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

Authors: van Wamelen, Daniel J. | Taddei, Raquel N. | Calvano, Alexander | Titova, Nataliya | Leta, Valentina | Shtuchniy, Igor | Jenner, Peter | Martinez-Martin, Pablo | Katunina, Elena | Chaudhuri, K. Ray

Article Type: Research Article

Abstract: Background: Previous studies have identified low serum uric acid (SUA) levels as a risk factor for the development of Parkinson’s disease (PD). Prodromal PD mainly manifests as a complex of non-motor features, but the association between SUA levels and nonmotor symptoms (NMS) burden level in advanced PD patients is poorly studied. Objective: To determine the association between SUA levels and NMS in PD patients. Methods: Data were gathered from an open label, cross sectional, study with analysis of SUA levels in 87 PD patients and were correlated to NMS through the NMS scale (NMSS). In addition, …we examined the possible relation between SUA and NMS burden levels and motor scores. Results: There was a moderate negative association between SUA levels and NMSS total score (ρ = –0.379, p  < 0.001). In line with this, we observed that higher NMS burden was associated with lower SUA levels (p  < 0.001). Within individual NMSS domains, a moderate negative correlation was observed between SUA levels and the cardiovascular/falls (ρ = –0.285, p  = 0.008), sleep/fatigue (ρ = –0.299, p  = 0.005), and miscellaneous domains (ρ = –0.318, p  = 0.003). Conclusion: In this observational study we observed that SUA levels were negatively associated to NMS burden in PD patients with a specific link to miscellaneous, sleep/fatigue and cardiovascular domains of the NMSS. Interestingly, we did not find a clear relation between SUA and motor scores. Future large-scale prospective studies in de novo and advanced PD are needed to evaluate and establish these associations. Show more

Keywords: Parkinson’s disease, biomarker, uric acid, non-motor symptoms

DOI: 10.3233/JPD-201988

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Nam, Daleum | Lee, Jee-Young | Lee, Minhyung | Kim, Janghwan | Seol, Wongi | Son, Ilhong | Ho, Dong Hwan

Article Type: Research Article

Abstract: Background: α -Synuclein (α -syn) is a major component of Lewy bodies, a pathologic marker of Parkinson’s disease (PD) in post-mortem studies. The use of α -syn as a practical PD biomarker has been investigated by numerous researchers. However, reports of differences in α -syn levels in bio fluids, such as cerebrospinal fluid, plasma, and saliva, between PD patients and controls are inconsistent. Recently, the measurement of α -syn oligomer levels has emerged as a novel approach to diagnose PD. Objective: Ly sates and culture media from two different types of dopaminergic neuronal cells or urine samples from …11 non-PD and 21 PD patients were collected and analyzed. Methods: We developed and performed an enzyme-linked immuno-absorbent assay (ELISA) to detect various oligomeric α -syn using distinct pairs of antibodies. Results: We validated our ELISA using rotenone-induced alterations of α -syn levels in human dopaminergic neurons. Total urinary α -syn levels, measured using our ELISA method, showed no difference between PD and non-PD individuals, but a higher level of α -syn oligomer recognized by MJFR-14-6-5-2 in PD urine samples was observed. Levels of distinct oligomeric α -syn detected by ASyO5 were lower in PD urine samples. Three different α -syn ELISA results were analyzed with respect to the severity of PD, but only the correlation between total α -syn levels and PD index was significant. Conclusion: Our findings suggest that detection of distinct oligomeric formations of α -syn and measurement of their levels in urine might be feasible for use in PD diagnostics. Show more

Keywords: Parkinson’s disease, α-Synuclein, ELISA, urine

DOI: 10.3233/JPD-201983

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Dorsey, E. Ray | Omberg, Larsson | Waddell, Emma | Adams, Jamie L. | Adams, Roy | Ali, Mohammad Rafayet | Amodeo, Katherine | Arky, Abigail | Augustine, Erika F. | Dinesh, Karthik | Hoque, Mohammed Ehsan | Glidden, Alistair M. | Jensen-Roberts, Stella | Kabelac, Zachary | Katabi, Dina | Kieburtz, Karl | Kinel, Daniel R. | Little, Max A. | Lizarraga, Karlo J. | Myers, Taylor | Riggare, Sara | Rosero, Spencer Z. | Saria, Suchi | Schifitto, Giovanni | Schneider, Ruth B. | Sharma, Gaurav | Shoulson, Ira | Stevenson, E. Anna | Tarolli, Christopher G. | Luo, Jiebo | McDermott, Michael P.

Article Type: Review Article

Abstract: Phenotype is the set of observable traits of an organism or condition. While advances in genetics, imaging, and molecular biology have improved our understanding of the underlying biology of Parkinson’s disease (PD), clinical phenotyping of PD still relies primarily on history and physical examination. These subjective, episodic, categorical assessments are valuable for diagnosis and care but have created gaps in our understanding of the PD phenotype. Sensors can provide objective, continuous, real-world data about the PD clinical phenotype, increase our knowledge of its pathology, enhance evaluation of therapies, and ultimately, improve patient care. In this paper, we explore the concept …of deep phenotyping—the comprehensive assessment of a condition using multiple clinical, biological, genetic, imaging, and sensor-based tools—for PD. We discuss the rationale for, outline current approaches to, identify benefits and limitations of, and consider future directions for deep clinical phenotyping. Show more

Keywords: Autonomic nervous system, gait, natural history, observational study, Parkinson’s disease, phenotype, real-world data, sleep, smartphone, social behavior

