Journal of Parkinson's Disease - Volume Pre-press, issue Pre-press

Authors: van den Heuvel, Lieneke | Dorsey, Ray R. | Prainsack, Barbara | Post, Bart | Stiggelbout, Anne M. | Meinders, Marjan J. | Bloem, Bastiaan R.

Article Type: Research Article

Abstract: Clinical decision making for Parkinson’s disease patients is supported by a combination of three distinct information resources: best available scientific evidence, professional expertise, and the personal needs and preferences of patients. All three sources have clear value but also share several important limitations, mainly regarding subjectivity, generalizability and variability. For example, current scientific evidence, especially from controlled clinical trials, is often based on selected study populations, making it difficult to translate the outcome to the care for individual patients in everyday clinical practice. Big data, including data from real-life unselected Parkinson populations, can help to bridge this information gap. Fine-grained …patient profiles created from big data have the potential to aid in identifying therapeutic approaches that will be most effective given each patient’s individual characteristics, which is particularly important for a disorder characterized by such tremendous interindividual variability as Parkinson’s disease. In this viewpoint, we argue that big data approaches should be acknowledged and harnessed, not to replace existing information resources, but rather as a fourth and complimentary source of information in clinical decision making, helping to represent the full complexity of individual patients. We introduce the ‘quadruple decision making’ model and illustrate its mode of action by showing how this can be used to pursue precision medicine for persons living with Parkinson’s disease. Show more

Keywords: Big data, data-driven science, evidence-based medicine, Parkinson’s disease, machine learning, personalized medicine, precision medicine, shared decision making

DOI: 10.3233/JPD-191712

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Peterson, Daniel S. | Mancini, Martina | Fino, Peter C. | Horak, Fay | Smulders, Katrijn

Article Type: Research Article

Abstract: Background: Gait speed is an important outcome that relates to mobility, function, and mortality, and is altered in people with Parkinson’s disease (PwPD). However, changes in gait speed may not reflect changes in other important aspects of gait. Objective: To characterize which outcomes change concomitantly with walking speed in PwPD. This information can inform the choice of outcome variables for characterizing and tracking gait performance in this population. Methods: 67 PwPD and 40 neurotypical adults completed 2-minute overground walking bouts at comfortable and fast self-selected speeds. Eight inertial sensors were used to characterize gait and turning. …We identified a subset of participants (38 per group) where the PD participant’s “fast” walk was similar speed to neurotypical participants “comfortable” walk, facilitating an across-group gait comparison controlling for gait speed. Results: Walking at fast gait speed compared to comfortable lead to significant changes in stride length, cadence, and stride time variability, but not in steps to turn, trunk ROM, and trunk and lumbar stability in PwPD. Sub-group analyses showed that despite walking at a similar speed as neurotypical adults, PwPD exhibit altered turning outcomes, lumbar stability, and stride length/cadence. Conclusions: Gait speed is a critical outcome for characterizing mobility. However, in PwPD, several important outcomes do not exhibit a uniform relationship with gait speed, and remain altered compared to neurotypical adults despite “normalizing” walking speed. Given the complex relationship between gait speed and other gait quality measures, care should be taken when choosing outcome measures to characterize the breadth of gait abnormality in PwPD. Show more

Keywords: Gait, kinematics, Parkinson’s disease, speed

DOI: 10.3233/JPD-191682

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: van IJzendoorn, Sven C. D. | Derkinderen, Pascal

Article Type: Review Article

Abstract: The intestinal barrier, which primarily consists of epithelial cells stitched together with connecting proteins called tight junctions, plays a critical role in health and disease. It is in close contact with the gut microbiota on its luminal side and with the enteric neurons on the tissue side. Both microbiota and the enteric nervous system are regulatory housekeepers of the intestinal barrier. Therefore, the recently observed enteric neuropathology along with gut dysbiosis in Parkinson’s disease have prompted research on intestinal permeability in this neurodegenerative disorder. In this mini-review we attempt to concisely summarize the current knowledge on intestinal barrier in Parkinson’s …disease. We envision future direction research that should be pursued in order to demonstrate its possible role in disease development and progression. Show more

