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

Authors: Simonet, Cristina | Galmes, Miquel A. | Lambert, Christian | Rees, Richard N. | Haque, Tahrina | Bestwick, Jonathan P. | Lees, Andrew J. | Schrag, Anette | Noyce, Alastair J.

Article Type: Research Article

Abstract: Background: Bradykinesia is the defining motor feature of Parkinson’s disease (PD). There are limitations to its assessment using standard clinical rating scales, especially in the early stages of PD when a floor effect may be observed. Objective: To develop a quantitative method to track repetitive tapping movements and to compare people in the early stages of PD, healthy controls, and individuals with idiopathic anosmia. Methods: This was a cross-sectional study of 99 participants (early-stage PD = 26, controls = 64, idiopathic anosmia = 9). For each participant, repetitive finger tapping was recorded over 20 seconds using a smartphone at 240 frames per …second. From each video, amplitude between fingers, frequency (number of taps per second), and velocity (distance travelled per second) was extracted. Clinical assessment was based on the motor section of the MDS-UPDRS. Results: People in the early stage of PD performed the task with slower velocity (p  <  0.001) and with greater frequency slope than controls (p  = 0.003). The combination of reduced velocity and greater frequency slope obtained the best accuracy to separate early-stage PD from controls based on metric thresholds alone (AUC = 0.88). Individuals with anosmia exhibited slower velocity (p  = 0.001) and smaller amplitude (p  <  0.001) compared with controls. Conclusion: We present a simple, proof-of-concept method to detect early motor dysfunction in PD. Mean tap velocity appeared to be the best parameter to differentiate patients with PD from controls. Patients with anosmia also showed detectable differences in motor performance compared with controls which may suggest that some are in the prodromal phase of PD. Show more

Keywords: Anosmia, bradykinesia, Parkinson’s disease, tapping test, technology

DOI: 10.3233/JPD-212683

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Kovaleva, Vera | Saarma, Mart

Article Type: Review Article

Abstract: Parkinson’s disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborisation and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2 + dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2 + -homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signalling machinery aimed at relieving of protein folding load in the ER. When …UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1α ) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical PD animal models. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation. Show more

Keywords: Parkinson’s disease, endoplasmic reticulum stress, unfolded protein response, growth factors, mesencephalic astrocyte-derived neurotrophic factor, cerebral dopamine neurotrophic factor

DOI: 10.3233/JPD-212673

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Christie, Richard H. | Abbas, Anzar | Koesmahargyo, Vidya

Article Type: Review Article

Abstract: Medication non-adherence during clinical trials is an ongoing challenge that can result in insufficient safety and efficacy data. For patients with Parkinson’s disease and other neurological disorders, symptomatology such as forgetfulness compounds traditional obstacles to adherence. Today, sponsors and clinical study sites can call upon various technology tools that improve adherence by monitoring and confirming dosage in near real-time. These tools have the potential to improve the quality of data gleaned from these studies.

Keywords: Digital phenotyping, Parkinson’s disease, remote measurement, treatment adherence

DOI: 10.3233/JPD-212537

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2021

Authors: Radojević, Branislava | Dragašević-Mišković, Nataša T. | Marjanović, Ana | Branković, Marija | Dobričić, Valerija | Milovanović, Andona | Tomić, Aleksandra | Svetel, Marina | Petrović, Igor | Jančić, Ivan | Stanisavljević, Dejana | Savić, Miroslav M. | Kostić, Vladimir S.

Article Type: Research Article

Abstract: Background: Recent studies explored polymorphisms of multiple genes as contributing to genetic susceptibility to psychosis in Parkinson’s disease (PDP). Objective: We aimed to examine the association of seven selected polymorphisms of genes related to dopamine pathways with PDP development. At the same time, demographic and clinical correlates of PDP were assessed. Methods: PD patients (n  = 234), treated with levodopa for at least two years, were genotyped for the rs4680 in COMT , rs6277, rs1076560, and rs2283265 in DRD2 , and rs1800497 and rs2734849 polymorphisms in ANKK1 genes. Also, variable number of tandem repeats polymorphism in …the DAT gene was examined. Each patient underwent comprehensive neurological examination, assessment of psychosis, as defined by the NINDS/NIMH criteria, as well as screening of depression, anxiety, and cognitive status. Results: Diagnostic criteria for PDP were met by 101 (43.2%) patients. They had longer disease duration, were taking higher doses of dopaminergic agents, and had higher scores of the motor and non-motor scales than the non-PDP group. Multivariate regression analysis revealed LEDD≥900 mg, Unified Parkinson’s Disease Rating Scale III part score, the Hamilton Depression Rating Scale score≥7, the Hamilton Anxiety Rating Scale score >  14,and GG homozygotes of rs2734849 ANKK1 as independent predictors of the onset of PDP. Conclusion: Besides previous exposure to dopaminergic drugs, impairment of motor status, depression and anxiety, as well-established clinical risk factors for the development of PDP, GG rs2734849 ANKK1 could also be a contributing factor, which requires addressing by future longitudinal studies. Show more

Keywords: COMT Val158Met , DAT1 SLC6A3 , DRD2 , genetic polymorphisms, hallucinations, Parkinson’s disease, psychosis

DOI: 10.3233/JPD-212716

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Abeliovich, Asa | Hefti, Franz | Sevigny, Jeffrey

Article Type: Review Article

Abstract: Human genetic studies as well as studies in animal models indicate that lysosomal dysfunction plays a key role in the pathogenesis of Parkinson’s disease. Among the lysosomal genes involved, GBA1 , has the largest impact on Parkinson’s disease risk. Deficiency in the GBA1 encoded enzyme glucocerebrosidase (GCase) leads to the accumulation of the GCase glycolipid substrates glucosylceramide and glucosylsphingosine and ultimately results in toxicity and inflammation and negatively affect many aspects of Parkinson’s disease, including disease risk, the severity of presentation, age of onset, and likelihood of progression to dementia. These findings support the view that re-establishing normal range …levels of GCase expression and enzyme activity may reduce the progression of Parkinson’s disease in patients carrying GBA1 mutations. Studies in mouse models indicate that PR001, a rAAV9 vector-based gene therapy designed to deliver a functional GBA1 gene to the brain, suggest that this therapeutic approach may slow or stop disease progression. PR001 is currently being evaluated in clinical trials with Parkinson’s disease patients carrying GBA1 mutations. Show more

Keywords: Gene therapy, GBA1, glucocerebrosidase, Gaucher, AAV9

DOI: 10.3233/JPD-212739

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Schechter, Meir | Sharon, Ronit

Article Type: Review Article

Abstract: Recent data support an involvement of defects in homeostasis of phosphoinositides (PIPs) in the pathophysiology of Parkinson’s disease (PD). Genetic mutations have been identified in genes encoding for PIP-regulating and PIP-interacting proteins, that are associated with familial and sporadic PD. Many of these proteins are implicated in vesicular membrane trafficking, mechanisms that were recently highlighted for their close associations with PD. PIPs are phosphorylated forms of the membrane phospholipid, phosphatidylinositol. Their composition in the vesicle’s membrane of origin, as well as membrane of destination, controls vesicular membrane trafficking. We review the converging evidence that points to the involvement of PIPs …in PD. The review describes PD- and PIP-associated proteins implicated in clathrin-mediated endocytosis and autophagy, and highlights the involvement of α -synuclein in these mechanisms. Show more

Keywords: Parkinson’s disease, phosphoinositides, vesicular membrane trafficking

DOI: 10.3233/JPD-212684

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-25, 2021

Authors: Jeong, Seong Ho | Yoo, Han Soo | Chung, Seok Jong | Jung, Jin Ho | Lee, Yang Hyun | Baik, Kyoungwon | Sohn, Young H. | Lee, Phil Hyu

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) are the most common non-motor symptom in Parkinson’s disease (PD). Objective: To investigate the association between the burden of NPS and motor prognosis in patients with PD. Methods: We enrolled 329 drug-naïve patients with PD, who was non-demented and followed-up≥2 years after their first visit to the clinic with baseline dopamine transporter (DAT) imaging and neuropsychiatric inventory (NPI) scores. We performed a survival analysis and a linear mixed model analysis to assess longitudinal motor outcomes according to the NPI total score. Results: The Kaplan-Meier analysis showed no difference in the …development of levodopa-induced dyskinesia and wearing-off according to the NPI total score. However, higher burden of NPI total score was associated with earlier freezing of gait (FOG) development in the time-dependent Cox regression models after adjusting for age at symptom onset, sex, disease duration, Unified PD Rating Scale motor score, baseline Mini-Mental State Examination score, DAT activity in the posterior putamen and levodopa-equivalent daily dose (LEDD) (Hazard ratio 1.047, p  = 0.002). A linear mixed model analysis revealed that patients with a higher NPI total score had a more rapid LEDD increment (NPI×time, p  = 0.003). Among 52 patients with PD who eventually developed FOG during the follow-up period, there was a significant correlation between the NPI total score and time with FOG development (γ = –0.472; p  = 0.001) after adjusting for confounding factors. Conclusion: The present study demonstrated that the severity of NPS is a predictor of early freezing and motor progression in patients with PD. Show more

Keywords: Parkinson’s disease, neuropsychiatric symptoms, motor prognosis

DOI: 10.3233/JPD-212660

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Beach, Thomas G. | Adler, Charles H. | Sue, Lucia I. | Shill, Holly A. | Driver-Dunckley, Erika | Mehta, Shyamal H. | Intorcia, Anthony J. | Glass, Michael J. | Walker, Jessica E. | Arce, Richard | Nelson, Courtney M. | Serrano, Geidy E.

