Journal of Parkinson's Disease - Volume 10, issue 4

Authors: Isaacson, Stuart H. | Coate, Bruce | Norton, James | Stankovic, Srdjan

Article Type: Research Article

Abstract: Background: Parkinson’s disease psychosis (PDP) is a common nonmotor symptom that affects up to 60% of patients. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, is approved for treating hallucinations and delusions associated with PDP. Objective: Evaluate the efficacy and tolerability of pimavanserin in an open-label extension (OLE) study. Methods: Patients completing a pivotal 6-week placebo-controlled trial (Core Study) could enroll in the OLE. All patients pimavanserin 34 mg once daily, blinded to previous treatment allocation. Prespecified blinded assessments at Week 4 were the Scale for the Assessment of Positive Symptoms (SAPS) PD version and SAPS H + D scales, …Caregiver Burden Scale (CBS), and Clinical Global Impression (CGI) Improvement and Severity scales. Results: Of 171 who entered the OLE, 148 (87%) completed Week 4. Among patients who received placebo in the Core Study, mean (SD) change from OLE baseline to OLE Week 4 for the SAPS-PD was – 3.4 (6.3); p  < 0.0001. Mean change from Core Study baseline to OLE Week 4 for SAPS-PD was similar among prior pimavanserin- and placebo-treated patients (–6.9 vs. –6.3). Improvement was similar with CGI-I, CGI-S, CBS, and SAPS-H + D in patients previously treated with placebo. Adverse events occurred in 92 (53.8%) patients during the 4-week OLE. Conclusion: Improvements at OLE Week 4 from pretreatment baseline were similar with placebo and pimavanserin in the Core Study. The beneficial effects observed with pimavanserin in the 6-week Core Study were maintained for 4 weeks in the blinded OLE, supporting the durability of response with pimavanserin 34 mg for PDP over 10 weeks. Show more

Keywords: Efficacy, Parkinson’s disease psychosis, pimavanserin, safety, tolerability

DOI: 10.3233/JPD-202047

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1389-1396, 2020

Authors: Roux, Amandine | Wang, Xinhe | Becker, Katelyn | Ma, Jiyan

Article Type: Research Article

Abstract: Background: Synucleinopathy is a group of neurodegenerative disorders characterized by neurodegeneration and accumulation of alpha-synuclein (α -syn) aggregates in various brain regions. The detailed mechanism of α -syn-caused neurotoxicity remains obscure, which is partly due to the lack of a suitable model that retains the in vivo three-dimensional cellular network and allows a convenient dissection of the neurotoxic pathways. Recent studies revealed that the pre-formed recombinant α -syn amyloid fibrils (PFFs) induce a robust accumulation of pathogenic α -syn species in cultured cells and animals. Objective: Our goal is to determine whether PFFs are able to induce …the pathogenic α -syn accumulation and neurotoxicity in organotypic brain slice culture, an ex vivo system that retains the in vivo three-dimensional cell-cell connections. Methods/Results: Adding PFFs to cultured wild-type rat or mouse brain slices induced a time-dependent accumulation of pathogenic α -syn species, which was indicated by α -syn phosphorylated at serine 129 (pα -syn). The PFF-induced pα -syn was abolished in brain slices prepared from α -syn null mice, suggesting that the pα -syn is from the phosphorylation of endogenous α -syn. Human PFFs also induced pα -syn in brain slices prepared from mice expressing human α -syn on a mouse α -syn-null background. Furthermore, the synaptophysin immunoreactivity was inversely associated with pα -syn accumulation and an increase of neuronal loss was detected. Conclusion: PFF-treatment of brain slices is able to induce key pathological features of synucleinopathy: pα -syn accumulation and neurotoxicity. This model will be useful for investigating the neurotoxic mechanism and evaluating efficacy of therapeutic approaches. Show more

Keywords: Alpha-synuclein, synucleinopathy, organotypic brain slice culture, pre-formed recombinant α-syn amyloid fibrils (PFFs), aggregation, neurotoxicity

DOI: 10.3233/JPD-202026

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1397-1410, 2020

Authors: Kulkarni, Aishwarya S. | del Mar Cortijo, Maria | Roberts, Elizabeth R. | Suggs, Tamara L. | Stover, Heather B. | Pena-Bravo, José I. | Steiner, Jennifer A. | Luk, Kelvin C. | Brundin, Patrik | Wesson, Daniel W.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) neuropathology is characterized by intraneuronal protein aggregates composed of misfolded α -Synuclein (α -Syn), as well as degeneration of substantia nigra dopamine neurons. Deficits in olfactory perception and aggregation of α -Syn in the olfactory bulb (OB) are observed during early stages of PD, and have been associated with the PD prodrome, before onset of the classic motor deficits. α -Syn fibrils injected into the OB of mice cause progressive propagation of α -Syn pathology throughout the olfactory system and are coupled to olfactory perceptual deficits. Objective: We hypothesized that accumulation of pathogenic α …-Syn in the OB impairs neural activity in the olfactory system. Methods: To address this, we monitored spontaneous and odor-evoked local field potential dynamics in awake wild type mice simultaneously in the OB and piriform cortex (PCX) one, two, and three months following injection of pathogenic preformed α -Syn fibrils in the OB. Results: We detected α -Syn pathology in both the OB and PCX. We also observed that α -Syn fibril injections influenced odor-evoked activity in the OB. In particular, α -Syn fibril-injected mice displayed aberrantly high odor-evoked power in the beta spectral range. A similar change in activity was not detected in the PCX, despite high levels of α -Syn pathology. Conclusion: Together, this work provides evidence that synucleinopathy impacts in vivo neural activity in the olfactory system at the network-level. Show more

Keywords: Parkinson’s disease, dementia, olfaction, synucleinopathy, Lewy pathology, piriform cortex, olfactory bulb, local field potential

DOI: 10.3233/JPD-202241

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1411-1427, 2020

Authors: von Euler Chelpin, Marianne | Söderberg, Linda | Fälting, Johanna | Möller, Christer | Giorgetti, Marco | Constantinescu, Radu | Blennow, Kaj | Zetterberg, Henrik | Höglund, Kina

Article Type: Research Article

Abstract: Background: Currently, there is no established biomarker for Parkinson's disease (PD) and easily accessible biomarkers are crucial for developing disease-modifying treatments. Objective: To develop a novel method to quantify cerebrospinal fluid (CSF) levels of α -synuclein protofibrils (α -syn PF) and apply it to clinical cohorts of patients with PD and atypical parkinsonian disorders. Methods: A cohort composed of 49 patients with PD, 12 with corticobasal degeneration (CBD), 22 with progressive supranuclear palsy, and 33 controls, that visited the memory clinic but had no biomarker signs of Alzheimer’s disease (AD, tau<350 pg/mL, amyloid-beta 42 (Aβ 42 )>530 pg/mL, …and phosphorylated tau (p -tau)<60 pg/mL) was used in this study. The CSF samples were analyzed with the Single molecule array (Simoa) technology. Total α -synuclein (α -syn) levels were analyzed with a commercial ELISA-kit. Results: The assay is specific to α -syn PF, with no cross-reactivity to monomeric α -syn, or the β - and γ -synuclein variants. CSF α -syn PF levels were increased in PD compared with controls (62.1 and 40.4 pg/mL, respectively, p  = 0.03), and CBD (62.1 and 34.2 pg/mL, respectively, p  = 0.02). The accuracy of predicting PD using α -syn PF is significantly different from controls (area under the curve 0.68, p  = 0.0097) with a sensitivity of 62.8% and specificity of 67.7%. Levels of total α -syn were significantly different between the PD and CBD groups (p  = 0.04). Conclusion: The developed method specifically quantifies α -syn PF in human CSF with increased concentrations in PD, but with an overlap with asymptomatic elderly controls. Show more

Keywords: Parkinson's disease, alpha-synuclein protofibrils, Simoa, biomarker, CSF, atypical parkinsonian disorders

DOI: 10.3233/JPD-202141

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1429-1442, 2020

Authors: Ye, Guanyu | Li, Yuanyuan | Zhou, Liche | Zhang, Yichi | Zhu, Lin | Zhao, Aonan | Kang, Wenyan | Liu, Jun

Article Type: Research Article

Abstract: Background: Idiopathic rapid eye movement sleep behavior disorder (iRBD) often precedes the development of α -synucleinopathy diseases. Objective: We aimed to assess the predictive value of clinical variables and biomarkers for the early development of α -synucleinopathy diseases in subjects with iRBD. Methods: 56 patients with RBD Screening Questionnaire (RBDSQ) scores ≥5 at baseline and subsequent visit were enrolled as probable iRBD from the Parkinson’s Progression Markers Initiative (PPMI) database. Baseline clinical data and biomarkers were analyzed. The endpoint was defined as disease progression to α -synucleinopathy diseases. Cox proportional hazard and Kaplan-Meier analyses were used …to evaluate the predictive values of the indicators. Results: During a mean follow-up duration of 5.1 years, 15 of 56 patients (26.8%) developed α -synucleinopathy diseases. Baseline clinical variables, including University of Pennsylvania Smell Identification Test (UPSIT, HR = 26.18, p  = 0.004), 15-item Geriatric Depression Scale (GDS, HR = 14.26, p  = 0.001), Montreal Cognitive Assessment (MoCA, HR = 3.56, p  = 0.025), and Hopkins Verbal Learning Test Total recall (HVLT-TR, HR = 3.70, p  = 0.014); genotype status of TMEM175 (HR = 3.74, p  = 0.017), SCN3A (HR = 5.81, p  = 0.022) and NUCKS1 (HR = 0.342, p  = 0.049); ratio of phosphorylated tau to total tau (p-tau/t-tau, HR = 8.36, p  = 0.001) in cerebrospinal fluid; and gray matter atrophy in inferior frontal gyrus (IFG, HR = 15.49, p  = 0.001) were associated with phenoconversion to α -synucleinopathy diseases. A model combined the three independent variables (UPSIT, TMEM175 and gray matter atrophy in IFG) exhibited significantly improved predictive performance. Conclusion: For patients with iRBD, progression to α -synucleinopathy diseases can be predicted with good accuracy using a model combining clinical variables and biomarkers, which could form a basis for future disease prevention. Show more

Keywords: Parkinson’s disease, REM sleep behavior disorder, synucleinopathies, multiple system atrophy, Lewy body dementia

DOI: 10.3233/JPD-202243

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1443-1455, 2020

Authors: Frings, Lars | Henninger, Franziska | Treppner, Martin | Köber, Göran | Boeker, Martin | Hellwig, Sabine | Buchert, Ralph | Meyer, Philipp T.

