Journal of Parkinson's Disease - Volume 9, issue 4

Authors: Tessitore, Alessandro | Cirillo, Mario | De Micco, Rosa

Article Type: Review Article

Abstract:  Resting-state functional magnetic resonance imaging (RS-fMRI) studies have been extensively applied to analyze the pathophysiology of neurodegenerative disorders such as Parkinson’s disease (PD). In the present narrative review, we attempt to summarize the most recent RS-fMRI findings highlighting the role of brain networks re-organization and adaptation in the course of PD. We also discuss limitations and potential definition of early functional connectivity signatures to track and predict future PD progression. Understanding the neural correlates and potential predisposing factors of clinical progression and complication will be crucial to guide novel clinical trials and to foster preventive strategies.

Keywords: Functional MRI, imaging, biomarkers, Parkinson’s disease, resting-state networks

DOI: 10.3233/JPD-191592

Citation: Journal of Parkinson's Disease, vol. 9, no. 4, pp. 637-652, 2019

Authors: Mele, Bria | Merrikh, Daria | Ismail, Zahinoor | Goodarzi, Zahra

Article Type: Research Article

Abstract: Background: Individuals experiencing apathy in Parkinson’s disease (PD) have a lack of emotion and motivation. Apathy often overlaps with comorbidities such as depression, and is sometimes difficult to detect. Objective: To examine diagnostic accuracy of apathy-screening tools compared with a gold standard (clinician diagnosis) among adult outpatients with PD. Methods: A systematic review was conducted. Six research databases were searched to May 23, 2018. Diagnostic accuracy measures, including sensitivity and specificity were gathered. Results: 1,007 full-text articles were reviewed with seven full-text articles included. The gold standard was considered a clinician diagnosis as apathy …is not defined in the DSM/ICD. Diagnostic accuracy measures were reported for the Lille Apathy Rating Scale (LARS) both informant- and observer-rated, Unified Parkinson’s Disease Rating Scale (UPDRS), Apathy Scale (AS), Apathy Evaluation Scale (AES), Non-Motor Symptoms Questionnaire (NMS-Q), and Dimensional Apathy Scale (DAS). The AES had the best reported sensitivity and specificity values, both 90%. The AS had the highest reported specificity at 100%, with 66% sensitivity. Pooled prevalence of apathy was 29.1% (95% CI 21.5%–36.6%). Conclusions: While 18 screening tools exist to screen for apathy in PD, only six have been validated against clinician diagnosis. The AES had the highest reported sensitivity and specificity and is a brief, easy to use tool. The AS was designed specifically for use in PD populations and has the highest reported specificity. Future research should focus on the development of an accepted gold standard, to further understand accuracy measures of all available apathy screening tools. Show more

Keywords: Parkinson’s disease, apathy, diagnosis, diagnostic tools

DOI: 10.3233/JPD-191619

Citation: Journal of Parkinson's Disease, vol. 9, no. 4, pp. 653-664, 2019

Authors: Chahine, Lana M. | Siderowf, Andrew | Barnes, Janel | Seedorff, Nicholas | Caspell-Garcia, Chelsea | Simuni, Tanya | Coffey, Christopher S. | Galasko, Douglas | Mollenhauer, Brit | Arnedo, Vanessa | Daegele, Nichole | Frasier, Mark | Tanner, Caroline | Kieburtz, Karl | Marek, Kenneth | The Parkinson’s Progression Markers Initiative

Article Type: Research Article

Abstract: Background: Improved prediction of Parkinson’s disease (PD) progression is needed to support clinical decision-making and to accelerate research trials. Objectives: To examine whether baseline measures and their 1-year change predict longer-term progression in early PD. Methods: Parkinson’s Progression Markers Initiative study data were used. Participants had disease duration ≤2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) score and …DAT specific binding ratios (SBR) using linear mixed-effects models. Results: Among 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (β= 0.351; 95% CI = 0.146, 0.555), male gender (β= 3.090; 95% CI = 0.310, 5.869), and baseline (β= –0.199; 95% CI = –0.315, –0.082) and 1-year change (β= 0.540; 95% CI = 0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (β= –0.6229; 95% CI = –1.2910, 0.0452), baseline (β= 7.232; 95% CI = 2.268, 12.195) and 1-year change (β= 45.918; 95% CI = 35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (β= –0.325;95% CI = –0.695, 0.045); predictors in the model accounted for 44.1% of the variance. Conclusions: Baseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding. Show more