DOI: 10.3233/JPD-202006

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2020

Authors: Su, Fang-Te | Tai, Chun-Hwei | Tan, Chun-Hsiang | Hwang, Wen-Juh | Yu, Rwei-Ling

Article Type: Research Article

Abstract: Background: Social functioning is crucial for the determinants of Parkinson’s disease (PD) with dementia; however, there is no social functioning scale applicable to PD. Objective: This study aimed to develop a social functioning scale specific to PD (PDSFS) and provide a cut-off score to improve diagnosis accuracy. Methods: The items were developed through literature, interview patients, and PD expertise. After the pilot study, one hundred fifty-seven patients and 74 healthy participants were enrolled and completed the Mini-Mental State Examination, Clock Drawing Test, Activities of Daily Living, Neuropsychiatric Inventory, Adaptive Behavior Assessment System–Second Edition (ABAS–II) and part …III of the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS–UPDRS). Results: The final PDSFS has 23 items. The exploratory factor analysis revealed three factors, including “Family Life, Hobbies and Self-Care”, “Interpersonal Relationship and Recreational Leisure”, and “Social Bond”. The internal consistency coefficient was 0.883, and the test-retest reliability was 0.774, respectively. The total score of the PDSFS was significantly related to the total score of ABAS–II (r  = 0.609, p  < 0.001), and was not correlated with the third part of MDS–UPDRS (p  = 0.736). A significant intergroup difference was found (p  < 0.001), and the healthy controls had the highest PDSFS score, followed by non-demented PD and PD dementia. The optimal cut-off score for PD patients with dementia was 39 (sensitivity: 0.735; specificity: 0.857). Conclusions: PDSFS is a practical and psychometrically sound tool to access the social functioning of the PD population. Show more

Keywords: Parkinson’s disease, cognitive impairment, social functioning, inventory, reliability, validity

DOI: 10.3233/JPD-201930

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Radder, Danique L.M. | Nonnekes, Jorik | van Nimwegen, Marlies | Eggers, Carsten | Abbruzzese, Giovanni | Alves, Guido | Browner, Nina | Chaudhuri, K. Ray | Ebersbach, Georg | Ferreira, Joaquim J. | Fleisher, Jori E. | Fletcher, Peter | Frazzitta, Giuseppe | Giladi, Nir | Guttman, Mark | Iansek, Robert | Khandhar, Suketu | Klucken, Jochen | Lafontaine, Anne-Louise | Marras, Connie | Nutt, John | Okun, Michael S. | Parashos, Sotirios A. | Munneke, Marten | Bloem, Bastiaan R.

Article Type: Research Article

Abstract: Background: Optimal management in expert centers for Parkinson’s disease (PD) usually involves pharmacological and non-pharmacological interventions, delivered by a multidisciplinary approach. However, there is no guideline specifying how this model should be organized. Consequently, the nature of multidisciplinary care varies widely. Objective: To optimize care delivery, we aimed to provide recommendations for the organization of multidisciplinary care in PD. Methods: Twenty expert centers in the field of multidisciplinary PD care participated. Their leading neurologists completed a survey covering eight themes: elements of optimal multidisciplinary care; team members; role of patients and care partners; team coordination; team …meetings; inpatient versus outpatient care; telehealth; and challenges towards multidisciplinary care. During a consensus meeting, outcomes were incorporated into concept recommendations that were reviewed by each center’s multidisciplinary team. Three patient organizations ranked the recommendations according to patient priorities. Based on this feedback, a final set of recommendations (essential elements for delivery of multidisciplinary care) and considerations (desirable elements) was developed. Results: We developed 30 recommendations and 10 considerations. The patient organizations rated the following recommendations as most important: care is organized in a patient-centered way; every newly diagnosed patient has access to a core multidisciplinary team; and each team has a coordinator. A checklist was created to further facilitate its implementation. Conclusion: We provide a practical tool to improve multidisciplinary care for persons with PD at the organizational level. Future studies should focus on implementing these recommendations in clinical practice, evaluating their potential applicability and effectiveness, and comparing alternative models of PD care. Show more

Keywords: Parkinson’s disease, multidisciplinary, interdisciplinary, organization of care, guideline, practice-based evidence

DOI: 10.3233/JPD-202078

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Zhao, Aonan | Li, Yuanyuan | Niu, Mengyue | Li, Guanglu | Luo, Ningdi | Zhou, Liche | Kang, Wenyan | Liu, Jun

Article Type: Research Article

Abstract: Background: α -Synuclein has been related to the pathogenesis of Parkinson’s disease (PD), but it has not thoroughly been investigated in idiopathic rapid eye movement sleep behavior disorder (iRBD). Objective: We aimed to explore whether there were different distributions of α -synuclein at a genetic and/or protein level in patients with iRBD. Methods: We included 30 patients with iRBD, 30 patients with PD, and 30 age- and sex-matched healthy controls (HCs) in this study. The SNCA methylation and mRNA levels were determined using bisulfite sequencing and quantitative reverse transcription polymerase chain reaction. The plasma levels …of exosome α -synuclein were measured using Meso Scale Discovery. Results: SNCA methylation showed different distribution among HC, iRBD and PD groups (HC vs RBD: p  = 0.011; HC vs PD: p  < 0.001; RBD vs PD: p  = 0.027). However, plasma exosomal α -synuclein levels were only elevated in patients with PD compared to those in HCs (p  = 0.027), and were associated with the SNCA methylation only in the PD group (p  = 0.030, r = –0.397). Conclusion: SNCA hypomethylation in leukocytes existed both in patients with iRBD and those with PD, indicating that SNCA methylation could be a potential biomarker for early PD diagnosis. Show more

