Journal of Parkinson's Disease - Volume 4, issue 3

Authors: Walker, Matthew D. | Volta, Mattia | Cataldi, Stefano | Dinelle, Katherine | Beccano-Kelly, Dayne | Munsie, Lise | Kornelsen, Rick | Mah, Chenoa | Chou, Patrick | Co, Kimberley | Khinda, Jaskaran | Mroczek, Marta | Bergeron, Sabrina | Yu, Katrina | Cao, Li Ping | Funk, Natalja | Ott, Thomas | Galter, Dagmar | Riess, Olaf | Biskup, Saskia | Milnerwood, Austen J. | Stoessl, A. Jon | Farrer, Matthew J. | Sossi, Vesna

Article Type: Research Article

Abstract: Background: A major risk-factor for developing Parkinson's disease (PD) is genetic variability in leucine-rich repeat kinase 2 (LRRK2), most notably the p.G2019S mutation. Examination of the effects of this mutation is necessary to determine the etiology of PD and to guide therapeutic development. Objective: Assess the behavioral consequences of LRRK2 p.G2019S overexpression in transgenic rats as they age and test the functional integrity of the nigro-striatal dopamine system. Conduct positron emission tomography (PET) neuroimaging to compare transgenic rats with previous data from human LRRK2 mutation carriers. Methods: Rats overexpressing human LRRK2 p.G2019S were generated by BAC transgenesis and compared to …non-transgenic (NT) littermates. Motor skill tests were performed at 3, 6 and 12 months-of-age. PET, performed at 12 months, assessed the density of dopamine and vesicular monoamine transporters (DAT and VMAT2, respectively) and measured dopamine synthesis, storage and availability. Brain tissue was assayed for D2, DAT, dopamine and cAMP-regulated phosphoprotein (DARPP32) and tyrosine hydroxylase (TH) expression by Western blot, and TH by immunohistochemistry. Results: Transgenic rats had no abnormalities in measures of striatal dopamine function at 12 months. A behavioral phenotype was present, with LRRK2 p.G2019S rats performing significantly worse on the rotarod than non-transgenic littermates (26% reduction in average running duration at 6 months), but with normal performance in other motor tests. Conclusions: Neuroimaging using dopaminergic PET did not recapitulate prior studies in human LRRK2 mutation carriers. Consistently, LRRK2 p.G2019S rats do not develop overt neurodegeneration; however, they do exhibit behavioral abnormalities. Show more

Keywords: Parkinson's disease, LRRK2 protein, human, dopaminergic neurons, transgenic rats, dopamine, brain imaging, positron-emission tomography

DOI: 10.3233/JPD-140344

Citation: Journal of Parkinson's Disease, vol. 4, no. 3, pp. 483-498, 2014

Authors: Fukae, Jiro | Ishikawa, Kei-ichi | Hatano, Taku | Yoritaka, Asako | Takanashi, Masashi | Shimo, Yasushi | Tsugawa, Jun | Tsuboi, Yoshio | Hattori, Nobutaka

Article Type: Research Article

Abstract: Background: Serum uric acid (UA) concentration is linked to the risk of progression of Parkinson's disease (PD). Objectives: The aim of this study was to examine the association between serum UA concentration and the occurrence of wearing-off fluctuation (WOF) in Japanese PD patients. Methods: A total of 123 Japanese patients with PD were enrolled in this study. We collected data on demographics, clinical features, medications, and laboratory findings including serum UA concentration, and examined the presence of WOF. The association between serum UA concentration and WOF was assessed using multivariate logistic regression analysis. Results: After adjusting for possible confounders, it …was found that the odds ratio (OR) for WOF decreased with increasing quartile of UA (highest quartile vs. lowest quartile, adjusted OR 0.218, 95% confidence interval [CI] 0.053–0.891). This association was significant only in male PD patients, regardless of the use of sex-specific quartiles of UA. Additionally, disease duration (OR 7.80, 95% CI 2.62–23.17) and daily levodopa dosage (OR 4.06, 95% CI 1.45–11.38) were associated with the occurrence of WOF. Conclusions: Our results showed that serum UA concentration was associated with the occurrence of WOF. Serum UA concentration may be a predictive factor for WOF. Show more

