Parkinson’s Disease http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Altered Spontaneous Brain Activity in Cortical and Subcortical Regions in Parkinson’s Disease Sun, 19 Jun 2016 06:54:43 +0000 http://www.hindawi.com/journals/pd/2016/5246021/ 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 http://www.hindawi.com/journals/pd/2016/2613401/ 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 http://www.hindawi.com/journals/pd/2016/9182946/ 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 http://www.hindawi.com/journals/pd/2016/5731734/ 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 http://www.hindawi.com/journals/pd/2016/9832839/ 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 http://www.hindawi.com/journals/pd/2016/9730319/ 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 http://www.hindawi.com/journals/pd/2016/6219249/ 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 http://www.hindawi.com/journals/pd/2016/8684130/ 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 http://www.hindawi.com/journals/pd/2016/7049108/ 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 http://www.hindawi.com/journals/pd/2016/2531812/ 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 http://www.hindawi.com/journals/pd/2016/7951840/ 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 http://www.hindawi.com/journals/pd/2016/4040185/ 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 http://www.hindawi.com/journals/pd/2016/7351985/ 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 http://www.hindawi.com/journals/pd/2016/5264743/ 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 http://www.hindawi.com/journals/pd/2016/3067426/ 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 http://www.hindawi.com/journals/pd/2016/9281790/ 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 http://www.hindawi.com/journals/pd/2016/1941034/ 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 http://www.hindawi.com/journals/pd/2016/4370674/ 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 http://www.hindawi.com/journals/pd/2016/3217960/ 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 http://www.hindawi.com/journals/pd/2016/9631041/ 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. Quantitative EEG and Cognitive Decline in Parkinson’s Disease Mon, 11 Apr 2016 15:21:02 +0000 http://www.hindawi.com/journals/pd/2016/9060649/ Cognitive decline is common with the progression of Parkinson’s disease (PD). Different candidate biomarkers are currently studied for the risk of dementia in PD. Several studies have shown that quantitative EEG (QEEG) is a promising predictor of PD-related cognitive decline. In this paper we briefly outline the basics of QEEG analysis and analyze the recent publications addressing the predictive value of QEEG in the context of cognitive decline in PD. The MEDLINE database was searched for relevant publications from January 01, 2005, to March 02, 2015. Twenty-four studies reported QEEG findings in various cognitive states in PD. Spectral and connectivity markers of QEEG could help to discriminate between PD patients with different level of cognitive decline. QEEG variables correlate with tools for cognitive assessment over time and are associated with significant hazard ratios to predict PD-related dementia. QEEG analysis shows high test-retest reliability and avoids learning effects associated with some neuropsychological testing; it is noninvasive and relatively easy to repeat. Vitalii V. Cozac, Ute Gschwandtner, Florian Hatz, Martin Hardmeier, Stephan Rüegg, and Peter Fuhr Copyright © 2016 Vitalii V. Cozac et al. All rights reserved. Mindfulness for Motor and Nonmotor Dysfunctions in Parkinson’s Disease Sun, 10 Apr 2016 15:57:54 +0000 http://www.hindawi.com/journals/pd/2016/7109052/ Background. Motor and nonmotor symptoms negatively influence Parkinson’s disease (PD) patients’ quality of life. Mindfulness interventions have been a recent focus in PD. The present study explores effectiveness of a manualized group mindfulness intervention tailored for PD in improving both motor and neuropsychiatric deficits in PD. Methods. Fourteen PD patients completed an 8-week mindfulness intervention that included 6 sessions. The Five Facet Mindfulness Questionnaire (FFMQ), Geriatric Anxiety Inventory, Hamilton Depression Rating Scale, PD Cognitive Rating Scale, Unified PD Rating Scale, PD Quality of Life Questionnaire, and Outcome Questionnaire (OQ-45) were administered before and after the intervention. Participants also completed the FFMQ-15 at each session. Gains at postassessment and at 6-month follow-up