Article Type: Research Article

Abstract: Background: Dopamine transporter SPECT is an established method to investigate nigrostriatal integrity in case of clinically uncertain parkinsonism. Objective: The present study explores whether a data-driven analysis of [123 I]FP-CIT SPECT is able to stratify patients according to mortality after SPECT. Methods: Patients from our clinical registry were included if they had received [123 I]FP-CIT SPECT between 10/2008 and 06/2016 for diagnosis of parkinsonism and if their vital status could be determined in 07/2017. Specific binding ratios (SBR) of the whole striatum, its asymmetry (asymmetry index, AI; absolute value), and the rostrocaudal gradient of striatal binding …(C/pP: caudate SBR divided by posterior putamen SBR) were used as input for hierarchical clustering of patients. We tested differences in survival between these groups (adjusted for age) with a Cox proportional hazards model. Results: Data from 518 patients were analyzed. Median follow-up duration was 3.3 years [95% C.I. 3.1 to 3.7]. Three subgroups identified by hierarchical clustering were characterized by relatively low striatal SBR, high AI, and low C/pP (group 1), low striatal SBR, high AI, and high C/pP (group 2), and high striatal SBR, low AI, and low C/pP (group 3). Mortality was significantly higher in group 1 compared to each of the other two groups (p  = 0.029 and p  = 0.003, respectively). Conclusion: Data-driven analysis of [123 I]FP-CIT SPECT identified a subgroup of patients with significantly increased mortality during follow-up. This suggests that [123 I]-FP-CIT SPECT might not only serve as a diagnostic tool to verify nigrostriatal degeneration but also provide valuable prognostic information. Show more

Keywords: Parkinsonism, Parkinson’s disease, dopamine transporter, [123I]FP-CIT SPECT

DOI: 10.3233/JPD-202214

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1457-1465, 2020

Authors: Feigl, Beatrix | Dumpala, Sunila | Kerr, Graham K. | Zele, Andrew J.

Article Type: Research Article

Abstract: Background: Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) signal the environmental light to mediate circadian photoentrainment and sleep-wake cycles. There is high prevalence of circadian and sleep disruption in people with Parkinson’s disease, however the underlying mechanisms of these symptoms are not clear. Objective: Based on recent evidence of anatomical and functional loss of melanopsin ganglion cells in Parkinson’s disease, we evaluate the link between melanopsin function, circadian, and sleep behavior. Methods: The pupil light reflex and melanopsin-mediated post-illumination pupil response were measured using chromatic pupillometry in 30 optimally medicated people with Parkinson’s disease and 29 …age-matched healthy controls. Circadian health was determined using dim light melatonin onset, sleep questionnaires, and actigraphy. Ophthalmic examination quantified eye health and optical coherence tomography measured retinal thickness. Results: The melanopsin-mediated post-illumination pupil response amplitudes were significantly reduced in Parkinson’s disease (p  < 0.0001) and correlated with poor sleep quality (r2  = 33; p  < 0.001) and nerve fiber layer thinning (r2  = 0.40; p  < 0.001). People with Parkinson’s disease had significantly poorer sleep quality with higher subjective sleep scores (p  < 0.05) and earlier melatonin onset (p  = 0.01). Pupil light (outer retinal) response metrics, daily light exposure and outer retinal thickness were similar between the groups (p  > 0.05). Conclusion: Our evidence-based data identify a mechanism through which inner retinal ipRGC dysfunction contributes to sleep disruption in Parkinson’s disease in the presence of normal outer retinal (rod-cone photoreceptor) function. Our findings provide a rationale for designing new treatment approaches in Parkinson’s disease through melanopsin photoreceptor-targeted light therapies for improving sleep-wake cycles. Show more

Keywords: Dim light melatonin onset, melanopsin, Parkinson’s disease, photoreceptors, PIPR, post-illumination pupil light response, sleep

DOI: 10.3233/JPD-202178

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1467-1476, 2020

Authors: West, Christine L. | Mao, Yu-Kang | Delungahawatta, Thilini | Amin, Jessica Y. | Farhin, Sohana | McQuade, Rachel M. | Diwakarla, Shanti | Pustovit, Ruslan | Stanisz, Andrew M. | Bienenstock, John | Barbut, Denise | Zasloff, Michael | Furness, John B. | Kunze, Wolfgang A.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder thought to be caused by accumulation of α -synuclein (α -syn) within the brain, autonomic nerves, and the enteric nervous system (ENS). Involvement of the ENS in PD often precedes the onset of the classic motor signs of PD by many years at a time when severe constipation represents a major morbidity. Studies conducted in vitro and in vivo , have shown that squalamine, a zwitterionic amphipathic aminosterol, originally isolated from the liver of the dogfish shark, effectively displaces membrane-bound α -syn. Objective: Here we explore the electrophysiological …effect of squalamine on the gastrointestinal (GI) tract of mouse models of PD engineered to express the highly aggregating A53T human α -syn mutant. Methods: GI motility and in vivo response to oral squalamine in PD model mice and controls were assessed using an in vitro tissue motility protocol and via fecal pellet output. Vagal afferent response to squalamine was measured using extracellular mesenteric nerve recordings from the jejunum. Whole cell patch clamp was performed to measure response to squalamine in the myenteric plexus. Results: Squalamine effectively restores disordered colonic motility in vivo and within minutes of local application to the bowel. We show that topical squalamine exposure to intrinsic primary afferent neurons (IPANs) of the ENS rapidly restores excitability. Conclusion: These observations may help to explain how squalamine may promote gut propulsive activity through local effects on IPANs in the ENS, and further support its possible utility in the treatment of constipation in patients with PD. Show more

Keywords: Parkinson’s disease, squalamine, intestinal motility, intrinsic primary afferent neuron, electrophysiology, gut-brain axis, vagus

DOI: 10.3233/JPD-202076

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1477-1491, 2020

Authors: Chiu, Shannon Y. | Tsuboi, Takashi | Hegland, Karen W. | Herndon, Nicole E. | Shukla, Aparna Wagle | Patterson, Addie | Almeida, Leonardo | Foote, Kelly D. | Okun, Michael S. | Ramirez-Zamora, Adolfo

Article Type: Research Article

Abstract: Background: Although earlier studies reported variable speech changes following subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson’s disease (PD) patients, the effects of globus pallidus internus (GPi) DBS on speech performance in PD remain largely unknown. Objective: We aimed to characterize speech changes following PD GPi-DBS. Methods: We retrospectively analyzed clinical and speech outcomes of 25 PD patients treated with bilateral GPi-DBS at a single center. Outcome measures included the Unified Parkinson’s Disease Rating Scale (UPDRS), speech subsystem domains (respiratory, laryngeal, resonance, orofacial, rate, prosody, rhythm, and naturalness), and overall speech intelligibility. Scores at baseline …were compared with those at 6 months, 1 year, and the longest clinical follow-up available. Results: In the off-medication state, activities of daily living and motor function based on UPDRS II and III significantly improved postoperatively. We observed unique patterns of speech changes in patients with PD following GPi-DBS in the short- (n  = 25) and longer-term (n  = 8) follow-up periods. Velopharyngeal (resonance), laryngeal components, and prosody worsened after bilateral GPi-DBS (p  < 0.015). Speech intelligibility did not worsen after GPi-DBS in the short-term, but there was a trend to deteriorate at long-term follow-up (e.g., one year and beyond). We observed worsening of hypokinetic dysarthria in individual patients. Also, a minority of patients developed stuttering, spastic dysarthria, or ataxic dysarthria. Conclusion: Bilateral GPi-DBS worsened several modalities of parkinsonian speech without compromising overall speech intelligibility. GPi-DBS can potentially worsen or induce hypokinetic dysarthria, stuttering, spastic dysarthria, or ataxic dysarthria. GPi-DBS may have different and variable effects on speech function when compared to STN-DBS. Show more

Keywords: Parkinson’s disease, globus pallidus, deep brain stimulation, dysarthria, speech intelligibility

DOI: 10.3233/JPD-202246

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1493-1502, 2020

Authors: Scheggi, Simona | Rossi, Francesca | Corsi, Sara | Fanni, Silvia | Tronci, Elisabetta | Ludovica, Congiu | Vargiu, Romina | Gambarana, Carla | Muñoz, Ana | Stancampiano, Roberto | Björklund, Anders | Carta, Manolo

Article Type: Research Article

Abstract: Background: We recently showed that striatal overexpression of brain derived neurotrophic factor (BDNF) by adeno-associated viral (AAV) vector exacerbated L-DOPA-induced dyskinesia (LID) in 6-OHDA-lesioned rats. An extensive sprouting of striatal serotonergic terminals accompanied this effect, accounting for the increased susceptibility to LID. Objective: We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D1 receptor agonists. Methods: Unilaterally 6-OHDA-lesioned rats received a striatal injection of an AAV vector to induce BDNF or GFP overexpression. Eight weeks later, animals received daily treatments with a low dose of …SKF82958 (0.02 mg/kg s.c.) and development of dyskinesia was evaluated. At the end of the experiment, D1 and D3 receptors expression levels and D1 receptor-dependent signaling pathways were measured in the striatum. Results: BDNF overexpression induced significant worsening of dyskinesia induced by SKF82958 compared to the GFP group and increased the expression of D3 receptor at striatal level, even in absence of pharmacological treatment; by contrast, D1 receptor levels were not affected. In BDNF-overexpressing striata, SKF82958 administration resulted in increased levels of D1 –D3 receptors co-immunoprecipitation and increased phosphorylation levels of Thr34 DARPP-32 and ERK1/2. Conclusion: Here we provide evidence for a functional link between BDNF, D3 receptors and D1 –D3 receptor close interaction in the augmented susceptibility to dyskinesia in 6-OHDA-lesioned rats. We suggest that D1 –D3 receptors interaction may be instrumental in driving the molecular alterations underlying the appearance of dyskinesia; its disruption may be a therapeutic strategy for treating dyskinesia in PD patients. Show more

Keywords: 6-OHDA, BDNF, dyskinesia, D3 receptors, Parkinson’s disease

DOI: 10.3233/JPD-202061

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1503-1514, 2020

Authors: Huang, Xuemei | Lewis, Mechelle M. | Van Scoy, Lauren Jodi | De Jesus, Sol | Eslinger, Paul J. | Arnold, Amy C. | Miller, Amanda J. | Fernandez-Mendoza, Julio | Snyder, Bethany | Harrington, William | Kong, Lan | Wang, Xi | Sun, Dongxiao | Delnomdedieu, Marielle | Duvvuri, Sridhar | Mahoney, Susan E. | Gray, David L. | Mailman, Richard B.