Keywords: Intestinal barrier, tight junctions, enteric nervous system, Parkinson’s disease

DOI: 10.3233/JPD-191707

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Stephenson, Diane | Hill, Derek | Cedarbaum, Jesse M. | Tome, Maria | Vamvakas, Spiros | Romero, Klaus | Conrado, Daniela J. | Dexter, David T. | Seibyl, John | Jennings, Danna | Nicholas, Timothy | Matthews, Dawn | Xie, Zhiyong | Imam, Syed | Maguire, Paul | Russell, David | Gordon, Mark Forrest | Stebbins, Glenn T. | Somer, Ed | Gallagher, Jill | Roach, Arthur | Basseches, Peter | Grosset, Donald | Ken Marek on behalf of the Critical Path for Parkinson’s Consortium

Article Type: Correction

DOI: 10.3233/JPD-199003

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2019

Authors: Hashimoto, Makoto | Ho, Gilbert | Takamatsu, Yoshiki | Wada, Ryoko | Sugama, Shuei | Takenouchi, Takato | Waragai, Masaaki | Masliah, Eliezer

Article Type: Research Article

Abstract: Aging-related neurodegenerative disorders are frequently associated with the aggregation of multiple amyloidogenic proteins (APs), although the reason why such detrimental phenomena have emerged in the post-reproductive human brain across evolution is unclear. Speculatively, APs might provide physiological benefits for the human brain during developmental/reproductive stages. Of relevance, it is noteworthy that cross-seeding (CS) of APs has recently been characterized in cellular and animal models of neurodegenerative disease, and that normal physiological CS of multiple APs has also been observed in lower organisms, including yeast and bacteria. In this context, our main objective is to discuss a possible involvement of the …CS of APs in promoting evolvability, a hypothetical view regarding the function of APs as an inheritance of acquired characteristics against human brain stressors, which are transgenerationally transmitted to offspring via germ cells. Mechanistically, the protofibrils formed by the CS of multiple APs might confer hormesis more potently than individual APs. By virtue of greater encoded stress information in parental brains being available, the brains of offspring can cope more efficiently with forth-coming stressors. On the other hand, subsequent neurodegeneration caused by APs in parental brain through the antagonistic pleiotropy mechanism in aging, may suggest that synergistically, multiple APs might be more detrimental compared to singular AP in neurodegeneration. Taken together, we suggest that the CS of multiple APs might be involved in both evolvability and neurodegenerative disease in human brain, which may be mechanistically and therapeutically important. Show more

Keywords: Alzheimer’s disease, Parkinson’s disease, amyloidogenic proteins, amyloid cascade hypothesis, evolvability hypothesis, cross-seeding, antimicrobial protection model

DOI: 10.3233/JPD-191675

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

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

Article Type: Brief Report

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 motors 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. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: de Schipper, Laura J. | Hafkemeijer, Anne | van der Grond, Jeroen | Marinus, Johan | Henselmans, Johanna M.L. | van Hilten, Jacobus J.

Article Type: Research Article

Abstract: Background: Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are considered subtypes of the α -synucleinopathy continuum that show similar and dissimilar clinical and morphological features. Objective: To further our understanding of brain abnormalities that might differentiate both disorders more clearly, we performed quantitative magnetic resonance (MR) imaging of the subcortical and cortical grey matter. Methods: Three-dimensional T1 weighted 3 tesla MR images of 14 DLB and 62 age- and gender-matched PD patients were examined to study cortical and subcortical grey matter structure. We used volumetric measurements to study total grey matter, and volumes of …the pallidum, amygdala, putamen, caudate nucleus, thalamus and hippocampus. Whole-brain and structural network-based methods were used to identify local differences in grey matter and vertex-based shape analysis was used to assess focal hippocampal changes. Results: Volumetric, whole-brain and network-based analyses showed reduced hippocampal (p  = 0.008) and right parahippocampal region volumes (p  = 0.030) in DLB compared to PD patients. Shape analysis showed atrophy in the head and body of the right (p  = 0.040) and in the head of the left (p  = 0.030) hippocampus of DLB patients. Conclusion: DLB patients showed atrophy of the hippocampus and parahippocampal gyrus compared to PD patients with a differential involvement of the head and body of the hippocampus. Further studies should examine if these group-based findings can be used to differentiate both disorders on an individual level. Show more

