Journal of Parkinson’s Disease

Sialorrhea may present as a troublesome symptom in patients suffering from Parkinson's disease. Current options for treatment include anticholinergic drugs, irradiation, surgery, oral-motor and behavioural therapies, and injection of botulinum neurotoxin (BoNT) in the salivary glands. The aim of this study is to evaluate the safety and administration of BoNT as a treatment for sialorrhea in patients with Parkinson's disease (PD) based on a review of the studies conducted so far in this field. A PubMed search was conducted using the major keywords sialorrhea, botulinum neurotoxin, botulinum toxin and Parkinson's disease. The literature search identified 12 articles, which were selected for further analysis. Few adverse effects were described in the studies included in this present review. Various treatment strategies, including different medication dosages, were applied in the studies. BoNT treatment is safe for sialorrhea in patients with PD. Positive effect is well documented, and there have been relatively few reported adverse effects, which have been mild and transient. Based on this review, a treatment algorithm is proposed. Ultrasound guidance may not be necessary when injecting the parotid gland but may improve the effect and safety of administration, especially when injecting the submandibular glands.

Previous studies have suggested that dopamine agonists have an antidepressant effect in Parkinson's disease (PD) patients. We examined whether fewer PD patients used antidepressant medication, when they were first treated with a dopamine agonist compared to other PD medications. PD patients diagnosed in Denmark were identified, and the diagnosis was confirmed by a review of the medical record. Antidepressant medication was assessed using the Danish National Prescription Registry. We used Cox proportional hazards regression to model the association between PD medications and time to antidepressant prescription. The type of PD medication first prescribed did not affect the subsequent use of antidepressants.

We evaluated the association between mild cognitive impairment (MCI) subtypes and quality of life (QoL) in 219 newly diagnosed Parkinson’s disease (PD) patients without dementia. Participants completed neuropsychological tests of attention, executive function, visuospatial function, memory, and language, and reported QoL using the Parkinson’s Disease Questionnaire. Impairments were most common in executive function, memory and attention. MCI subtypes were classified according to Movement Disorder Society Task Force criteria. More severe cognitive impairment was associated with poorer quality of life (p = 0.01), but subtype of impairment was not (p > 0.10), suggesting that the nature of cognitive impairment is less significant than its severity.

A recent study by Aviles-Olmos and colleagues suggests that 12 months of treatment with the glucagon-like peptide-1 receptor agonist exenatide improves motor and cognitive symptoms in Parkinson's disease (PD), and that the effect persists as long as 12 months after termination of the treatment. Due to the lack of a placebo control, one cannot exclude that the observed differences between patients receiving daily injections of exenatide and non-treated controls are due to a placebo effect. We discuss that large group differences in two independent functional measures remain for at least 12 months following the cessation of exenatide treatment and that this warrants a double-blind placebo-controlled trial with exenatide in PD.

Background: Parkinson's disease (PD) is a complex multi-system age-related neurodegenerative disorder. Targeting the ongoing neuroinflammation in PD patients is one strategy postulated to slow down or halt disease progression. Proof-of-concept studies from our group demonstrated that selective inhibition of soluble Tumor Necrosis Factor (solTNF) by intranigral delivery of dominant negative TNF (DN-TNF) inhibitors reduced neuroinflammation and nigral dopamine (DA) neuron loss in endotoxin and neurotoxin rat models of nigral degeneration. Objective: As a next step toward human clinical trials, we aimed to determine the extent to which peripherally administered DN-TNF inhibitor XPro^®1595 could: i) cross the blood-brain-barrier in therapeutically relevant concentrations, ii) attenuate neuroinflammation (microglia and astrocyte), and iii) mitigate loss of nigral DA neurons in rats receiving a unilateral 6-hydroxydopamine (6-OHDA) striatal lesion. Methods: Rats received unilateral 6-OHDA (20 μg into the right striatum). Three or 14 days after lesion, rats were dosed with XPro^®1595 (10 mg/kg in saline, subcutaneous) every third day for 35 days. Forelimb asymmetry was used to assess motor deficits after the lesion; brains were harvested 35 days after the lesion for analysis of XPro^®1595 levels, glial activation and nigral DA neuron number. Results: Peripheral subcutaneous dosing of XPro^®1595 achieved plasma levels of 1–8 microgram/mL and CSF levels of 1–6 ng/mL depending on the time the rats were killed after final XPro^®1595 injection. Irrespective of start date, XPro^®1595 significantly reduced microglia and astrocyte number in SNpc whereas loss of nigral DA neurons was attenuated when drug was started 3, but not 14 days after the 6-OHDA lesion. Conclusions: Our data suggest that systemically administered XPro^®1595 may have disease-modifying potential in PD patients where inflammation is part of their pathology.