were compared to baseline using paired -tests and Wilcoxon nonparametric tests. Results. A significant increase in FFMQ-Observe subscale, a reduction in anxiety, depression, and OQ-45 symptom distress, an increase in PDCRS-Subcortical scores, and an improvement in postural instability, gait, and rigidity motor symptoms were observed at postassessment. Gains for the PDCRS were sustained at follow-up. Conclusion. The mindfulness intervention tailored for PD is associated with reduced anxiety and depression and improved cognitive and motor functioning. A randomised controlled trial using a large sample of PD patients is warranted. Nadeeka N. W. Dissanayaka, Farah Idu Jion, Nancy A. Pachana, John D. O’Sullivan, Rodney Marsh, Gerard J. Byrne, and Paul Harnett Copyright © 2016 Nadeeka N. W. Dissanayaka et al. All rights reserved. Levodopa-Induced Dyskinesia Is Related to Indirect Pathway Medium Spiny Neuron Excitotoxicity: A Hypothesis Based on an Unexpected Finding Wed, 06 Apr 2016 12:27:06 +0000 http://www.hindawi.com/journals/pd/2016/6461907/ A serendipitous pharmacogenetic finding links the vulnerability to developing levodopa-induced dyskinesia to the age of onset of Huntington’s disease. Huntington’s disease is caused by a polyglutamate expansion of the protein huntingtin. Aberrant huntingtin is less capable of binding to a member of membrane-associated guanylate kinase family (MAGUKs): postsynaptic density- (PSD-) 95. This leaves more PSD-95 available to stabilize NR2B subunit carrying NMDA receptors in the synaptic membrane. This results in increased excitotoxicity for which particularly striatal medium spiny neurons from the indirect extrapyramidal pathway are sensitive. In Parkinson’s disease the sensitivity for excitotoxicity is related to increased oxidative stress due to genetically determined abnormal metabolism of dopamine or related products. This probably also increases the sensitivity of medium spiny neurons for exogenous levodopa. Particularly the combination of increased oxidative stress due to aberrant dopamine metabolism, increased vulnerability to NMDA induced excitotoxicity, and the particular sensitivity of indirect pathway medium spiny neurons for this excitotoxicity may explain the observed increased prevalence of levodopa-induced dyskinesia. Svetlana A. Ivanova and Anton J. M. Loonen Copyright © 2016 Svetlana A. Ivanova and Anton J. M. Loonen. All rights reserved. Protection against Mitochondrial and Metal Toxicity Depends on Functional Lipid Binding Sites in ATP13A2 Thu, 17 Mar 2016 09:52:16 +0000 http://www.hindawi.com/journals/pd/2016/9531917/ The late endo-/lysosomal P-type ATPase ATP13A2 (PARK9) is implicated in Parkinson’s disease (PD) and Kufor-Rakeb syndrome, early-onset atypical Parkinsonism. ATP13A2 interacts at the N-terminus with the signaling lipids phosphatidic acid (PA) and phosphatidylinositol (3,5) bisphosphate (PI(3,5)P2), which modulate ATP13A2 activity under cellular stress conditions. Here, we analyzed stable human SHSY5Y cell lines overexpressing wild-type (WT) or ATP13A2 mutants in which three N-terminal lipid binding sites (LBS1–3) were mutated. We explored the regulatory role of LBS1–3 in the cellular protection by ATP13A2 against mitochondrial stress induced by rotenone and found that the LBS2-3 mutants displayed an abrogated protective effect. Moreover, in contrast to WT, the LBS2 and LBS3 mutants responded poorly to pharmacological inhibition of, respectively, PI(3,5)P2 and PA formation. We further demonstrate that PA and PI(3,5)P2 are also required for the ATP13A2-mediated protection against the toxic metals Mn2+, Zn2+, and Fe3+, suggesting a general lipid-dependent activation mechanism of ATP13A2 in various PD-related stress conditions. Our results indicate that the ATP13A2-mediated protection requires binding of PI(3,5)P2 to LBS2 and PA to LBS3. Thus, targeting the N-terminal lipid binding sites of ATP13A2 might offer a therapeutic approach to reduce cellular toxicity of various PD insults including mitochondrial stress. Shaun Martin, Sarah van Veen, Tine Holemans, Seyma Demirsoy, Chris van den Haute, Veerle Baekelandt, Patrizia Agostinis, Jan Eggermont, and Peter Vangheluwe Copyright © 2016 Shaun Martin et al. All rights reserved. Subjective Visual Vertical in PD Patients with Lateral Trunk Flexion Thu, 17 Mar 2016 06:50:01 +0000 http://www.hindawi.com/journals/pd/2016/7489105/ Lateral trunk flexion (LTF) is a common phenomenon in patients with Parkinson’s disease (PD) and has recently been associated with peripheral vestibular dysfunction. Since deviation of the subjective visual vertical (SVV) is a well-recognized feature of disorders involving vestibular processing, we analyzed SVV angles in 30 PD patients with and without LTF to assess the possible role of vestibular dysfunction in the pathogenesis of LTF in PD. Quantification of SVV was obtained using a simple bedside test. PD patients with LTF had significantly greater SVV angles as compared to PD patients without LTF (median: 4.3° [range: 0.1–17.7], , versus 0.8° [0.1–1.9], ; ). 