Parkinson’s Disease The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . 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. Quantitative EEG and Cognitive Decline in Parkinson’s Disease Mon, 11 Apr 2016 15:21:02 +0000 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 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 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 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 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 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 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 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 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 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. Deletion of Herpud1 Enhances Heme Oxygenase-1 Expression in a Mouse Model of Parkinson’s Disease Tue, 23 Feb 2016 05:48:59 +0000 Herp is an endoplasmic reticulum- (ER-) resident membrane protein that plays a role in ER-associated degradation. We studied the expression of Herp and its effect on neurodegeneration in a mouse model of Parkinson’s disease (PD), in which both the oxidative stress and the ER stress are evoked. Eight hours after administering a PD-related neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to mice, the expression of Herp increased at both the mRNA and the protein levels. Experiments using Herpud1+/+ and Herpud1−/− mice revealed that the status of acute degeneration of nigrostriatal neurons and reactive astrogliosis was comparable between two genotypes after MPTP injection. However, the expression of a potent antioxidant, heme oxygenase-1 (HO-1), was detected to a higher degree in the astrocytes of Herpud1−/− mice than in the astrocytes of Herpud1+/+ mice 24 h after MPTP administration. Further experiments using cultured astrocytes revealed that the stress response against MPP+, an active form of MPTP, and hydrogen peroxide, both of which cause oxidative stress, was comparable between the two genotypes. These results suggest that deletion of Herpud1 may cause a slightly higher level of initial damage in the nigrastrial neurons after MPTP administration but is compensated for by higher induction of antioxidants such as HO-1 in astrocytes. Thuong Manh Le, Koji Hashida, Hieu Minh Ta, Mika Takarada-Iemata, Koichi Kokame, Yasuko Kitao, and Osamu Hori Copyright © 2016 Thuong Manh Le et al. All rights reserved. Insula Volume and Salience Network Are Associated with Memory Decline in Parkinson Disease: Complementary Analyses of Voxel-Based Morphometry versus Volume of Interest Sun, 21 Feb 2016 11:43:06 +0000 Objective. We investigated structural brain change in subjects with a clinical diagnosis of Parkinson disease with mild cognitive impairment (PD-MCI) and examined its relationship with memory impairment. Methods. Twenty-three PD-MCI patients were enrolled and underwent cognitive evaluation and 3-dimensional T1-weighted imaging. Voxel-based morphometry (VBM) was used to assess brain-behavior correlations and examine the relationship between insula and memory score. VOI methods replicated results obtained from VBM. Results. VBM uncovered the notion that memory scores were positively correlated with the gray matter (GM) density in the insular cortex and a significant positive correlation between overall cognitive performance and concentration of GM within the lateral temporal cortex. In VOI analyses, our results suggested a positive correlation between the insula and composite free-recall verbal memory (, ) and the delayed free-recall verbal memory subdomain (, ). Furthermore, we found a positive correlation between the insula and caudate (, ) and putamen volume (, ). Conclusions. In patients with PD-MCI, atrophic changes in the insula may be related to memory deficits, and the brain-behavior correlation may be associated with atrophic change in the striatum within the salience network. Yan-Ting Lu, Wen-Neng Chang, Chiung-Chih Chang, Cheng-Hsien Lu, Nai-Ching Chen, Chi-Wei Huang, Wei-Che Lin, and Ya-Ting Chang Copyright © 2016 Yan-Ting Lu et al. All rights reserved. National Trends of Antiparkinsonism Treatment in Taiwan: 2004–2011 Thu, 18 Feb 2016 13:41:52 +0000 Background. Several guidelines for Parkinson’s disease (PD) management were recently updated. We examined temporal trends for antiparkinsonism drugs in Taiwan. Methods. Antiparkinsonism prescriptions, including levodopa, ergot/nonergot dopamine agonists (DAs), amantadine, selegiline, entacapone, and anticholinergics, were identified in the Taiwan National Health Insurance Database from 2004 to 2011. Time trend analyses were estimated assuming Poisson distribution. Results. A total of 19,302 PD patients in 2004 and 41,606 PD patients in 2011 were analyzed. Antiparkinsonism prescriptions increased