Article Type: Research Article

Abstract: Background: Braak and others have proposed that Lewy-type α-synucleinopathy in Parkinson’s disease (PD) may arise from an exogenous pathogen that passes across the gastric mucosa and then is retrogradely transported up the vagus nerve to the medulla. Objective: We tested this hypothesis by immunohistochemically staining, with a method specific for p-serine 129 α-synuclein (pSyn), stomach and vagus nerve tissue from an autopsy series of 111 normal elderly subjects, 33 with incidental Lewy body disease (ILBD) and 53 with PD. Methods: Vagus nerve samples were taken adjacent to the carotid artery in the neck. Stomach samples were …taken from the gastric body, midway along the greater curvature. Formalin-fixed paraffin-embedded sections were immunohistochemically stained for pSyn, shown to be highly specific and sensitive for α-synuclein pathology. Results: Median disease duration for the PD group was 13 years. In the vagus nerve none of the 111 normal subjects had pSyn in the vagus, while 12/26 ILBD (46%) and 32/36 PD (89%) subjects were pSyn-positive. In the stomach none of the 102 normal subjects had pSyn while 5/30 (17%) ILBD and 42/52 (81%) of PD subjects were pSyn-positive. Conclusion: As there was no pSyn in the vagus nerve or stomach of subjects without brain pSyn, these results support initiation of pSyn in the brain. The presence of pSyn in the vagus nerve and stomach of a subset of ILBD cases indicates that synucleinopathy within the peripheral nervous system may occur, within a subset of individuals, at preclinical stages of Lewy body disease. Show more

Keywords: Pathology, etiology, autopsy, gastrointestinal, peripheral nerve, pathogenesis

DOI: 10.3233/JPD-212733

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Youssef, Priscilla | Kim, Woojin S. | Halliday, Glenda M. | Lewis, Simon J.G. | Dzamko, Nicolas

Article Type: Research Article

Abstract: Background: The identification of reliable biomarkers in Parkinson’s disease (PD) would provide much needed diagnostic accuracy, a means of monitoring progression, objectively measuring treatment response, and potentially allowing patient stratification within clinical trials. Whilst the assessment of total alpha-synuclein in biofluids has been identified as a promising biomarker, conflicting trends in these levels across patient plasma samples relative to controls has limited its use. Different commercially available assay platforms that have been used to measure alpha-synuclein may contribute to different study outcomes. Objective: To compare different platform immunoassays for the measurement of total alpha-synuclein using the same plasma …samples from 49 PD patients and 47 controls. Methods: Total plasma alpha-synuclein concentrations were assessed using the BioLegend, MesoScale Discovery, and Quanterix platform in plasma samples from PD patients and matched controls. Results: A significant increase in total plasma alpha-synuclein was observed in PD patients using the Biolegend (10%), Mesoscale Discovery (13%) and Quanterix (39%) assays. The Mesoscale Discovery and Quanterix assays showed the strongest correlations (r  = 0.78, p  < 0.0001) with each other, whilst the Quanterix platform demonstrated the lowest variation and highest effect size. Inclusion of age, sex and hemoglobin levels as covariates in the analysis of total alpha-synuclein improved the ability of all three immunoassays to detect a significant difference between patients and controls. Conclusion: All three immunoassays were sensitive enough to detect group level differences between PD patients and controls, with the largest effect size observed with the Quanterix assay. These results may help inform assay choices in ongoing clinical trials. Show more

Keywords: Parkinson’s disease, ELISA, SIMOA, alpha-synuclein, blood

DOI: 10.3233/JPD-212694

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Dos Santos, Altair B. | Skaanning, Line K. | Mikkelsen, Eyd | Romero-Leguizamón, Cesar R. | Kristensen, Morten P. | Klein, Anders B. | Thaneshwaran, Siganya | Langkilde, Annette E. | Kohlmeier, Kristi A.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a neurodegenerative disorder associated with insoluble pathological aggregates of the protein α -synuclein. While PD is diagnosed by motor symptoms putatively due to aggregated α -synuclein-mediated damage to substantia nigra (SN) neurons, up to a decade before motor symptom appearance, patients exhibit sleep disorders (SDs). Therefore, we hypothesized that α -synuclein, which can be present in monomeric, fibril, and other forms, has deleterious cellular actions on sleep-control nuclei. Objective: We investigated whether native monomer and fibril forms of α -synuclein have effects on neuronal function, calcium dynamics, and cell-death-induction in two sleep-controlling nuclei: …the laterodorsal tegmentum (LDT), and the pedunculopontine tegmentum (PPT), as well as the motor-controlling SN. Methods: Size exclusion chromatography, Thioflavin T emission, and circular dichroism spectroscopy were used to isolate structurally defined forms of recombinant, human α -synuclein. Neuronal and viability effects of characterized monomeric and fibril forms of α -synuclein were determined on LDT, PPT, and SN neurons using electrophysiology, calcium imaging, and neurotoxicity assays. Results: In LDT and PPT, both forms of α -synuclein induced excitation and increased calcium, and the monomeric form heightened putatively excitotoxic neuronal death, whereas, in the SN we saw inhibition, decreased intracellular calcium, and monomeric α -synuclein was not associated with heightened cell death. Conclusion: Nucleus-specific differential effects suggest mechanistic underpinnings of SDs’ prodromal appearance in PD. While speculative, we hypothesize that the monomeric form of α -synuclein compromises functionality of sleep-control neurons, leading to the presence of SDs decades prior to motor dysfunction. Show more

Keywords: Biomarkers, excessive daytime sleepiness, mechanism of disease, neurodegenerative diseases, neuronal alterations, prodromal phase, REM sleep behavior disorder

DOI: 10.3233/JPD-212554

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: McFarthing, Kevin | Rafaloff, Gary | Baptista, Marco | Wyse, Richard K. | Stott, Simon R. W.

Article Type: Research Article

Abstract: Background: Despite the COVID-19 pandemic, there has been considerable activity in the clinical development of novel and improved drug-based therapies for the neurodegenerative condition of Parkinson’s disease (PD) during 2020. The agents that were investigated can be divided into “symptomatic” (alleviating the features of the condition) and “disease modifying” (attempting to address the underlying biology of PD) treatments, ST and DMT respectively, with further categorisation possible based on mechanism of action and class of therapy. Objective: Our goal in this report was to provide an overview of the pharmacological therapies –both ST and DMT - in clinical trials …for PD during 2020–2021, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst commercial and academic researchers as well as between the research and patient communities. Methods: We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of February 18th 2021. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next. Results: We identified 142 trials on ClinicalTrials.gov and 14 studies on the WHO registries that met our analysis criteria. Of these 156 trials, 91 were ST and 65 were DMT, Of the 145 trials registered on ClinicalTrials.gov in our 2020 analysis, 45 fell off the list and 42 were added. Despite this change, the balance of ST to DMT; the distribution across phases; the profile of therapeutic categories; and the proportion of repurposed therapies (33.5%); all remained very similar. There are only two DMTs in phase 3, and we identified 33 in-between-phase projects. Conclusions: Despite the effects of the coronavirus pandemic, investment and effort in clinical trials for PD appears to remain strong. There has been little change in the profile of the clinical trial landscape even though, over the past year, there has been considerable change to the content of the list. Show more

Keywords: Clinical trials, studies, Parkinson’s, disease modification, neuroprotection, immunotherapy, inflammation, gene therapy

DOI: 10.3233/JPD-219006

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Wenzel, Gregor R. | Roediger, Jan | Brücke, Christof | Marcelino, Ana Luísa de A. | Gülke, Eileen | Pötter-Nerger, Monika | Scholtes, Heleen | Wynants, Kenny | Juárez Paz, León M. | Kühn, Andrea A.

Article Type: Research Article

Abstract: Background: Recent technological advances in deep brain stimulation (DBS) (e.g., directional leads, multiple independent current sources) lead to increasing DBS-optimization burden. Techniques to streamline and facilitate programming could leverage these innovations. Objective: We evaluated clinical effectiveness of algorithm-guided DBS-programming based on wearable-sensor-feedback compared to standard-of-care DBS-settings in a prospective, randomized, crossover, double-blind study in two German DBS centers. Methods: For 23 Parkinson’s disease patients with clinically effective DBS, new algorithm-guided DBS-settings were determined and compared to previously established standard-of-care DBS-settings using UPDRS-III and motion-sensor-assessment. Clinical and imaging data with lead-localizations were analyzed to evaluate characteristics of …algorithm-derived programming compared to standard-of-care. Six different versions of the algorithm were evaluated during the study and 10 subjects programmed with uniform algorithm-version were analyzed as a subgroup. Results: Algorithm-guided and standard-of-care DBS-settings effectively reduced motor symptoms compared to off-stimulation-state. UPDRS-III scores were reduced significantly more with standard-of-care settings as compared to algorithm-guided programming with heterogenous algorithm versions in the entire cohort. A subgroup with the latest algorithm version showed no significant differences in UPDRS-III achieved by the two programming-methods. Comparing active contacts in standard-of-care and algorithm-guided DBS-settings, contacts in the latter had larger location variability and were farther away from a literature-based optimal stimulation target. Conclusion: Algorithm-guided programming may be a reasonable approach to replace monopolar review, enable less trained health-professionals to achieve satisfactory DBS-programming results, or potentially reduce time needed for programming. Larger studies and further improvements of algorithm-guided programming are needed to confirm these results. Show more

Keywords: Deep brain stimulation, Parkinson’s disease, algorithm, wearable device feedback, double-blind, subthalamic nucleus

DOI: 10.3233/JPD-202480

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Park, Sang Hyun | Nam, Ga Eun | Han, Kyungdo | Huh, Youn | Kim, Wonsock | Lee, Min-Kyung | Koh, Eun-Sil | Kim, Eun Sook | Kim, Mee Kyung | Kwon, Hyuk-Sang | Kim, Seon Mee | Cho, Kyung Hwan | Park, Yong Gyu