Keywords: Parkinson’s disease, SNCA hypomethylation, exosome, biomarker

DOI: 10.3233/JPD-201912

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Boussac, Mathilde | Arbus, Christophe | Dupouy, Julia | Harroch, Estelle | Rousseau, Vanessa | Ory-Magne, Fabienne | Rascol, Olivier | Moreau, Caroline | Maltête, David | Rouaud, Tiphaine | Meyer, Mylène | Houvenaghel, Jean Francois | Marsé, Claire | Tranchant, Christine | Hainque, Elodie | Jarraya, Béchir | Ansquer, Solène | Bonnet, Marie | Belamri, Lhaouas | Tir, Mélissa | Marques, Ana-Raquel | Danaila, Teodor | Eusebio, Alexandre | Devos, David | Brefel-Courbon, Christine | for the PREDI-STIM study group

Article Type: Research Article

Abstract: Abstract. Background: Parkinson’s disease (PD) negatively affects patients’ Quality of Life (QoL) which depends on both objective criteria such as physical health and subjective ones such as worries and norms according to personal believes. Therefore, QoL could be also associated to personality dimensions in chronic neurological diseases such as PD. Objective: Our objective was thus to study the potential association between personality dimensions and QoL in PD patients with motor fluctuations before Deep Brain Stimulation of the Sub-Thalamic Nucleus (DBS-STN). Methods: Data were obtained from the French multicentric cohort study Predi-Stim. All PD patients awaiting DBS-STN …and responding to the inclusion criteria at the time of the study were included. All participants answered the “Temperament and Character Inventory” (TCI) and the PDQ-39 before surgery. Analyses were made using adjusted univariate generalized linear regression models to evaluate a potential association between TCI dimensions and PDQ-39 scores. Results: Three hundred thirty-three consecutive patients were included. The temperament Harm Avoidance was negatively associated with QoL (p  = 1e-4, R2 = 0.33), whereas the character Self-Directedness was positively associated with mental component of QoL (p  = 2e-4, R2 = 0.33) in PD patients with motor fluctuations awaiting DBS-STN. Conclusions: PD patients with motor fluctuations, with lower Harm Avoidance and higher Self-Directedness scores have the best QoL mainly at an emotional and social level. Therapeutic education of these PD patients focusing on their personal resources may thus be important to improve their well-being. Show more

Keywords: Character, Parkinson’s disease, personality, quality of life, temperament

DOI: 10.3233/JPD-191903

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Fedorova, Tatyana D. | Knudsen, Karoline | Sommerauer, Michael | Svendsen, Kristina B. | Otto, Marit | Borghammer, Per

Article Type: Short Communication

Abstract: Isolated REM sleep behaviour disorder (iRBD) is a predictive marker of prodromal Lewy body disease. iRBD prevalence in the general population is around 1%, but it remains under-diagnosed, even though symptoms are alleviated by medication. We developed a population screening strategy and identified 16 iRBD patients by conducting telephone interviews and polysomnography examinations. We compared our population-screened cohort with sleep-center referred patients and found higher MoCA scores and lower MDS-UPDRS-III scores in our patients. In conclusion, screening can be used to identify iRBD patients in a cost-effective manner with the benefit of identifying patients at a very early disease stage.

Keywords: REM sleep behavior disorder, Lewy body disease, Parkinson’s disease, screening, polysomnography

DOI: 10.3233/JPD-202020

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2020

Authors: Javidnia, Monica | Shoulson, Ira | Kieburtz, Karl | Venuto, Charles

Article Type: Short Communication

Abstract: Parkinson’s disease (PD) patients experience a range of non-motor symptoms that are believed to be related to disease pathophysiology, many of which are treatable by medications. Among newly-diagnosed PD participants in the Parkinson’s Progression Markers Initiative study, we describe (1) the frequency of medication use for common non-motor symptoms, and (2) when non-motor symptomatic treatment was initiated relative to PD diagnosis. Non-motor medication use was reported by 73% of participants, most commonly for depression, constipation, and anxiety. Treatment of some non-motor symptoms, notably depression, antedated diagnosis. These data may be useful for studies of non-motor symptoms in PD.

Keywords: Non-motor symptoms, pharmacotherapies, anxiety, depression, sleep

DOI: 10.3233/JPD-201973

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2020

Authors: Cubo, Esther | Hassan, Anhar | Bloem, Bas R. | Mari, Zoltan | on behalf of the MDS-Telemedicine Study Group

Article Type: Editorial

DOI: 10.3233/JPD-202108

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2020

Authors: Bouça-Machado, Raquel | Jalles, Constança | Guerreiro, Daniela | Pona-Ferreira, Filipa | Branco, Diogo | Guerreiro, Tiago | Matias, Ricardo | Ferreira, Joaquim J.

Article Type: Review Article

Abstract: Background: Gait impairments are common and highly disabling for Parkinson’s disease (PD) patients. With the development of technology-based tools, it is now possible to measure the spatiotemporal parameters of gait with a reduced margin of error, thereby enabling a more accurate characterization of impairment. Objective: To summarize and critically appraise the characteristics of technology-based gait analysis in PD and to provide mean and standard deviation values for spatiotemporal gait parameters. Methods: A systematic review was conducted using the databases CENTRAL, MEDLINE, Embase, and PEDro from their inception to September 2019 to identify all observational and experimental …studies conducted in PD or atypical parkinsonism that included a technology-based gait assessment. Two reviewers independently screened citations and extracted data. Results: We included 95 studies, 82.1% (n  = 78) reporting a laboratory gait assessment and 61.1% (n  = 58 studies) using a wearable sensor. The most frequently reported parameters were gait velocity, stride and step length, and cadence. A statistically significant difference was found when comparing the mean values of each of these parameters in PD patients versus healthy controls. No statistically significant differences were found in the mean value of the parameters when comparing wearable versus non-wearable sensors, different types of wearable sensors, and different sensor locations. Conclusion: Our results provide useful information for performing objective technology-based gait assessment in PD, as well as mean values to better interpret the results. Further studies should explore the clinical meaningfulness of each parameter and how they behave in a free-living context and throughout disease progression. Show more

Keywords: Parkinson’s disease, gait, objective assessment, technology, wearable sensor

DOI: 10.3233/JPD-201969

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Nonnekes, Jorik | Bloem, Bastiaan R.