significantly from 187,137 in 2004 to 414,587 in 2011. Levodopa monotherapy or combination therapy was the mainstay. Levodopa monotherapy comprised 37.4% of prescriptions in 2004 and 44.2% in 2011, with an annual increase rate of 18.14%. There was a substantially increasing trend of DA prescriptions, which were higher in younger-aged patients (<60 years) than in older-aged group (). Among combination therapy, DA combined with levodopa or other antiparkinsonism medications became the main combinations for younger-aged patients after 2009. After 2005, the proportion of ergot DA usage markedly decreased and PD patients using nonergot DA increased. Conclusions. Levodopa was the major treatment from 2004 to 2011. There was a steeply increased trend of DA use, especially in younger-aged patients. Nonergot agents comprised the major DA group after 2005. Weng-Ming Liu, Ruey-Meei Wu, Chia-Hsuin Chang, Jou-Wei Lin, Ying-Chun Liu, and Chin-Hsien Lin Copyright © 2016 Weng-Ming Liu et al. All rights reserved. Rotigotine Objectively Improves Sleep in Parkinson’s Disease: An Open-Label Pilot Study with Actigraphic Recording Sun, 14 Feb 2016 10:28:53 +0000 Sleep disturbances represent important predictors of poor quality of life (QoL) in Parkinson’s disease (PD). This open-label pilot study aimed to objectively assess, by means of actigraphic recording, effect of rotigotine on sleep in PD patients with self-reported sleep complaints. 15 PD patients underwent one-week actigraphic recording before (T0) and during (T1) rotigotine treatment, which was titrated to the dose subjectively improving motor symptoms (4–8 mg/24 h). Sleep disturbances, daytime sleepiness, cognitive performance, QoL, and depression were also evaluated with questionnaires. Actigraphic recordings showed a significant reduction in nocturnal motor activity and mean duration of wake episodes after sleep onset during rotigotine treatment compared to baseline. In 10 patients presenting objective evidence of poor sleep quality at T0 (sleep efficiency ≤ 85%), rotigotine also significantly improved other sleep parameters and further reduced nocturnal motor activity and mean duration of wake episodes. A significant decrease in number and duration of daytime sleep episodes was also observed at T1. Finally we confirmed that rotigotine significantly improves perceived sleep quality and QoL. Our study showed for the first time that rotigotine is associated with an objective improvement of nocturnal and diurnal sleep disturbances in PD patients with self-reported sleep complaints. This study is registered with AIFA-observational study registry number 12021. Giovanna Calandra-Buonaura, Pietro Guaraldi, Andrea Doria, Stefano Zanigni, Stefania Nassetti, Valentina Favoni, Sabina Cevoli, Federica Provini, and Pietro Cortelli Copyright © 2016 Giovanna Calandra-Buonaura et al. All rights reserved. Comparative mRNA Expression of eEF1A Isoforms and a PI3K/Akt/mTOR Pathway in a Cellular Model of Parkinson’s Disease Sun, 14 Feb 2016 09:20:53 +0000 The PI3K/Akt/mTOR pathway is one of dysregulated pathways in Parkinson’s disease (PD). Previous studies in nonneuronal cells showed that Akt regulation can be increased by eukaryotic protein elongation factor 1 alpha 2 (eEF1A2). eEF1A2 is proposed to contribute protection against apoptotic death, likely through activation of the PI3K/Akt pathway. Whether eEF1A2 plays a role in the prevention of cell death in PD has not been investigated. Recently, gene profiling on dopaminergic neurons from postmortem PD patients showed both upregulation and downregulation of some PI3K and mTOR genes. In this paper, the expression of all gene members of the PI3K/Akt/mTOR pathway in relation to those of the eEF1A isoforms in a cellular model of PD was investigated at the mRNA level. The results showed a similar trend of upregulation of genes of the eEF1A isoforms (eEF1A1 and eEF1A2) and of the PI3K (classes I–III)/Akt (Akt1, Akt2, and Akt3)/mTOR (mTORC1 and mTORC2) pathway in both nondifferentiated and differentiated SH-SY5Y dopaminergic cells treated with 1-methyl-4-phenylpyridinium (MPP+). Upregulation of eEF1A2, Akt1, and mTORC1 was consistent with the relative increase of eEF1A2, Akt, phospho-Akt, and mTORC1 proteins. The possible role of eEF1A isoforms in the regulation of the PI3K/Akt/mTOR pathway in PD is discussed. Kawinthra Khwanraj, Suriyat Madlah, Khwanthana Grataitong, and Permphan Dharmasaroja Copyright © 2016 Kawinthra Khwanraj et al. All rights reserved. Blindfolded Balance Training in Patients with Parkinson’s Disease: A Sensory-Motor Strategy to Improve the Gait Tue, 09 Feb 2016 13:44:12 +0000 Aim. Recent evidence suggested that the use of treadmill training may improve gait parameters. Visual deprivation could engage alternative sensory strategies to