Keywords: Parkinson’s disease, Lewy body dementia, magnetic resonance imaging, hippocampus, structure, shape

DOI: 10.3233/JPD-191600

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Gilat, Moran

Article Type: Short Communication

Abstract: Visually scoring freezing of gait (FOG) from video is increasingly recognized as the gold-standard for assessing FOG severity in Parkinson’s disease. Surprisingly, no guidelines exist on how to visually score FOG. Here, I present a free template that can be implemented in open-source software to annotate FOG from video. I provide a user guide on how to implement the template and standardize the scoring of FOG and the percentage of time spent with FOG (% FOG). It is hoped that by disseminating this method investigators will be better able to employ % FOG as an outcome in their studies and …therapeutic trials. Show more

Keywords: Parkinson’s disease, gait, gait analysis, outcome assessment, falls, software

DOI: 10.3233/JPD-191700

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2019

Authors: Lees, Andrew | Ferreira, Joaquim J | Rocha, José-Francisco | Rascol, Olivier | Poewe, Werner | Soares-da-Silva, Patr’ıcio

Article Type: Research Article

Abstract: Background: Opicapone is a new 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. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Boertien, Jeffrey M. | Pereira, Pedro A.B. | Aho, Velma T.E. | Scheperjans, Filip

Article Type: Review Article

Abstract: Gut microbiota have been studied in relation to the pathophysiology of Parkinson’s disease (PD) due to the early gastrointestinal symptomatology and presence of alpha-synuclein pathology in the enteric nervous system, hypothesized to ascend via the vagal nerve to the central nervous system. Accordingly, sixteen human case-control studies have published gut microbiome composition changes in PD and reported over 100 differentially abundant taxa covering all taxonomic levels from phylum to genus or species, depending on methodology. While certain findings were replicated across several studies, various contradictory findings were reported. Here, differences in methodologies and the presence of possible confounders in the …study populations are assessed for their potential to confound the results of gut microbiome studies in PD. Gut microbiome studies in PD exhibited considerable variability with respect to the study population, sample transport conditions, laboratory protocols and sequencing, bioinformatics pipelines, and biostatistical methods. To move from the current heterogeneous dataset towards clinically relevant biomarkers and the identification of putative therapeutic targets, recommendations are derived from the limitations of the available studies to increase the future comparability of microbiome studies in PD. In addition, integration of currently available data on the gut microbiome in PD is proposed to identify robust gut microbiome profiles in PD. Furthermore, expansion of the current dataset to atypical parkinsonism cohorts, prodromal and treatment-naïve de novo PD subjects, measurements of fecal microbial concentrations and a multi-omics assessment are required to provide clinically relevant biomarkers and reveal therapeutic targets within the gut microbiome of PD. Show more

Keywords: Parkinson disease, gut microbiome, case-control studies, systematic review

DOI: 10.3233/JPD-191711

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 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. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Hoogland, Jeroen | Post, Bart | de Bie, Rob M.A.