Background: Previous phase III studies in patients with advanced Parkinson's disease (PD) not adequately controlled on levodopa demonstrated significant reduction of ‘off’ time with rotigotine transdermal system up to 16 mg/24 h. However, the minimal effective dose has not been established. Objective: This international, randomized, double-blind, placebo-controlled study (SP921; NCT00522379) investigated rotigotine dose response up to 8 mg/24 h. Methods: Patients with advanced idiopathic PD (≥2.5 h of daily ‘off’ time on stable doses of levodopa) were randomized 1:1:1:1:1 to receive rotigotine 2, 4, 6, or 8 mg/24 h or placebo, titrated over 4 weeks and maintained for 12 weeks. The primary efficacy variable was change from baseline to end of maintenance in absolute time spent ‘off’. Results: 409/514 (80%) randomized patients completed maintenance. Mean (±SD) baseline daily ‘off’ times (h/day) were placebo: 6.4 (±2.5), rotigotine 2–8 mg/24 h: 6.4 (±2.6). Rotigotine 8 mg/24 h was the minimal dose to significantly reduce ‘off’ time versus placebo. LS mean (±SE) absolute change in daily ‘off’ time (h/day) from baseline was −2.4 (±0.28) with rotigotine 8 mg/24 h, and −1.5 (±0.26) with placebo; absolute change in ‘off’ time in the 8 mg/24 h group compared with placebo was −0.85 h/day (95% CI −1.59, −0.11; p = 0.024). There was an apparent dose-dependent trend. Adverse events (AEs) reported at a higher incidence in the rotigotine 8 mg/24 h group versus placebo included application site reactions, nausea, dry mouth, and dyskinesia; there was no worsening of insomnia, somnolence, orthostatic hypotension, confusional state or hallucinations, even in patients ≥75 years of age. Conclusions: The minimal statistically significant effective dose of rotigotine to reduce absolute ‘off’ time was 8 mg/24 h. The AE profile was similar to previous studies.

Background: Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by degeneration of dopaminergic neurons in the substantia nigra (SN). Destruction of the SN can lead to gastric dyskinesis accompanied by decreased expression of choline acetyltransferase (ChAT) and increased expression of tyrosine hydroxylase (TH) in the dorsal vagus complex (DVC), which includes the dorsal motor nucleus of the vagus (DMV) and nucleus tractus solitarius (NTS). However, it is unclear if the SN and DVC are directly connected. Objective: To investigate the neural projection from the SN to the DVC in rats. Methods: Retrograde and anterograde tracing techniques combined with double-labeling immunofluorescence technique were used. Results: Destruction of the SN significantly decreases ChAT immunoreactivity (IR) and increases TH-IR in the DVC. After injection of the retrograde tracer fluoro-gold (FG) into the DVC, FG-labeled neurons were observed in the hypothalamic paraventricular nucleus (PVN), lateral hypothalamus (LH), inferior olive (IO), and locus coeruleus (LC). No FG-positive cells were observed in the SN or striatum. Furthermore, after injection of anterograde tracer biotinylated dextran amine (BDA) into the SN, BDA-positive fibers were observed in the caudate putamen (Cpu), globus pallidus (GP), LC, and LH but not in the DVC. Conclusion: This study is the first to demonstrate that neurons in the SN do not directly innervate the DVC in rats. The DVC might be indirectly innervated by the SN through the hypothalamus and/or the LC. These data provide important morphological insights into the potential mechanism underlying the gastroparesis observed in PD patients.

