. The trial is registered with ISRCTN16584442 (DOI 10.1186/ISRCTN16584442 13/04/2015). Tamlyn J. Watermeyer, John V. Hindle, Julie Roberts, Catherine L. Lawrence, Anthony Martyr, Huw Lloyd-Williams, Andrew Brand, Petra Gutting, Zoe Hoare, Rhiannon Tudor Edwards, and Linda Clare Copyright © 2016 Tamlyn J. Watermeyer et al. All rights reserved. Altered Spontaneous Brain Activity in Cortical and Subcortical Regions in Parkinson’s Disease Sun, 19 Jun 2016 06:54:43 +0000 Purpose. The present study aimed to explore the changes of amplitude of low-frequency fluctuations (ALFF) at rest in patients with Parkinson’s disease (PD). Methods. Twenty-four PD patients and 22 healthy age-matched controls participated in the study. ALFF was measured on the whole brain of all participants. A two-sample -test was then performed to detect the group differences with age, gender, education level, head motion, and gray matter volume as covariates. Results. It was showed that PD patients had significantly decreased ALFF in the left thalamus/caudate and right insula/inferior prefrontal gyrus, whereas they had increased ALFF in the right medial prefrontal cortex (BA 8/6) and dorsolateral prefrontal cortex (BA 9/10). Conclusions. Our results indicated that significant alterations of ALFF in the subcortical regions and prefrontal cortex have been detected in PD patients, independent of age, gender, education, head motion, and structural atrophy. The current findings further provide insights into the biological mechanism of the disease. Jie Xiang, Xiuqin Jia, Huizhuo Li, Jiawei Qin, Peipeng Liang, and Kuncheng Li Copyright © 2016 Jie Xiang et al. All rights reserved. Chaperone-Mediated Autophagy and Mitochondrial Homeostasis in Parkinson’s Disease Thu, 16 Jun 2016 11:57:20 +0000 Parkinson’s disease (PD), a complex neurodegenerative disorder, is pathologically characterized by the formation of Lewy bodies and loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Mitochondrial dysfunction is considered to be one of the most important causative mechanisms. In addition, dysfunction of chaperone-mediated autophagy (CMA), one of the lysosomal proteolytic pathways, has been shown to play an important role in the pathogenesis of PD. An exciting and important development is recent finding that CMA and mitochondrial quality control may be linked. This review summarizes the studies revealing the link between autophagy and mitochondrial function. Discussions are focused on the connections between CMA and mitochondrial failure and on the role of MEF2D, a neuronal survival factor, in mediating the regulation of mitochondria in the context of CMA. These new findings highlight the need to further explore the possibility of targeting the MEF2D-mitochondria-CMA network in both understanding the PD pathogenesis and developing novel therapeutic strategies. Ruixin Yang, Guodong Gao, Zixu Mao, and Qian Yang Copyright © 2016 Ruixin Yang et al. All rights reserved. Evaluation of Nonmotor Symptoms in Diagnosis of Parkinsonism and Tremor Tue, 14 Jun 2016 11:40:44 +0000 Background. Nonmotor symptoms particularly olfactory dysfunction, RBD, depression, hallucinations, and constipation are currently not included in the typical clinical criteria for diagnosing Lewy body Parkinsonian disorders (LBPD). The aim of this study is to determine the diagnostic value of nonmotor symptoms in patients presenting with Parkinsonism and tremor. Methods. All new patients seen between January 2007 and May 2013 in the Movement Disorders Specialist Clinics of the Royal Melbourne Hospital (RMH), who were referred with a possible neurodegenerative syndrome or concerns of Parkinsonism and/or tremor, were included. Patients underwent routine evaluation with the four-minute “Sniffin Sticks” test, RBD, depression, and constipation. Results. 