Keywords: Parkinson's disease, uric acid, wearing-off fluctuation, sex difference

DOI: 10.3233/JPD-140353

Citation: Journal of Parkinson's Disease, vol. 4, no. 3, pp. 499-505, 2014

Authors: Jaakkola, Elina | Kaasinen, Valtteri | Siri, Chiara | Martikainen, Kirsti | Cilia, Roberto | Niemelä, Solja | Joutsa, Juho

Article Type: Research Article

Abstract: Background: Impulse control disorders can have serious adverse consequences to the life of a patient with Parkinson's disease. Although impulse control disorders are common, a possible psychiatric comorbidity has not been fully characterized. Objective: The aim of this study was to investigate the psychiatric symptoms exhibited by Parkinson's disease patients with impulse control disorders. Methods: The study was conducted as a postal survey to patients in the registry of the Finnish Parkinson Association. A total of 290 Parkinson's disease patients were evaluated for impulse control disorders using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease. Psychiatric symptoms were systematically screened …using the Symptom Checklist 90. Results: We found that 108 of the evaluated patients had one or more impulse control disorders. Patients with impulse control disorders had markedly higher scores for symptoms of psychoticism (Bonferroni corrected p < 0.001), interpersonal sensitivity (p < 0.001), obsessive-compulsive disorder (p < 0.001), and depression (p = 0.01) when compared with patients without impulse control disorders. Impulse control disorders were shown to be independently associated with these symptoms. Patients with multiple impulse control disorders had higher scores for depression and obsessive-compulsive symptoms when compared with patients that exhibited only one impulse control disorder. Counclusions: Our results confirm the previous observations that impulse control disorders in Parkinson's disease are linked with multiple psychiatric symptoms, including psychoticism, interpersonal sensitivity, obsessive-compulsive symptoms and depression. Clinicians treating these patients should acknowledge the concomitant psychiatric symptoms. Show more

Keywords: Impulse control disorders, SCL-90, depression, obsessive-compulsive symptoms, psychoticism

DOI: 10.3233/JPD-140351

Citation: Journal of Parkinson's Disease, vol. 4, no. 3, pp. 507-515, 2014

Authors: Soileau, Michael J. | Persad, Carol | Taylor, Jennifer | Patil, Parag G. | Chou, Kelvin L.

Article Type: Research Article

Abstract: Background: Little is known about caregiver burden in Parkinson disease (PD) patients undergoing brain stimulation (DBS) surgery. Objective: The aim of this exploratory analysis was to evaluate whether caregiver burden improves after bilateral subthalamic nucleus (STN) DBS for PD patients and identify baseline factors associated with caregiver burden. Methods: We analyzed the motor, cognitive and behavioral data of 12 PD patients (9 men/3 women) who underwent bilateral STN DBS and whose caregivers completed the Caregiver Burden Inventory (CBI) both before and approximately 6 months after bilateral STN DBS. Results: Total CBI score did not change from baseline (17.8 ± 10.7) …to the 6 month evaluation (18.7 ± 13.1), despite a 29% improvement in the MDS-UPDRS motor score (baseline 40.3 ± 12.1 compared to 28.7 ± 8.4 at 6 months, p = 0.01). Change in total CBI score did not correlate with change in MDS-UPDRS Parts I–IV or MoCA from baseline to 6 months. In post-hoc analyses looking at baseline characteristics that may correlate with caregiver burden, only the disinhibition subscore on the Frontal Systems Behavioral Scale correlated positively with the baseline total CBI score (ρ = 0.763, p = 0.004). Conclusion: Caregiver burden for PD patients (as measured by the CBI) does not change 6 months after bilateral STN DBS, despite significant improvement in motor function. Only baseline behavioral problems, specifically disinhibition, correlated with higher baseline caregiver burden. Clinicians may need to better counsel patients on expectations for caregiver burden after DBS. Show more