Article Type: Research Article

Abstract: Background: The longitudinal association between dynamic changes in the metabolic syndrome (MS) status and Parkinson’s disease (PD) has been poorly studied. Objective: We examined whether dynamic changes in MS status are associated with altered risk for PD. Methods: This study was a nationwide retrospective cohort study. We enrolled 5,522,813 individuals aged≥40 years who had undergone health examinations under the National Health Insurance Service between 2009 and 2010 (two health examinations with a 2-year interval). Participants were followed up until the end of 2017. The participants were categorized into four groups according to MS status changes over …2 years: non-MS, improved MS, incident MS, and persistent MS groups. Multivariable Cox hazard regression was performed. Results: During the 7-year median follow-up, there were 20,524 cases of newly developed PD. Compared with non-MS group, improved, incident, and persistent MS groups for 2 years were significantly associated with higher risks of PD (model 3; hazard ratio: 1.12, 95%confidence interval: 1.06–1.19 [improved MS]; 1.15, 1.09–1.22 [incident MS]; and 1.25, 1.20–1.30 [persistent MS]). Individuals with incident and persistent abdominal obesity, low levels of high-density lipoprotein cholesterol, hypertriglyceridemia, and hyperglycemia had a significantly increased risks of PD compared with those without either condition over 2 years. Conclusion: Persistent and incident MS and its components may be risk factors for incident PD. Ever exposure to MS may also be associated with PD risk. Appropriate intervention for preventing and improving MS may be crucial in decreasing the PD incidence. Show more

Keywords: Metabolic syndrome, Parkinson’s disease, metabolic change, cohort

DOI: 10.3233/JPD-212589

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Riggare, Sara | Hägglund, Maria | Bredenoord, Annelien L. | de Groot, Martijn | Bloem, Bastiaan R.

Article Type: Article Commentary

Abstract: Using Parkinson’s disease as an exemplary chronic condition, this Commentary discusses ethical aspects of using self-tracking for personal science, as compared to using self-tracking in the context of conducting clinical research on groups of study participants. Conventional group-based clinical research aims to find generalisable answers to clinical or public health questions. The aim of personal science is different: to find meaningful answers that matter first and foremost to an individual with a particular health challenge. In the case of personal science, the researcher and the participant are one and the same, which means that specific ethical issues may arise, such …as the need to protect the participant against self-harm. To allow patient-led research in the form of personal science in the Parkinson field to evolve further, the development of a specific ethical framework for self-tracking for personal science is needed. Show more

Keywords: Parkinson’s disease, self-tracking, ethics, remote monitoring, selfcare, patient empowerment

DOI: 10.3233/JPD-212647

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Marie, Anaıs | Darricau, Morgane | Touyarot, Katia | Parr-Brownlie, Louise C. | Bosch-Bouju, Clémentine

Article Type: Review Article

Abstract: Evidence shows that altered retinoic acid signaling may contribute to the pathogenesis and pathophysiology of Parkinson’s disease (PD). Retinoic acid is the bioactive derivative of the lipophilic vitamin A. Vitamin A is involved in several important homeostatic processes, such as cell differentiation, antioxidant activity, inflammation and neuronal plasticity. The role of vitamin A and its derivatives in the pathogenesis and pathophysiology of neurodegenerative diseases, and their potential as therapeutics, has drawn attention for more than 10 years. However, the literature sits in disparate fields. Vitamin A could act at the crossroad of multiple environmental and genetic factors of PD. The …purpose of this review is to outline what is known about the role of vitamin A metabolism in the pathogenesis and pathophysiology of PD. We examine key biological systems and mechanisms that are under the control of vitamin A and its derivatives, which are (or could be) exploited for therapeutic potential in PD: the survival of dopaminergic neurons, oxidative stress, neuroinflammation, circadian rhythms, homeostasis of the enteric nervous system, and hormonal systems. We focus on the pivotal role of ALDH1A1, an enzyme expressed by dopaminergic neurons for the detoxification of these neurons, which is under the control of retinoic acid. By providing an integrated summary, this review will guide future studies on the potential role of vitamin A in the management of symptoms, health and wellbeing for PD patients. Show more

Keywords: Neuroinflammation, vitamin A, retinoic acid, ALDH1A1, oxidative stress, RAR RXR receptors

DOI: 10.3233/JPD-212671

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2021

Authors: Hug, Kristina

Article Type: Research Article

Abstract: Advanced therapies for Parkinson’s disease (PD) constitute a broad range of treatments, each presenting specific ethical challenges. Some of these therapies are established and in clinical use, like device-aided therapies, and others, based on advanced therapeutic medicinal products (ATMPs), are still in early stage of clinical trials. This paper focuses on some common ethical issues arising in these two categories of advanced therapies, especially challenges arising when advanced therapies are proposed to PD patients in the form of advanced care, under a clinical trial, or, in case of ATMPs, under the “hospital exemption” rule. The ethical issues covered here relate …mainly to ensuring informed consent in these different contexts, to the stakeholder role of patient’s non-professional caretakers, such as family, and to patient safety in treatments under “hospital exemption”. To illustrate the points discussed in connection with “hospital exemption” rule, the example of the EU has been chosen. This paper does not claim completeness of ethical issues raised by bringing advanced therapies for PD to the clinic, but rather presents examples of ethical challenges in this context. Show more

Keywords: Parkinson’s disease, advanced therapies, advanced therapeutic medicinal products, ethics

DOI: 10.3233/JPD-212639

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Sandoval, Ivette M. | Marmion, David J. | Meyers, Kimberly T. | Manfredsson, Fredric P.

Article Type: Research Article

Abstract: The protein alpha-Synuclein (α-Syn) is a key contributor to the etiology of Parkinson’s disease (PD) with aggregation, trans-neuronal spread, and/or depletion of α-Syn being viewed as crucial events in the molecular processes that results in neurodegeneration. The exact succession of pathological occurrences that lead to neuronal death are still largely unknown and are likely to be multifactorial in nature. Despite this unknown, α-Syn dose and stability, autophagy-lysosomal dysfunction, and inflammation, amongst other cellular impairments, have all in been described as participatory events in the neurodegenerative process. To that end, in this review we discuss the logical points for gene therapy …to intervene in α-Syn-mediated disease and review the preclinical body of work where gene therapy has been used, or could conceptually be used, to ameliorate α-Syn induced neurotoxicity. In this review, we discuss gene therapy in the traditional sense of modulating gene expression, as well as the use of viral vectors and nanoparticles as methods to deliver other therapeutic modalities. Show more

Keywords: Parkinson’s disease, alpha-synuclein, gene therapy, lewy pathology, synucleinopathies

DOI: 10.3233/JPD-212679

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Villar-Conde, Sandra | Astillero-Lopez, Veronica | Gonzalez-Rodriguez, Melania | Villanueva-Anguita, Patricia | Saiz-Sanchez, Daniel | Martinez-Marcos, Alino | Flores-Cuadrado, Alicia | Ubeda-Bañon, Isabel

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a prevalent neurodegenerative disease that is pathologically described as a six-stage α-synucleinopathy. In stage 4, α-synuclein reaches the hippocampus, inducing cognitive deficits, from which it progresses to the isocortex, leading to dementia. Among hippocampal fields, cornu ammonis 2 is particularly affected by this α-synucleinopathy and critical for cognitive decline. Volumetric studies using magnetic resonance imaging have produced controversial results, with only some reporting volume loss, whereas stereological data obtained using nonspecific markers do not reveal volume changes, neural or glial loss. Proteomic analysis has not been carried out in the hippocampus of patients with …PD. Objective: This study aims to explain hippocampal changes in patients with PD at the cellular and proteomic levels. Methods: α-Synuclein inclusions, volume and neural (NeuN), microglial (Iba-1) and astroglial (GFAP) populations were stereologically analyzed. SWATH-MS quantitative proteomic analysis was also conducted. Results: Area fraction fractionator probe revealed a higher area fraction α-synucleinopathy in cornu ammonis 2 . No volume change, neurodegeneration, microgliosis or astrogliosis was detected. Proteomic analysis identified 1,634 proteins, of which 83 were particularly useful for defining differences among PD and non-PD groups. Among them, upregulated (PHYIP, CTND2, AHSA1 and SNTA1) and downregulated (TM163, REEP2 and CSKI1) proteins were related to synaptic structures in the diseased hippocampus. Conclusion: The distribution of α-synuclein in the hippocampus is not associated with volumetric, neural or glial changes. Proteomic analysis, however, reveals a series of changes in proteins associated with synaptic structures, suggesting that hippocampal changes occur at the synapse level during PD. Show more

Keywords: Parkinson disease, hippocampus, human, alpha synuclein, neurons, microglia, astrocytes

DOI: 10.3233/JPD-202465

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2021

Authors: van Gastel, Bernard E. | Jacobs, Bart | Popma, Jean

Article Type: Research Article

Abstract: This paper describes an advanced form of pseudonymisation in a large cohort study on Parkinson’s disease, called Personalized Parkinson Project (PPP). The study collects various forms of biomedical data of study participants, including data from wearable devices with multiple sensors. The participants are all from the Netherlands, but the data will be usable by research groups worldwide on the basis of a suitable data use agreement. The data are pseudonymised, as required by Europe’s General Data Protection Regulation (GDPR). The form of pseudonymisation that is used in this Parkinson project is based on cryptographic techniques and is ‘polymorphic’: it gives …each participating research group its own ‘local’ pseudonyms. Still, the system is globally consistent, in the sense that if one research group adds data to PPP under its own local pseudonyms, the data become available for other groups under their pseudonyms. The paper gives an overview how this works, without going into the cryptographic details. Show more