291 patients were included in the analysis. Conclusion. We found that lower olfaction scores based on “Sniffin Sticks” testing combined with reports of depression and constipation are independent predictors for the diagnosis of the spectrum of Lewy body Parkinsonian disorders (LBPD). Parkinson’s disease (PD) cannot be reliably clinically differentiated from other causes of Parkinsonism that share symptomatology and structural abnormalities. Andrew H. Evans and Chiun-Hian Chai Copyright © 2016 Andrew H. Evans and Chiun-Hian Chai. All rights reserved. The Association between C9orf72 Repeats and Risk of Alzheimer’s Disease and Amyotrophic Lateral Sclerosis: A Meta-Analysis Wed, 08 Jun 2016 09:57:17 +0000 C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Caucasian populations. However, the relationship between C9orf72 repeats and Alzheimer’s disease (AD) was not clear. Additionally, there were few articles assessing C9orf72 in other ethnicities with ALS. In this meta-analysis, we aimed to investigate the relationship between C9orf72 repeat expansions (≥30 repeats) and intermediate repeat copies (20–29 repeats) and AD or ALS. The results suggested positive correlations between C9orf72 repeat expansions and the risk of Alzheimer’s disease (OR = 6.36, 95% CI = 3.13–12.92, and ), while intermediate repeat copies of C9orf72 gene were not associated with the risk of the disease. C9orf72 repeat expansions were positively correlated with the risk of familial and sporadic ALS (OR = 293.25, 95% CI = 148.17–580.38, and ; OR = 35.57, 95% CI = 19.61–64.51, and ). There was a positive correlation between the gene variations and ALS risk among Caucasians and Asians (OR = 57.56, 95% CI = 36.73–90.22, and ; OR = 6.35, 95% CI = 1.39–29.02, and ). Li Shu, Qiying Sun, Yuan Zhang, Qian Xu, Jifeng Guo, Xinxiang Yan, and Beisha Tang Copyright © 2016 Li Shu et al. All rights reserved. Pathophysiology of Motor Dysfunction in Parkinson’s Disease as the Rationale for Drug Treatment and Rehabilitation Mon, 06 Jun 2016 06:16:48 +0000 Cardinal motor features of Parkinson’s disease (PD) include bradykinesia, rest tremor, and rigidity, which appear in the early stages of the disease and largely depend on dopaminergic nigrostriatal denervation. Intermediate and advanced PD stages are characterized by motor fluctuations and dyskinesia, which depend on complex mechanisms secondary to severe nigrostriatal loss and to the problems related to oral levodopa absorption, and motor and nonmotor symptoms and signs that are secondary to marked dopaminergic loss and multisystem neurodegeneration with damage to nondopaminergic pathways. Nondopaminergic dysfunction results in motor problems, including posture, balance and gait disturbances, and fatigue, and nonmotor problems, encompassing depression, apathy, cognitive impairment, sleep disturbances, pain, and autonomic dysfunction. There are a number of symptomatic drugs for PD motor signs, but the pharmacological resources for nonmotor signs and symptoms are limited, and rehabilitation may contribute to their treatment. The present review will focus on classical notions and recent insights into the neuropathology, neuropharmacology, and neurophysiology of motor dysfunction of PD. These pieces of information represent the basis for the pharmacological, neurosurgical, and rehabilitative approaches to PD. Francesca Magrinelli, Alessandro Picelli, Pierluigi Tocco, Angela Federico, Laura Roncari, Nicola Smania, Giampietro Zanette, and Stefano Tamburin Copyright © 2016 Francesca Magrinelli et al. All rights reserved. Characteristics of Nonmotor Symptoms in Progressive Supranuclear Palsy Sun, 05 Jun 2016 06:43:28 +0000 Objectives. To explore the clinical correlates of nonmotor symptoms (NMS) in progressive supranuclear palsy (PSP) and their differences from healthy controls and patients with Parkinson’s disease (PD). Methods. Twenty-seven PSP patients, 27 age- and gender-matched healthy controls (HC), and 27 age- and gender-matched PD patients were included for this case-control study. NMS were assessed using the Nonmotor Symptoms Scale (NMSS, including 9 domains). Results. All PSP patients reported NMS. The frequency and severity of “sleep/fatigue,” “mood/apathy,” “attention/memory,” “gastrointestinal,” “sexual dysfunction,” and “miscellaneous” domains in PSP group were significantly higher than those in HC group (). The frequency of “mood/apathy,” “attention/memory,” and “sexual dysfunction” domains and the severity of “attention/memory” and “gastrointestinal” domains in PSP group were significantly higher than those in PD group (). The “attention/memory” domain in PSP had a significant but weak-to-moderate correlation with age (, ) and onset age (, ). Conclusions. NMS are common in PSP patients. Patients with PSP seem to be subjected to more frequent and severe specific NMS compared to healthy aging subjects and PD patients. Older PSP patients and late-onset patients are likely to be subjected to