Article Type: Research Article

Abstract: Background: Current drug treatments have little efficacy in advanced-to-end-stage Parkinson’s disease (advPD), yet there are no reports of interventional trials in advPD. D1 dopamine agonists have the potential to provide benefit. Objective: To determine the feasibility and safety of the selective D1 /D5 dopamine partial agonist PF 06412562 in advPD. Methods: A two-week, randomized, double blind, crossover phase Ib study in advPD patients compared standard-of-care (SoC) carbidopa/levodopa with PF 06412562. Each week, there was a Day 1 baseline evaluation with overnight levodopa washout, then treatment on Days 2 and 3 with either SoC or …PF-06412562 (split dose 25 + 20 mg), followed by discharge on Day 4. Primary endpoints were safety and tolerability. Secondary endpoints were global clinical impression of change (GCI-C) rated by clinicians and caregivers. Results: Eight advPD patients and their caregivers consented to participate and six were randomized (average disease duration: 22 y). None withdrew voluntarily. One participant with baseline Day 1 dehydration, pre-renal kidney injury, and autonomic dysfunction experienced symptomatic and serious hypotension after receiving PF-06412562 in Week 1 and was discontinued from the study. All other adverse events were rated mild (PF-06412562: n  = 1, SoC: n  = 0), moderate (PF-06412562: n  = 1, SoC: n  = 1), or severe but non-serious (PF-06412562: n  = 3, SoC: n  = 2). No clinically meaningful laboratory changes were observed. Among the five participants who completed the study, GCI-C favored PF-06412562 in two per clinicians’ and four participants per caregivers’ rating. Conclusion: PF-06412562 was tolerated in advPD patients. This study provides the feasibility for future safety and efficacy studies in this population with unmet needs. Show more

Keywords: D1 dopamine receptor, dopamine D1 agonists, advanced Parkinson’s disease, levodopa, safety, feasibilityTrial Registration#: ClinicalTrials.gov:NCT03665454

DOI: 10.3233/JPD-202188

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1515-1527, 2020

Authors: Nyholm, Dag | Adnan, Malak | Senek, Marina

Article Type: Research Article

Abstract: Background: Levodopa/carbidopa intestinal gel (LCIG) infusion is an efficacious treatment of motor and non-motor fluctuations in people with Parkinson’s disease (PD). Real-life use of the treatment is not previously studied. Objective: The aims of the study were to explore the use of LCIG and to determine how extra doses of LCIG are used in daily life. Methods: Twenty-five PD patients with ongoing LCIG therapy were consecutively included. Pump data was retrieved from 30 days on average, by means of software, extracting the most recent pump events. Results: The daily duration of infusion was 15 …hours on average, in 18 patients, whereas the remaining 7 patients used 24-hour infusion. Morning doses ranged from 38–190 mg levodopa, for patients who utilized this function. Median number of daily extra doses was 2.5 (range: 0–10.6) and median size of the extra dose was 24 mg (0–80 mg) levodopa. Median total daily levodopa intake with LCIG was 1201 mg (range: 417–2322 mg). Conclusion: Retrieving pump data is possible and may be important for evaluating the at-home use of LCIG, to optimize the therapy. Adherence to treatment should be monitored, which is not technically difficult, at least in device-aided treatments for PD. Show more

Keywords: Levodopa, carbidopa intestinal gel, infusion pump, Parkinson’s disease, medication adherence

DOI: 10.3233/JPD-202114

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1529-1534, 2020

Authors: Leta, Valentina | van Wamelen, Daniel J. | Sauerbier, Anna | Jones, Shelley | Parry, Miriam | Rizos, Alexandra | Chaudhuri, K. Ray

Article Type: Short Communication

Abstract: Combined catechol-O -methyl-transferase-inhibition and Levodopa-Carbidopa intestinal gel (LCIG) infusion has the potential to reduce LCIG daily dose and the costs of this therapy. In this retrospective analysis, we report on Parkinson’s disease (PD) patients on LCIG with concomitant Opicapone. In 11 patients, the introduction of Opicapone led to LCIG daily dose being reduced by 24.8% (p  = 0.05) without any significant worsening of dyskinesia. Three patients withdrew from Opicapone due to side effects or inefficacy. LCIG daily dose reduction could lead to cost savings of £142,820.63/year in the United Kingdom while maintaining clinical care.

Keywords: Levodopa-Carbidopa intestinal gel, intrajejunal Levodopa infusion, Catechol-O-methyl-transferase-inhibitor, Opicapone, cost savings

DOI: 10.3233/JPD-202022

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1535-1539, 2020

Authors: Chung, Seok Jong | Lee, Sangwon | Yoo, Han Soo | Lee, Yang Hyun | Lee, Hye Sun | Choi, Yonghoon | Lee, Phil Hyu | Yun, Mijin | Sohn, Young H.

Article Type: Research Article

Abstract: Background: Striatal dopamine deficits play a key role in the pathogenesis of Parkinson’s disease (PD), and several non-motor symptoms (NMSs) have a dopaminergic component. Objective: To investigate the association between early NMS burden and the patterns of striatal dopamine depletion in patients with de novo PD. Methods: We consecutively recruited 255 patients with drug-naïve early-stage PD who underwent 18 F-FP-CIT PET scans. The NMS burden of each patient was assessed using the NMS Questionnaire (NMSQuest), and patients were divided into the mild NMS burden (PDNMS-mild) (NMSQuest score <6; n  = 91) and severe NMS burden groups …(PDNMS-severe) (NMSQuest score >9; n  = 90). We compared the striatal dopamine transporter (DAT) activity between the groups. Results: Patients in the PDNMS-severe group had more severe parkinsonian motor signs than those in the PDNMS-mild group, despite comparable DAT activity in the posterior putamen. DAT activity was more severely depleted in the PDNMS-severe group in the caudate and anterior putamen compared to that in the PDMNS-mild group. The inter-sub-regional ratio of the associative/limbic striatum to the sensorimotor striatum was lower in the PDNMS-severe group, although this value itself lacked fair accuracy for distinguishing between the patients with different NMS burdens. Conclusion: This study demonstrated that PD patients with severe NMS burden exhibited severe motor deficits and relatively diffuse dopamine depletion throughout the striatum. These findings suggest that the level of NMS burden could be associated with distinct patterns of striatal dopamine depletion, which could possibly indicate the overall pathological burden in PD. Show more

Keywords: Dopamine transporter, non-motor, Parkinson’s disease, subtype

DOI: 10.3233/JPD-202127

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1541-1549, 2020

Authors: Nance, Martha A. | Boettcher, Lesa | Edinger, Germaine | Gardner, Joan | Kitzmann, Ron | Erickson, Lauren O. | Wichmann, Rose | Wielinski, Catherine L.

Article Type: Research Article

Abstract: Background: Patients hospitalized with Parkinson’s disease (PD) require timely delivery of carbidopa-levodopa (C/L) medication. Ill-timed administration of C/L doses is associated with greater morbidity and longer lengths of stay. Objective: To understand the barriers to timely C/L administration, and implement strategies to improve the administration of the drug to hospitalized PD patients. Methods: Several key strategies were employed in 2015 to improve the timely delivery of C/L doses: 1. three kinds of nursing alert in the electronic medical record (EMR); 2. staff in-service education; 3. stocking immediate-release C/L into automated medication dispensing machines on key hospital …units; 4. reports to nurse unit managers on timeliness of C/L administration; and 5. reconciliation of inpatient and outpatient levodopa orders by the hospital pharmacist upon admission. The primary outcome was the percent of C/L doses administered within 60, 30, and 15 minutes of scheduled time. Results: Our urban hospital, affiliated with a Parkinson’s Foundation Center of Excellence, had 5,939 C/L administrations in 2018. There was sustained improvement in timely delivery of doses, from 89.3% in 2012 to 96.5% in 2018 (within 60 minutes of the scheduled time), 65.5% to 86.4% (30 minutes), and 42.3% to 71.1% (15 minutes) (all p  < 0.001). Conclusions: With multifaceted but relatively simple measures, we were able to “change the culture” so that hospitalized patients with Parkinson’s disease receive levodopa on time. Show more

Keywords: Parkinson’s disease, levodopa, quality improvement, nursing care, hospital

DOI: 10.3233/JPD-202024

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1551-1559, 2020

Authors: Suwijn, Sven R. | Samim, Hamdia | Eggers, Carsten | Espay, Alberto J. | Fox, Susan | Lang, Anthony E. | Samuel, Mike | Silverdale, Monty | Verschuur, Constant V.M. | Dijk, Joke M. | Verberne, Hein J. | Booij, Jan | de Bie, Rob M. A.

Article Type: Research Article

Abstract: Background: In clinical trials that recruited patients with early Parkinson’s disease (PD), 4–15% of the participants with a clinical diagnosis of PD had normal dopamine transporter single photon emission computed tomography (DAT SPECT) scans, also called “scans without evidence of dopaminergic deficit” (SWEDD). Objective: To investigate in patients with a clinical diagnosis of PD, if specific clinical features are useful to distinguish patients with nigrostriatal degeneration from those that have no nigrostriatal degeneration. Methods: We performed a diagnostic test accuracy study. Patients that participated in the Levodopa in Early Parkinson’s disease trial, a clinical trial in …patients with early PD, were asked to participate if they had not undergone DAT SPECT imaging earlier. The index tests were specific clinical features that were videotaped. A panel of six neurologists in training (NT), six general neurologists (GN), and six movement disorders experts (MDE) received a batch of ten videos consisting of all SWEDD subjects and a random sample of patients with abnormal DAT SPECT scans. The raters analyzed the videos for presence of specific signs and if they suspected the patient to have SWEDD. The reference test was visually assessed DAT SPECT imaging. Results: Of a total of 87 participants, three subjects were SWEDDs (3.4%). The overall intraclass correlation coefficient (ICC) of the Parkinsonian signs was poor to moderate with ICCs ranging from 0.14 to 0.67. NT correctly identified 50.0% of the SWEDD subjects, GN 33.3%, and MDE 66.7%. Conclusion: Our study suggests that the selected videotaped clinical features cannot reliably distinguish patients with a clinical diagnosis of PD and an abnormal DAT SPECT from patients with clinical PD and a SWEDD. Show more

Keywords: DAT SPECT, diagnostic accuracy, clinical features, Parkinson’s disease, SWEDD, neurodegeneration, inter-rater agreement

DOI: 10.3233/JPD-202090

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1561-1569, 2020

Authors: Hasimoglu, Yasemin G. | Chen, Xiqun | Bakshi, Rachit | Schwarzschild, Michael A. | Macklin, Eric A.