Article Type: Short Communication

Abstract:  The relation between freezing of gait in Parkinson’s disease and levodopa is complex. Here, we describe a new phenotype of freezing of gait, namely levodopa-induced freezing of gait with a biphasic pattern. Our observation supports the idea that freezing of gait might emerge because of a mismatch between cognitive/limbic loops and motor loops involved in gait control. Moreover, it underscores the importance of assessing the influence of dopaminergic medication in daily clinical practice, including objective assessment in all three dopaminergic states. The possibility of biphasic freezing will only emerge after such a comprehensive evaluation, and will have immediate therapeutic consequences.

Keywords: Gait, freezing of gait, levodopa, Parkinson’s disease, parkinsonism, biphasic

DOI: 10.3233/JPD-201997

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2020

Authors: Shah, Vrutangkumar V. | McNames, James | Mancini, Martina | Carlson-Kuhta, Patricia | Nutt, John G. | El-Gohary, Mahmoud | Lapidus, Jodi A. | Horak, Fay B. | Curtze, Carolin

Article Type: Research Article

Abstract: Background: Identifying digital biomarkers of mobility is important for clinical trials in Parkinson’s disease (PD). Objective: To determine which digital outcome measures of mobility discriminate mobility in people with PD from healthy control (HC) subjects over a week of continuous monitoring. Methods: We recruited 29 people with PD, and 27 age-matched HC subjects. Subjects were asked to wear three inertial sensors (Opal by APDM) attached to both feet and to the lumbar region, and a subset of subjects also wore two wrist sensors, for a week of continuous monitoring. We derived 43 digital outcome measures of …mobility grouped into five domains. An Area Under Curve (AUC) was calculated for each digital outcome measures of mobility, and logistic regression employing a ‘best subsets selection strategy’ was used to find combinations of measures that discriminated mobility in PD from HC. Results: Duration of recordings was 66±14 hours in the PD and 59±16 hours in the HC. Out of a total of 43 digital outcome measures of mobility, we found six digital outcome measures of mobility with AUC > 0.80. Turn angle (AUC = 0.89, 95% CI: 0.79–0.97) and swing time variability (AUC = 0.87, 95% CI: 0.75–0.96) were the most discriminative individual measures. Turning measures were most consistently selected via the best subsets strategy to discriminate people with PD from HC, followed by gait variability measures. Conclusion: Clinical studies and clinical practice with digital biomarkers of daily life mobility in PD should include turning and variability measures. Show more

Keywords: Parkinson’s disease, digital outcome measures of mobility, inertial sensors, biomarkers, continuous monitoring

DOI: 10.3233/JPD-201914

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Victorino, Daniella Balduino | Guimarães-Marques, Marcia | Nejm, Mariana | Scorza, Fulvio Alexandre | Scorza, Carla Alessandra

Article Type: Article Commentary

DOI: 10.3233/JPD-202073

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2020

Authors: Alarcón, Fernando | Maldonado, Juan-Carlos | Cañizares, Miguel | Molina, José | Noyce, Alastair | Lees, Andrew J.

Article Type: Research Article

Abstract: Background: Recognition of motor signs in the prodromal stage could lead to best identify populations at risk for developing Parkinson’s disease (PD). Objective: This study identified motor symptoms and signs in individuals suspected of having PD but who did not have a progressive reduction in the speed and amplitude of finger tapping or other physical signs indicative of bradykinesia. Methods: 146 patients, who had symptoms or signs suggestive of PD, were serially evaluated by a movement disorder specialist, using the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III and video recordings. If the …patients ‘converted’ to PD during follow-up, they were categorized as cases and compared with those who did not meet PD criteria during follow-up (non-cases). Results: The 82 cases were more likely to have action dystonia or postural/action/rest tremor of a limb (OR 2.8; 95% CI 1.10–7.09; p  = 0.02), a reduced blink rate at rest (OR 2.32; 95% CI 1.18–4.55; p  = 0.01), anxiety (OR 8.91; 95% CI 2.55–31.1; p  <  0.001), depression (OR 7.03; 95% CI 2.86–17.2; p  <  0.001), or a frozen shoulder (OR 3.14; 95% CI 1.58–6.21) than the 64 ’non-cases’. A reduction of the fast blink rate was common in patients who met the criteria for PD (p  <  0.001). Conclusions: This study emphasizes that motor dysfunction is a component of the clinical prodrome seen in some patients with PD. Show more

Keywords: Parkinson’s disease, prodrome, motor dysfunction

DOI: 10.3233/JPD-191851

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Vorderwülbecke, Bernd J. | Lehmann, Rebekka | Breuer, Eva

Article Type: Short Communication

Abstract: REM sleep behavior disorder (RBD) might render patients with Parkinson’s disease prone to sleep-disordered breathing. This retrospective polysomonographic study assessed the prevalence of sleep-disordered breathing in 108 consecutive patients with either both Parkinson’s disease and RBD (n  = 37), Parkinson’s disease without RBD (n  = 21), or isolated RBD (n  = 50). Across all patients, 25% had at least moderate sleep-related breathing disorder, without significant differences between groups. Following multivariable analysis, RBD influenced sleep-related breathing parameters modestly but not significantly, whereas body mass index had a prominent impact. Further studies with larger patient cohorts are needed, and confounders like body mass index must …adequately be controlled for. Show more

Keywords: Body mass index, Parkinson’s disease, REM sleep behavior disorder, sleep apnea syndromes

DOI: 10.3233/JPD-201996

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2020

Authors: Cheong, Julia L.Y. | de Pablo-Fernandez, Eduardo | Foltynie, Thomas | Noyce, Alastair J.