cognitive decline. Ruwei Ou, Wei Song, Qianqian Wei, Ke Chen, Bei Cao, Yanbing Hou, Bi Zhao, and Huifang Shang Copyright © 2016 Ruwei Ou et al. All rights reserved. Essential Oils May Lead α-Synuclein towards Toxic Fibrils Formation Tue, 24 May 2016 09:10:48 +0000 α-Synuclein (α-Syn) fibrillation links with Parkinson’s disease (PD) and several related syndromes. It is believed that exposure to the factors which promote fibrillation may induce and progress such neurodegenerative diseases (NDs). Herein, the effects of some wildly used essential oils including Myrtus communis (M. communis) on α-Syn fibrillation were examined. M. communis particularly increased α-Syn fibrillation in a concentration dependent manner. Given that applications of M. communis are very extensive in Asian societies, especially Zoroastrians, this study was extended towards its role on α-Syn fibrillation/cytotoxicity. By using a unilamellar vesicle, it was shown that the aggregated species with tendency to perturb membrane were increased in the presence of M. communis. In this regard, the cytotoxicity of α-Syn on SH-SH5Y cells was also increased significantly. Inappropriately, the effects of fibrillation inhibitors, baicalein and cuminaldehyde, were modulated in the presence of M. communis. However, major components of M. communis did not induce fibrillation and also the effect of M. communis was limited on other fibrinogenic proteins. Assuming that essential oils have the ability to pass through the blood brain barrier (BBB) along with the popular attention on aromatherapy for the incurable ND, these findings suggest an implementation of fibrillation tests for essential oils. Dina Morshedi and Mahour Nasouti Copyright © 2016 Dina Morshedi and Mahour Nasouti. All rights reserved. Hepcidin Plays a Key Role in 6-OHDA Induced Iron Overload and Apoptotic Cell Death in a Cell Culture Model of Parkinson’s Disease Thu, 19 May 2016 14:15:22 +0000 Background. Elevated brain iron levels have been implicated in the pathogenesis of Parkinson’s disease (PD). However, the precise mechanism underlying abnormal iron accumulation in PD is not clear. Hepcidin, a hormone primarily produced by hepatocytes, acts as a key regulator in both systemic and cellular iron homeostasis. Objective. We investigated the role of hepcidin in 6-hydroxydopamine (6-OHDA) induced apoptosis in a cell culture model of PD. Methods. We downregulated hepcidin using siRNA interference in N27 dopaminergic neuronal cells and made a comparison with control siRNA transfected cells to investigate the role of hepcidin in 6-OHDA induced neurodegeneration. Results. Hepcidin knockdown (32.3%, ) upregulated ferroportin 1 expression and significantly () decreased intracellular iron by 25%. Hepcidin knockdown also reduced 6-OHDA induced caspase-3 activity by 42% () and DNA fragmentation by 29% () and increased cell viability by 22% (). In addition, hepcidin knockdown significantly attenuated 6-OHDA induced protein carbonyls by 52% () and intracellular iron by 28% (), indicating the role of hepcidin in oxidative stress. Conclusions. Our results demonstrate that hepcidin knockdown protected N27 cells from 6-OHDA induced apoptosis and that hepcidin plays a major role in reducing cellular iron burden and oxidative damage by possibly regulating cellular iron export mediated by ferroportin 1. Qi Xu, Anumantha G. Kanthasamy, Huajun Jin, and Manju B. Reddy Copyright © 2016 Qi Xu et al. All rights reserved. Parkinson’s Disease: The Mitochondria-Iron Link Tue, 17 May 2016 14:31:32 +0000 Mitochondrial dysfunction, iron accumulation, and oxidative damage are conditions often found in damaged brain areas of Parkinson’s disease. We propose that a causal link exists between these three events. Mitochondrial dysfunction results not only in increased reactive oxygen species production but also in decreased iron-sulfur cluster synthesis and unorthodox activation of Iron Regulatory Protein 1 (IRP1), a key regulator of cell iron homeostasis. In turn, IRP1 activation results in iron accumulation and hydroxyl radical-mediated damage. These three occurrences—mitochondrial dysfunction, iron accumulation, and oxidative damage—generate a positive feedback loop of increased iron accumulation and oxidative stress. Here, we review the evidence that points to a link between mitochondrial dysfunction and iron accumulation as early events in the development of sporadic and genetic cases of Parkinson’s disease. Finally, an attempt is done to contextualize the possible relationship between mitochondria dysfunction and iron dyshomeostasis. Based on published evidence, we propose that iron chelation—by decreasing iron-associated oxidative damage and by inducing cell survival and cell-rescue pathways—is a viable therapy for retarding this cycle. Yorka Muñoz, Carlos M. Carrasco, Joaquín D. Campos, Pabla Aguirre, and Marco T. Núñez Copyright © 2016 Yorka Muñoz et al. All rights reserved. Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson’s Disease? The Potential Role of Zolpidem in the Treatment of Parkinson’s Disease Tue, 17 May 2016 12:49:15 +0000 At present, patients with advanced Parkinson’s disease (PD) are unsatisfactorily controlled by currently used anti-Parkinsonian dopaminergic drugs. Various studies suggest that therapeutic strategies based on nondopaminergic drugs might be helpful in PD. Zolpidem, an imidazopyridine widely used as sleep inducer, shows high affinity only for receptors containing the α-1 subunit and facilitates GABAergic neurotransmission through a positive allosteric modulation of receptors. Various observations, although preliminary, consistently suggest that in PD patients zolpidem may induce beneficial (and sometimes remarkable) effects on motor symptoms even after single doses and may also improve dyskinesias. Since a high density of zolpidem binding sites is in the two main output structures of the basal ganglia which are abnormally overactive in PD (internal globus pallidus, GPi, and substantia nigra pars reticulata, SNr), it was hypothesized that in PD patients zolpidem may induce through receptors an inhibition of GPi and SNr (and, possibly, of the subthalamic nucleus also), resulting in an increased activity of motor cortical areas (such as supplementary motor area), which may give rise to improvement of motor symptoms of PD. Randomized clinical trials are needed in order to assess the efficacy, safety, and tolerability of zolpidem in treating motor symptoms of PD. Antonio Daniele, Francesco Panza, Antonio Greco, Giancarlo Logroscino, and Davide Seripa Copyright © 2016 Antonio Daniele et al. All rights reserved. Impact of Sex on the Nonmotor Symptoms and the Health-Related Quality of Life in Parkinson’s Disease Mon, 16 May 2016 07:58:20 +0000 Background. Female Parkinson’s disease (PD) patients seem to experience not only more severe motor complications and postural instability but also more pronounced depression, anxiety, pain, and sleep disturbances. Objective. The aim of the present study was to evaluate the role of sex as a possible independent predictor of HRQoL in PD. Methods. In this cross-sectional study, 621 consecutive patients treated at the University of Pécs were enrolled. Severity of PD symptoms was assessed by MDS-UPDRS, UDysRS, Non-Motor Symptoms Scale, PDSS-2, Hamilton Anxiety Scale, Montgomery-Asberg Depression Rating Scale, Lille Apathy Rating Scale, and Addenbrooke Cognitive Examination. HRQoL was assessed by PDQ-39 and EQ-5D. Multiple regression analysis was performed to estimate the PDQ-39 and EQ-5D index values based on various clinical factors. Results. Although females received significantly lower dosage of levodopa, they had significantly more disabling dyskinesia and worse postural instability. Anxiety, pain, sleep disturbances, and orthostatic symptoms were more frequent among females while sexual dysfunction, apathy, and daytime sleepiness were more severe among males. Women had worse HRQoL than men (EQ-5D index value: versus , , and PDQ-39 SI: versus , ). Based on multiple regression analysis, sex was an independent predictor for HRQoL in PD. Conclusions. Based on our results, female sex is an independent predictor for having worse HRQoL in PD. Márton Kovács, Attila Makkos, Zsuzsanna Aschermann, József Janszky, Sámuel Komoly, Rita Weintraut, Kázmér Karádi, and Norbert Kovács Copyright © 2016 Márton Kovács et al. All rights reserved. Relationships among Depression, Anxiety, Sleep, and Quality of Life in Patients with Parkinson’s Disease in Taiwan Sun, 15 May 2016 12:22:52 +0000 The aim of this study was to examine the relationships among depression, anxiety, sleep disturbances, Parkinson’s disease (PD) symptoms, PD medications, and health-related quality of life (QOL) and to identify the predictors of health-related