Keywords: Computer security, privacy, big data, data protection

DOI: 10.3233/JPD-202431

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Seger, Aline | Gulberti, Alessandro | Vettorazzi, Eik | Braa, Hanna | Buhmann, Carsten | Gerloff, Christian | Hamel, Wolfgang | Moll, Christian K.E. | Pötter-Nerger, Monika

Article Type: Research Article

Abstract: Background: Gait disturbances and balance remain challenging issues in Parkinsonian patients (PD) with deep brain stimulation (DBS). Short pulse deep brain stimulation (spDBS) increases the therapeutic window in PD patients, yet the effect on gait and postural symptoms remains unknown. Objective: We assessed the efficacy of spDBS compared to conventional DBS (cDBS) within the subthalamic nucleus (STN) on Parkinsonian gait. Methods: The study was a single-centre, randomized, double-blind, clinical short-term trial. 20 PD patients were studied postoperatively in three different conditions (DBS stimulation switched off (off DBS), spDBS with 40μs pulse width, cDBS with 60μs pulse …width) on regular medication. The primary endpoint was the relative difference of gait velocity at self-paced speed during quantitative gait analysis between stimulation conditions. Secondary endpoints were changes of further measures of quantitative gait analysis, Ziegler course, Berg balance scale, FOG questionnaire, MDS-UPDRS, PDQ-39, and HADS. Mixed-model analysis and post-hoc t -tests were performed. Results: Both spDBS and cDBS improved gait velocity at self-paced speed compared to off DBS, however, there was no significant difference between both stimulation modes. Still, nearly half of the patients preferred spDBS over cDBS subjectively. Both stimulation modes were equally effective in improving secondary endpoints of gait, balance, motor and non-motor performances. Conclusion: The use of spDBS and cDBS is equally effective in improving gait and balance in PD and might be beneficial in specified cohorts of PD patients. Show more

Keywords: Deep brain stimulation, freezing of gait, gait disorder, Parkinson’s disease, short pulse width, subthalamic nucleus

DOI: 10.3233/JPD-202492

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Quek, Dione Y. L. | Economou, Kristin | MacDougall, Hamish | Lewis, Simon J.G. | Ehgoetz Martens, Kaylena A.

Article Type: Research Article

Abstract: Background: Although prior research has established that freezing of gait (FOG) in Parkinson’s disease (PD) is associated with anxiety, only one study to date has directly manipulated anxiety levels to induce FOG. Objective: The current study aimed to replicate these previous findings and evaluate whether a seated version of a ‘threat’ virtual reality (VR) paradigm could induce anxiety and provoke FOG. Methods: Twenty-four PD patients with FOG were assessed across various threat conditions in both a walking VR paradigm (Experiment 1) and a seated VR paradigm (Experiment 2). Both paradigms manipulated the height (i.e., elevated vs …ground) and width (wide vs narrow) of the planks participants were instructed to walk across. Results: Across both experiments, the Elevated + Narrow condition provoked significantly greater number of freezing episodes compared to all other conditions. Higher levels of self-reported anxiety were reported during the Elevated+Narrow condition compared to all other conditions in Experiment 1, and compared to the Ground condition in Experiment 2. Conclusion: These findings confirm that anxiety contributes to FOG and validates the use of a seated VR threat paradigm for provoking anxiety-related freezing. This enables future studies to combine this paradigm with functional MRI to explore the neural correlates underlying the role of anxiety in FOG. Show more

Keywords: Virtual reality, anxiety, freezing of gait, threat, Parkinson’s disease

DOI: 10.3233/JPD-212619

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Poewe, Werner | Volc, Dieter | Seppi, Klaus | Medori, Rossella | Lührs, Petra | Kutzelnigg, Alexandra | Djamshidian, Atbin | Thun-Hohenstein, Caroline | Meissner, Wassilios | Rascol, Olivier | Schneeberger, Achim | Staffler, Günther | on behalf of the AFF011 investigators | AFF011 study investigators: | Poewe, Werner | Seppi, Klaus | Djamshidian, Atbin | deMarzi, Roberto | Heim, Beatrice | Mangesius, Stefanie | Stolz, Raphaela | Wachowicz, Katarzyna | Volc, Dieter | Thun-Hohenstein, Caroline | Riha, Constanze | Schneeberger, Achim | Bürger, Vera | Galabova, Gergana

Article Type: Research Article

Abstract: Background: Immunotherapies targeting α-synuclein aim to limit its extracellular spread in the brain and prevent progression of pathology in Parkinson’s disease (PD). PD03A is a specific active immunotherapy (SAIT) involving immunization with a short peptide formulation. Objective: This phase 1 study characterized the safety and tolerability of PD03A in patients with early PD. A key secondary objective was to evaluate immunological activity following immunization. Methods: This was a phase 1 study of two different doses of PD03A versus placebo in PD patients. Patients were randomized (1:1:1) to receive four priming plus one booster vaccination of PD03A …15μg, PD03A 75μg or placebo and were followed for 52 weeks. Results: Overall, 36 patients were randomized, of which 35 received five immunizations and completed the study. All patients experienced at least one adverse event. Transient local injection site reactions affected all but two patients; otherwise most AEs were considered unrelated to study treatment. A substantial IgG antibody response against PD03 was observed with a maximum titer achieved at Week-12. Differences in titers between both active groups versus placebo were statistically significant from the second immunization at Week-8 until Week-52. Conclusion: The safety profile and positive antibody response of PD03A supports the further development of active immunotherapeutic approaches for the treatment of PD. Show more

Keywords: Parkinson’s disease, α-synuclein, immunization, active immunotherapy

DOI: 10.3233/JPD-212594

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Weber Boutros, Sydney | Raber, Jacob | Unni, Vivek K.

Article Type: Research Article

Abstract: Background: Alpha-synuclein (αsyn) characterizes neurodegenerative diseases known as synucleinopathies. The phosphorylated form (psyn) is the primary component of protein aggregates known as Lewy bodies (LBs), which are the hallmark of diseases such as Parkinson’s disease (PD). Synucleinopathies might spread in a prion-like fashion, leading to a progressive emergence of symptoms over time. αsyn pre-formed fibrils (PFFs) induce LB-like pathology in wild-type (WT) mice, but questions remain about their progressive spread and their associated effects on behavioral performance. Objective: To characterize the behavioral, cognitive, and pathological long-term effects of LB-like pathology induced after bilateral motor cortex PFF injection in …WT mice and to assess the ability of mouse αsyn-targeted antisense oligonucleotides (ASOs) to ameliorate those effects. Methods: We induced LB-like pathology in the motor cortex and connected brain regions of male WT mice using PFFs. Three months post-PFF injection (mpi), we assessed behavioral and cognitive performance. We then delivered a targeted ASO via the ventricle and assessed behavioral and cognitive performance 5 weeks later, followed by pathological analysis. Results: At 3 and 6 mpi, PFF-injected mice showed mild, progressive behavioral deficits. The ASO reduced total αsyn and psyn protein levels, and LB-like pathology, but was also associated with some deleterious off-target effects not involving lowering of αsyn, such as a decline in body weight and impairments in motor function. Conclusions: These results increase understanding of the progressive nature of the PFF model and support the therapeutic potential of ASOs, though more investigation into effects of ASO-mediated reduction in αsyn on brain function is needed. Show more

Keywords: Alpha-synuclein, antisense oligonucleotides, preformed fibril, synucleinopathies, lewy body, learning, memory

DOI: 10.3233/JPD-212566

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2021

Authors: Sackner-Bernstein, Jonathan

Article Type: Research Article

Abstract: Background: The hallmark of Parkinson’s disease is depletion of dopamine in the basal ganglia. Models of Parkinson’s disease include dopamine as a contributor to disease progression. However, intraneuronal levels of dopamine have not been reported. Objective: Meta-analytic methods were utilized to determine intracellular dopamine levels in Parkinson’s disease. Methods: A systematic review of the literature and frequentist meta-analyses were performed. Dopamine levels were scaled for cell and axon numbers as well as VMAT2 protein levels. Results: Reduced tissue dopamine, dopaminergic cell bodies and VMAT2 protein were confirmed. The ratio of Parkinson’s to normal brain …intracellular dopamine scaled for either cell or axon number, each with VMAT2 level in the caudate ranged from 1.49 to 1.87 (p  = 0.51 and p  = 0.12, respectively) and in the putamen from 0.75 to 4.61 (p  = 0.40 and 0.001, respectively). Conclusion: Free, intracellular dopamine levels are not reduced in Parkinson’s disease compared to normals to a similar degree as are total tissue concentrations, supporting the relevance of modulating VMAT2, neuromelanin and/or dopamine synthesis as rational neuroprotective strategies. Show more

Keywords: Parkinson’s disease, dopamine, dopaminergic neurons, cytosolic dopamine, intracellular dopamine, dopamine toxicity, dopamine oxidation

DOI: 10.3233/JPD-212715

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Lawson, Rachael A. | Williams-Gray, Caroline H. | Camacho, Marta | Duncan, Gordon W. | Khoo, Tien K. | Breen, David P. | Barker, Roger A. | Rochester, Lynn | Burn, David J. | Yarnall, Alison J. | on behalf of the ICICLE-PD study group