control dynamic equilibrium and stabilize gait based on vestibulospinal reflexes (VSR). We aimed to investigate the efficacy of a blindfolded balance training (BBT) in the improvement of stride phase percentage reliable gait parameters in patients with Parkinson’s Disease (PD) compared to patients treated with standard physical therapy (PT). Methods. Thirty PD patients were randomized in two groups of 15 patients, one group treated with BBT during two weeks and another group treated with standard PT during eight weeks. We evaluated gait parameters before and after BBT and PT interventions, in terms of double stance, swing, and stance phase percentage. Results. BBT induced an improvement of double stance phase as revealed (decreased percentage of double stance phase during the gait cycle) in comparison to PT. The other gait parameters swing and stance phase did not differ between the two groups. Discussion. These results support the introduction of complementary rehabilitative strategies based on sensory-motor stimulation in the traditional PD patient’s rehabilitation. Further studies are needed to investigate the neurophysiological circuits and mechanism underlying clinical and motor modifications. M. Tramontano, S. Bonnì, A. Martino Cinnera, F. Marchetti, C. Caltagirone, G. Koch, and A. Peppe Copyright © 2016 M. Tramontano et al. All rights reserved. Genetic Profile, Environmental Exposure, and Their Interaction in Parkinson’s Disease Sun, 31 Jan 2016 12:13:07 +0000 The discovery of causative mutations for Parkinson’s disease (PD) as well as their functional characterization in cellular and animal models has provided crucial insight into the pathogenesis of this disorder. Today, we know that PD pathogenesis involves multiple related processes including mitochondrial dysfunction, oxidative and nitrative stress, microglial activation and inflammation, and aggregation of α-synuclein and impaired autophagy. However, with the exception of a few families with Mendelian inheritance, the cause of PD in most individuals is yet unknown and the identified genetic susceptibility factors have only small effect size. Epidemiologic studies have found increased risk of PD associated with exposure to environmental toxicants such as pesticides, organic solvents, metals, and air pollutants, while reduced risk of PD associated with smoking cigarettes and coffee consumption. The role of environmental exposure, as well as the contribution of single genetic risk factors, is still controversial. In most of PD cases, disease onset is probably triggered by a complex interplay of many genetic and nongenetic factors, each of which conveys a minor increase in the risk of disease. This review summarizes the current knowledge on causal mutation for PD, susceptibility factors increasing disease risk, and the genetic factors that modify the impact of environmental exposure. Letizia Polito, Antonio Greco, and Davide Seripa Copyright © 2016 Letizia Polito et al. All rights reserved. Postural Stability in Parkinson’s Disease Patients Is Improved after Stochastic Resonance Therapy Tue, 26 Jan 2016 13:55:57 +0000 Background. Postural instability in Parkinson’s disease (PD) increases the risk of falls and is not improved by pharmacological therapy. Objective. We performed a double-blind, randomized sham-controlled study to test the effects of stochastic resonance (whole body vibration) therapy on postural stability in PD. Methods. Fifty-six PD participants were allocated to either experimental or sham groups. The experimental group received four series of vibration over eight days, with each series consisting of six stimulus trains of 60-second duration using a randomized whole body vibration. Participants allocated to the control group received a sham treatment. Results. Within-group analysis revealed that postural stability in the experimental group improved by 17.5% () comparing experimental and sham groups. The between-group analysis of change after treatment comparing both groups also showed a significant improvement of postural stability (). Only in the within-group analysis several items were improved after Bonferroni correction, too, rigor 41.6% (), bradykinesia 23.7% (), tremor 30.8% (), and sum score 23.9% (), but did not reach the level of significance in the between-group analysis. Conclusions. Stochastic resonance therapy significantly enhanced postural stability even in individuals with increased risk of falling. Thus it offers a potential supplementation to canonical treatments of PD. Oliver Kaut, Daniel Brenig, Milena Marek, Niels Allert, and Ullrich Wüllner Copyright © 2016 Oliver Kaut et al. All rights reserved. Risk Factors of Fatigue in Idiopathic Parkinson’s Disease in a Polish Population Tue, 26 Jan 2016 13:47:48 +0000 Introduction. Fatigue syndrome is one of the nonmotor symptoms in Parkinson’s disease (PD). The aim of the study was assessment of prevalence of fatigue syndrome in PD and answering the question what are the independent risk factors connected with intensity of fatigue in PD. Methods. 