Article Type: Review Article

Abstract: In recent years, an emerging body of evidence has forged links between Parkinson’s disease (PD) and type 2 diabetes mellitus (T2DM). In observational studies, those with T2DM appear to be at increased risk of developing PD, as well as experiencing faster progression and a more severe phenotype of PD, with the effects being potentially mediated by several common cellular pathways. The insulin signalling pathway, for example, may be responsible for neurodegeneration via affecting insulin dysregulation, aggregation of amyloids, neuroinflammation, mitochondrial dysfunction and altered synaptic plasticity. In light of these potential shared disease mechanisms, clinical trials are now investigating the use …of established diabetes drugs targeting insulin resistance in the management of PD. This review will discuss the epidemiological links between T2DM and PD, the potential shared cellular mechanisms, and assess the relevant treatment options for disease modification of PD. Show more

Keywords: Parkinson’s disease, type 2 diabetes mellitus, epidemiology, therapeutics, mechanisms

DOI: 10.3233/JPD-191900

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Miocinovic, Svjetlana | Ostrem, Jill L. | Okun, Michael S. | Bullinger, Katie L. | Riva-Posse, Patricio | Gross, Robert E. | Buetefisch, Cathrin M.

Article Type: Article Commentary

Abstract: Most medical centers are postponing elective procedures and deferring non-urgent clinic visits to conserve hospital resources and prevent spread of COVID-19. The pandemic crisis presents some unique challenges for patients currently being treated with deep brain stimulation (DBS). Movement disorder (Parkinson’s disease, essential tremor, dystonia), neuropsychiatric disorder (obsessive compulsive disorder, Tourette syndrome, depression), and epilepsy patients can develop varying degrees of symptom worsening from interruption of therapy due to neurostimulator battery reaching end of life, device malfunction or infection. Urgent intervention to maintain or restore stimulation may be required for patients with Parkinson’s disease who can develop a rare but …potentially life-threatening complication known as DBS-withdrawal syndrome. Similarly, patients with generalized dystonia can develop status dystonicus, patients with obsessive compulsive disorder can become suicidal, and epilepsy patients can experience potentially life-threatening worsening of seizures as a result of therapy cessation. DBS system infection can require urgent, and rarely emergent surgery. Elective interventions including new implantations and initial programming should be postponed. For patients with existing DBS systems, the battery status and electrical integrity interrogation can now be performed using patient programmers, and employed through telemedicine visits or by phone consultations. The decision for replacement of the implantable pulse generator to prevent interruption of DBS therapy should be made on a case-by-case basis taking into consideration battery status and a patient’s tolerance to potential therapy disruption. Scheduling of the procedures, however, depends heavily on the hospital system regulations and on triage procedures with respect to safety and resource utilization during the health crisis. Show more

Keywords: COVID-19, coronavirus, battery depletion, telemedicine, DBS withdrawal

DOI: 10.3233/JPD-202072

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Kane, Patrick Bodilly | Benjamin, Daniel M. | Barker, Roger A. | Lang, Anthony E. | Sherer, Todd | Kimmelman, Jonathan

Article Type: Research Article

Abstract: Background: Projections about when research milestones will be attained are often of interest to patients and can help inform decisions about research funding and health system planning. Objective: To collect aggregated expert forecasts on the attainment of 11 major research milestones in Parkinson’s disease (PD). Methods: Experts were asked to provide predictions about the attainment of 11 milestones in PD research in an online survey. PD experts were identified from: 1) The Michael J. Fox Foundation for Parkinson’s Research data base, 2) doctors specializing in PD at the ranked neurology centers in the US and Canada, …and 3) corresponding authors of articles on PD in top medical journals. Judgments were aggregated using coherence weighting. We tested the relationship between demographic variables and individual judgments using a linear regression. Results: 249 PD experts completed the survey. In the aggregate, experts believed that new treatments like gene therapy for monogenic PD, immunotherapy and cell therapy had 56.1%, 59.7%, and 66.6% probability, respectively of progressing in the clinical approval process within the next 10 years. Milestones involving existing management approaches, like the approval of a deep brain stimulation device or a body worn sensor had 78.4% and 82.2% probability of occurring within the next 10 years. Demographic factors were unable to explain deviations from the aggregate forecast (R2  = 0.029). Conclusions: Aggregated expert opinion suggests that milestones for the advancement of new treatment options for PD are still many years away. However, other improvements in PD diagnosis and management are believed to be near at hand. Show more

Keywords: Parkinson’s disease, prediction, forecasting

DOI: 10.3233/JPD-201933

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Bailey, Meagan | Anderson, Sharlet | Hall, Deborah A.