QOL in PD patients. To do this, we administered a battery of questionnaires and rating scales (validated Chinese versions), including the Unified Parkinson’s Disease Rating Scale, 39-item Parkinson’s Disease Questionnaire, Parkinson’s Disease Sleep Scale-2, Beck Depression Inventory, and Beck Anxiety Inventory, to 134 patients with PD whose Minimental State Examination scores were ≥24. We found that patients who reported having poorer QOL had longer disease durations, more severe PD symptoms, higher Hoehn and Yahr stages, and higher levodopa dosages, as well as higher levels of anxiety and depression, more sleep disturbances, and poorer overall cognitive statuses. Among these variables, the cognitive status, dependency of activities of daily living, depression, and anxiety were identified as predictors of QOL in PD patients and were all significant and independent factors of poor QOL in PD patients. The clinicians should be aware of the effects of these factors on QOL and attempt to treat comorbid psychiatric conditions to improve the PD patients’ QOL. Jun-Yu Fan, Bao-Luen Chang, and Yih-Ru Wu Copyright © 2016 Jun-Yu Fan et al. All rights reserved. Activation Mechanism of LRRK2 and Its Cellular Functions in Parkinson’s Disease Thu, 12 May 2016 09:55:10 +0000 Human LRRK2 (Leucine-Rich Repeat Kinase 2) has been associated with both familial and idiopathic Parkinson’s disease (PD). Although several LRRK2 mediated pathways and interaction partners have been identified, the cellular functions of LRRK2 and LRRK2 mediated progression of PD are still only partially understood. LRRK2 belongs to the group of Roco proteins which are characterized by the presence of a Ras-like G-domain (Roc), a C-terminal of Roc domain (COR), a kinase, and several protein-protein interaction domains. Roco proteins exhibit a complex activation mechanism involving intramolecular signaling, dimerization, and substrate/effector binding. Importantly, PD mutations in LRRK2 have been linked to a decreased GTPase and impaired kinase activity, thus providing putative therapeutic targets. To fully explore these potential targets it will be crucial to understand the function and identify the pathways responsible for LRRK2-linked PD. Here, we review the recent progress in elucidating the complex LRRK2 activation mechanism, describe the accumulating evidence that link LRRK2-mediated PD to mitochondrial dysfunction and aberrant autophagy, and discuss possible ways for therapeutically targeting LRRK2. Katharina E. Rosenbusch and Arjan Kortholt Copyright © 2016 Katharina E. Rosenbusch and Arjan Kortholt. All rights reserved. An Expert Diagnosis System for Parkinson Disease Based on Genetic Algorithm-Wavelet Kernel-Extreme Learning Machine Thu, 05 May 2016 08:07:59 +0000 Parkinson disease is a major public health problem all around the world. This paper proposes an expert disease diagnosis system for Parkinson disease based on genetic algorithm- (GA-) wavelet kernel- (WK-) Extreme Learning Machines (ELM). The classifier used in this paper is single layer neural network (SLNN) and it is trained by the ELM learning method. The Parkinson disease datasets are obtained from the UCI machine learning database. In wavelet kernel-Extreme Learning Machine (WK-ELM) structure, there are three adjustable parameters of wavelet kernel. These parameters and the numbers of hidden neurons play a major role in the performance of ELM. In this study, the optimum values of these parameters and the numbers of hidden neurons of ELM were obtained by using a genetic algorithm (GA). The performance of the proposed GA-WK-ELM method is evaluated using statical methods such as classification accuracy, sensitivity and specificity analysis, and ROC curves. The calculated highest classification accuracy of the proposed GA-WK-ELM method is found as 96.81%. Derya Avci and Akif Dogantekin Copyright © 2016 Derya Avci and Akif Dogantekin. All rights reserved. Dysautonomia Differentially Influences the Effect of Affective Pain Perception on Quality of Life in Parkinson’s Disease Patients Thu, 28 Apr 2016 12:46:09 +0000 Background. Our aim was to evaluate the real effect of dysautonomic symptoms on the influence of affective pain perception on quality of life in PD patients. Methods. An observational cross-sectional study was carried out using 105 Parkinson’s disease (PD) patients of the Movement Disorders