Keywords: Parkinson’s disease, biomarkers, disease progression, surrogate endpoint

DOI: 10.3233/JPD-181518

Citation: Journal of Parkinson's Disease, vol. 9, no. 4, pp. 665-679, 2019

Authors: Seki, Morinobu | Seppi, Klaus | Mueller, Christoph | Potrusil, Thomas | Goebel, Georg | Reiter, Eva | Nocker, Michael | Kremser, Christian | Wildauer, Matthias | Schocke, Michael | Gizewski, Elke R. | Wenning, Gregor K. | Poewe, Werner | Scherfler, Christoph

Article Type: Research Article

Abstract: Background: The diagnostic potential of multimodal MRI approaches to discriminate among progressive supranuclear palsy (PSP), Parkinson variant of multiple system atrophy (MSA-P) and Parkinson’s disease (PD) has not been well investigated. Objective: To identify disease-specific neurodegenerative patterns and evaluate the diagnostic accuracy of dedicated MRI, iron concentration (R2*), microstructural integrity (mean diffusivity; MD and fractional anisotropy; FA) as well as volumes were analyzed in patients with PSP, MSA-P and PD. Methods: 3T MRI of 18 PSP and 16 MSA-P patients were compared with 16 PD patients matched for age and disease duration as well as 21 …healthy controls. Statistical parametric mapping (SPM) was applied to objectively identify focal MRI changes throughout the whole-brain. Following dimensionality reduction of significant and multiple comparison-corrected SPM clusters through principal component analysis (PCA), stepwise receiver-operating characteristic curve analysis (ROC) was applied to determine the diagnostic potential of multimodal MRI parameters. Results: PCA revealed two components involving multiple regions identified from SPM analysis. The first component was primarily composed of the mean MD value of the thalamus and the mean MD and FA values of the dentatorubrothalamic tract and the corpus callosum. The second component mainly consisted of mean MD and FA values of the middle cerebellar peduncle. ROC analysis showed 92% of PSP patients were differentiated correctly from MSA-P and PD and 80% of MSA-P patients could be distinguished from PD. Conclusion: Multimodal MRI improved the detection of disease-specific neurodegenerative patterns in PSP and MSA-P and highlights its potential to improve the diagnostic accuracy of atypical parkinsonian disorders. Show more

Keywords: Multimodal MRI, principal component analysis, R2*, diffusion tensor imaging, progressive supranuclear palsy, multiple system atrophy

DOI: 10.3233/JPD-181568

Citation: Journal of Parkinson's Disease, vol. 9, no. 4, pp. 681-691, 2019

Authors: Löhle, Matthias | Hermann, Wiebke | Hausbrand, Denise | Wolz, Martin | Mende, Julia | Beuthien-Baumann, Bettina | Oehme, Liane | van den Hoff, Jörg | Kotzerke, Jörg | Reichmann, Heinz | Hermann, Andreas | Storch, Alexander

Article Type: Research Article

Abstract: Background and Objective: To investigate the predictive value of striatal dopamine turnover in patients with de novo Parkinson’s disease (PD) for later occurrence of major non-motor health outcomes. Methods: This retrospective, observer-blinded cohort study followed up 29 patients with de novo PD for a median of 10.7 years, who completed 18 Fluorodopa PET imaging to measure striatal effective distribution volume ratio (EDVR, inverse of dopamine turnover) prior to antiparkinsonian treatment. Outcomes were assessed with a battery of non-motor, health-related quality-of-life and non-motor fluctuation (WOQ-19) measures and survival. Results: During follow-up, 52% of patients developed …wearing-off, 43% neuropsychiatric fluctuations, 35% sensory fluctuations, 32% dementia, 46% depression, 30% psychosis, and PD-related mortality was 26%. Patients with wearing-off and neuropsychiatric fluctuations showed significantly lower baseline EDVR (higher dopamine turnover) in the putamen but not in the caudate nucleus than those without these fluctuations. Consistently, baseline EDVR in the putamen predicted development of wearing-off and neuropsychiatric fluctuations with a lower risk with higher EDVR (lower dopamine turnover), whereas EDVR in caudate nucleus did not correlate with these fluctuations. No relationships were observed between baseline PET measures and the presence of other major health outcomes including survival. Conclusions: Lower putaminal dopamine turnover in de novo PD is associated with reduced risk for later neuropsychiatric fluctuations comprising a disease-intrinsic predisposing factor for their development, similar as reported for levodopa-induced motor complications. Striatal (putaminal/caudate) dopamine turnover is not predictive for other long-term major health outcomes. These results should be treated as hypothesis generating and require confirmation. Show more