Article Type: Research Article

Abstract: Background: Earlier research showed that Parkinson’s disease is related to increased overall mortality, but it remains unclear which patient level factors are predictive of increased mortality in Parkinson’s disease. Objective: To jointly evaluate potential risk factors for overall and Parkinson’s disease (PD) related mortality, we collected detailed information from a cohort of newly diagnosed PD patients which was consequently followed for over a decade. Methods: A total of 133 consecutive patients with newly diagnosed PD were followed for at least 13 years. Survival analysis of observed mortality was used to evaluate risk factors for overall mortality, …whereas survival analysis of mortality as corrected for the general population was used to evaluate risk factors for PD-related mortality. Results: Overall mortality increased with age, male sex, higher levodopa equivalent dose, and presence of mild cognitive impairment. PD-related mortality increased with earlier onset of Parkinson’s disease, higher levodopa equivalent dose, and mild cognitive impairment. Conclusions: Our findings provide confirmation and extension of risk factors for overall mortality and generate new insights into PD-related mortality. Show more

Keywords: Parkinson disease, mortality, cohort studies, survival analyses

DOI: 10.3233/JPD-191652

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 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. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Borghammer, Per | Van Den Berge, Nathalie

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is a highly heterogeneous disorder, which probably consists of multiple subtypes. Aggregation of misfolded alpha-synuclein and propagation of these proteinacious aggregates through interconnected neural networks is believed to be a crucial pathogenetic factor. It has been hypothesized that the initial pathological alpha-synuclein aggregates originate in the enteric or peripheral nervous system (PNS) and invade the central nervous system (CNS) via retrograde vagal transport. However, evidence from neuropathological studies suggests that not all PD patients can be reconciled with this hypothesis. Importantly, a small fraction of patients do not show pathology in the dorsal motor nucleus of the …vagus. Here, it is hypothesized that PD can be divided into a PNS-first and a CNS-first subtype. The former is tightly associated with REM sleep behavior disorder (RBD) during the prodromal phase and is characterized by marked autonomic damage before involvement of the dopaminergic system. In contrast, the CNS-first phenotype is most often RBD-negative during the prodromal phase and characterized by nigrostriatal dopaminergic dysfunction prior to involvement of the autonomic PNS. The existence of these subtypes is supported by in vivo imaging studies of RBD-positive and RBD-negative patient groups and by histological evidence— reviewed herein. The present proposal provides a fresh hypothesis-generating framework for future studies into the etiopathogenesis of PD and seems capable of explaining a number of discrepant findings in the neuropathological literature. Show more

Keywords: Parkinson’s disease, autonomic nervous system, imaging, PET, MRI, prion-like, etiology, histology, alpha-synuclein, dopamine

DOI: 10.3233/JPD-191721

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Ratti, Pietro-Luca | Faraci, Francesca | Hackethal, Sandra | Mascheroni, Alessandro | Ferlito, Clara | Caverzasio, Serena | Amato, Ninfa | Choe, Eun-Kyoung | Luo, Yuhan | Nunes-Ferreira, Paulo-Edson | Galati, Salvatore | Puiatti, Alessandro | Kaelin-Lang, Alain

Article Type: Research Article

Abstract: Background: Subjective symptoms, which are retrospectively assessed during clinical interviews in the office, may be influenced by patient recall in Parkinson’s disease (PD). Prospective collection of subjective data might be an effective tool to overcome this bias. Objective: We investigated the correspondence between prospectively and retrospectively assessed motor symptoms in PD. Methods: Forty-two consecutive patients (9 females, 67±9.8 years old) with mild to moderate PD reported their symptoms four times a day for two weeks, using the “SleepFit ” application (app) for tablets. This app incorporates a new Visual Analogue Scale assessing global mobility (m-VAS), and …the Scales for Outcome in Parkinson Assessment Diary Card (SCOPA-DC). At day 14, the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) parts II and IV questionnaire were completed at the hospital. Agreement (root mean square difference) and the tendency to under- or overestimate their symptoms by patients (relative difference after normalization) were calculated to compare prospectively vs. retrospectively collected information. Results: Although agreement was good for overall scores (m-VAS: 10.0%; SCOPA-DC: 18.3%), and for single motor symptoms (involuntary movements, hand dexterity, walking, changing position; each <20%), some individuals with more advanced disease, higher fatigue or worse sleep quality showed poor symptom recall in retrospect. Moreover, a subgroup of patients (16.7%) either over- or underestimated symptom severity. Conclusions: Regular, prospective monitoring of motor symptoms is suitable in PD patients. SleepFit might be a useful tool in routine practice to identify patients tending to under- or overestimate their symptoms, and for their follow-up. Show more