Article Type: Research Article

Abstract: Background: Cognitive impairment is common in Parkinson’s disease (PD), with 80% cumulatively developing dementia (PDD). Objective: We sought to identify tests that are sensitive to change over time above normal ageing so as to refine the neuropsychological tests predictive of PDD. Methods: Participants with newly diagnosed PD (n  = 211) and age-matched controls (n  = 99) completed a range of clinical and neuropsychological tests as part of the ICICLE-PD study at 18-month intervals over 72 months. Impairments on tests were determined using control means (<1-2SD) and median scores. Mild cognitive impairment (PD-MCI) was classified using 1-2SD below normative …values. Linear mixed effects modelling assessed cognitive decline, while Cox regression identified baseline predictors of PDD. Results: At 72 months, 46 (cumulative probability 33.9%) participants had developed PDD; these participants declined at a faster rate in tests of global cognition, verbal fluency, memory and attention (p  <  0.05) compared to those who remained dementia-free. Impaired baseline global cognition, visual memory and attention using median cut-offs were the best predictors of early PDD (area under the curve [AUC] = 0.88, p  <  0.001) compared to control-generated cut-offs (AUC = 0.76–0.84, p  <  0.001) and PD-MCI (AUC] = 0.64–0.81, p  <  0.001). Impaired global cognition and semantic fluency were the most useful brief tests employable in a clinical setting (AUC = 0.79, p  <  0.001). Conclusion: Verbal fluency, attention and memory were sensitive to change in early PDD and may be suitable tests to measure therapeutic response in future interventions. Impaired global cognition, attention and visual memory were the most accurate predictors for developing a PDD. Future studies could consider adopting these tests for patient clinical trial stratification. Show more

Keywords: Parkinson’s disease, neurocognitive disorders, cognitive dysfunction, neuropsychological tests

DOI: 10.3233/JPD-212581

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Kim, Seung Woo | Chung, Seok Jong | Lee, Sangwon | Oh, KyeongTaek | Yoo, Sun Kook | Lee, Phil Hyu | Kim, Seung Min | Young Shin, Ha | Yun, Mijin

Article Type: Research Article

Abstract: Background: Sudomotor dysfunction is common in patients with multiple system atrophy (MSA). Postganglionic sudomotor dysfunction in MSA, which can be assessed using quantitative sudomotor axon reflex testing (QSART), results from the degeneration of preganglionic sympathetic neurons and direct loss of postganglionic fibers. Objective: We investigate whether abnormal QSART responses in patients with MSA are associated with disease severity. Methods: In this retrospective study, patients with probable MSA who underwent both 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG-PET/CT) and autonomic function tests were included. Autonomic function test results were integrated divided into three sub-scores, including sudomotor, …cardiovagal, and adrenergic sub-scores. The sudomotor sub-score represented postganglionic sudomotor function. Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, Part II, and sum of Part I and II scores (Part I + II) to reflect disease severity and 18 F-FDG-PET/CT results were collected. Results: Of 74 patients with MSA, 62.2%demonstrated abnormal QSART results. The UMSARS Part I + II score was significantly higher in the abnormal QSART group than in the normal QSART group (p  = 0.037). In the regression analysis, both UMSARS Part I (β= 1.185, p  = 0.013) and Part II (β= 1.266, p  = 0.021) scores were significantly associated with the sudomotor sub-score. On 18 F-FDG-PET/CT, the abnormal QSART group exhibited more severely decreased metabolic activity in the cerebellum and basal ganglia in patients with MSA-P and MSA-C, respectively. The sudomotor sub-score was significantly associated with regional metabolism in these areas. Conclusion: Patients with MSA and postganglionic sudomotor dysfunction may have worse disease severity and greater neuropathological burden than those without. Show more

Keywords: Multiple system atrophy, sudomotor dysfunction, autonomic dysfunction, brain metabolism.

DOI: 10.3233/JPD-202524

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Yoo, Sang-Won | Ha, Seunggyun | Yoon, Hyukjin | Yoo, Ji-Yeon | Lee, Kwang-Soo | Kim, Joong-Seok

Article Type: Research Article

Abstract: Background: Orthostatic hypotension (OH) may antedate Parkinson’s disease (PD) or be found in early stages of the disease. OH may induce a PD brain to chronic hypotensive insults. 18 F-Florbetaben (18 F-FBB) tracer has a high first-pass influx rate and can be used with positron emission tomography (PET) as a surrogate marker for early- and late-phase evaluation of cerebral perfusion and cerebral amyloidosis, respectively. Objective: In this study, we evaluated whether 18 F-FBB uptake in the early- and late-phases of PD was related to OH. This study manipulated the imaging modality to illustrate the physiology of cerebral flow …with OH in PD (PD + OH). Methods: A group of 73 early-stage PD patients was evaluated with a head-up tilt-test and 18 F-FBB PET imaging. The cognitive status was assessed by a comprehensive battery of neuropsychological tests. PET images were normalized, and both early- and late-phase standardized uptake value ratios (SUVRs) of pre-specified regions were obtained. The associations between regional SUVRs and OH and cognitive status were analyzed. Results: Twenty (27.4%) participants had OH. Thirteen (17.8%) patients were interpreted as having amyloid pathology based on regional 18 F-FBB uptake. Early-phase SUVRs were higher in specific brain regions of PD + OH patients those without OH. However, late-phase SUVRs did not differ between the groups. The early-phase SUVRs were not influenced by amyloid burden or by interaction between amyloid and orthostatic hypotension. Cognitive functions were not disparate when PD + OH patients were contrasted with non-OH patients in this study. Conclusion: Cerebral blood flow was elevated in patients with early PD + OH. This finding suggests augmented cerebral perfusion in PD + OH might be a compensatory regulation in response to chronic OH. Show more

Keywords: Parkinson’s disease, orthostatic hypotension, cerebral perfusion, cerebral autoregulation, 18F-Florbetaben (FBB), positron emission tomography

DOI: 10.3233/JPD-212596

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Tolosa, Eduardo | Ebersbach, Georg | Ferreira, Joaquim J. | Rascol, Olivier | Antonini, Angelo | Foltynie, Thomas | Gibson, Rachel | Magalhaes, Diogo | Francisco Rocha, J. | Lees, Andrew

Article Type: Research Article

Abstract: Background: A greater understanding of the everyday experiences of people with Parkinson’s disease (PD) and their carers may help improve clinical practice. Objective: The Parkinson’s Real-world Impact assesSMent (PRISM) study evaluated medication use, health-related quality of life (HRQoL) and the use of healthcare resources by people with PD and their carers. Methods: PRISM is an observational cross-sectional study, in which people with PD and their carers completed an online survey using structured questionnaires, including the Parkinson’s Disease Quality of Life Questionnaire (PDQ-39), Non-Motor Symptoms Questionnaire (NMSQuest) and Zarit Burden Interview (ZBI). Results: Data were …collected from 861 people with PD (mean age, 65.0 years; mean disease duration, 7.7 years) and 256 carers from six European countries. People with PD reported a large number of different co-morbidities, non-motor symptoms (mean NMSQuest score, 12.8), and impaired HRQoL (median PDQ-39 summary score, 29.1). Forty-five percent of people with PD reported at least one impulse control behaviour. Treatment patterns varied considerably between different European countries. Levodopa was taken in the last 12 months by 85.9% of participants, and as monotherapy by 21.8% . Carers, who were mostly female (64.8%) and the partner/spouse of the person with PD (82.1%), reported mild to moderate burden (mean ZBI total score, 26.6). Conclusions: The PRISM study sheds light on the lives of people with PD and those who care for them, re-emphasising the many challenges they face in everyday life. The study also provides insights into the current treatment of PD in Europe. Show more

Keywords: Caregivers, catechol o-methyltransferase inhibitors, comorbidity, dopamine agonists, Europe, levodopa, observational study, Parkinson’s disease, quality of life, surveys and questionnaires

DOI: 10.3233/JPD-212611

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Renko, Juho-Matti | Mahato, Arun Kumar | Visnapuu, Tanel | Valkonen, Konsta | Karelson, Mati | Voutilainen, Merja H. | Saarma, Mart | Tuominen, Raimo K. | Sidorova, Yulia A.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a progressive neurological disorder where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor symptoms. Currently, no treatment is able to halt the progression of PD. Glial cell line-derived neurotrophic factor (GDNF) rescues degenerating dopamine neurons both in vitro and in animal models of PD. When tested in PD patients, however, the outcomes from intracranial GDNF infusion paradigms have been inconclusive, mainly due to poor pharmacokinetic properties. Objective: We have developed drug-like small molecules, named BT compounds that activate signaling through GDNF’s receptor, the …transmembrane receptor tyrosine kinase RET, both in vitro and in vivo and are able to penetrate through the blood-brain barrier. Here we evaluated the properties of BT44, a second generation RET agonist, in immortalized cells, dopamine neurons and rat 6-hydroxydopamine model of PD. Methods: We used biochemical, immunohistochemical and behavioral methods to evaluate the effects of BT44 on dopamine system in vitro and in vivo . Results: BT44 selectively activated RET and intracellular pro-survival AKT and MAPK signaling pathways in immortalized cells. In primary midbrain dopamine neurons cultured in serum-deprived conditions, BT44 promoted the survival of the neurons derived from wild-type, but not from RET knockout mice. BT44 also protected cultured wild-type dopamine neurons from MPP + -induced toxicity. In a rat 6-hydroxydopamine model of PD, BT44 reduced motor imbalance and could have protected dopaminergic fibers in the striatum. Conclusion: BT44 holds potential for further development into a novel, possibly disease-modifying therapy for PD. Show more

Keywords: BT44, RET agonist, glial cell line-derived neurotrophic factor, receptor tyrosine kinase RET, AKT pathway, MAPK pathway, rat 6-hydroxydopamine (6-OHDA) model, neuroprotection, Parkinson’s disease

DOI: 10.3233/JPD-202400

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2021

Authors: Morizane, Asuka | Takahashi, Jun

Article Type: Review Article

Abstract: Stem cell-based therapies for Parkinson’s disease are now being applied clinically. Notably, studies have shown that controlling the graft-induced immune response improves the results. In this mini-review, we concisely summarize current approaches used for this control. We focus on four modes of stem cell-based therapies: autologous transplantation, allogeneic transplantation with human leukocyte antigen-matching and allogeneic transplantation without, and finally the application of “universal” pluripotent stem cells. We also discuss immuno-suppressive treatments and the monitoring of immune reactions in the brain.