114 patients with idiopathic PD (mean age 62.2 + 10.8 years) were enrolled. The fatigue was assessed according to the Fatigue Severity Scale (FSS). We analyzed associations between fatigue and sex, age, education, duration and severity of the disease, everyday activity, intensity of the main symptoms, treatment, presence of dyskinesias and fluctuations, depression and excessive sleep during the day, and presence of pain and nycturia. Results. The fatigue syndrome was detected in 57.9% of patients. The score in the FSS was 1 to 7 points, 4.3 average. Greater fatigue intensity correlated with higher total daily levodopa equivalent dose. Patients with moderate depression had significantly greater fatigue. Conclusions. Fatigue syndrome affects 57.9% of patients with PD. Use of higher LED and presence of moderate depression are independent risk factors of greater intensity of fatigue. Monika Gołąb-Janowska, Dariusz Kotlęga, Krzysztof Safranow, Agnieszka Meller, Anna Budzianowska, and Krystyna Honczarenko Copyright © 2016 Monika Gołąb-Janowska et al. All rights reserved. Variations in Incidence and Prevalence of Parkinson’s Disease in Taiwan: A Population-Based Nationwide Study Tue, 19 Jan 2016 14:15:59 +0000 Demographic, socioeconomic, and urbanization level variations in Parkinson’s disease (PD) are rarely investigated, especially in Asia. This study describes an eight-year trend in PD incidence and prevalence in Taiwan as well as assessing the effects of sociodemographics and urbanization on the incidence and prevalence of PD. The data analyzed were acquired from the Taiwan National Health Insurance Research Database (NHIRD) entries between 2002 and 2009. The calendar year, sex, and age-specific rates were standardized, and the effects of the sociodemographics and urbanization on PD were assessed using Poisson regression analysis. PD incidence and prevalence showed a significantly increasing trend, with a greater magnitude noted for prevalence than for incidence (87.3% versus 9.2%). The PD incidence and prevalence increased with age and were slightly higher in men than in women. The people who were not under the labor force (i.e., dependents) or with lower monthly incomes were at significantly increased adjusted incidence rate ratio (1.50–1.56) and adjusted prevalence rate ratio (1.66–1.71) of PD. Moreover, significantly higher PD incidence and prevalence were noted in areas with lesser urbanization. This information emphasizes the need for preventive and clinical care strategies targeting the segment of Taiwanese population that exhibited a greater incidence and prevalence of PD. Chih-Ching Liu, Chung-Yi Li, Pei-Chen Lee, and Yu Sun Copyright © 2016 Chih-Ching Liu et al. All rights reserved. Clinical Pain and Neuropsychological Functioning in Parkinson’s Disease: Are They Related? Wed, 13 Jan 2016 06:49:27 +0000 Introduction. Pain is an important nonmotor symptom of Parkinson’s disease (PD). Brain areas such as the hippocampus and the prefrontal cortex play an important role in the processing of pain. Since these brain areas are also involved in cognitive functioning, for example, episodic memory and executive functions, respectively, we examined whether a relationship exists between cognitive functioning and spontaneous pain in PD. Methods. Forty-eight patients with PD and 57 controls participated. Cognitive functioning was measured by a comprehensive battery of neuropsychological tests. Both the sensory-discriminative aspect and the motivational-affective aspect of pain were assessed. Multiple linear regression analyses were performed to assess a relation between cognition and pain. Results. Cognition was related to neither the sensory nor the affective aspect of pain in our sample of PD patients. Variance in pain measures was primarily explained by symptoms of depression and anxiety. Discussion. The difference between the affective and the sensory aspect of pain might be due to the neuropathology of PD, which is mainly present in areas processing the affective aspect of pain. Pain treatment might improve when mood is taken into account. We provide several explanations for the lack of an association between pain and cognition. Gwenda Engels, Wouter D. Weeda, Annemarie M. M. Vlaar, Henry C. Weinstein, and Erik J. A. Scherder Copyright © 2016 Gwenda Engels et al. All rights reserved. Abnormal Echogenicity of the Substantia Nigra, Raphe Nuclei, and Third-Ventricle Width as Markers of Cognitive Impairment in Parkinsonian Disorders: A Cross-Sectional Study Sun, 10 Jan 2016 09:44:46 +0000 Background. Patients with Parkinson’s disease (PD) have a high risk of cognitive problems. Objective. This study assesses whether abnormal echogenicity of the substantia nigra (SN) and raphe nuclei (RN) and the diameter of third ventricle are markers of cognitive impairment in patients with PD and other forms of parkinsonism. Methods. 