Article Type: Short Communication

Abstract: Higher serum urate concentration is associated with decreased risk of Parkinson’s disease (PD) as well as slower disease progression, but its relationship with severity of PD remains unclear. This study investigated whether changes in serum urate concentration over 5 years were associated with disease progression assessed by MDS-UPDRS Part III score, Hoehn and Yahr stage, or DaTscan imaging. Average serum urate concentration was stable over time and change in serum urate concentration did not correlate with worsening of measures of PD progression. These results suggest that serum urate concentration is not a monitoring biomarker of PD progression in early stages.

Keywords: Parkinson’s disease, urate, disease progression, longitudinal study

DOI: 10.3233/JPD-202064

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1571-1576, 2020

Authors: Fullard, Michelle | Thibault, Dylan | Zisling, Hanan | Crispo, James A. | Willis, Allison

Article Type: Research Article

Abstract: Background: Advances in the treatment of Parkinson’s disease (PD) have allowed for improvements in mortality and quality survival, making the management of comorbid conditions of aging, such as osteoarthritis, crucial. Objective: To determine the extent to which PD impacts hospitalization outcomes after an elective orthopedic procedure. Methods: This retrospective cohort study used data from the National Readmissions Database and included adults ages 40 and above with and without PD. Primary outcomes included length of stay of the index admission, discharge disposition and 30-day readmission. Logistic regression was used to compare the odds of readmission for PD …patients compared to non-PD. Clinical conditions associated with readmission were compared between the two groups. Results: A total of 4,781 subjects with PD and 947,475 subjects without PD met inclusion criteria. Length of stay (LOS) during the index admission was longer for PD patients. PD patients were much more likely to be discharged to inpatient post-acute care (49.3% vs 26.2%) while non-PD subjects were more likely to be discharged home with (31.9% [PD] vs 44.8% [non-PD]) or without home health (18.7% [PD] vs 28.9% [non-PD]). A total of 271 PD patients (5.66%) and 28,079 non-PD patients (2.96%) were readmitted within 30 days following surgery. After adjusting for age, sex, socioeconomic status, expected payer, comorbidities, index admission LOS, year and discharge disposition, PD subjects were 31% more likely to be readmitted than non-PD subjects (AOR 1.31, 1.07–1.62). Conclusions: Parkinson’s disease patients were readmitted more often than non-PD patients, although the rate of readmission was still low. Show more

Keywords: Parkinson’s disease, cohort studies, arthroplasty, knee replacement, hip replacement

DOI: 10.3233/JPD-201992

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1577-1586, 2020

Authors: Tremblay, Cécilia | Iravani, Behzad | Aubry Lafontaine, Émilie | Steffener, Jason | Fischmeister, Florian Ph.S | Lundström, Johan N. | Frasnelli, Johannes

Article Type: Research Article

Abstract: Background: Olfactory dysfunction (OD) is a frequent symptom of Parkinson’s disease (PD) that appears years prior to diagnosis. Previous studies suggest that PD-related OD is different from non-parkinsonian forms of olfactory dysfunction (NPOD) as PD patients maintain trigeminal sensitivity as opposed to patients with NPOD who typically exhibit reduced trigeminal sensitivity. We hypothesize the presence of a specific alteration of functional connectivity between trigeminal and olfactory processing areas in PD. Objective: We aimed to assess potential differences in functional connectivity within the chemosensory network in 15 PD patients and compared them to 15 NPOD patients, and to 15 …controls. Methods: Functional MRI scanning session included resting-state and task-related scans where participants carried out an olfactory and a trigeminal task. We compared functional connectivity, using a seed-based correlation approach, and brain network modularity of the chemosensory network. Results: PD patients had impaired functional connectivity within the chemosensory network while no such changes were observed for NPOD patients. No group differences we found in modularity of the identified networks. Both patient groups exhibited impaired connectivity when executing an olfactory task, while network modularity was significantly weaker for PD patients than both other groups. When performing a trigeminal task, no changes were found for PD patients, but NPOD patients exhibited impaired connectivity. Conversely, PD patients exhibited a significantly higher network modularity than both other groups. Conclusion: In summary, the specific pattern of functional connectivity and chemosensory network recruitment in PD-related OD may explain distinct behavioral chemosensory features in PD when compared to NPOD patients and healthy controls. Show more

Keywords: Parkinson’s disease, olfactory dysfunction, trigeminal system, functional connectivity, fMRI, resting-state

DOI: 10.3233/JPD-202062

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1587-1600, 2020

Authors: Roper, Jaimie A. | Schmitt, Abigail C. | Gao, Hanzhi | He, Ying | Wu, Samuel | Schmidt, Peter | Okun, Michael S. | Hass, Chris J. | Cubillos, Fernando | on behalf of the Parkinson’s Foundation Quality Improvement Initiative Investigators

Article Type: Research Article

Abstract: Background: The impact of concurrent osteoarthritis on mobility and mortality in individuals with Parkinson’s disease is unknown. Objective: We sought to understand to what extent osteoarthritis severity influenced mobility across time and how osteoarthritis severity could affect mortality in individuals with Parkinson’s disease. Methods: In a retrospective observational longitudinal study, data from the Parkinson’s Foundation Quality Improvement Initiative was analyzed. We included 2,274 persons with Parkinson’s disease. The main outcomes were the effects of osteoarthritis severity on functional mobility and mortality. The Timed Up and Go test measured functional mobility performance. Mortality was measured as the …osteoarthritis group effect on survival time in years. Results: More individuals with symptomatic osteoarthritis reported at least monthly falls compared to the other groups (14.5% vs. 7.2% without reported osteoarthritis and 8.4% asymptomatic/minimal osteoarthritis, p  = 0.0004). The symptomatic group contained significantly more individuals with low functional mobility (TUG≥12 seconds) at baseline (51.5% vs. 29.0% and 36.1%, p  < 0.0001). The odds of having low functional mobility for individuals with symptomatic osteoarthritis was 1.63 times compared to those without reported osteoarthritis (p  < 0.0004); and was 1.57 times compared to those with asymptomatic/minimal osteoarthritis (p  = 0.0026) after controlling pre-specified covariates. Similar results hold at the time of follow-up while changes in functional mobility were not significant across groups, suggesting that osteoarthritis likely does not accelerate the changes in functional mobility across time. Coexisting symptomatic osteoarthritis and Parkinson’s disease seem to additively increase the risk of mortality (p  = 0.007). Conclusion: Our results highlight the impact and potential additive effects of symptomatic osteoarthritis in persons with Parkinson’s disease. Show more

Keywords: Comorbidity, Parkinson’s disease, arthritis, mobility, mortality

DOI: 10.3233/JPD-202170

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1601-1610, 2020

Authors: Cubo, Esther | Martínez-Martín, Pablo | González-Bernal, Jerónimo | Casas, Elena | Arnaiz, Sandra | Miranda, Javier | Gámez, Pedro | Santos-García, Diego | Coppadis Study Group:

Collaborators: Adarmes, AD | Almeria, M | Alonso Losada, MG | Alonso Cánovas, A | Alonso Frech, F | Álvarez, I | Álvarez Sauco, M | Aneiros Díaz, A | Arnáiz, S | Arribas, S | Ascunce Vidondo, A | Aguilar, M | Ávila, MA | Bernardo Lambrich, N | Bejr-Kasem, H | Blázquez Estrada, M | Botí, M | Borrue, C | Buongiorno, MT | Cabello González, C | Cabo López, I | Caballol, N | Cámara Lorenzo, A | Carrillo, F | Carrillo Padilla, FJ | Casas, E | Catalán, MJ | Clavero, P | Cortina Fernández, A | Cosgaya, M | Cots Foraster, A | Crespo Cuevas, A | Cubo, E | de Deus Fonticoba, T | de Fábregues-Boixar, O | Díez-Fairen, M | Erro, E | Escalante, S | Estelrich Peyret, E | Fernández Guillán, N | Gámez, P | Gallego, M | García Caldentey, J | García Campos, C | García Moreno, JM | Gastón, I | Gómez Garre, MP | Gómez Mayordomo, V | González Aloy, J | González-Aramburu, I | González Ardura, J | González García, B | González Palmás, MJ | González Toledo, GR | Golpe Díaz, A | Grau Solá, M | Guardia, G | Hernández Vara, J | Horta-Barba, A | Idoate Calderón, D | Infante, J | Jesús, S | Kulisevsky, J | Kurtis, M | Labandeira, C | Labrador, MA | Lacruz, F | Lage Castro, M | Lastres Gómez, S | Legarda, I | López Ariztegui, N | López Díaz, LM | López Manzanares, L | López Seoane, B | Lucas del Pozo, S | Macías, Y | Mata, M | Martí Andres, G | Martí, MJ | Martínez Castrillo, JC | Martinez-Martin, P | McAfee, D | Meitín, MT | Menéndez González, M | Méndez del Barrio, C | Mir, P | Miranda Santiago, J | Morales Casado, MI | Moreno Diéguez, A | Nogueira, V | Novo Amado, A | Novo Ponte, S | Ordás, C | Pagonabarraga, J | Pareés, I | Pascual-Sedano, B | Pastor, P | Pérez Fuertes, A | Pérez Noguera, R | Planas-Ballvé, A | Planellas, L | Prats, MA | Prieto Jurczynska, C | Puente, V | Pueyo Morlans, M | Redondo Rafales, N | Rodríguez Méndez, L | Rodríguez Pérez, AB | Roldán, F | Ruíz De Arcos, M | Ruíz Martínez, J | Sánchez Alonso, P | Sánchez-Carpintero, M | Sánchez Díez, G | Sánchez Rodríguez, A | Santacruz, P | Santos García, D | Segundo Rodríguez, JC | Seijo, M | Sierra Peña, M | Solano Vila, B | Suárez Castro, E | Tartari, JP | Valero, C | Vargas, L | Vela, L | Villanueva, C | Vives, B | Villar, MD