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disease, though evidence suggests that this disorder does not affect all racial groups similarly. Research in African Americans, in particular, has been conflicting. Some studies have found similar prevalence rates in African Americans and whites whereas other studies have found much lower prevalence and incidence rates in African Americans. A few studies identify potential factors underlying these discrepancies, including biologic differences as well as disparities in healthcare access. However, African Americans remain underrepresented in research studies, which make understanding the underlying reasons for these differences difficult. The purpose of this paper …is to summarize existing research in African Americans with PD, highlight some of the reasons why differences exist in diagnostic rates of PD in this population, and briefly discuss interventions that may need to be made in order to ensure adequate care is provided to these patients. Show more

Keywords: Parkinson’s disease, African Americans, healthcare disparities, epidemiology

DOI: 10.3233/JPD-191823

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Nguy, Vanessa | Barry, Benjamin K. | Moloney, Niamh | Hassett, Leanne M. | Canning, Colleen G. | Lewis, Simon J.G. | Allen, Natalie E.

Article Type: Research Article

Abstract: Background: Pain is common in Parkinson’s disease (PD). In general and chronic pain populations, physical inactivity, poor sleep, and anxiety are associated with worse pain. However, little is known about these potential predictors of pain in PD. Objective: This cross-sectional observational study investigated associations between measures of physical activity, sleep, and mood with pain in people with PD. Methods: Pain was measured using the King’s PD Pain Scale and the Brief Pain Inventory (pain severity and interference) in 52 participants with PD. Independent variables were categorised by demographics (age, gender), disease severity (MDS-UPDRS) and duration, central …sensitization (Central Sensitization Inventory), physical activity (Incidental and Planned Exercise Questionnaire), sleep (Pittsburgh Sleep Quality Index), and mood (Hospital Anxiety and Depression Scale). Results: Univariate regression analyses showed that increased disease severity, longer disease duration, greater central sensitization, increased physical activity, poor sleep, anxiety, and depression were associated with worse pain in one or more pain measures (p  < 0.05). Multivariate regression models accounted for 56% of the variance in the King’s Pain Scale, 25% pain severity and 36% in pain interference. Poor sleep independently contributed to worse pain scores in all models (β 0.3–0.4, p  < 0.05). Conclusion: Increased physical activity, poor sleep, anxiety, and depression are associated with worse pain scores in people with PD. For optimal management of pain in people with PD, sleep and mood may need to be addressed. Further, the nature of the relationship between physical activity and pain in PD requires further investigation. Show more

Keywords: Parkinson’s disease, pain, physical activity, sleep, depression, anxiety

DOI: 10.3233/JPD-201938

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Vilas, Dolores | Tolosa, Eduard | Quintana, María | Pont-Sunyer, Claustre | Santos, Meritxell | Casellas, Aina | Valldeoriola, Francesc | Compta, Yaroslau | Martí, María José | Mullol, Joaquim

Article Type: Research Article

Abstract: Background: Studies on olfaction in LRRK2 -associated Parkinson’s disease (LRRK2 -PD) have yielded variable results. The impact of smell dysfunction upon daily life activities have been rarely assessed in PD. Objective: To characterize the olfactory deficit in LRRK2 -PD and its impact on daily life activities. Methods: Twenty-four LRRK2 -PD, 40 idiopathic PD (IPD), and 49 age-sex-matched controls were interviewed about olfactory characteristics and the impact of smell on daily life activities. The Barcelona Smell Identification test (BAST-24) and the Spanish-version of the 40-item University of Pennsylvania smell test (UPSIT) were applied. Results: Nineteen …(79.2%) LRRK2 -PD patients reported subjective smell impairment with a low impact upon daily living activities. UPSIT score was higher in LRRK2- PD than in IPD (22.54±7.98 vs 18.84±6.03; p  = 0.042). All IPD and 95.8% LRRK2 -PD patients had hyposmia/anosmia, assessed by means of the UPSIT. No differences were found between LRRK2 -PD and IPD regarding smell detection, memory or forced-choice identification. Conclusion: Most LRRK2 -PD patients reported subjective smell impairment and presented hyposmia, according to validated smell tests, with a low impact of the smell dysfunction on daily life activities. Show more

Keywords: Parkinson’s disease, LRRK2, olfaction, hyposmia

DOI: 10.3233/JPD-201972

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: De Roy, Jessie | Postuma, Ronald B. | Brillon-Corbeil, Marina | Montplaisir, Jacques | Marchand, Daphné Génier | Escudier, Frédérique | Panisset, Michel | Chouinard, Sylvain | Gagnon, Jean-François

Article Type: Research Article

Abstract: Background: More than 75% of Parkinson’s disease (PD) patients will develop dementia. Previous studies on the cognitive predictors of dementia in PD had some methodological limitations and the cognitive tests identified as good predictors vary greatly. Objective: This prospective cohort study aims to identify the optimal cognitive predictors of dementia in PD using complementary statistical methods. Methods: Eighty PD patients without dementia underwent polysomnographic recording, a neurological examination, and a complete neuropsychological assessment at baseline. They were then followed for a mean of 4.3 years. Baseline group comparisons and survival analyses were used to identify optimal …cognitive predictors. Moreover, patients who developed dementia were pair-matched at baseline according to age, sex, and education to healthy controls (2 : 1), and receiver operating characteristic curves were calculated for cognitive tests. Results: At follow-up, 23 patients (29%) developed dementia. PD patients who developed dementia had poorer baseline performance and a higher proportion of clinically impaired performance on several cognitive tests. Impaired baseline performance on the Block Design subtest was the best independent predictor of dementia (HR = 8). Moreover, the Trail Making Test part B (time) and Verbal Fluency (semantic) had the best psychometric properties (area under the curve >0.90) for identifying PD patients at risk of dementia. Conclusion: The present study identified three cognitive tests as the most accurate to detect individuals with PD at high risk of developing dementia. Show more