Keywords: Parkinson disease, ecological momentary assessment, self report, symptom assessment, software

DOI: 10.3233/JPD-191662

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Baille, Guillaume | Perez, Thierry | Devos, David | Machuron, François | Dujardin, Kathy | Chenivesse, Cécile | Defebvre, Luc | Moreau, Caroline

Article Type: Research Article

Abstract: Background: Dyspnea is a multidimensional sensation that is reported in Parkinson’s disease (PD). The multidimensional dyspnea profile (MDP) questionnaire can help to distinguish the perceptive dimension and the emotion response. Objective: The aim was to assess the clinical features associated with dyspnea using the MDP questionnaire in order to determine which aspects of the symptom was linked with anxiety, depression or motor severity of the disease. Methods: Non-demented patients were asked whether they experienced shortness of breath in the last month. In case of positive answer, dyspnea was assessed by the MDP. MDS-UPDRS, global cognitive performance, …non-motor symptoms and quality of life were assessed. Results: 60/163 patients were dyspneic since 4.6±2.4 years. The most frequent best sensory quality (SQ) described were: hyperpnoea (35% ), physical breathing effort (25% ) and air hunger (20% ). Hyperpnoea and air hunger had the highest SQ intensity. Anxiety had the highest intensity in the emotional domain. Conclusion: Dyspnea is a frequent symptom in PD, with specific presentations and two main aspects: one related with anxiety and another with ventilation control impairment. Show more

Keywords: Parkinson’s disease, dyspnea, non-motor symptom, anxiety, ventilatory dysfunction

DOI: 10.3233/JPD-191713

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

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. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Tang, Peng | Hou, Chen | Liu, Yue | Liu, Peng | Zhang, Xin | Zhang, Lina | Chong, Li | Li, Rui

Article Type: Research Article

Abstract: Background/Objective: Easily applicable, quantitative assessment of movement is widely needed in various clinical settings, especially in the evaluation of Parkinson’s disease (PD). Methods: We developed a highly repeatable tablet computer-based finger movement assessment system (FMAS) to record finger movement profile in a visual-motor task both in PD (n  = 217) and healthy participants (n  = 221). Results: We found age-related declines in finger movement performance among the healthy participants but not in PD patients with the FMAS. Significant differences in movement time (MT) and latency/MT ratio but not in latency were observed in PD patients as compared with …healthy subjects (P  < 0.000). Meanwhile, we identified the latency/MT ratio as the optimal parameter to differentiate PD from age-matched healthy subjects in an age-independent manner (cut-off 1.08 with corresponding AUC = 0.861). In addition, a significant correlation was found between finger movement parameters and the Hoehn and Yahr scale (H-Y scale), UPDRS III score and the duration of the disease in PD patients (P  < 0.01). Conclusion: It was suggested that the tablet computer-based evaluation of finger movement provided an easily applicable quantitative method to assess the conditions of PD patients. Show more

Keywords: Parkinson’s disease, hypokinesia, finger movement profile, visual motor task, quantitative assessment

DOI: 10.3233/JPD-191695

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 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. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-15, 2019

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

Article Type: Review 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. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Houghton, Richard | Boess, Frank | Verselis, Lynne | Ding, Yingjie | Freitas, Rita | Constantinovici, Niculae | Ong, Rose