Keywords: Parkinson disease, caregiver burden, deep brain stimulation, subthalamic nucleus

DOI: 10.3233/JPD-140380

Citation: Journal of Parkinson's Disease, vol. 4, no. 3, pp. 517-521, 2014

Authors: Muthukumaran, Krithika | Smith, Jessica | Jasra, Harshil | Sikorska, Marianna | Sandhu, Jagdeep K. | Cohen, Jerome | Lopatin, Daniel | Pandey, Siyaram

Article Type: Retraction

Abstract: IOS Press and the Editors were contacted by Pubpeer of suspected image manipulation of Figure 1, where a western blot image is turned and repeated (https://pubpeer.com/publications/6DCC9037670DD855DE16341C5842A3#1 ). After detailed considerations including discussion with the author, reviewers and editorial office, in the end the editorial office decided the scientific integrity could not be guaranteed. In this light the journal cannot condone publication of this paper and has decided to retract it from its online catalogue. The author states: “It was an error and an oversight on my behalf. We stand by all the corrected data, and we have all the slides, …we confirmed similar findings in other models. This project was approved from our Animal Care Committee.” Show more

DOI: 10.3233/JPD-140368

Citation: Journal of Parkinson's Disease, vol. 4, no. 3, pp. 523-530, 2014

Authors: McDowell, Kimberly A. | Shin, David | Roos, Kenneth P. | Chesselet, Marie-Françoise

Article Type: Research Article

Abstract: Background: Sleep disruptions occur early and frequently in Parkinson’s disease (PD). PD patients also show a slowing of resting state activity. Alpha-synuclein is causally linked to PD and accumulates in sleep-related brain regions. While sleep problems occur in over 75% of PD patients and severely impact the quality of life of patients and caregivers, their study is limited by a paucity of adequate animal models. Objective: The objective of this study was to determine whether overexpression of wildtype alpha-synuclein could lead to alterations in sleep patterns reminiscent of those observed in PD by measuring sleep/wake activity with rigorous …quantitative methods in a well-characterized genetic mouse model. Methods: At 10 months of age, mice expressing human wildtype alpha-synuclein under the Thy-1 promoter (Thy1-aSyn) and wildtype littermates underwent the subcutaneous implantation of a telemetry device (Data Sciences International) for the recording of electromyograms (EMG) and electroencephalograms (EEG) in freely moving animals. Surgeries and data collection were performed without knowledge of mouse genotype. Results: Thy1-aSyn mice showed increased non-rapid eye movement sleep during their quiescent phase, increased active wake during their active phase, and decreased rapid eye movement sleep over a 24-h period, as well as a shift in the density of their EEG power spectra toward lower frequencies with a significant decrease in gamma power during wakefulness. Conclusions: Alpha-synuclein overexpression in mice produces sleep disruptions and altered oscillatory EEG activity reminiscent of PD, and this model provides a novel platform to assess mechanisms and therapeutic strategies for sleep dysfunction in PD. Show more

Keywords: Parkinson disease, Thy1-aSyn mice, rapid eye movement sleep, EEG, power spectra, gamma oscillations, implantable telemetry

DOI: 10.3233/JPD-140374

Citation: Journal of Parkinson's Disease, vol. 4, no. 3, pp. 531-539, 2014

Authors: Zis, Panagiotis | Rizos, Alexandra | Martinez-Martin, Pablo | Pal, Suvankar | Silverdale, Monty | Sharma, Jagdish C. | Sauerbier, Anna | Chaudhuri, Kallol Ray