Article Type: Research Article

Abstract: Background: The asymmetry of motor manifestations present in Parkinson’s disease (PD) suggests the existence of differences between both hemispheres. As a consequence, this asymmetry might contribute to different PD clinical phenotypes. Objective: To study the relationship between motor symptom laterality with motor, non-motor symptoms (NMS), freezing of gait (FOG), and quality of life (QoL) impairment in PD. Methods: In this cross-sectional study, we measured motor symptoms severity and complications with the Unified Parkinsons’ disease Rating Scale (UPDRS), FOG with the FOG questionnaire, QoL with the 39-item PD Quality of Life Questionnaire Summary Index, and NMS with …the NMS, Visual Analogue Scales for Pain and Fatigue, Beck Depression Inventory-II, Impulsive-Compulsive Disorders, and PD Sleep and Cognitive Rating scales. We defined left and right motor laterality using the UPDRS part III. We used comparative, regression, and effect size analyses to evaluate the impact of asymmetry on motor and NMS, FOG, and QoL. Results: 342 left (LPD) and 310 right (RPD) patients, with a mean age of 62.0±8.8 years, were included. In multivariate regression analysis, LPD was associated with a greater motor (OR = 1,50, 95% CI 1.02–2.21), FOG (OR = 1.56, 95% CI 1.01–2.41), and overall NMS impairment (OR = 1.43, 95% CI 1.001–2.06), and better QoL (OR = 0.52 95% CI 0.32–0.85). Overall, only a mild effect size was found for all comparisons in which significant differences were present. Conclusion: In this large multicenter study, motor symptom laterality seems to carry a mild but significant impact on PD clinical manifestations, and QoL. Show more

Keywords: Parkinson’s disease, asymmetry, motor, non-motor symptoms, quality of life

DOI: 10.3233/JPD-202067

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1611-1620, 2020

Authors: Vela-Desojo, Lydia | Urso, Daniele | Kurtis-Urra, Monica | García-Ruiz, Pedro J. | Pérez-Fernández, Elia | Lopez-Valdes, Eva | Posada-Rodriguez, Ignacio | Ybot-Gorrin, Isabel | Lopez-Manzanares, Lydia | Mata, Marina | Borrue, Carmen | Ruiz- Huete, Cristina | del Valle, Maria | Martinez-Castrillo, Juan Carlos

Article Type: Research Article

Abstract: Background: Sexual dysfunction (SD) is one of the least studied non-motor symptoms in Parkinson’s disease (PD). Objectives: To assess sexual function in a cohort of patients with early-onset PD (EOPD) and compare it to a group of healthy controls. Methods: In this cross-sectional multicenter study, SD was assessed with gender-specific multi-dimensional self-reported questionnaires: The Brief Male Sexual Function Inventory (BSFI-M) and the Female Sexual Function Index (FSFI). Scores between patients and controls were compared and associations between SD and demographical and clinical variables were studied. Results: One hundred and five patients (mean age 47.35±7.8, …disease duration 6 (3–11) years, UPDRS part III 17 (10–23) and 90 controls were recruited. The BSFI-M total score was lower in EOPD men than in controls, and specific items were also significantly lower, such as drive, erections, ejaculation, and satisfaction. EOPD women had lower scores than controls in total FSFI, and certain domains such as lubrication and pain. SD was present in 70.2% of patients and 52.5% of controls. Sexual satisfaction in 35.2% of patients and 81.2% of controls. By gender, male and female patients had more SD than controls but only male patients had more dissatisfaction than controls. Gender, higher depression scores and urinary dysfunction were associated with SD in multivariate analysis; and gender, UPDRS and urinary dysfunction with sexual satisfaction Conclusion: In this Spanish cohort, SD and sexual dissatisfaction was more prevalent in EOPD patients than in the general population. Gender and urinary disfunction were associated with SD and sexual dissatisfaction. Show more

Keywords: Sexual dysfunction, sexual satisfaction, non-motor symptoms, Parkinson’s disease, EOPD

DOI: 10.3233/JPD-202066

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1621-1629, 2020

Authors: Lennaerts-Kats, Herma | Ebenau, Anne | Steppe, Maxime | van der Steen, Jenny T. | Meinders, Marjan J. | Vissers, Kris | Munneke, Marten | Groot, Marieke | Bloem, Bastiaan R.

Article Type: Research Article

Abstract: Background: Family caregivers provide the majority of care for people with Parkinson’s disease (PD) in the palliative care phase. For many this is a demanding experience, affecting their quality of life. Objective: We set out to map the experiences of bereaved family caregivers during the period of informal care in the palliative care phase as well as after the death of their loved one with PD. Methods: Ten bereaved family caregivers participated in this qualitative study. Semi-structured interviews were conducted and interpretative phenomenological analysis was used executed. Results: We identified four main themes. 1) …Feeling like a professional caregiver: while caring for a person with PD, the family caregivers took over many roles and tasks of the person with PD. 2) Healthcare professionals do not always know what PD really means: most interviewees had negative experiences with knowledge and understanding of PD of, especially, (practice) nurses. 3) Being on your own: many respondents had felt highly responsible for their loved one’s care and lacked time and space for themselves. Grief and feelings of guilt were present during the caregiving period and after death. 4) Being behind the times: to provide palliative care in line with patients’ preferences and to feel prepared for the palliative care phase of PD, proactive palliative care planning was considered important. However, the interviewees told that this was most often not provided. Conclusion: These findings indicate that caring for a person with PD in the palliative care phase is a demanding experience for family caregivers. They experience psychological problems for many years before and after the death of the person with PD. Increasing healthcare professionals’ awareness of family and bereaved caregivers’ needs may mitigate these long-term detrimental effects. Show more

Keywords: Anticipatory bereavement, bereaved family caregivers, grief, palliative care, Parkinson’s disease, post-caregiving

DOI: 10.3233/JPD-191884

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1631-1642, 2020

Authors: Gryc, Wojciech | Roberts, Kathryn A. | Zabetian, Cyrus P. | Weintraub, Daniel | Trojanowski, John Q. | Quinn, Joseph F. | Hiller, Amie L. | Chung, Kathryn A. | Poston, Kathleen L. | Yang, Laurice | Hu, Shu-Ching | Edwards, Karen L. | Montine, Thomas J. | Cholerton, Brenna A.

Article Type: Short Communication

Abstract: Neuropsychiatric symptoms are common in Parkinson’s disease (PD). We investigated the relationship between neuropsychiatric symptoms and current and future diagnosis of PD dementia (PDD). Individuals with PD who had a study partner were enrolled (n  = 696). Study partners were administered the Neuropsychiatric Inventory or Neuropsychiatric Inventory Questionnaire at baseline. Participants were assigned a cognitive diagnosis at baseline and follow up visits. Hallucinations were significantly associated with a diagnosis of PDD cross-sectionally (p  < 0.001) and with shortened time to dementia longitudinally among initially nondemented participants (n  = 444; p  = 0.005). Screening for hallucinations may be useful for assessing risk of dementia in …participants with PD. Show more

Keywords: Behavioral symptoms, cognition, dementia, hallucinations, Parkinson’s disease

DOI: 10.3233/JPD-202116

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1643-1648, 2020

Authors: Fardell, Camilla | Torén, Kjell | Schiöler, Linus | Nissbrandt, Hans | Åberg, Maria

Article Type: Research Article

Abstract: Background: High education level and high occupational complexity have been implicated as risk factors for Parkinson’s disease (PD). Objective: The objective was to determine whether cognitive capacity, measured as IQ, in early adulthood is associated with the subsequent development of PD. Method: Data on IQ were retrieved from the Swedish Military Service Conscription Registry, comprising Swedish males who enlisted for military service in the period 1968–1993 (N = 1,319,235). After exclusion, 1,189,134 subjects in total were included in the present study. Individuals who later developed PD (N = 1,724) were identified using the Swedish National Patient Register and the Swedish …Cause of Death Register. Results: High education level was associated with PD. High IQ was associated with PD (p  < 0.0001), both when analyzed as a continuous variable and when divided into three categories. The hazard ratio for the high IQ category compared to the low IQ category was 1.35 (95% confidence interval 1.17–1.55). Strong test results on the subtests, measuring verbal, logic, visuospatial and technical abilities, were also associated with PD. In a subgroup, smoking was inversely associated with PD, as well as with IQ. Conclusions: This study identifies high IQ to be a risk factor for PD. Show more

Keywords: Parkinson’s disease, IQ, cognition, smoking, education

DOI: 10.3233/JPD-202050

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1649-1656, 2020

Authors: Glover, Aliyah | Pillai, Lakshmi | Doerhoff, Shannon | Virmani, Tuhin

Article Type: Research Article

Abstract: Background: Freezing of gait (FOG) is a debilitating feature of Parkinson’s disease (PD) for which treatments are limited. To develop neuroprotective strategies, determining whether disease progression is different in phenotypic variants of PD is essential. Objective: To determine if freezers have a faster decline in spatiotemporal gait parameters. Methods: Subjects were enrolled in a longitudinal study and assessed every 3– 6 months. Continuous gait in the levodopa ON-state was collected using a gait mat (Protokinetics). The slope of change/year in spatiotemporal gait parameters was calculated. Results: 26 freezers, 31 non-freezers, and 25 controls completed …an average of 6 visits over 28 months. Freezers had a faster decline in mean stride-length, stride-velocity, swing-%, single-support-%, and variability in single-support-% compared to non-freezers (p  < 0.05). Gait decline was not correlated with initial levodopa dose, duration of levodopa therapy, change in levodopa dose or change in Montreal Cognitive Assessment scores (p  > 0.25). Gait progression parameters were required to obtain 95% accuracy in categorizing freezers and non-freezers groups in a forward step-wise binary regression model. Change in mean stride-length, mean stride-width, and swing-% variability along with initial foot-length variability, mean swing-% and apathy scores were significant variables in the model. Conclusion: Freezers had a faster temporal decline in objectively quantified gait, and inclusion of longitudinal gait changes in a binary regression model greatly increased categorization accuracy. Levodopa dosing, cognitive decline and disease severity were not significant in our model. Early detection of this differential decline may help define freezing prone groups for testing putative treatments. Show more

Keywords: Freezing of gait, gait, falls, Parkinson’s disease, predictive modeling

DOI: 10.3233/JPD-201961

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1657-1673, 2020

Authors: Weersink, Joyce B. | Gefferie, Silvano R. | van Laar, Teus | Maurits, Natasha M. | de Jong, Bauke M.