Keywords: Cognitive tests, dementia, neuropsychology, Parkinson’s disease, parkinsonism

DOI: 10.3233/JPD-191857

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Aye, Yin Minn | Liew, Gerald M. | Ng, Samuel Y.E. | Wen, Ming-Ching | Lim, Linda L.H. | Chua, Shu-Ting | Chotphoksap, Usanee | Chao, Yinxia | Ng, Adeline S.Y. | Tan, Eng King | Tan, Louis Chew Seng | Xu, Zheyu

Article Type: Research Article

Abstract: Background: Mild parkinsonian signs (MPS) are common in the older adult and associated with a wide range of adverse health outcomes. There is limited data on the prevalence of MPS and its significance. Objective: To determine the prevalence of MPS in the community ambulant population and to evaluate the relationship of MPS with prodromal features of Parkinson’s disease (PD) and cognition. Methods: This cross-sectional community-based study involved participants aged ≥50 years. Parkinsonian signs were assessed using the modified Unified Parkinson’s Disease Rating Scale (mUPDRS) and cognition using the Montreal Cognitive Assessment (MoCA). Premotor symptoms of PD …were screened using a self-reported questionnaire. Linear regression was used to assess the association of MPS with premotor symptoms of PD and cognitive impairment. Results: Of 392 eligible participants, MPS was present in 105 (26.8%). Mean age of participants with MPS was 68.8±6.9 years and without MPS was 66.1±5.9 years (p  < 0.001). Multivariate analysis revealed that MoCA scores were significantly lower in the MPS group (β= –0.152, 95% CI = –0.009, –0.138, p  < 0.05). A significant correlation between the presence of REM sleep behavior disorder (RBD) and total MPS scores (β= 0.107, 95% CI = 0.053, 1.490, p  < 0.05) was also found. Neither vascular risk factors nor other premotor symptoms were significantly associated with MPS. Conclusion: MPS is common and closely related to cognitive impairment and increasing age. Presence of RBD is predictive of higher MPS scores. This study highlights the necessity of other investigations or sensitive risk markers to identify subjects at future risk of PD. Show more

Keywords: Mild parkinsonian signs, REM sleep behavior disorder (RBD), premotor symptoms

DOI: 10.3233/JPD-191849

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Yahalom, Gilad | Rigbi, Amihai | Israeli-Korn, Simon | Krohn, Lynne | Rudakou, Uladzislau | Ruskey, Jennifer A. | Benshimol, Lior | Tsafnat, Tal | Gan-Or, Ziv | Hassin-Baer, Sharon | Greenbaum, Lior

Article Type: Research Article

Abstract: Background: Both genetic and environmental factors contribute to Parkinson’s disease (PD) risk. Objective: We investigated the potential association of several relevant variables with PD age at onset (AAO), focusing on LRRK2 p.G2019S and GBA p.N370S mutations. Methods: Ashkenazi Jewish (AJ) PD patients, screened for LRRK2 and GBA mutations, underwent an interview regarding exposure to the following environmental and lifestyle factors: cigarette smoking, consumption of coffee, tea and alcohol, history of head injury and rural living. Multivariate linear regression (adjusted for sex) was used to examine the association with AAO, and models included …LRRK2 and GBA mutation status (carrier/non-carriers), single environmental variable and their interactions terms, as independent variables. Results: 225 Israeli AJ PD patients were enrolled: 65 LRRK2 p.G2019S mutation carriers, 60 GBA p.N370S carriers and 100 non-carries of both mutations. In the dichotomized exposure/non-exposure analyses, positive LRRK2 p.G2019S status was associated with younger AAO in all models, at nominal or near significant levels (p  = 0.033–0.082). Cigarette smoking was associated with older AAO (p  = 0.032), and the interaction between GBA p.N370S and history of head injury was associated with younger AAO (p  = 0.049), both at nominal significance. There was no indication of a consistent main effect for GBA p.N370S status or significant LRRK2 p.G2019S-environmental factor interaction. In the dose-dependent analysis, increased coffee and tea consumption levels were associated with older AAO (p  = 0.001 and p  = 0.002, respectively). Conclusions: Our results suggest that both genetic and environmental factors may affect AAO in PD patients, but validation in additional samples is required. Show more

Keywords: Parkinson’s disease, age at onset, GBA p.N370S, LRRK2 p.G2019S, environmental factors, lifestyle habits, smoking, caffeine, tea, head injury, gene-environment interaction

DOI: 10.3233/JPD-191829

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Simoni, Simone | Paoletti, Federico Paolini | Eusebi, Paolo | Cappelletti, Giulia | Filidei, Marta | Brahimi, Elona | Nigro, Pasquale | Santangelo, Valerio | Parnetti, Lucilla | Calabresi, Paolo | Tambasco, Nicola