Keywords: Non-motor fluctuations, motor complication, long-term major health outcomes, dopamine turnover, prediction

DOI: 10.3233/JPD-191672

Citation: Journal of Parkinson's Disease, vol. 9, no. 4, pp. 693-704, 2019

Authors: Green, Holly F. | Khosousi, Shervin | Svenningsson, Per

Article Type: Short Communication

Abstract: The nature of the inflammatory response in Parkinson’s disease (PD) remains to be better understood. Here, we used highly sensitive Single Molecule Array (SIMOA) technology to measure the levels of the inflammatory mediators Interleukin 6 (IL-6), Interleukin 17A (IL-17A), Tumour Necrosis Factor α (TNFα ) and Transforming Growth Factor β (TGFβ) in plasma from PD patients and age- and gender-matched healthy controls. We report that IL-17A correlates with non-motor symptoms (NMS) scores, while IL-6 positively correlates with motor scores. We found no correlations between cytokines and disease duration suggesting that IL-6 and IL-17A are associated with disease severity rather …than disease duration in this cohort, furthermore IL-17A may be involved in the underlying pathophysiology of NMS in PD. Show more

Keywords: Parkinson’s disease, biomarker, plasma, inflammation

DOI: 10.3233/JPD-191699

Citation: Journal of Parkinson's Disease, vol. 9, no. 4, pp. 705-709, 2019

Authors: Du, Juanjuan | Huang, Pei | Qian, Yiwei | Yang, Xiaodong | Cui, Shishuang | Lin, Yiqi | Gao, Chao | Zhang, Pingchen | He, Yixi | Xiao, Qin | Chen, Shengdi

Article Type: Research Article

Abstract: Background and Objective: To explore the alterations of microbial 16s ribosomal (rRNA) gene in the feces and blood of Chinese patients with multiple system atrophy (MSA) and its relationships with clinical features. Methods: 40 MSA patients (MSA-P/MSA-C: 23/17) and their healthy spouses were recruited. Fecal and blood microbiota were investigated by high-throughput IllUmina Miseq sequencing targeted on the V3-V4 functional region of 16s rRNA gene. The relationships between microbiota and clinical characteristics were analyzed. Results: The abundances of Lactobacillus, Gordonibacter, Phascolarctobacterium, and Haemophilus in feces and abundances of Leucobacter, and Bacteroides in blood were different between …MSA patients and healthy controls (HC). Combining the taxa from feces and blood, six genera were identified to be predictive of MSA, achieving an area under the curve (AUC) of 0.853. The abundances of Phascolarctobacterium and Ruminococcus in feces were lower in MSA-P than those in MSA-C. The abundances of Blastococcus, Bacillus, and Acinetobacter in blood were different between MSA subtypes. These five genera differentiated MSA subtypes with an AUC of 0.898. Functional predictions indicated that gene functions involving biosynthetic metabolism and bacterial secretion systems were significantly different between the MSA and HC. The differential genera were associated with disease duration, anxiety, and autonomic dysfunctions. Conclusions: We confirmed the alterations of microbial 16s rRNA gene in the feces and blood occurs in Chinese patients with MSA. Microbiota dysbiosis was related to MSA clinical manifestations. Elucidating these differences in microbiomes will be helpful to improve our knowledge of the microbiota in the pathogenesis of MSA. Show more

Keywords: Multiple system atrophy, 16s rRNA gene, microbiota, blood, feces

DOI: 10.3233/JPD-191612

Citation: Journal of Parkinson's Disease, vol. 9, no. 4, pp. 711-721, 2019

Authors: Ohlhauser, Lisa | Smart, Colette M. | Gawryluk, Jodie R.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is characterized by distinct motor symptoms which do not manifest until significant neurodegeneration has already occurred. Therefore, preventative treatments depend on PD being detected in a prodromal phase. To date, prodromal PD (pPD) has been conceptualized based on conditions such as REM Sleep Behavior Disorder (RBD), which has a high conversion rate to clinical PD (cPD). However, few studies have examined microstructural differences between healthy controls (HC), pPD, and cPD. Objective: The current study examined white matter microstructure in different phases of PD progression. Methods: Participants included 21 HC, 20 pPD (14 …with RBD and 6 with hyposmia), and 17 cPD from the Parkinson’s Progression Markers Initiative database. Tract-based spatial statistics were used to determine between group differences in fractional anisotropy (FA) and mean diffusivity (MD). Results: Mean diffusivity was significantly increased in pPD relative to cPD in widespread, but mostly right lateralized regions. Post-hoc analyses indicated that this pattern was particular to individuals with RBD. There were no microstructural differences between HC and pPD or cPD. The pPD group had significantly higher RBD symptoms and the cPD group had significantly higher motor symptoms. Conclusions: Observed microstructural deterioration in individuals with RBD relative to cPD may indicate an altered pattern of neurodegeneration associated with RBD as a prodromal symptom of PD. Future studies should aim to further characterize possible differential patterns of progression from various non-motor symptoms (e.g., RBD, hyposmia) to cPD using longitudinal designs. Show more