14 of 21 patients with LTF showed pathological SVV, while all 9 patients without LTF had normal SVV. Abnormal SVV was more frequent when LTF was reversible in the supine position compared to fixed LTF. In a subgroup of PD patients with LTF, pathological SVV suggests vestibular dysbalance, which might be involved in the pathophysiological mechanisms underlying LTF. F. Gandor, D. Basta, D. Gruber, W. Poewe, and G. Ebersbach Copyright © 2016 F. Gandor et al. All rights reserved. Altered Mitochondrial Respiration and Other Features of Mitochondrial Function in Parkin-Mutant Fibroblasts from Parkinson’s Disease Patients Tue, 08 Mar 2016 06:00:41 +0000 http://www.hindawi.com/journals/pd/2016/1819209/ Mutations in the parkin gene are the most common cause of early-onset Parkinson’s disease (PD). Parkin, an E3 ubiquitin ligase, is involved in respiratory chain function, mitophagy, and mitochondrial dynamics. Human cellular models with parkin null mutations are particularly valuable for investigating the mitochondrial functions of parkin. However, published results reporting on patient-derived parkin-mutant fibroblasts have been inconsistent. This study aimed to functionally compare parkin-mutant fibroblasts from PD patients with wild-type control fibroblasts using a variety of assays to gain a better understanding of the role of mitochondrial dysfunction in PD. To this end, dermal fibroblasts were obtained from three PD patients with homozygous whole exon deletions in parkin and three unaffected controls. Assays of mitochondrial respiration, mitochondrial network integrity, mitochondrial membrane potential, and cell growth were performed as informative markers of mitochondrial function. Surprisingly, it was found that mitochondrial respiratory rates were markedly higher in the parkin-mutant fibroblasts compared to control fibroblasts (p = 0.0093), while exhibiting more fragmented mitochondrial networks (). Moreover, cell growth of the parkin-mutant fibroblasts was significantly higher than that of controls (). These unanticipated findings are suggestive of a compensatory mechanism to preserve mitochondrial function and quality control in the absence of parkin in fibroblasts, which warrants further investigation. William Haylett, Chrisna Swart, Francois van der Westhuizen, Hayley van Dyk, Lize van der Merwe, Celia van der Merwe, Ben Loos, Jonathan Carr, Craig Kinnear, and Soraya Bardien Copyright © 2016 William Haylett et al. All rights reserved. A Feed-Forward Circuit of Endogenous PGC-1α and Estrogen Related Receptor α Regulates the Neuronal Electron Transport Chain Thu, 03 Mar 2016 11:01:23 +0000 http://www.hindawi.com/journals/pd/2016/2405176/ Peroxisome proliferator-activated receptor  γ coactivator 1α (PGC-1α) is a central regulator of cellular and mitochondrial metabolism. Cellular bioenergetics are critically important in “energy-guzzling” neurons, but the components and wiring of the transcriptional circuit through which PGC-1α regulates the neuronal electron transport chain have not been established. This information may be vital for restoring neuronal bioenergetics gene expression that is compromised during incipient Parkinson’s neuropathology and in aging-dependent brain diseases. Here we delineate a neuronal transcriptional circuit controlled by endogenous PGC-1α. We show that a feed-forward circuit of endogenous neuronal PGC-1α and the orphan nuclear estrogen-related receptor α (ERRα) activates the nuclear-encoded mitochondrial electron transport chain. PGC-1α not only trans-activated expression of ERRα, but also coactivated ERRα target genes in complexes I, II, IV, and V of the neuronal electron transport chain via association with evolutionary conserved ERRα promoter binding motifs. Chemical activation of this transcriptional program induced transcription of the neuronal electron transport chain. These data highlight a neuronal transcriptional circuit regulated by PGC-1α that can be therapeutically targeted for Parkinson’s and other neurodegenerative diseases. Rachit Bakshi, Shuchi Mittal, Zhixiang Liao, and Clemens R. Scherzer Copyright © 2016 Rachit Bakshi et al. All rights reserved. Methyl-Arginine Profile of