Article Type: Research Article

Abstract: Background: Dopaminergic medications in Parkinson’s disease (PD) are usually associated with the development of both levodopa-induced dyskinesias (LID) and impulse control and repetitive behavior disorders (ICRB). Objective: To assess the prevalence and the severity of ICRB in a cohort of moderate and advanced PD patients and to investigate the potential interplay between ICRB, LID and dopaminergic therapies. Methods: 117 PD patients were consecutively recruited. LID were assessed by using the Rush Dyskinesia Rating Scale (RDRS). ICRB were tested by means of Questionnaire for Impulsive Compulsive Disorders in Parkinson’s Disease Rating Scale (QUIP-RS). Results: 55 …patients were affected by LID. Among them, 37 were treated only by oral therapy, OT (LID/OT), while 18 were on treatment with jejunal levodopa infusion, JLI (LID/JLI). 62 patients were not affected by LID (NLID) and all of them were on therapy only with oral drugs. The overall prevalence of clinically significant ICRB was 34% (95% CI = 26% to 43%) and the mean value (±SD) of QUIP-RS total score was 5.4±8.5. Prevalence of clinically significant ICRB, as well as severity of ICRB, was higher in patients with LID compared to NLID patients (p  = 0.016 and p  < 0.001, respectively). When considering LID/JLI, LID/OT and NLID groups, QUIP-RS total score was significantly higher in LID/OT patients compared to LID/JLI (10.4±11.8 vs. 4.9±6.0, p  = 0.019) and NLID (10.4±11.8 vs. 2.5±4.8, p  < 0.001) groups. Conclusion: PD patients with LID show ICRB more frequently and more severely than patients without LID. Among LID patients, those treated by JLI showed a lower severity of ICRB than those on OT, suggesting a potential protective effect of JLI on ICRB. Show more

Keywords: Dyskinesia, Parkinson’s disease, dopamine, ICD, impulse control disorders, repetitive behavior disorders, levodopa

DOI: 10.3233/JPD-191833

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Mann, Elizabeth | Jackson, Michael | Lincoln, Louise | Fisher, Ria | Rose, Sarah | Duty, Susan

Article Type: Research Article

Abstract: Background: Increased firing across glutamatergic synapses may contribute to both the motor dysfunction and L-DOPA-induced dyskinesia seen in Parkinson’s disease. Given their ability to reduce glutamate release, activation of group III metabotropic glutamate receptors such as metabotropic glutamate receptor 4 may prove effective against both motor dysfunction and dyskinesia in Parkinson’s disease. Objective: We hypothesised that activation of metabotropic glutamate receptor 4 by an orthosteric agonist ((2S)-2-amino-4-(hydroxy(hydroxy(4-hydroxy-3-methoxy-nitrophenyl)methyl)phosphoryl)butanoic acid, LSP1-2111) would produce antiparkinsonian activity and reduce expression of dyskinesia in a 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset model of Parkinson’s disease. Methods: Common marmosets were previously treated with MPTP and …pre-primed with L-DOPA for up to 28 days to express dyskinesia. LSP1-2111 (1, 3, or 6 mg/kg s.c.) or vehicle (0.9% saline s.c.) were administered immediately prior to L-DOPA (8 mg/kg + benserazide (10 mg/kg) p.o.) or vehicle (10% sucrose p.o.). Locomotor activity was measured in automated test cages and animals were scored for dyskinesia and disability. Results: As expected, L-DOPA reversed motor disability and induced moderate dyskinesia. By contrast, LSP1-2111 alone significantly reduced the motor disability without any accompanying expression of dyskinesia. When administered in combination with L-DOPA, LSP1-2111 did not significantly reduce the severity of L-DOPA-induced dyskinesia. Conclusion: Systemic administration of LSP1-2111 reduces motor disability without causing dyskinesia in MPTP-treated marmosets, supporting a role for metabotropic glutamate receptor 4 orthosteric agonists as promising monotherapy for PD. Conversely, this study found no evidence to support their use as antidyskinetic agents within the dose range tested. Show more

Keywords: Dyskinesia, levodopa, motor disability, Parkinson’s disease

DOI: 10.3233/JPD-191824

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Molsberry, Samantha | Bjornevik, Kjetil | Hughes, Katherine C. | Zhang, Zhongli Joel | Jeanfavre, Sarah | Clish, Clary | Healy, Brian | Schwarzschild, Michael | Ascherio, Alberto

Article Type: Research Article

Abstract: Background: Although there is evidence of shared dysregulated pathways between diabetes and Parkinson’s disease, epidemiologic research on an association between the two diseases has produced inconsistent results. Objective: We aimed to assess whether known metabolomic markers of insulin resistance and diabetes are also associated with Parkinson’s disease development. Methods: We conducted a nested case-control study among Nurses’ Health Study and Health Professionals Follow-up Study participants who had provided blood samples up to twenty years prior to Parkinson’s diagnosis. Cases were matched to risk-set sampled controls by age, sex, fasting status, and time of blood collection. Participants …provided covariate information via regularly collected cohort questionnaires. We used conditional logistic regression models to assess whether plasma levels of branched chain amino acids, acylcarnitines, glutamate, or glutamine were associated with incident development of Parkinson’s disease. Results: A total of 349 case-control pairs were included in this analysis. In the primary analyses, none of the metabolites of interest were associated with Parkinson’s disease development. In investigations of the association between each metabolite and Parkinson’s disease at different time intervals prior to diagnosis, some metabolites showed marginally significant association but, after correction for multiple testing, only C18 : 2 acylcarnitine was significantly associated with Parkinson’s disease among subjects for whom blood was collected less than 60 months prior to case diagnosis. Conclusions: Plasma levels of diabetes-related metabolites did not contribute to predict risk of Parkinson’s disease. Further investigation of the relationship between pre-diagnostic levels of diabetes-related metabolites and Parkinson’s disease in other populations is needed to confirm these findings. Show more

Keywords: Parkinson’s disease, diabetes mellitus, metabolomics, epidemiology

DOI: 10.3233/JPD-191896

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Ospina, Beatriz Muñoz | Chaparro, Jaime Andres Valderrama | Paredes, Juan David Arango | Pino, Yor Jaggy Castaño | Navarro, Andres | Orozco, Jorge Luis

Article Type: Correction

DOI: 10.3233/JPD-200001

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2020