Article Type: Research Article

Abstract: Background: The supplementary motor area (SMA) is implicated in both motor initiation and stereotypic multi-limb movements such as walking with arm swing. Gait in Parkinson’s disease exhibits starting difficulties and reduced arm swing, consistent with reduced SMA activity. Objective: We tested whether enhanced arm swing could improve Parkinson gait initiation and assessed whether increased SMA activity during preparation might facilitate such improvement. Methods: Effects of instructed arm swing on cortical activity, muscle activity and kinematics were assessed by ambulant EEG, EMG, accelerometers and video in 17 Parkinson patients and 19 controls. At baseline, all participants repeatedly …started walking after a simple auditory cue. Next, patients started walking at this cue, which now meant starting with enhanced arm swing. EEG changes over the putative SMA and leg motor cortex were assessed by event related spectral perturbation (ERSP) analysis of recordings at Fz and Cz. Results: Over the putative SMA location (Fz), natural PD gait initiation showed enhanced alpha/theta synchronization around the auditory cue, and reduced alpha/beta desynchronization during gait preparation and movement onset, compared to controls. Leg muscle activity in patients was reduced during preparation and movement onset, while the latter was delayed compared to controls. When starting with enhanced arm swing, these group differences virtually disappeared. Conclusion: Instructed arm swing improves Parkinson gait initiation. ERSP normalization around the cue indicates that the attributed information may serve as a semi-internal cue, recruiting an internalized motor program to overcome initiation difficulties. Show more

Keywords: Arm swing, Parkinson’s disease, gait initiation, supplementary motor area, ambulant electroencephalography

DOI: 10.3233/JPD-202112

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1675-1693, 2020

Authors: Ngo, Angeline B. | Smith, Kara M.

Article Type: Short Communication

Abstract: We investigated patient and clinician impressions of cognitive impairment and whether they correlated with objective measures of cognitive impairment. Cognitive categorization, neuropsychological assessment scores, and Montreal Cognitive Assessment scores were documented at baseline, 3 years, and 7 years for 388 PD patients in the Parkinson’s Progression Markers Initiative (PPMI). We found that both patient and clinician impressions of cognitive decline were significantly associated with gold-standard criteria for cognitive impairment to a similar degree. Both patient and clinician perspectives should be considered in determining cognitive status and should be followed up with diagnostic testing.

Keywords: Cognitive impairment, subjective cognitive decline, Parkinson’s disease, Parkinson’s progression markers initiative

DOI: 10.3233/JPD-202110

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1695-1698, 2020

Authors: Ruck, Laura | Unger, Marcus M. | Spiegel, Jörg | Bürmann, Jan | Dillmann, Ulrich | Faßbender, Klaus | Reith, Wolfgang | Backens, Martin | Mühl-Benninghaus, Ruben | Yilmaz, Umut

Article Type: Research Article

Abstract: Background: Altered gastric motility is a frequent non-motor symptom of Parkinson’s disease (PD). It has been hypothesized that disturbed gastric motility contributes to motor fluctuations in PD due to an erratic gastro-duodenal transport and an unpredictable absorption of drugs. Objective: We investigated whether patient-reported fluctuations are associated with parameters of gastric motility visualized by real-time magnetic resonance imaging (MRI) of the stomach. Methods: We analyzed real-time MRI-scans of the stomach after an overnight fasting period in 16 PD patients and 20 controls. MRI was performed 1) in the fasting state, 2) directly after a test meal, …and 3) 4 hours postprandially. Gastric motility indices were calculated and compared between groups. Results: MRI showed an attenuated gastric motility in PD patients compared to controls. The difference was most obvious in the early postprandial phase. Gastric motility was not associated with patient-reported motor fluctuations. Using an iron-containing capsule we were able to retrace retention of drugs in the stomach. Conclusion: The results of this study stress the importance of considering the phase of digestion when investigating gastric motility in PD. Despite theoretical considerations, we did not find robust evidence for an association between MRI parameters of gastric motility and patient-reported motor fluctuations. For future studies that aim to investigate gastric motility in PD by MRI, we suggest multiple short-time MRIs to better track the whole gastro-duodenal phase in PD. Such an approach would also allow to retrace the retention of drugs in the stomach as shown by our approach using an iron-containing capsule. Show more

Keywords: Parkinson’s disease, gastrointestinal motility, stomach, real-time magnetic resonance imaging

DOI: 10.3233/JPD-202144

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1699-1707, 2020

Authors: Di Luca, Daniel G. | Sambursky, Jacob A. | Margolesky, Jason | Cordeiro, Joacir Graciolli | Diaz, Anthony | Shpiner, Danielle S. | Moore, Henry P. | Singer, Carlos | Luca, Corneliu

Article Type: Research Article

Abstract: Background: Randomized clinical trials (RCTs) in Parkinson’s disease (PD) have historically enrolled a low number of underrepresented minorities, lessening the generalizability of therapeutic developments. Although there are racial disparities in PD, little is known regarding neuropsychiatric symptoms and other nonmotor manifestations across all races/ethnicities. Objective: To assess minority participation in PD trials evaluating the treatment of neuropsychiatric symptoms and explore underlying reasons. Methods: We systematically searched PubMed and Embase for RCTs with a primary goal of treating neuropsychiatric symptoms in PD patients from 2000-2019. The pooled prevalence and 95% confidence interval (CI) of being white and …enrolled in a clinical trial was calculated using the inverse variance method. I-square was calculated as a measure of heterogeneity and meta-regression was used to evaluate temporal trends. Results: We included 63 RCTs with a total of 7,973 patients. In pooled analysis, 11 (17.5%) RCTs reported race/ethnicity. Of studies reporting this data, 5 African American (0.2%), 16 Hispanics (0.64%), and 539 Asians (21.44%) were enrolled. The pooled prevalence of being white in clinical trials was 98% (CI 0.97–0.98, p  < 0.001), with 1,908 patients (75.8%). NIH-funded studies were most likely to report racial data when compared to non-NIH trials (p  = 0.032). Conclusion: This large pooled analysis found a small percentage of RCTs reporting race/ethnicity when evaluating treatment of neuropsychiatric symptoms in PD. There was a disproportionally high number of white patients when compared to African Americans and Hispanics. More studies are needed to investigate this discrepancy and improve rates of & minority enrollment in PD trials. Show more

Keywords: Health care disparities, meta-analysis, neuropsychiatry, Parkinson’s disease, randomized clinical trials

DOI: 10.3233/JPD-202045

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1709-1716, 2020

Authors: Del Pino, Rocio | Díez-Cirarda, Maria | Peña, Javier | Ibarretxe-Bilbao, Naroa | Ojeda, Natalia

Article Type: Research Article

Abstract: Background: The estimation of premorbid intelligence (PI) is needed for an accurate diagnosis. Objective: This study aimed to estimate the cognitive performance taking into account the PI in Parkinson’s disease (PD) compared to healthy controls (HC); and to analyze the discrepancies between the current and the predicted cognitive performance based on the PI. Method: Semantic fluency, verbal and visual memory, and executive functions were assessed in 39 PD and 162 HC. A linear regression model was used to analyze the discrepancies between the predicted cognitive performance and the current raw scores through PI variables (Word Accentuation …Test (WAT), Pseudo-Words (PW) Reading subtest from PROLEC-R, age, and years of education). ROC analyses were performed to assess their diagnostic properties. Results: Significant differences were found in the raw cognitive scores between patients and HC [semantic fluency (t  = 6.07; p  < 0.001), verbal memory (t  = 6.63; p  < 0.001), and executive functions (t  = 2.57; p  = 0.013), and in visual memory (t  = 1.97; p  = 0.055 marginally significant)]. Compared to HC, PD patients presented higher discrepancies between the predicted cognitive performance and the raw scores in semantic fluency, verbal memory, visual memory, executive functions (AUC = 0.78, 0.78; 0.64, 0.61, respectively). Conclusion: The magnitude of the discrepancies scores between the current and the predicted cognitive performance based on PI indicates the presence of cognitive decline in the specific cognitive domain in PD patients. This study underlines the usefulness of premorbid measures and variables, such as WAT, PW, age, and years of education, to more accurately estimate the cognitive performance in PD. Show more

Keywords: Neuropsychological assessment, Parkinson’s disease, premorbid intelligence, pseudo-words, WAT

DOI: 10.3233/JPD-202142

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1717-1725, 2020

Authors: Claus, Inga | Muhle, Paul | Suttrup, Judith | Labeit, Bendix | Suntrup-Krueger, Sonja | Dziewas, Rainer | Warnecke, Tobias

Article Type: Research Article

Abstract: Background: Diagnosis of pharyngeal dysphagia in patients with Parkinson’s disease is often difficult as reliable screening methods are lacking so far and clinical examination fails to adequately assess the pharyngeal phase of swallowing. Objective: To identify clinical predictors indicating the presence of pharyngeal dysphagia in patients at risk. Methods: We examined pharyngeal dysphagia in a large cohort of patients with Parkinson’s disease (n  = 200) divided in three clinical subtypes (tremor-dominant (TD), mainly bradykinetic (BK) and early postural instability and gait difficulty PIGD)) by using flexible endoscopic evaluation of swallowing. ANOVA-multivariance analysis and following t -tests as …well as binary logistic regression analysis were performed to detect group differences and to identify clinical predictors for dysphagia. Results: Statistically significant differences were found in the dysphagic group: age, male gender, disease duration, stage of the disease, Levodopa equivalent dose and higher scores on the Unified Parkinson’s disease rating scale III and II, item 7. The PIGD subtype was affected more frequently than the TD and BK subtype. In a logistic regression model higher age (>63.5 years p  < 0.05) and Levodopa equivalent dose (>475 mg, p  < 0.01) were identified to be independent predictors for the presence of pharyngeal dysphagia. Conclusion: Particularly patients with an age > 63.5 years and a daily Levodopa equivalent dose >475 mg show an increased risk for pharyngeal dysphagia. These findings may partly be influenced by presbyphagia but are likely to represent disease progression. The PIGD subtype seems to be a risk factor due to more pronounced dyscoordination of oropharyngeal muscle movements. Show more