Keywords: Parkinson’s disease, immune response, human leukocyte antigen, autologous, allogeneic

DOI: 10.3233/JPD-212608

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Sieurin, Johanna | Zhan, Yiqiang | Pedersen, Nancy L. | Wirdefeldt, Karin

Article Type: Research Article

Abstract: Background: The relationship among neuroticism, smoking, and Parkinson’s disease (PD) is less examined. Objective: To examine the causal associations between neuroticism, smoking initiation, and the risk of PD. Methods: We performed a two-sample Mendelian randomization (MR) design in a network framework. Summary statistics from meta-analyses of genome-wide association studies (GWAS) were based on large cohorts of European ancestry. Study participants were from various cohort studies for neuroticism and smoking initiation, and case-control studies or cohort studies of PD from previously published GWAS meta-analyses. Patients with PD were ascertained from either clinical visit or self-reported. …Results: The two-sample MR analysis showed no evidence for a causal association between neuroticism and PD risk (odds ratio [OR] 0.86, 95%confidence intervals [CIs] 0.67 to 1.12). While we did not find a significant association between neuroticism and PD, one SNP, rs58879558 (located in MAPT region), was associated with both neuroticism and PD. We found a significant association of neuroticism on smoking initiation (OR: 1.10, 95%CI: 1.05 to 1.14). Further, our results provided evidence for a protective effect of smoking initiation on the risk of PD (OR: 0.75, 95%CI: 0.62 to 0.91). Conclusion: These findings do not support a causal association of neuroticism on PD risk. However, they provide evidence for a causal relationship between neuroticism and smoking initiation and a strong causal effect of smoking initiation on a reduced risk of PD. Show more

Keywords: Neuroticism, smoking, Parkinson’s disease, mendelian randomization.

DOI: 10.3233/JPD-202522

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Wang, Keran | Luo, Zhehui | Li, Chenxi | Huang, Xuemei | Shiroma, Eric J. | Simonsick, Eleanor M. | Chen, Honglei

Article Type: Research Article

Abstract: Background: Literature shows an inverse association of circulating cholesterol level with the risk of Parkinson’s disease (PD); this finding has important ramifications, but its interpretation has been debated. Objective: To longitudinally examine how blood total cholesterol changes during the development of PD. Methods: In the Health, Aging and Body Composition study (n  = 3,075, 73.6±2.9 years), blood total cholesterol was measured at clinic visit years 1, 2, 4, 6, 8, 10, and 11. We first examined baseline cholesterol in relation to PD risk, adjusting for potential confounders and competing risk of death. Then, by contrasting the observed …with expected cholesterol levels, we examined the trajectory of changes in total cholesterol before and after disease diagnosis. Results: Compared to the lowest tertile of baseline total cholesterol, the cumulative incident ratio of PD and 95%confidence interval was 0.41 (0.20, 0.86) for the second tertile, and 0.69 (0.35, 1.35) for the third tertile. In the analysis that examined change of total cholesterol level before and after PD diagnosis, we found that its level began to decrease in the prodromal stage of PD and became statistically lower than the expected values∼4 years before disease diagnosis (observed-expected difference, –6.68 mg/dL (95%confidence interval: –13.14, –0.22)). The decreasing trend persisted thereafter; by year-6 post-diagnosis, the difference increased to –13.59 mg/dL (95%confidence interval: –22.12, –5.06), although the linear trend did not reach statistical significance (p  = 0.10). Conclusion: Circulating total cholesterol began to decrease in the prodromal stage of PD, which may in part explain its reported inverse association with PD. Show more

Keywords: Parkinson’s disease, cholesterol, longitudinal studies, prodromal symptoms

DOI: 10.3233/JPD-212670

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Thaler, Avner | Omer, Nurit | Giladi, Nir | Gurevich, Tanya | Bar-Shira, Anat | Gana-Weisz, Mali | Goldstein, Orly | Kestenbaum, Meir | Shirvan, Julia C. | Cedarbaum, Jesse M. | Orr-Urtreger, Avi | Regev, Keren | Shenhar-Tsarfaty, Shani | Mirelman, Anat

Article Type: Research Article

Abstract: Background: Inflammation is an integral part of neurodegeneration including in Parkinson’s disease (PD). Ashkenazi Jews have high rates of genetic PD with divergent phenotypes among GBA -PD and LRRK2 -PD. The role of inflammation in the prodromal phase of PD and the association with disease phenotype has yet to be elucidated. Objective: To assess central and peripheral cytokines among PD patients with mutations in the LRRK2 and GBA genes and among non-manifesting carriers (NMC) of these mutations in order to determine the role of inflammation in genetic PD. Methods: The following cytokines were assessed …from peripheral blood and cerebrospinal fluid (CSF): TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10 and INF- γ . A comprehensive intake including general medical conditions, use of anti-inflammatory treatments, motor and cognitive assessments and additional laboratory measures were recorded, enabling the construction of the MDS probable prodromal score. Results: Data from 362 participants was collected: 31 idiopathic PD (iPD), 30 LRRK 2-PD, 77 GBA -PD, 3 homozygote GBA -PD, 3 GBA -LRRK2 -PD, 67 LRRK2 -NMC, 105 GBA -NMC, 14 LRRK2 -GBA -NMC, and 32 healthy controls. No between-group differences in peripheral or CSF cytokines were detected. No correlation between disease characteristics or risk for prodromal PD could be associated with any inflammatory measure. Conclusion: In this study, we could not detect any evidence on dysregulated immune response among GBA and LRRK2 PD patients and non-manifesting mutation carriers. Show more

Keywords: Parkinson’s disease, LRRK2, GBA, inflammation

DOI: 10.3233/JPD-212624

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Vidal, Benjamin | Levigoureux, Elise | Chaib, Sarah | Bouillot, Caroline | Billard, Thierry | Newman-Tancredi, Adrian | Zimmer, Luc

Article Type: Research Article

Abstract: Background: The gold-standard treatment for Parkinson’s disease is L-DOPA, which in the long term often leads to levodopa-induced dyskinesia. Serotonergic neurons are partially responsible for this, by converting L-DOPA into dopamine before uncontrolled release as a “false neurotransmitter”. The stimulation of 5-HT1A receptors can reduce involuntary movements but this mechanism is poorly understood. Objective: This study aimed to investigate the functionality of 5-HT1A receptor using positron emission tomography in hemiparkinsonian rats with or without dyskinesia induced by 3-weeks daily treatment with L-DOPA. Imaging sessions were performed “off” L-DOPA. Methods: Each rat underwent a positron …emission tomography scan with [18 F]F13640, a 5-HT1A R agonist (which labels receptors in a high affinity state for agonists) or [18 F]MPPF, a 5-HT1A R antagonist (which labels all the receptors). Results: There were decreases of [18 F]MPPF binding in hemiparkinsonian rats in cortical areas. In dyskinetic animals, changes were slighter but also found in other regions. In hemiparkinsonian rats, [18 F]F13640 uptake was decreased in the globus pallidus and thalamus. On the contralateral side, binding was increased in the insula, the hippocampus and the amygdala. In dyskinetic animals, [18 F]F13640 binding was strongly increased in cortical and limbic areas, especially in the non-lesioned side. Conclusion: These data suggest that agonist and antagonist 5-HT1A receptor-binding sites are differently modified in Parkinson’s disease and levodopa-induced dyskinesia. In particular, these observations suggest an important involvement of the functional state of 5-HT1A R in levodopa-induced dyskinesia and emphasize the need to characterize this state using agonist radiotracers in physiological and pathological conditions. Show more

Keywords: 5-HT1A, Parkinson’s disease, serotonin, levodopa-induced dyskinesia, GPCR

DOI: 10.3233/JPD-212580

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Honeycutt, Lucy | Gagnon, Jean-François | Pelletier, Amélie | Montplaisir, Jacques Y. | Gagnon, Geneviève | Postuma, Ronald B.

Article Type: Research Article

Abstract: Background: Depression and anxiety are common in synucleinopathies and often present during prodromal stages, including idiopathic/isolated REM sleep behavior disorder (iRBD). However, the specific profiles of depression/anxiety and their predictive values for phenoconversion remain unclear. Objective: To assess the predominant manifestations, predictive value, and changes over time in depressive and anxiety symptoms in iRBD. Methods: Patients with polysomnography-confirmed iRBD (n  = 114) and healthy controls (n  = 44) were recruited. The Beck Depression Inventory and Beck Anxiety Inventory were administered at baseline, which was repeated prospectively over follow-up. Factor solutions were generated to delineate symptom clusters within the …scales, and to help disentangle primary mood symptoms from other neurodegenerative confounds. Total scores, individual scale items, and factors were evaluated to 1) compare patients and controls, 2) assess progression of symptoms over time, and 3) assess predictive value for phenoconversion. Results: At baseline, iRBD patients had more severe depressive (9.0 = 6.7 vs 5.8 = 4.8) and anxiety (7.0 = 7.9 vs 4.5 = 6.0) symptoms than controls. Increased scores were seen in numerous individual scale items and most scales’ factors. For depressive symptoms, there was no progression of total scores or factors over time. However, anxiety scores worsened slightly over prospective follow-up (annual slope = 0.58 points, p  <  0.05). Over an average 2.4 = 3.1-year follow-up, 37 patients phenoconverted and 72 remained disease-free. Neither baseline depressive nor anxiety symptoms predicted phenoconversion to clinical neurodegenerative disease. Conclusions: Depressive and anxiety symptoms are common in iRBD. However, they do not predict phenoconversion and show only modest progression over time, solely for anxiety. Show more

Keywords: REM sleep behaviour disorder, depression, anxiety, progression, prodromal

DOI: 10.3233/JPD-212625

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Mak, Margaret K.Y. | Wong-Yu, Irene S.K.