126 outpatients with early signs of parkinsonism underwent transcranial sonography (TCS). The scales for the outcome of Parkinson’s disease cognition (SCOPA-COG) were used as cognitive measure. Definite neurological diagnosis was established after two-year follow-up. Results. One-third of the patients with PD and half of those with APS had signs of cognitive impairment. The echogenicity of the SN was not related to cognitive impairment. The diameter of the third ventricle was significantly larger in PD patients with cognitive impairment compared to those without. In patients with APS we found a significantly higher frequency of hypoechogenic RN in patients with cognitive problems. Conclusions. Cognitive impairment is already present in a substantial proportion of patients with PD and APS at first referral. In patients with APS the frequency of hypoechogenic RN points to the direction of other pathophysiology with more emphasis on deficits in the serotonergic neurotransmitter system. The larger diameter of the third ventricle in PD patients with cognitive impairment may reflect Alzheimer like brain atrophy, as has been reported in earlier studies. Angela E. P. Bouwmans, Albert F. G. Leentjens, Werner H. Mess, and Wim E. J. Weber Copyright © 2016 Angela E. P. Bouwmans et al. All rights reserved. Exposure to Early Life Stress Results in Epigenetic Changes in Neurotrophic Factor Gene Expression in a Parkinsonian Rat Model Sun, 03 Jan 2016 11:08:53 +0000 Early life adversity increases the risk of mental disorders later in life. Chronic early life stress may alter neurotrophic factor gene expression including those for brain derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF) that are important in neuronal growth, survival, and maintenance. Maternal separation was used in this study to model early life stress. Following unilateral injection of a mild dose of 6-hydroxydopamine (6-OHDA), we measured corticosterone (CORT) in the blood and striatum of stressed and nonstressed rats; we also measured DNA methylation and BDNF and GDNF gene expression in the striatum using real time PCR. In the presence of stress, we found that there was increased corticosterone concentration in both blood and striatal tissue. Further to this, we found higher DNA methylation and decreased neurotrophic factor gene expression. 6-OHDA lesion increased neurotrophic factor gene expression in both stressed and nonstressed rats but this increase was higher in the nonstressed rats. Our results suggest that exposure to early postnatal stress increases corticosterone concentration which leads to increased DNA methylation. This effect results in decreased BDNF and GDNF gene expression in the striatum leading to decreased protection against subsequent insults later in life. Thabisile Mpofana, Willie M. U. Daniels, and Musa V. Mabandla Copyright © 2016 Thabisile Mpofana et al. All rights reserved. Foetal Cell Transplantation for Parkinson’s Disease: Focus on Graft-Induced Dyskinesia Thu, 31 Dec 2015 13:36:07 +0000 Transplantation of dopamine- (DA-) rich foetal ventral mesencephalic cells emerged as a promising therapy for Parkinson’s disease (PD), as it allowed significant improvement of motor symptoms in several PD patients in open-label studies. However, double-blind clinical trials have been largely disappointing. The general agreement in the field is that the lack of standardization of tissue collection and preparation, together with the absence of postsurgical immunosuppression, played a key role in the failure of these studies. Moreover, a further complication that emerged in previous studies is the appearance of the so-called graft-induced dyskinesia (GID), in a subset of grafted patients, which resembles dyskinesia induced by L-DOPA but in the absence of medication. Preclinical evidence pointed to the serotonin neurons as possible players in the appearance of GID. In agreement, clinical investigations have shown that grafted tissue may contain a large number of serotonin neurons, in the order of half of the DA cells; moreover, the serotonin 5-HT1A receptor agonist buspirone has been found to produce significant dampening of GID in grafted patients. In this paper, we will review the recent preclinical and clinical studies focusing on cell transplantation for PD and on the mechanisms underlying GID. Elisabetta Tronci, Camino Fidalgo, and Manolo Carta Copyright © 2015 Elisabetta Tronci et al. All rights reserved.