Background: According to Braak staging of Parkinson's disease (PD), detection of autonomic dysfunction would help with early diagnosis of PD. Objective: To determine whether the autonomic nervous system is involved in the early stage of PD, we evaluated cardiovascular and sudomotor function in early untreated PD patients. Methods: Orthostatic blood pressure regulation, heart rate variability, skin vasomotor function, and palmar sympathetic sweat responses were examined in 50 early untreated PD patients and 20 healthy control subjects. Results: The mean decrease in systolic blood pressure during head-up tilt in PD patients was mildly but significantly larger than in controls (p = 0.0001). There were no differences between the 2 groups in heart rate variability, with analysis of low frequency (LF; mediated by baroreflex feedback), and high frequency (HF; mainly reflecting parasympathetic vagal) modulation. However, LF/HF, an index of sympatho-parasympathetic balance, was lower in the PD group than in controls (p = 0.02). Amplitudes of palmar sweat responses to deep inspiration (p = 0.004), mental arithmetic (p = 0.01), and exercise (p = 0.01) in PD patients were lower than in controls, with negative correlations with motor severity. Amplitudes of palmar skin vasomotor reflexes in PD patients did not differ from controls. Conclusions: Our study indicates impairment of sympathetic cardiovascular and sudomotor function with orthostatic dysregulation of blood pressure control, reduced LF/HF and reduction in palm sweat responses even in early untreated PD patients.

Background: Cognitive pretesting, a qualitative step in scale development, precedes field testing and assesses the difficulty of instrument completion for examiners and respondents. Cognitive pretesting assesses respondent interest, attention span, discomfort, and comprehension, and highlights problems with the logical structure of questions/response options that can affect understanding. In the past this approach was not consistently used in the development or revision of movement disorders scales. Methods: We applied qualitative cognitive pretesting using testing guides in development of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The guides were based on qualitative techniques, verbal probing and “think-aloud” interviewing, to identify problems with the scale from the patient and rater perspectives. English-speaking Parkinson's disease patients and movement disorders specialists (raters) from multiple specialty clinics in the United States, Western Europe and Canada used the MDS-UPDRS and completed the testing guides. Results: Two rounds of cognitive pretesting were necessary before proceeding to field testing of the revised scale to assess clinimetric properties. Scale revisions based on cognitive pretesting included changes in phrasing, simplification of some questions, and addition of a reassuring statement explaining that not all PD patients experience the symptoms described in the questions. Conclusions: The strategy of incorporating cognitive pretesting into scale development and revision provides a model for other movement disorders scales. Cognitive pretesting is being used in translating the MDS-UPDRS into multiple languages to improve comprehension and acceptance and in the development of a new Unified Dyskinesia Rating Scale for Parkinson's disease patients.

Background: Parkinson's disease (PD) involves the degeneration of dopaminergic neurons in substantia nigra (SN) compacta. However, it is still a contentious issue whether magnetic resonance imaging (MRI) can detect the nigral volume loss in PD patients. Objective: We synthesized the results of published research on SN volumetry using a meta-analysis method in order to clarify this issue. Methods: A comprehensive literature search yielded 8 eligible studies. Nigral size was expressed as the standardized mean difference (SMD) between normal controls and PD patients. In addition, subgroup analysis was performed in order to identify the best condition for nigral volumetry. The proportion of variation due to heterogeneity was computed and expressed as I². Results: Eight studies involved 172 normal control and 193 PD patients. The overall effect indicated that nigral volume in PD was significantly smaller than normal controls with homogeneous studies (SMD = −0.65, P < 0.0001; I² = 47%). Maximum of subgroup effect was observed in ‘volumetry’ among three approaches (‘thickness’: SMD = −0.35, P = 0.18, I² = not available; ‘area’: SMD = −0.39, P = 0.14, I² = 0%; ‘volumetry’: SMD = −0.82, P = 0.0006, I² = 56%). The approach including T1-weighted images (T1WI) showed larger effect (‘with T1WI’: SMD = −1.11, P < 0.00001, I² = 36%; ‘without T1WI’: SMD = −0.32, P = 0.04, I² = 0%). Conclusions: These findings suggest that volumetry based on T1WI could be the most sensitive option to identify nigral volume loss in PD patients.

Background: After several years duration of Parkinson's disease, with or without deep brain stimulation, axial signs (such as postural instability, freezing of gait) may worsen. High-voltage, low-frequency stimulation has been shown to improve severe gait disorders in some patients. Objective: To identify predictive factors for the efficacy of low-frequency stimulation. Methods: We assessed the respective effects of low- and high-frequency stimulation using an acute stand-walk- sit test, and on motor performance in 22 patients with longstanding, bilateral sub-thalamic nucleus stimulation. We calculated the difference in the number of steps (delta steps) between high and low -frequency stimulation during the stand-walk-sit test. Our aim was to establish a profile for low-frequency responders, which was defined by a positive value for delta steps. Results: Low frequency responders presented higher age, a severe axial phenotype five years after surgery and a lower L-dopa responsiveness of (i) the Unified Parkinson's Disease Rating Scale part III score and its akinesia subscore before surgery and (ii) the axial subscore one year after surgery. Conclusion: Here we defined a specific and severe axial profile of minority of patients who could benefit from low frequency stimulation parameters. Our findings challenge the conventional treatment approach (i.e. high-frequency stimulation) in patients who develop gait disorders after several years of stimulation.