Keywords: Parkinson’s disease, oropharyngeal dysphagia, deglutition disorders, swallowing disorders

DOI: 10.3233/JPD-202081

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1727-1735, 2020

Authors: Tang, Chris C. | Holtbernd, Florian | Ma, Yilong | Spetsieris, Phoebe | Oh, Alice | Fink, Gereon R. | Timmermann, Lars | Eggers, Carsten | Eidelberg, David

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is characterized by brain metabolic networks, specifically associated with motor and cognitive manifestations. Few studies have investigated network changes in cerebral hemispheres ipsilateral and contralateral to the clinically more affected body side. Objective: We examined hemispheric network abnormalities and their relationship to striatal dopaminergic deficits in PD patients at different stages. Methods: 45 PD patients underwent dual-tracer positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG) and 18 F-fluorodopa (FDOPA) in a high-resolution PET scanner. In all patients, we computed expression levels for the PD-related motor/cognition metabolic patterns (PDRP/PDCP) as well as putamen/caudate …FDOPA uptake values in both hemispheres. Resulting hemispheric measures in the PD group were compared with corresponding healthy control values and assessed across disease stages. Results: Hemispheric PDRP and PDCP expression was significantly elevated contralateral and ipsilateral to the more affected body side in patients with unilateral symptoms (H&Y 1: p  < 0.01) and in patients with bilateral limb involvement (H&Y 2-3: p  < 0.001; H&Y 4: p  < 0.003). Elevations in pattern expression were symmetrical at all disease stages. By contrast, FDOPA uptake in the caudate and putamen was reduced bilaterally (p  < 0.002), with lower values on both sides at more advanced disease stages. Hemispheric uptake was asymmetrical in both striatal regions, with lower contralateral values at all disease stages. The magnitude of hemispheric uptake asymmetry was smaller with more advanced disease, reflecting greater change ipsilaterally. Conclusion: Symmetrical network expression in PD represents bilateral functional effects unrelated to nigrostriatal dopaminergic asymmetries. Show more

Keywords: Parkinson’s disease, brain metabolic networks, PET, brain metabolism, dopaminergic function

DOI: 10.3233/JPD-202117

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1737-1749, 2020

Authors: DeKarske, Daryl | Alva, Gustavo | Aldred, Jason L. | Coate, Bruce | Cantillon, Marc | Jacobi, Lori | Nunez, Rene | Norton, James C. | Abler, Victor

Article Type: Research Article

Abstract: Background: Many patients with Parkinson’s disease (PD) experience depression. Objective: Evaluate pimavanserin treatment for depression in patients with PD. Methods: Pimavanserin was administered as monotherapy or adjunctive therapy to a selective serotonin reuptake inhibitor or serotonin/noradrenaline reuptake inhibitor in this 8-week, single-arm, open-label phase 2 study (NCT03482882). The primary endpoint was change from baseline to week 8 in Hamilton Depression Scale–17-item version (HAMD-17) score. Safety, including collection of adverse events and the Mini-Mental State Examination (MMSE) and Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS III) scores, was assessed in …patients who received ≥1 pimavanserin dose. Results: Efficacy was evaluated in 45 patients (21 monotherapy, 24 adjunctive therapy). Mean (SE) baseline HAMD-17 was 19.2 (3.1). Change from baseline to week 8 (least squares [LS] mean [SE]) in the HAMD-17 was –10.8 (0.63) (95% CI, –12.0 to –9.5; p  < 0.0001) with significant improvement seen at week 2 (p  < 0.0001) and for both monotherapy (week 8, –11.2 [0.99]) and adjunctive therapy (week 8,–10.2 [0.78]). Most patients (60.0%) had ≥50% improvement at week 8, and 44.4% of patients reached remission (HAMD-17 score ≤7). Twenty-one of 47 patients experienced 42 treatment-emergent adverse events; the most common by system organ class were gastrointestinal (n  = 7; 14.9%) and psychiatric (n  = 7; 14.9%). No negative effects were observed on MMSE or MDS-UPDRS Part III. Conclusion: In this 8-week, single-arm, open-label study, pimavanserin as monotherapy or adjunctive therapy was well tolerated and associated with early and sustained improvement of depressive symptoms in patients with PD. Show more

Keywords: Parkinson’s disease, depression, dementia, pimavanserin, adjunctive therapy, monotherapy

DOI: 10.3233/JPD-202058

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1751-1761, 2020

Authors: Gaßner, Heiko | Sanders, Philipp | Dietrich, Alisa | Marxreiter, Franz | Eskofier, Bjoern M. | Winkler, Jürgen | Klucken, Jochen

Article Type: Research Article

Abstract: Background: Gait impairments in Parkinson’s disease (PD) are quantified using inertial sensors under standardized test settings in the hospital. Recent studies focused on the assessment of free-living gait in PD. However, the clinical relevance of standardized gait tests recorded at the patient’s home is unclear. Objective: To evaluate the reliability of supervised, standardized sensor-based gait outcomes at home compared to the hospital. Methods: Patients with PD (n  = 20) were rated by a trained investigator using the Unified Parkinson Disease Rating Scale (UPDRS-III). Gait tests included a standardized 4×10 m walk test and the Timed Up and Go …Test (TUG). Tests were performed in the hospital (HOSPITAL) and at patients’ home (HOME), and controlled for investigator, time of the day, and medication. Statistics included reliability analysis using Intra-Class correlations and Bland-Altman plots. Results: UPDRS-III and TUG were comparable between HOSPITAL and HOME. PD patients’ gait at HOME was slower (gait velocity Δ = –0.07±0.11 m/s, –6.1%), strides were shorter (stride length Δ = –9.2±9.4 cm; –7.3%), and shuffling of gait was more present (maximum toe-clearance Δ = –0.7±2.5 cm; –8.8%). Particularly, narrow walkways (<85 cm) resulted in a significant reduction of gait velocity at home. Reliability analysis (HOSPITAL vs. HOME) revealed excellent ICC coefficients for UPDRS-III (0.950, p  < 0.000) and gait parameters (e.g., stride length: 0.898, p  < 0.000; gait velocity: 0.914, p  < 0.000; stance time: 0.922, p  < 0.000; stride time: 0.907, p  < 0.000). Conclusion: This pilot study underlined the clinical relevance of gait parameters by showing excellent reliability for supervised, standardized gait tests at HOSPITAL and HOME, even though gait parameters were different between test conditions. Show more

Keywords: Parkinson’s disease, gait analysis, wearable sensors, telemedicine, home monitoring

DOI: 10.3233/JPD-202129

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1763-1773, 2020

Authors: Tosserams, Anouk | Nijkrake, Maarten J. | Sturkenboom, Ingrid H.W.M. | Bloem, Bastiaan R. | Nonnekes, Jorik

Article Type: Short Communication

Abstract: Compensation strategies are an essential part of managing gait impairments in people with Parkinson’s disease (PD). We conducted an online survey among 320 healthcare professionals with specific expertise in PD management, to evaluate their knowledge of compensation strategies for gait impairments in people with PD, and whether they applied these in daily practice. Only 35% of professionals was aware of all categories of compensation strategies. Importantly, just 23% actually applied all seven available categories of strategies when treating people with PD in clinical practice. We discuss the clinical implications, and provide recommendations to overcome this knowledge gap.

Keywords: Parkinson’s disease, rehabilitation, compensation strategies, healthcare, survey

DOI: 10.3233/JPD-202176

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1775-1778, 2020

Authors: Tarolli, Christopher G. | Andrzejewski, Kelly | Zimmerman, Grace A. | Bull, Michael | Goldenthal, Steven | Auinger, Peggy | O’Brien, Michael | Dorsey, E. Ray | Biglan, Kevin | Simuni, Tanya

Article Type: Research Article

Abstract: Background: There is rising interest in remote clinical trial assessments, particularly in the setting of the COVID-19 pandemic. Objective: To demonstrate the feasibility, reliability, and value of remote visits in a phase III clinical trial of individuals with Parkinson’s disease. Methods: We invited individuals with Parkinson’s disease enrolled in a phase III clinical trial (STEADY-PD III) to enroll in a sub-study of remote video-based visits. Participants completed three remote visits over one year within four weeks of an in-person visit and completed assessments performed during the remote visit. We evaluated the ability to complete scheduled assessments …remotely; agreement between remote and in-person outcome measures; and opinions of remote visits. Results: We enrolled 40 participants (mean (SD) age 64.3 (10.4), 29% women), and 38 (95%) completed all remote visits. There was excellent correlation (ICC 0.81–0.87) between remote and in-person patient-reported outcomes, and moderate correlation (ICC 0.43–0.51) between remote and in-person motor assessments. On average, remote visits took around one quarter of the time of in-person visits (54 vs 190 minutes). Nearly all participants liked remote visits, and three-quarters said they would be more likely to participate in future trials if some visits could be conducted remotely. Conclusion: Remote visits are feasible and reliable in a phase III clinical trial of individuals with early, untreated Parkinson’s disease. These visits are shorter, reduce participant burden, and enable safe conduct of research visits, which is especially important in the COVID-19 pandemic. Show more

Keywords: Clinical trial protocol, Parkinson’s disease, phase III clinical trial, technology, telemedicine

DOI: 10.3233/JPD-202163

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1779-1786, 2020

Authors: Pona-Ferreira, Joana | Ferreira, Joaquim J.