Article Type: Research Article

Abstract: Background: In Parkinson’s disease (PD), sustained aerobic exercise is a promising therapy in delaying motor disability. Brisk walking is a moderate intensity aerobic training, which could be translated to community practice at low cost, but its effects on motor symptoms remains unclear. Objective: To determine the effectiveness of a six-month brisk walking and balance program in alleviating motor symptoms, and promoting functional, gait, and balance performance in people with PD. Methods: Seventy individuals with mild to moderate PD were randomly assigned to a brisk walking (BW) group or an active control (CON) group. BW group received …ten 90-minute supervised brisk walking and balance exercise for six months (weeks 1–6: once/week, weeks 7–26: once/month). CON group received upper limb training. Both groups performed 2-3 self-practice sessions weekly. Primary outcome was Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor score. Secondary outcomes were fast gait speed (FGS), timed-up-and-go (TUG) time, six-minute walk distance (6MWD), and Mini-Balance Evaluation Systems Test (Mini-BEST) score. Results: Sixty-four participants (33 BW/31 CON) completed training. BW group showed greater significant decreases from baseline than CON group in MDS-UPDRS motor score after six weeks (–5.5 vs –1.6, p  <  0.001) and 6 months (–6.0 vs –1.4, p  <  0.001) of training. BW group also showed greater significant improvement from the baseline than CON group for TUG time, FGS, 6MWD, and mini-BEST score (all p  <  0.05). Conclusion: The six-month brisk walking and balance program alleviates motor symptoms, promotes functional and gait performance, walking capacity, and dynamic balance in people with mild to moderate PD. Show more

Keywords: Parkinson’s disease, rehabilitation, aerobic exercise, recovery of function, postural balance

DOI: 10.3233/JPD-202503

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Beckers, Milan | Lees, Andrew J. | Nutt, John G. | Bloem, Bastiaan R.

Article Type: Letter

Keywords: Neurological examination, expertise, clinical skills, Parkinson’s disease, movement disorders

DOI: 10.3233/JPD-212711

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2021

Authors: Mathur, Soania | Stamford, Jon

Article Type: Research Article

Abstract: There is an urgent unmet need in the Parkinson’s disease community—advanced therapies to modify the inevitable decline that occurs in those affected by this progressive neurodegenerative disease for which there is no cure. This will require collaboration from all stakeholders and central to those partnerships are patients themselves. But participation in clinical trials and clinical use of advanced therapies have their own risk profile above and beyond standard therapeutics as evidenced by past invasive procedures. Therefore, it is of utmost importance that clear, evidence-based information about these potential treatments be clearly communicated by those exploring their use to ensure safe …and informed participation from the patient community. Likewise, patients must weigh the benefits of these treatments their limitations and risks in order to truly give informed consent to participate in bringing these treatments to the clinic. Here we explore these issues from the patient perspective. Show more

Keywords: Parkinson’s disease, advanced treatments, clinical research, recruitment, patient-centered, gene therapy, stem cell replacement, patient risk

DOI: 10.3233/JPD-212650

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2021

Authors: Schedlich-Teufer, Charlotte | Jost, Stefanie Theresa | Krack, Paul | Witt, Karsten | Weintraub, Daniel | Baldermann, Juan Carlos | Sommerauer, Michael | Amstutz, Deborah | van Eimeren, Thilo | Dafsari, Haidar Salimi | Kalbe, Elke | Visser-Vandewalle, Veerle | Fink, Gereon Rudolf | Kessler, Josef | Barbe, Michael Thomas

Article Type: Research Article

Abstract: Background: Assessment of affective-behavioral states in patients with Parkinson’s disease (PD) undergoing deep brain stimulation (DBS) is essential. Objective: To analyze well-established questionnaires as a pilot-study with the long term aim to develop a screening tool evaluating affective-behavioral dysfunction, including depression, anxiety, apathy, mania, and impulse control disorders, in PD patients screened for DBS. Methods: Two hundred ninety-seven inpatients with PD underwent standardized neuropsychiatric testing including German versions of Beck Depression Inventory-II, Hospital Anxiety and Depression Scale, Apathy Evaluation Scale, Self-Report Manic Inventory, and Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale, to assess appropriateness for DBS. …Statistical item reduction was based on exploratory factor analysis, Cronbach’s alpha, item-total correlations, item difficulty, and inter-item correlations. Confirmatory factor analysis was conducted to assess factorial validity. An expert rating was performed to identify clinically relevant items in the context of PD and DBS, to maintain content validity. We compared the shortened subscales with the original questionnaires using correlations. To determine cutoff points, receiver operating characteristics analysis was performed. Results: The items of the initial questionnaires were reduced from 129 to 38 items. Results of confirmatory factor analyses supported the validity of the shortened pool. It demonstrated high internal consistency (Cronbach’s alpha = 0.72–0.83 across subscales), and the individual subscales were correlated with the corresponding original scales (rs  = 0.84–0.95). Sensitivities and specificities exceeded 0.7. Conclusion: The shortened item pool, including 38 items, provides a good basis for the development of a screening tool, capturing affective-behavioral symptoms in PD patients before DBS implantation. Confirmation of the validity of such a screening tool in an independent sample of PD patients is warranted. Show more

Keywords: Parkinson’s disease, deep brain stimulation, screening tool, questionnaire, depression, anxiety, apathy, mania, impulse control disorders, hallucinations

DOI: 10.3233/JPD-202375

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Björklund, Anders

Article Type: Article Commentary

Abstract: In two recent postmortem studies, Jeffrey Kordower and colleagues report new findings that open up for an interesting discussion on the status of GDNF/NRTN signaling in patients with Parkinson’s disease (PD), adding an interesting perspective on the, admittedly very limited, signs of restorative effects previously seen in GDNF/NRTN-treated patients. Their new findings show that the level of the GDNF signaling receptor Ret is overall reduced by about 65% relative to non-PD controls, and most severely, up to 80%, in nigral neurons containing α -synuclein inclusions, accompanied by impaired signaling downstream of the Ret receptor. Notably, however, the vast majority of …the remaining nigral neurons retained a low level of Ret expression, and hence a threshold level of signaling. Further observations made in two patients who had received AAV-NRTN gene therapy 8–10 years earlier suggest the intriguing possibility that NRTN is able to restore Ret expression and upregulate its own signaling pathway. This “wind-up” mechanism, which is likely to depend on an interaction with dopaminergic transcription factor Nurr1, has therapeutic potential and should encourage renewed efforts to turn GDNF/NRTN therapy into success, once the recurring problem of under-dosing is resolved. Show more

Keywords: Parkinson’s disease, neurturin, Ret, Nurr1, phospho-S6

DOI: 10.3233/JPD-212706

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2021

Authors: Ma, Ling-Zhi | Zhang, Can | Wang, Han | Ma, Ya-Hui | Shen, Xue-Ning | Wang, Jian | Tan, Lan | Dong, Qiang | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Neurofilament light (NfL) can reflect the extent of neuron/axon damage, thus providing an opportunity to examine the severity and progression of the diseases with such damage. Objective: Whether serum NfL can be used as an indicator to monitor the cognitive progress of de novo Parkinson’s disease (PD) remains unclear. Methods: In this research, 144 healthy controls and 301 de novo PD patients from Parkinson’s Progression Markers Initiative (PPMI) were recruited. Linear mixed effects models were used to examine the associations of baseline/longitudinal serum NfL with cognitive decline. Cox regression was used to detect cognitive progression …in PD participants. Results: We found PD patients had higher serum NfL than controls at baseline (p  = 0.031), and NfL increase was faster in PD group (p  < 0.001). Both baseline serum NfL and its rate of change predicted measurable cognitive decline in early PD (MoCA, β= –0.014, p  < 0.001; β= –0.002, p  < 0.001, respectively). Additionally, we observed that NfL levels were also able to predict progression in different diagnostic groups and Amyloid- PD and Amyloid+PD groups. After an average follow-up of 6.37±1.84 years, the baseline NfL of the third tertile of high concentrations was associated with a future high risk of PD dementia (adjusted HR 6.33, 95% CI 2.62–15.29, p  < 0.001). Conclusion: In conclusion, our results indicated that the serum NfL concentration could function as an easily accessible biomarker to monitor the severity and progression of cognitive decline in PD. Show more

Keywords: Parkinson’s disease, neurofilament light, Parkinson’s progression markers initiative, cognition, tau

DOI: 10.3233/JPD-212535

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: He, Xiaoqin | Qian, Yiwei | Xu, Shaoqing | Zhang, Yi | Mo, Chengjun | Guo, Wentian | Yang, Xiaodong | Xiao, Qin