Background and Objectives: The differential diagnosis between mild Parkinson's disease (PD) and Scan Without Evidence of Dopaminergic Deficit(SWEDD) is challenging. Progressive reduction in amplitude and speed of finger tapping (sequence effect) has been considered as the most useful sign for discriminating PD from SWEDD. However, a video analysis reported that sequence effect is a major confounding factor for the misdiagnosis of PD. Our objective was to perform a kinematic analysis of finger tapping to explore parameters for distinguishing between patients with PD and SWEDD. Methods: We enrolled 14 patients with PD, 17 patients with SWEDD and 18 age- and sex-matched healthy controls. Amplitude, speed and frequency of finger tapping were measured using gyroscopes, and the means, decrement and variability in kinematic parameters for specific tapping duration were calculated. Results: Compared to SWEDD group, PD group showed more decrement in amplitude and speed of the first 20 taps, more decrement in frequency after 20 taps and more variability in speed of 15 seconds of taps. However, none of parameters was a practically useful indicator distinguishing individual patients with PD from those with SWEDD. Conclusions: Analysis of finger tapping, even using an apparatus, is not useful for distinguishing mild PD and SWEDD.

Background: Motor fluctuations in Parkinson's disease (PD) cause major disabling symptoms. Objective: We aimed to assess the efficacy of relaxation guided imagery in PD patients with motor fluctuation. Methods: In a prospective pilot, case cohort, PD patients underwent (i) a relaxation session with relaxation guided imagery, and (ii) a control session of relaxing music. Three-day diaries were completed at baseline and after each intervention. Subsequently, patients received discs for home listening-a relaxation guided imagery disc and a relaxing music disc. After three months the patients were interviewed by phone. Results: Twenty one PD patients participated and 19 completed this study. There was a significant increase in the percent of “on” time after listening to the relaxation guided imagery disc as compared with baseline (from 47.7% to 62.8%, 95% CI 5.26–25.03, p = 0.005). Relaxing music caused no significant change in percent of “on” time from baseline (from 47.7% to 53.0%, p = 0.161). Although all sessions were performed in “on” state, there was a significant decrease in UPDRS motor subscores after each of the two sessions as compared with the UPDRS score before the session (relaxation guided imagery mean reduction −3.81 p = 0.0002 and after relaxing music mean reduction −1.95, p = 0.001), significantly more so after the relaxation guided imagery (p = 0.020). After 3 months listening to the relaxation guided imagery disc increased “on” time from baseline by 12.6% (95% CI 3.19–28.39, p = 0.111) but this did not reach statistical significance. Conclusion: In this pilot study we showed that relaxation guided imagery is a promising treatment for PD.

Background: Mirror movements are often reported in the early stages of Parkinson's disease (PD) and have been attributed to bilateral activation of the primary motor cortex; however, the precise cortical mechanisms are still unclear. Subclinical mirror activation (MA) that accompanies mirror movement has also been reported in healthy aging adults. Objective: To characterize mirror activation and determine the cortical mechanisms of MA in individuals with PD who demonstrate mirror movements. Hypothesis: 5 Hz rTMS to the supplementary motor area (SMA) will reduce MA by increasing interhemispheric inhibition (IHI) of the ipsilateral motor cortex. Methods: MA was assessed using surface electromyography during maximal and submaximal unimanual contractions of the first dorsal interosseous in 7 individuals with PD with mirror movements (PD-MM: 70.9 ± 13.9 years; UPDRS III: 28.0 ± 8.2), 7 individuals with PD without mirror movements (PD-NM: 71 ± 10.1 years; UPDRS III: 27.8 ± 6.7) and 7 healthy controls (74.4 ± 6.0 years). IHI of the ipsilateral motor cortex was assessed using paired-pulse transcranial magnetic stimulation. Results: MA was enhanced in both PD groups during submaximal contractions, with the latest onset of activation in PD-NM. Ipsilateral motor cortex excitability was the highest in PDMM; however, IHI did not differ between PD and controls. 5 Hz rTMS to the SMA reduced IHI in PD-NM; however, did not affect MA. Conclusions: IHI may not be the sole contributor to the expression of overt mirror movements in PD. Expression of overt mirror movement may be due to the combination of enhanced ipsilateral motor cortex excitability and an earlier onset of electromyographic activation in the mirror hand (mirror activation) in PDMM.