Article Type: Research Article

Abstract: Background: Treatment patterns in Parkinson’s disease (PD) have not been extensively studied for nearly two decades. Insurance claims are appropriate for such analysis. Objective: To understand the standard of care use of symptomatic treatments in new cases of PD and factors associated with treatment choice. Methods: Retrospective cohort study using claims data from the United States between 2008 and 2016. We used Kaplan–Meier methodology to estimate time to treatment start and switch or add-on therapy and Cox proportional hazards models to identify predictors. Results: We identified 68,532 patients eligible for treatment pattern analyses. Median …time from diagnosis until first treatment was 37 days (95% confidence interval: 36–38). Two distinct patterns of treatment initiation were identified: fast initiators and patients with delayed treatment start (or no recorded treatment). Levodopa therapies were the most commonly prescribed treatment class (52.6%). Increased age was associated with shorter time to start of treatment with levodopa. Younger age was associated with shorter time to initiation of dopamine agonists and other symptomatic treatments. Patients that initiated treatment with levodopa/combinations had the fewest switches/add-ons [30.4%; median time 7.29 (6.71, 8.13) years]. Older patients had fewer switch/add-on therapies, but only in the group that started with levodopa/combination therapy. Conclusions: Time from diagnosis to treatment start was relatively short, suggesting that PD diagnosis, as reflected in the database, is closely linked to start of symptomatic treatment. Levodopa treatment remains the most common treatment, especially for older patients. Delayed treatment start was associated with increased age and comorbidity. Show more

Keywords: Charlson comorbidities, claims data, Parkinson’s disease, treatment patterns, United States

DOI: 10.3233/JPD-191636

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Marxreiter, Franz | Buttler, Ulrike | Gassner, Heiko | Gandor, Florin | Gladow, Till | Winkler, Jürgen | Ebersbach, Georg | Klucken, Jochen

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is an age dependent neurodegenerative disorder with increasing prevalence. Digital technologies like computers and smartphones offer mobile telecommunication, diagnostic and monitoring and may connect the patient continuously with his healthcare team, providing disease related information, and support healthcare. Since the use of these technologies in western civilization is age dependent, possession and usage cannot be regarded as given in PD. In contrast to increasing efforts to implement digital technology into PD patient care, little is known about the use of computers, smartphones, and internet-affinity in PD patients. Objective: We evaluated the use of digital …technologies in different age groups of PD patients. Methods: We developed a questionnaire adapted to the annual German microcensus on “use of digital communication technologies”, allowing a comparison to the general population in Germany. Results: 190 PD patients completed the questionnaire. About 75% of PD patients access disease related information on the internet. Patients across all age groups used computers and the internet as frequent or more frequently compared to the German population. Use of computers, smartphones, and the internet in PD was age dependent. Advanced PD patients with higher motor impairment used smartphones less often, while mobile phone usage was not reduced. Conclusion: The adoption of a digital lifestyle is present in the PD population, apart from smartphone usage, which is impaired by motor symptoms. Thus, future healthcare technologies are not hampered by the inability of PD patients to use the necessary tools, however, fine motor-skill requirements have to be acknowledged. Show more

Keywords: Smartphones, digital media, Parkinson’s disease, movement disorder, digital healthcare

DOI: 10.3233/JPD-191698

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-12, 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. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Jeziorska, Maria | Atkinson, Andrew | Kass-Iliyya, Lewis | Kobylecki, Christopher | Gosal, David | Marshall, Andrew | Malik, Rayaz A. | Silverdale, Monty

Article Type: Short Communication

Abstract: We assessed small nerve fibre degeneration and regeneration in more and less affected sides in Parkinson’s disease (PD). Bilateral skin biopsies from 23 PD patients were immunostained for PGP9.5 for Intraepidermal Nerve Fibre Density (IENFD) and GAP-43 for mean axonal length (MAL), total epidermal (TNFL) and subepidermal nerve fibre length (SKTNFL). IENFD (p  < 0.001) and SKTNFL (p  < 0.001) were lower, whilst MAL (p  < 0.001) and TNFL (p  < 0.05) were higher in more affected versus less affected side. These results suggest increased small nerve fibre degeneration accompanied by enhanced nerve regeneration on the side more affected by PD and GAP-43 usefulness …in skin biopsy assessment. Show more

Keywords: Parkinson’s disease, peripheral neuropathy, intraepidermal nerve fibre

DOI: 10.3233/JPD-191697

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Article Type: Correction

DOI: 10.3233/JPD-189001

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2018