Article Type: Research Article

Abstract: Background: Recent studies have demonstrated that, contrary to common perception non-motor symptoms (NMS) occur and may dominate early and untreated stage of Parkinson's disease (PD). Objective: The aim of this ongoing study was to describe the overall NMS profile and burden in drug naïve PD patients (DNPD) compared to a group of long-term PD patients (LTPD, disease duration ≥15 years). Methods: Cross sectional UK data from a multicenter (16 sites) collaboration were obtained and specifically NMS dataset from validated scales were analysed in DNPD and LTPD patients. The NMS scale (NMSS) was used as the primary outcome variable. Results: Out …of a current database of 468 PD patients, 57 were DNPD (58% males, mean age 64.8 years, median Hoehn and Yahr stage 1) and 25 were LTPD (44%, mean age 67.6 years, median Hoehn and Yahr stage 3). DNPD patients had a significantly lower (p = 0.001) NMSS score (mean 45.5, range 1–150) compared to the LTPD patients (mean 74.0, range 6–155), but 26.3% had severe and 19.3% had very severe burden of NMSS using NMSS cutoff scores. In comparison, 20.0% of the LTPD patients had severe and 60.0% very severe burden of NMS (p = 0.003). Conclusions: NMS are common in DNPD patients and over 45% may have severe to very severe burden of NMS, which is a key determinant of quality of life. In LTPD patients not only the burden of “very severe” NMS is significantly higher, but there are also differences in the profile of expression of NMS. Show more

Keywords: Parkinson's disease, non-motor symptoms, NMS scale, drug naïve

DOI: 10.3233/JPD-140372

Citation: Journal of Parkinson's Disease, vol. 4, no. 3, pp. 541-547, 2014

Authors: Trupp, Miles | Jonsson, Pär | Öhrfelt, Annika | Zetterberg, Henrik | Obudulu, Ogonna | Malm, Linus | Wuolikainen, Anna | Linder, Jan | Moritz, Thomas | Blennow, Kaj | Antti, Henrik | Forsgren, Lars

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a progressive, multi-focal neurodegenerative disease for which there is no effective disease modifying treatment. A critical requirement for designing successful clinical trials is the development of robust and reproducible biomarkers identifying PD in preclinical stages. Objective: To investigate the potential for a cluster of biomarkers visualized with multiple analytical platforms to provide a clinically useful tool. Methods: Gas Chromatography-Mass Spectrometry (GC-TOFMS) based metabolomics and immunoassay-based protein/peptide analyses on samples from patients with PD diagnosed in Northern Sweden. Low molecular weight compounds from both plasma and cerebrospinal fluid (CSF) from 20 healthy …subjects (controls) and 20 PD patients at the time of diagnosis (baseline) were analyzed. Results: In plasma, we found a significant increase in several amino acids and a decrease in C16-C18 saturated and unsaturated fatty acids in patients as compared to control subjects. We also observed an increase in plasma levels of pyroglutamate and 2-oxoisocaproate (ketoleucine) that may be indicative of increased metabolic stress in patients. In CSF, there was a generally lower level of metabolites in PD as compared to controls, with a specific decrease in 3-hydroxyisovaleric acid, tryptophan and creatinine. Multivariate analysis and modeling of metabolites indicates that while the PD samples can be separated from control samples, the list of detected compounds will need to be expanded in order to define a robust predictive model. CSF biomarker immunoassays of candidate peptide/protein biomarkers revealed a significant decrease in the levels of Aβ-38 and Aβ-42, and an increase in soluble APPα in CSF of patients. Furthermore, these peptides showed significant correlations to each other, and positive correlations to the CSF levels of several 5- and 6-carbon sugars. However, combining these metabolites and proteins/peptides into a single model did not significantly improve the statistical analysis. Conclusions: Together, this metabolomics study has detected significant alterations in plasma and CSF levels of a cluster of amino acids, fatty acids and sugars based on clinical diagnosis and levels of known protein and peptide biomarkers. Show more

Keywords: Parkinson’s, CSF, metabolomics, Abeta peptides, alpha-synuclein, GC-TOFMS, multivariate analysis, amino acids, long-chain fatty acids, carbohydrates

DOI: 10.3233/JPD-140389

Citation: Journal of Parkinson's Disease, vol. 4, no. 3, pp. 549-560, 2014

Article Type: Correction

DOI: 10.3233/JPD-149005

Citation: Journal of Parkinson's Disease, vol. 4, no. 3, pp. 561-561, 2014