Brain from Aged PINK1-KO+A53T-SNCA Mice Suggests Altered Mitochondrial Biogenesis Tue, 01 Mar 2016 09:25:01 +0000 http://www.hindawi.com/journals/pd/2016/4686185/ Hereditary Parkinson’s disease can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) or the autosomal recessive deficiency of PINK1. We recently showed that the combination of PINK1-knockout with overexpression of A53T-SNCA in double mutant (DM) mice potentiates phenotypes and reduces survival. Now we studied brain hemispheres of DM mice at age of 18 months in a hypothesis-free approach, employing a quantitative label-free global proteomic mass spectrometry scan of posttranslational modifications focusing on methyl-arginine. The strongest effects were documented for the adhesion modulator CMAS, the mRNA decapping/deadenylation factor PATL1, and the synaptic plasticity mediator CRTC1/TORC1. In addition, an intriguing effect was observed for the splicing factor PSF/SFPQ, known to interact with the dopaminergic differentiation factor NURR1 as well as with DJ-1, the protein responsible for the autosomal recessive PARK7 variant of PD. CRTC1, PSF, and DJ-1 are modulators of PGC1alpha and of mitochondrial biogenesis. This pathway was further stressed by dysregulations of oxygen sensor EGLN3 and of nuclear TMPO. PSF and TMPO cooperate with dopaminergic differentiation factors LMX1B and NURR1. Further dysregulations concerned PRR18, TRIO, HNRNPA1, DMWD, WAVE1, ILDR2, DBNDD1, and NFM. Thus, we report selective novel endogenous stress responses in brain, which highlight early dysregulations of mitochondrial homeostasis and midbrain vulnerability. Georg Auburger, Suzana Gispert, and Nadine Brehm Copyright © 2016 Georg Auburger et al. All rights reserved. Using Tractography to Distinguish SWEDD from Parkinson’s Disease Patients Based on Connectivity Mon, 29 Feb 2016 17:27:32 +0000 http://www.hindawi.com/journals/pd/2016/8704910/ Background. It is critical to distinguish between Parkinson’s disease (PD) and scans without evidence of dopaminergic deficit (SWEDD), because the two groups are different and require different therapeutic approaches. Objective. The aim of this study was to distinguish SWEDD patients from PD patients using connectivity information derived from diffusion tensor imaging tractography. Methods. Diffusion magnetic resonance images of SWEDD () and PD () were obtained from a research database. Tractography, the process of obtaining neural fiber information, was performed using custom software. Group-wise differences between PD and SWEDD patients were quantified using the number of connected fibers between two regions, and correlation analyses were performed based on clinical scores. A support vector machine classifier (SVM) was applied to distinguish PD and SWEDD based on group-wise differences. Results. Four connections showed significant group-wise differences and correlated with the Unified Parkinson’s Disease Rating Scale sponsored by the Movement Disorder Society. The SVM classifier attained 77.92% accuracy in distinguishing between SWEDD and PD using these identified connections. Conclusions. The connections and regions identified represent candidates for future research investigations. Mansu Kim and Hyunjin Park Copyright © 2016 Mansu Kim and Hyunjin Park. All rights reserved. Freezing of Gait in Parkinson’s Disease Is Associated with Reduced 6-[18F]Fluoro-L-m-tyrosine Uptake in the Locus Coeruleus Tue, 23 Feb 2016 13:08:06 +0000 http://www.hindawi.com/journals/pd/2016/5430920/ Freezing of gait (FOG) is a common disorder in Parkinson’s disease (PD) and could be attributed to a reduction in brain noradrenaline. The aim of this study was to determine the relationship between aromatic L-amino acid decarboxylase (AADC) activity in the locus coeruleus (LC) and FOG in PD using high-resolution positron emission tomography with an AADC tracer, 6-[18F]fluoro-L-m-tyrosine (FMT). We assessed 40 patients with PD and 11 age-matched healthy individuals. PD was diagnosed based on the UK Brain Bank criteria by two movement disorder experts. FOG was directly observed by the clinician and assessed using a patient questionnaire. FMT uptake in the LC, caudate, and putamen was analyzed using PMOD software on coregistered magnetic resonance images. FOG was present in 30 patients. The severity of FOG correlated with the decrease of FMT uptake in the LC regardless of disease duration and the severity of other motor impairments, indicating dysfunction of the noradrenergic network in FOG. Sayaka Asari Ono, Toshihiko Sato, and Shin-ichi Muramatsu Copyright © 2016 Sayaka Asari Ono et al. All rights reserved.