Unit, Hospital de Cruces (Bilbao, Spain) [men 59 (56.2%), women 46 (43.85%)]. Statistical analysis was made in order to evaluate the possible association of pain with life quality. Results. Quality of life measured by PDQ-39 (Parkinson’s Disease Questionnaire for quality of life) was statistically associated with affective dimension of pain (PRIA, affective pain rating index). However, the influence of this dimension on PDQ-39 was different in the specific case of PD patients that experimented a high score (>12) in SCOPA-AUT (Scale for Outcomes in PD-Autonomic scale). Conclusions. These results confirm the effect of affective perception of pain in life quality of PD patients, indicating the critical role of autonomic symptoms in the modulation of the influence of pain on quality of life and showing the possible utility of dysautonomia as clinical prognostic indicator of quality of life in PD patients affected by pain. D. Rada, J. Seco, E. Echevarría, B. Tijero, L. C. Abecia, and J. C. Gómez-Esteban Copyright © 2016 D. Rada et al. All rights reserved. Association Analysis of NALCN Polymorphisms rs1338041 and rs61973742 in a Chinese Population with Isolated Cervical Dystonia Thu, 28 Apr 2016 11:37:55 +0000 Background. A genome-wide association study (GWAS) demonstrated a possible association between cervical dystonia (CD) and a sodium leak channel, nonselective (NALCN) gene. However, the association between NALCN and CD was largely unknown in Asian population. The present study was carried out to examine the associations between the two single nucleotide polymorphisms (SNPs) rs1338041 and rs61973742 in the NALCN gene and CD in a Chinese population. Methods. In a cohort of 201 patients with isolated CD, we genotyped the two SNPs rs1338041 and rs61973742 using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). We also included 289 unrelated, age- and sex-matched healthy controls (HCs) from the same region. Result. No significant differences were observed in either the genotype distributions or the minor allele frequencies (MAFs) of the two SNPs between the CD patients and the HCs. There were no significant differences between early-onset and late-onset CD patients, between patients with and without a positive family history of dystonia, or between patients with and without tremor or sensory tricks. Conclusion. Lack of association between the SNPs of NALCN and CD suggests that the SNPs of NALCN do not play a role in CD in a Chinese population. Qingqing Zhou, Jing Yang, Bei Cao, Yongping Chen, Qianqian Wei, Ruwei Ou, Wei Song, Bi Zhao, Ying Wu, and Huifang Shang Copyright © 2016 Qingqing Zhou et al. All rights reserved. Reliability of Three Disability Scales for Detection of Independence Loss in Parkinson’s Disease Sun, 24 Apr 2016 15:37:50 +0000 Background. Loss of independence is considered an important outcome measure in Parkinson’s disease (PD), but tools to assess dependency have not been tested in PD. Methods. In this study of 158 PD patients, we examined the two most widely used scales and cut-offs for dependency evaluation in PD, the Hoehn and Yahr (HY) stage > 3 and the Schwab and England (SE) scale score < 80%, against a standardized clinical interview assessing dependency in activities of daily living (ADL). We also examined the performance of the generic Barthel ADL index. In addition, we determined whether alternative cut-offs improved the utility of these tools. Results. Compared to clinical interview as gold standard, HY stage > 3 had 21% sensitivity and 98% specificity in detecting dependency in ADL. Corresponding figures for SE score < 80% were 55% and 92%, respectively. Using alternative cut-off values improved the overall diagnostic accuracy only slightly. Barthel ADL index had 67% sensitivity and 78% specificity in detecting dependency at its optimal cut-off value. Conclusion. Both the disease-specific HY staging and SE scale and the generic Barthel ADL index are suboptimal tools for assessing independence loss in PD. Clinical interview should be the assessment of choice in studies of dependency. Anders Bjornestad, Ole-Bjorn Tysnes, Jan Petter Larsen, and Guido Alves Copyright © 2016 Anders Bjornestad et al. All rights reserved. Nonmotor Features in Parkinson’s Disease: What Are the Most Important Associated Factors? Tue, 19 Apr 2016 13:34:01 +0000 Introduction. The purpose of this study was to demonstrate the frequency and severity of nonmotor symptoms and their correlations with a wide range of demographic and clinical factors in a large cohort of patients with Parkinson’s disease (PD). Methods. 