Article Type: Letter

DOI: 10.3233/JPD-202226

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1787-1788, 2020

Authors: Cao, Zichun | Luo, Zhehui | Huang, Xuemei | Pinto, Jayant M. | Simonsick, Eleanor M. | Shiroma, Eric J. | Chen, Honglei

Article Type: Research Article

Abstract: Background: Poor olfaction is a prodromal symptom of Parkinson’s disease (PD); however, self-reported sense of smell is often dismissed as unreliable. Objective: To assess self-reported and objectively assessed sense of smell, independently and jointly, in relation to future risk for PD. Methods: We conducted a prospective analysis using data from 2,424 participants, ages 71–82 at baseline, from the Health, Aging, and Body Composition study. Exposures were self-reported poor sense of smell or taste and the objectively measured 12-item Brief Smell Identification Test score. The outcome was incident PD, analyzed using Cox proportional hazard models adjusted for …age, sex, race, and cognitive function. Results: After approximately 10 years of follow-up, both self-reported and objectively tested poor sense of smell were independently associated with a higher risk of developing PD: the hazard ratios (95% confidence interval) were 2.8 (1.3, 5.9) and 4.0 (2.1, 7.5), respectively. When analyzed jointly, compared with participants who reported and tested normal, the hazard ratio was 2.2 (1.0, 4.6) for those reported poor sense of smell but tested normal, 3.6 (1.9, 6.9) for reported normal but tested poor, and 7.8 (3.2, 19.4) for both reported and tested poor. We did not find significant interactions between self-reported and objectively tested sense of smell in predicting PD risk. Conclusion: This study provides preliminary evidence that self-reported poor sense of smell or taste should not be simply dismissed as useless in predicting risk of PD. Future studies should confirm our finding and evaluate whether structured questionnaires may further improve the predictability. Show more

Keywords: Parkinson’s disease, self-report, olfaction, sense of smell

DOI: 10.3233/JPD-202164

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1789-1795, 2020

Authors: Diederich, Nico J. | Sauvageot, Nicolas | Pieri, Vannina | Hipp, Géraldine | Vaillant, Michel

Article Type: Research Article

Abstract: Background: Non-motor symptoms (NMS) of various anatomical origins are seen in early stage idiopathic Parkinson’s disease (IPD). Objective: To analyse when and how NMS are linked together at this stage of the disease. Methods: Prospective study recruiting 64 IPD patients with ≤3 years of disease duration and 71 age-matched healthy controls (HC). NMS were clustered in 7 non-motor domains (NMD): general cognition, executive function, visuospatial function, autonomic function, olfaction, mood, and sleep. Correlation coefficients ≥|0.3| were considered as significant. Bootstrapped correlation coefficients between the scores were generated in both groups. Fourteen IPD patients and 19 HC …were available for a follow-up study two years later. Results: The mean age of both groups was similar. 58% of IPD patients and 37% of HC were male (p  = 0.01). At baseline IPD patients performed less well than HC on all NMD (p value between 0.0001 and 0.02). Out of 91 possible correlations between NMD, 21 were significant in IPD patients and 14 in HC at the level of ≥|0.3|. The mean correlation level was higher in IPD patients than in HC, as evidenced by the higher box plot of correlation coefficients. Visuospatial scores at baseline were predictive of the motor deterioration at the follow-up exam. Conclusion: At early IPD stage various NMS are linked together, although not connected by anatomical networks. Such a clinical NMD connectome suggests almost synchronous disease initiation at different sites as also supported by fMRI findings. Alternatively, there may be compensation-driven interconnectivity of NMD. Show more

Keywords: Parkinson’s disease, non-motor symptoms, connectome, compensation

DOI: 10.3233/JPD-202102

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1797-1806, 2020

Authors: Fernandez-Baizan, Cristina | Paula Fernandez Garcia, M. | Diaz-Caceres, Elena | Menendez-Gonzalez, Manuel | Arias, Jorge L. | Mendez, Marta

Article Type: Research Article

Abstract: Background: Visuospatial skills are impaired in Parkinson’s disease (PD). Other related skills exist, such as spatial orientation have been poorly studied. The egocentric (based on internal cues) and allocentric frameworks (based on external cues) are used in daily spatial orientation. Depending on PD onset, the allocentric framework may have a higher level of impairment in tremor-dominant and the egocentric one in akinetic-rigid. Objective: To evaluate spatial orientation and visuospatial functions in PD patients and controls, and to assess whether their performance is related to disease duration and the PD subtype (tremor-dominant and akinetic-rigid). Methods: We evaluated …egocentric and allocentric spatial orientation (Egocentric and Allocentric Spatial Memory Tasks) and visuospatial abilities, span and working memory in 59 PD patients and 51 healthy controls. Results: Visuospatial skills, visuospatial span, and egocentric and allocentric orientation are affected in PD. Visuospatial skills and allocentric orientation undergo deterioration during the first 5 years of the disease progression, while egocentric orientation and visuospatial span do so at later stages (9–11 years). The akinetic-rigid subtype presents worse results in all the spatial abilities that were measured when compared to controls, and worse scores in visuospatial working memory, visuospatial abilities and allocentric orientation when compared to the tremor-dominant group. The tremor-dominant group performed worse than controls in egocentric and allocentric orientation. Conclusion: PD patients show deficits in their visuospatial abilities and in their egocentric and allocentric spatial orientation compared to controls, specifically in akinetic-rigid PD. Only spatial orientation are affected in tremor-dominant PD patients. Allocentric orientation is affected earlier in the progression of the disease. Show more

Keywords: Parkinson’s disease, spatial frameworks, spatial orientation, spatial learning

DOI: 10.3233/JPD-202122

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1807-1816, 2020

Authors: Ghosh, Pritha | Imbriani, Paola | Caputi, Nicoletta | Natoli, Silvia | Schirinzi, Tommaso | Di Lazzaro, Giulia | Covington, Lindsey | Sparks, Andrew D. | Salnikova, Yekaterina | Rukavina, Katarina | Ray Chaudhuri, K. | Pisani, Antonio

Article Type: Research Article

Abstract: Background: Pain is a disabling and often underestimated non-motor symptom (NMS) detrimentally affecting the quality of life of patients with Parkinson’s disease (PD). Objective: Here, we conducted a cross-sectional, observational international study on 167 patients with idiopathic PD in order to analyze the potential relationship between pain and other NMS. Methods: Subjects were assessed with the Unified Parkinson’s Disease Rating Scale (UPDRS) part III, Hoehn and Yahr (H&Y) stage, King’s Parkinson’s Disease Pain Scale (KPPS), Brief Pain Inventory (BPI), Non-Motor Symptoms Scale (NMSS), and Beck Depression Inventory (BDI). Spearman’s rank correlation coefficient, multiple regression and multiple …index-based clustering algorithms were used for data analysis. Results: The prevalence of pain was 88.6%, was not correlated with age, motor severity (UPDRS part III) or disease duration, whereas a weak correlation with female gender and H&Y stage >2.5 was found. Multiple NMS correlated significantly with pain. Specifically, sleep disturbance had the strongest correlation with pain, followed by depression, gastrointestinal and cardiovascular disturbances. Further analyses showed that sleep and cardiovascular disturbance were independently associated with pain, and that these symptoms clustered together in a subset of PD patients. The relationship between pain, sleep and dysautonomia persisted independently from dopamine replacement therapy. Conclusion: Our study suggests that sleep disruption and cardiovascular disturbance are associated with pain in PD, and possibly identifies a specific subtype within PD patients with pain. Our data also indicate that sleep disruption, pain and dysautonomia may have a common pathophysiology, possibly involving non-dopaminergic pathways. Show more

Keywords: Neurodegeneration, noradrenergic pathway, pain, parkinsonism, serotonergic pathway

DOI: 10.3233/JPD-202088

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1817-1825, 2020

Authors: Dominey, Thea | Kehagia, Angie A. | Gorst, Terry | Pearson, Emma | Murphy, Fiona | King, Emma | Carroll, Camille

Article Type: Research Article

Abstract: In an effort to provide timely clinical input for people with Parkinson’s disease (PD) in the face of increasing demand and resource limitation in our UK based service, we introduced remote management in place of clinic appointment, including the use of the Parkinson’s KinetiGraph (PKG™), a wrist-worn device that provides a continuous measure of movement. We evaluated our reporting methods and findings, the nature of unmet need we identified, our treatment recommendations and the degree of their implementation in our patients whose feedback guided our service developments. Our evaluation highlighted opportunities and challenges associated with incorporating digital data into care …traditionally delivered via in-person contact. Show more

Keywords: Parkinson’s disease, PKG, remote sensing technology, wearable devices

DOI: 10.3233/JPD-202101

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1827-1832, 2020

Authors: Tamás, Gertrúd | Fabbri, Margherita | Falup-Pecurariu, Cristian | Teodoro, Tiago | Kurtis, Mónica M. | Aliyev, Rahim | Bonello, Michael | Brozova, Hana | Coelho, Miguel Soares | Contarino, Maria Fiorella | Corvol, Jean-Christophe | Dietrichs, Espen | Ben Djebara, Mouna | Elmgreen, Søren Bruno | Groppa, Sergiu | Kadastik-Eerme, Liis | Khatiashvili, Irine | Kostić, Vladimir | Krismer, Florian | Hassan Mansour, Alia | Odin, Per | Gavriliuc, Olga | Olszewska, Diana Angelika | Relja, Maja | Scheperjans, Filip | Skorvanek, Matej | Smilowska, Katarzyna | Taba, Pille | Tavadyan, Zaruhi | Valante, Ramona | Vujovic, Balsa | Waldvogel, Daniel | Yalcin-Cakmakli, Gul | Chitnis, Shilpa | Ferreira, Joaquim J.

Article Type: Research Article

Abstract: Background: Little information is available on the official postgraduate and subspecialty training programs in movement disorders (MD) in Europe and North Africa. Objective: To survey the accessible MD clinical training in these regions. Methods: We designed a survey on clinical training in MD in different medical fields, at postgraduate and specialized levels. We assessed the characteristics of the participants and the facilities for MD care in their respective countries. We examined whether there are structured, or even accredited postgraduate, or subspecialty MD training programs in neurology, neurosurgery, internal medicine, geriatrics, neuroradiology, neuropediatrics, and general practice. Participants …also shared their suggestions and needs. Results: The survey was completed in 31/49 countries. Structured postgraduate MD programs in neurology exist in 20 countries; structured neurology subspecialty training exists in 14 countries and is being developed in two additional countries. Certified neurology subspecialty training was reported to exist in 7 countries. Recommended reading lists, printed books, and other materials are the most popular educational tools, while courses, lectures, webinars, and case presentations are the most popular learning formats. Mandatory activities and skills to be certified were not defined in 15/31 countries. Most participants expressed their need for a mandatory postgraduate MD program and for certified MD sub-specialization programs in neurology. Conclusion: Certified postgraduate and subspecialty training exists only in a minority of European countries and was not found in the surveyed Egypt and Tunisia. MD training should be improved in many countries. Show more

Keywords: Movement disorders, Parkinson’s disease, education, curriculum, neurology

DOI: 10.3233/JPD-202000

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1833-1843, 2020