Keywords: Parkinson’s disease, diffusion tensor imaging, rapid eye movement sleep behavior disorder, white matter

DOI: 10.3233/JPD-191688

Citation: Journal of Parkinson's Disease, vol. 9, no. 4, pp. 723-731, 2019

Authors: Lees, Andrew | Ferreira, Joaquim J. | Rocha, José-Francisco | Rascol, Olivier | Poewe, Werner | Gama, Helena | Soares-da-Silva, Patrício

Article Type: Research Article

Abstract: Background: Opicapone is a catechol O-methyltransferase (COMT) inhibitor indicated for use as adjunct to levodopa therapy in patients with Parkinson’s disease (PD) and motor fluctuations. Objective: To characterize the safety and tolerability of adjunct opicapone (25 and 50 mg) in a pooled population of levodopa-treated PD patients who participated in the opicapone Phase-3 clinical program. Methods: Patient-level data (placebo, opicapone 25 mg and 50 mg) from the BIPARK-1 and BIPARK-2 double-blind and open-label studies were combined. Results: Pooled analyses included 766 patients from the double-blind studies and 848 patients from the open-label studies. In the double-blind studies, …63.3% of opicapone-treated patients reported treatment-emergent adverse events (TEAEs) versus 57.2% in the placebo group. The most common TEAEs reported in the opicapone group compared to placebo were dyskinesia, constipation and insomnia. The incidence of serious TEAEs was similar across opicapone and placebo groups (3.5% versus 4.3%, respectively). Overall, 71.3% patients treated with open-label opicapone reported at least one TEAE; most occurred within the first 2 months of the open-label studies, and then decreased thereafter. Throughout the Phase-3 clinical program, there were no serious AEs suggestive of hepatic toxicity, and the incidence of gastrointestinal disorders such as nausea and diarrhea remained low (<2%). There were no relevant changes in laboratory parameters including liver enzymes, vital signs, physical or neurological examinations, or ECG readings. Conclusions: Long-term use of opicapone once-daily over 1-year at doses of 25 mg or 50 mg was generally safe and well tolerated, supporting its clinical usefulness in the management of PD motor fluctuations. Show more

Keywords: Clinical trials, motor fluctuations, opicapone, Parkinson’s disease, safety

DOI: 10.3233/JPD-191593

Citation: Journal of Parkinson's Disease, vol. 9, no. 4, pp. 733-740, 2019

Authors: Kim, Young Eun | Jeon, Beomseok | Yun, Ji Young | Yang, Hui-Jun | Kim, Han-Joon

Article Type: Research Article

Abstract: Background: Dyskinesia, wearing off (WO) and freezing of gait (FOG) are troublesome complications degrading quality of life in the course of Parkinson’s disease (PD). Objective: This study evaluated the gross chronological trend of 4 motor complications - peak dose dyskinesia (PDSK), diphasic dyskinesia (DDSK), WO and FOG in a large PD population with stratification by age at disease onset according to the PD duration. Methods: The motor complications of 1212 Korean PD patients were analyzed using Kaplan-Meier curves and Cox proportional hazards models. Results: PDSK and WO appeared first as motor complications and showed …accelerated development around the 5 year-PD-duration, while DDSK showed a rather constant development over time and FOG developed around the 10 year-disease duration at an accelerated rate (p  < 0.001). A younger age at PD onset predicted an earlier appearance of PDSK, DDSK and WO (p  < 0.001), while an older age at onset (≥60 years) was a predictor for FOG (p  = 0.014). Conclusion: Motor complications developed with a distinguishing inclination over the PD duration. This study provides insight into the chronological trend of motor complications in PD at a glance. Show more

DOI: 10.3233/JPD-191624

Citation: Journal of Parkinson's Disease, vol. 9, no. 4, pp. 741-747, 2019