Background: Parkinson's disease (PD) can result in cognitive impairment. Executive dysfunction often appears early, followed by more widespread deficits later in the course of the disease. Disruption of parallel basal ganglia thalamo-cortical loops that subserve motor and cognitive function has been described in PD. However, there is emerging evidence that the default mode network, a cortical network that is active at rest with reduced activation during task performance, may also play a role in disease related cognitive decline. Objective: To determine the relative contribution of the executive control and default mode networks to parkinsonian executive dysfunction in medicated non-demented patients. Methods: We used BOLD fMRI to measure resting state functional connectivity in the executive control and default mode (DM) networks, and examined switching, processing speed, working memory/attention and motor performance in 14 medicated non-demented PD participants and 20 controls. Results: Performance on neuropsychological measures was similar across groups. Functional connectivity was not different across disease conditions in the executive control network. DMN functional connectivity was decreased in the PD group, specifically between posterior cingulate, medial prefrontal, and inferior parietal nodes. Greater DMN functional connectivity was associated with faster processing speed in the PD group. Conclusions: The continuous relationship between DMN disconnection and executive task performance indicates a possible biological contributor to parkinsonian cognitive deficits. The dynamics of executive control network change may be different than that of the DMN, suggesting less sensitivity to early cognitive deficits.

Background: The PDQ-39 is the most thoroughly validated and widely used self-report instrument for the assessment of health-related quality of life in people with Parkinson's (PwP). Given the breadth of its use and increasing emphasis on electronic data capture, there may be significant benefit in validating an electronic version of the PDQ-39. Objective: Firstly, to migrate the paper-based version of the PDQ-39 to a computer based platform and assess its usability and acceptability to respondents. Secondly, to investigate the impact of implementing non-response options on response rates and data completeness. Methods: Six PwP participated in cognitive interviews in order to assess the usability and acceptability of the electronic version of the PDQ-39, the ePDQ. This was followed by an online survey of 129 PwP, randomly assigned to one of two groups; one required to provide a response to every item and one with the option to skip any item they did not wish to answer. Results: Cognitive interviews indicated that the ePDQ is acceptable to PwP, with positive feedback regarding layout, features and functionality. 125 PwP fully completed the ePDQ. Following randomization 60 participants completed the forced response ePDQ and 65 completed the non-forced version. Response rates of 98.4% were achieved for the forced response ePDQ and 95.6% for the non-forced. Missing value analyses calculated levels of missing data at below 5% in the non-forced sample. Conclusions: The ePDQ is user-friendly and acceptable to respondents. Additionally, there appears little difference when implementing non-response options on response rates and data completeness.

Background: The magnitude of malnutrition in the Parkinson's disease (PD) population has yet to be accurately quantified. Objective: We aimed to estimate and compare the prevalence of malnourished and those at risk of malnutrition in Iranian PD patients with a matched control group using the mini nutritional assessment (MNA) and anthropometric measurements. Methods: Nutritional status was evaluated in 143 Iranian PD patients (case group) and 145 age- and sex-matched healthy controls (control group) using the validated Persian version of the MNA. Individuals suffering from chronic comorbidities influencing nutritional state (hypertension and diabetes), following special diets and those with cognitive impairment were excluded. Using the MNA, a total score of <17 indicated malnutrition and scores of 17–23.5 signified cases at risk for malnutrition. Results: The mean of total MNA score was not significantly different between two study groups [24.4 (SD = 3.8) in controls vs. 25.1 (SD = 3.4) in PD patients; P = 0.094]. Three (2.1%) PD patients were suffering from malnutrition and another 37 (25.9%) were at risk of malnutrition; while in control group similar feature was observed (2.0% malnourished and 35.2% at risk of malnutrition; P = 0.228). The mean of calf circumference (CC) was significantly lower in PD patients [34.9 (SD = 3.8) cm vs. 36.0 (SD = 5.1) cm; P = 0.046]. Conclusions: Our findings indicate the same nutritional status among mild to moderate PD patients compared with healthy controls. However, more than a quarter of the PD population was found to be at risk of malnutrition necessitating more attention towards nutritional assessment in PD.

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.

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.

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.

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.

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.”

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.

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.