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

Authors: Beauchamp, Leah C. | Finkelstein, David I. | Bush, Ashley I. | Evans, Andrew H. | Barnham, Kevin J.

Article Type: Review Article

Abstract: Since the initial reports of COVID-19 in December 2019, the world has been gripped by the disastrous acute respiratory disease caused by the SARS-CoV-2 virus. There are an ever-increasing number of reports of neurological symptoms in patients, from severe (encephalitis), to mild (hyposmia), suggesting the potential for neurotropism of SARS-CoV-2. This Perspective investigates the hypothesis that the reliance on self-reporting of hyposmia has resulted in an underestimation of neurological symptoms in COVID-19 patients. While the acute effect of the virus on the nervous system function is vastly overshadowed by the respiratory effects, we propose that it will be important to …monitor convalescent individuals for potential long-term implications that may include neurodegenerative sequelae such as viral-associated parkinsonism. As it is possible to identify premorbid harbingers of Parkinson’s disease, we propose long-term screening of SARS-CoV-2 cases post-recovery for these expressions of neurodegenerative disease. An accurate understanding of the incidence of neurological complications in COVID-19 requires long-term monitoring for sequelae after remission and a strategized health policy to ensure healthcare systems all over the world are prepared for a third wave of the virus in the form of parkinsonism. Show more

Keywords: Parkinson’s disease, parkinsonism, COVID-19, SARS-CoV-2

DOI: 10.3233/JPD-202211

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 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 the 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 nerve fiber layer 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: We demonstrate evidence-based mechanisms 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. Pre-press, no. Pre-press, pp. 1-10, 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 | Mailman, Richard

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. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: van de Wetering-van Dongen, Veerle A. | Kalf, Johanna G. | van der Wees, Philip J. | Bloem, Bastiaan R. | Nijkrake, Maarten J.

Article Type: Review Article

Abstract: Background: Signs of respiratory dysfunction can be present already early in the course of Parkinson’s disease (PD). Respiratory training could alleviate this, but its effectiveness is not well understood. Objective: The purpose of this systematic review is to review the efficacy of different respiratory training interventions in PD. Methods: A search strategy was performed in four databases: PubMed, Physiotherapy Evidence Database (PEDro), Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature (CINAHL). Methodological quality of original full-text articles was assessed using the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) and the …Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for the controlled trials (CTs). Levels of evidence were rated by the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Results: Six papers reporting on four randomized controlled trials and another four controlled trials were included. Positive effects were reported for inspiratory muscle strength training (IMST), expiratory muscle strength training (EMST), air stacking, breath-stacking, incentive spirometry and postural training on respiratory muscle strength, swallowing safety, phonatory aspects and chest wall volumes. Best methodological quality was found for breath-stacking and incentive spirometry. Best levels of evidence were found for EMST, IMST and EMST plus air stacking. Conclusion: Respiratory training shows positive effects and should be considered when people with PD experience respiratory dysfunction. Future studies should focus on standardizing both training devices, instruments to measure outcomes and intervention protocols to further increase the level of evidence. Show more

Keywords: Respiratory training, breathing exercises, respiratory muscles, respiratory function tests, Parkinson’s disease

DOI: 10.3233/JPD-202223

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 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. Pre-press, no. Pre-press, pp. 1-10, 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 Marker 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 marker initiative

DOI: 10.3233/JPD-202110

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 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. Pre-press, no. Pre-press, pp. 1-17, 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. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Brown, Ethan G. | Chahine, Lana M. | Goldman, Samuel M. | Korell, Monica | Mann, Emerald | Kinel, Daniel R. | Arnedo, Vanessa | Marek, Kenneth L. | Tanner, Caroline M.

Article Type: Research Article

Abstract: Background: The effect of the COVID-19 pandemic on people with Parkinson’s disease (PD) is poorly understood. Objective: To rapidly identify areas of need and improve care in people with PD during the COVID-19 pandemic, we deployed a survey to assess COVID-19 symptoms and the pandemic’s effect among those with and without COVID-19. Methods: People with and without PD participating in the online study Fox Insight (FI) were invited to complete a survey between April 23 and May 23, 2020. Among people reporting COVID-19 diagnoses, we compared symptoms and outcomes in people with and without PD. Among …people not reporting COVID-19, we assessed access to healthcare and services and PD symptoms. Results: 7,209/9,762 active FI users responded (approximately 74% response rate), 5,429 people with PD and 1,452 without PD. COVID-19 diagnoses were reported by 51 people with and 26 without PD. Complications were more frequent in people with longer PD duration. People with PD and COVID-19 experienced new or worsening motor (63%) and nonmotor (75%) symptoms. People with PD not diagnosed with COVID-19 reported disrupted medical care (64%), exercise (21%), and social activities (57%), and worsened motor (43%) and non-motor (52%) symptoms. Disruptions were more common for those living alone, with lower income and non-white race. Conclusions: The COVID-19 pandemic is associated with wide-ranging effects on people with PD, and certain groups may be at particular risk. FI provides a rapid, patient-centered means to assess these effects and identify needs that can be used to improve the health of people with PD. Show more

Keywords: COVID-19, Parkinson’s disease, social isolation, health care access, telemedicine

DOI: 10.3233/JPD-202249

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