268 PD patients were assessed using the validated Movement Disorders Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), the Beck Depression Inventory (BDI), Parkinson’s Disease Questionnaire (PDQ-39), the Hoehn and Yahr scale (HY), the Schwab and England Activities of Daily Living (SE-ADL) Scale, and the Minimental State Examination (MMSE). Results. Nonmotor symptoms had a strong positive relationship with depression and lower quality of life. Also, age, duration and severity of PD, cognitive impairment, daily dose, and duration of levodopa treatment correlated with the burden of nonmotor symptoms. Patients with postural instability and gait disorder (PIGD) dominance or with the presence of motor complications had higher MDS-UPDRS Part I scores expressing the load of nonmotor features, compared to participants with other disease subtypes or without motor complications. Conclusions. Though the severity of individual nonmotor symptoms was generally rated by PD patients as “mild” or less, we found a significant cumulative effect of nonmotor symptoms on patients’ mood, daily activities, and quality of life. Liis Kadastik-Eerme, Mari Muldmaa, Stella Lilles, Marika Rosenthal, Nele Taba, and Pille Taba Copyright © 2016 Liis Kadastik-Eerme et al. All rights reserved. Structural Neuroimaging Markers of Cognitive Decline in Parkinson’s Disease Thu, 14 Apr 2016 14:08:29 +0000 Cognitive impairment in patients with Parkinson’s disease is a major challenge since it has been established that 25 to 40% of patients will develop cognitive impairment early in the disease. Furthermore, it has been reported that up to 80% of Parkinsonian patients will eventually develop dementia. Thus, it is important to improve the diagnosing procedures in order to detect cognitive impairment at early stages of development and to delay as much as possible the developing of dementia. One major challenge is that patients with mild cognitive impairment exhibit measurable cognitive deficits according to recently established criteria, yet those deficits are not severe enough to interfere with daily living, hence being avoided by patients, and might be overseen by clinicians. Recent advances in neuroimaging brain analysis allowed the establishment of several anatomical markers that have the potential to be considered for early detection of cognitive impairment in Parkinsonian patients. This review aims to outline the neuroimaging possibilities in diagnosing cognitive impairment in patients with Parkinson’s disease and to take into consideration the near-future possibilities of their implementation into clinical practice. Alexandru Hanganu and Oury Monchi Copyright © 2016 Alexandru Hanganu and Oury Monchi. All rights reserved. Whole-Brain Atrophy Rate in Idiopathic Parkinson’s Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy Thu, 14 Apr 2016 07:59:26 +0000 In multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), the absence of surrogate endpoints makes clinical trials long and expensive. We aim to determine annualized whole-brain atrophy rates (a-WBAR) in idiopathic Parkinson’s disease (IPD), MSA, and PSP. Ten healthy controls, 20 IPD, 12 PSP, and 8 MSA patients were studied using a volumetric MRI technique (SIENA). In controls, the a-WBAR was (CI 95% 0.17–0.57), while in IPD a-WBAR was (CI 95% 0.32–0.68). The IPD patients did not differ from the controls. In PSP, the a-WBAR was (CI 95%: 0.95–1.58). In MSA, a-WBAR was (CI 95%: 0.71–2.59). MSA did not differ from PSP. The a-WBAR in PSP and MSA were significantly higher than in the IPD group ( and , resp.). In PSP, the use of a-WBAR required one-half of the patients needed for clinical scales to detect a 50% reduction in their progression. In MSA, one-quarter of the patients would be needed to detect the same effect. a-WBAR is a reasonable candidate to consider as a surrogate endpoint in short clinical trials using smaller sample sizes. The confidence intervals for a-WBAR may add a potential retrospective application for a-WBAR to improve the diagnostic accuracy of MSA and PSP versus IPD. C. Guevara, K. Bulatova, G. J. Barker, G. Gonzalez, N. Crossley, and M. J. Kempton Copyright © 2016 C. Guevara et al. All rights reserved.