Article Type: Research Article

Abstract: Background: Multiple system atrophy (MSA) and Parkinson’s disease (PD) have overlapping symptoms, making diagnosis challenging. Short-chain fatty acids (SCFAs) are produced exclusively by gut microbiota and were reduced in feces of MSA patients. However, plasma SCFA concentrations in MSA patients have not been investigated. Objective: We aimed to investigate the plasma SCFAs in MSA patients and to identify the potential differential diagnostic ability. Methods: Plasma SCFA were measured in 25 MSA patients, 46 healthy controls, and 46 PD patients using gas chromatography-mass spectrometry. Demographic and clinical characteristics of the participants were evaluated. Results: Acetic …acid concentration was lower in MSA patients than in healthy controls. Acetic acid and propionic acid concentrations were lower in MSA and MSA with predominant parkinsonism (MSA-P) patients than in PD patients. A receiver operating characteristic curve (ROC) analysis revealed reduced acetic acid concentration discriminated MSA patients from healthy controls with 76% specificity but only 57% sensitivity and an area under the curve (AUC) of 0.68 (95% confidence interval (CI): 0.55–0.81). Combined acetic acid and propionic acid concentrations discriminated MSA patients from PD patients with an AUC of 0.82 (95% CI: 0.71–0.93), 84% specificity and 76% sensitivity. Especially, with combined acetic acid and propionic acid concentrations, MSA-P patients were separated from PD patients with an AUC of 0.89 (95% CI: 0.80–0.97), 91% specificity and 80% sensitivity. Conclusion: Plasma SCFAs were decreased in MSA patients. The combined acetic acid and propionic acid concentrations may be a potential biomarker for differentiating MSA patients from PD patients. Show more

Keywords: Multiple system atrophy, Parkinson’s disease, short-chain fatty acids, biomarker

DOI: 10.3233/JPD-212604

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Phanhdone, Tiffany | Drummond, Patrick | Meisel, Talia | Friede, Naomi | Di Rocco, Alessandro | Chodosh, Joshua | Fleisher, Jori

Article Type: Research Article

Abstract: Background: Patients with Parkinson’s disease (PD) are at higher risk of vaccine-preventable respiratory infections. However, advanced, homebound individuals may have less access to vaccinations. In light of COVID-19, understanding barriers to vaccination in PD may inform strategies to increase vaccine uptake. Objective: To identify influenza and pneumococcal vaccination rates, including barriers and facilitators to vaccination, among homebound and ambulatory individuals with PD and related disorders. Methods: Cross-sectional US-based study among individuals with PD, aged > 65 years, stratified as homebound or ambulatory. Participants completed semi-structured interviews on vaccination rates and barriers, and healthcare utilization. Results: Among …143 participants, 9.8% had missed all influenza vaccinations in the past 5 years, and 32.2% lacked any pneumococcal vaccination, with no between-group differences. Homebound participants (n  = 41) reported difficulty traveling to clinic (p  < 0.01) as a vaccination barrier, and despite similar outpatient visit frequencies, had more frequent emergency department visits (31.7% vs. 9.8%, p  < 0.01) and hospitalizations (14.6% vs. 2.9%, p  = 0.03). Vaccine hesitancy was reported in 35% of participants, vaccine refusal in 19%, and 13.3% reported unvaccinated household members, with no between-group differences. Nearly 13% thought providers recommended against vaccines for PD patients, and 31.5% were unsure of vaccine recommendations in PD. Conclusion: Among a sample of homebound and ambulatory people with PD, many lack age-appropriate immunizations despite ample healthcare utilization. Many participants were unsure whether healthcare providers recommend vaccinations for people with PD. In light of COVID-19, neurologist reinforcement that vaccinations are indicated, safe, and recommended may be beneficial. Show more

Keywords: Vaccine hesitancy, vaccination, Parkinson’s disease, COVID-19, influenza, pneumonia, health services, homebound

DOI: 10.3233/JPD-202497

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Shin, Jung Hwan | Yu, Ri | Ong, Jed Noel | Lee, Chan Young | Jeon, Seung Ho | Park, Hwanpil | Kim, Han-Joon | Lee, Jehee | Jeon, Beomseok

Article Type: Research Article

Abstract: Background: Clinician-based rating scales or questionnaires for gait in Parkinson’s disease (PD) are subjective and sensor-based analysis is limited in accessibility. Objective: To develop an easily accessible and objective tool to evaluate gait in PD patients, we analyzed gait from a single 2-dimensional (2D) video. Methods: We prospectively recorded 2D videos of PD patients (n  = 16) and healthy controls (n  = 15) performing the timed up and go test (TUG). The gait was simultaneously evaluated with a pressure-sensor (GAITRite). We estimated the 3D position of toes and heels with a deep-learning based pose-estimation algorithm and calculated gait …parameters including step length, step length variability, gait velocity and step cadence which was validated with the result from the GAITRite. We further calculated the time and steps required for turning. Then, we applied the algorithm to previously recorded and archived videos of PD patients (n  = 32) performing the TUG. Results: From the validation experiment, gait parameters derived from video tracking were in excellent agreement with the parameters obtained with the GAITRite. (Intraclass correlation coefficient > 0.9). From the analysis with the archived videos, step length, gait velocity, number of steps, and the time required for turning were significantly correlated (Absolute R  > 0.4, p  < 0.005) with the Freezing of gait questionnaire, Unified PD Rating scale part III total score, HY stage and postural instability. Furthermore, the video-based tracking objectively measured significant improvement of step length, gait velocity, steps and the time required for turning with antiparkinsonian medication. Conclusion: 2D video-based tracking could objectively evaluate gait in PD patients. Show more

Keywords: Parkinson disease, gait, deep-learning, video tracking

DOI: 10.3233/JPD-212544

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Hughes, Katherine C. | Gao, Xiang | Baker, Jessica M. | Stephen, Christopher D. | Kim, Iris Y. | Valeri, Linda | Schwarzschild, Michael A. | Ascherio, Alberto

Article Type: Research Article

Abstract: Background: Non-motor symptoms are common in Parkinson’s disease (PD) and some, including hyposmia, constipation, and REM sleep behavior disorder, often precede the clinical diagnosis. Objective: To assess the relation between combinations of non-motor features and presence of PD among women. Methods: A nested case-control study was conducted among women in the Nurses’ Health Study. Women were eligible if they responded to screening questions for constipation and probable REM sleep behavior disorder (pRBD) on a 2012 questionnaire and were under age 85 on January 1, 2012. 87 women with confirmed PD and 14,170 women without PD agreed …to participate and completed in 2015 the Brief Smell Identification Test to assess hyposmia, as well as a questionnaire to assess parkinsonism and other non-motor PD features, including depressive symptoms, excessive daytime sleepiness, impaired color vision, and body pain. Results: In age-adjusted logistic models, each non-motor feature was significantly associated with PD, and the odds of PD increased exponentially with the number of features. Women with constipation, pRBD, and hyposmia had an age-adjusted OR for PD of 211 (95%CI 84.2–529) compared to women with none of these features. The odds of having PD rose further with the presence of additional non-motor signs. Comparing women with at least 6 of the 7 features assessed in this study to women with one or none, the age-adjusted OR for PD was 356 (95%CI 113–1126). Conclusion: Results suggest that these non-motor features could be useful in discriminating PD patients from controls in women, and since they often appear during the prodromal period of PD, their combinations may prove useful for identifying populations at high risk of developing PD. Show more

Keywords: Parkinson’s disease, REM sleep behavior disorder, hyposmia

DOI: 10.3233/JPD-202409

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Hughes, Laura P. | Pereira, Marilia M.M. | Hammond, Deborah A. | Kwok, John B. | Halliday, Glenda M. | Lewis, Simon J.G. | Dzamko, Nicolas

Article Type: Research Article

Abstract: Background: Reduced activity of lysosomal glucocerebrosidase is found in brain tissue from Parkinson’s disease patients. Glucocerebrosidase is also highly expressed in peripheral blood monocytes where its activity is decreased in Parkinson’s disease patients, even in the absence of GBA mutation. Objective: To measure glucocerebrosidase activity in cryopreserved peripheral blood monocytes from 30 Parkinson’s disease patients and 30 matched controls and identify any clinical correlation with disease severity. Methods: Flow cytometry was used to measure lysosomal glucocerebrosidase activity in total, classical, intermediate, and non-classical monocytes. All participants underwent neurological examination and motor severity was assessed by …the Movement Disorders Society Unified Parkinson’s Disease Rating Scale. Results: Glucocerebrosidase activity was significantly reduced in the total and classical monocyte populations from the Parkinson’s disease patients compared to controls. GCase activity in classical monocytes was inversely correlated to motor symptom severity. Conclusion: Significant differences in monocyte glucocerebrosidase activity can be detected in Parkinson’s disease patients using cryopreserved mononuclear cells and monocyte GCase activity correlated with motor features of disease. Being able to use cryopreserved cells will facilitate the larger multi-site trials needed to validate monocyte GCase activity as a Parkinson’s disease biomarker. Show more

Keywords: Parkinson’s disease, glucocerebrosidase, monocyte, inflammation, toll-like receptor

DOI: 10.3233/JPD-202508

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Piscicelli, Céline | Castrioto, Anna | Jaeger, Marie | Fraix, Valerie | Chabardes, Stephan | Moro, Elena | Krack, Paul | Debû, Bettina | Pérennou, Dominic

Article Type: Research Article

Abstract: Background: Verticality perception is frequently altered in Parkinson’s disease (PD) with Pisa syndrome (PS). Is it the cause or the consequence of the PS? Objective: We tested the hypothesis that both scenarios coexist. Methods: We performed a double-blind within-person randomized trial (NCT02704910) in 18 individuals (median age 63.5 years) with PD evolving for a median of 17.5 years and PS for 2.5 years and treated with bilateral stimulation of the subthalamus nuclei (STN-DBS) for 6.5 years. We analyzed whether head and trunk orientations were congruent with the visual (VV) and postural (PV) vertical, and whether switching …on one or both sides of the STN-DBS could modulate trunk orientation via verticality representation. Results: The tilted verticality perception could explain the PS in 6/18 (33%) patients, overall in three right-handers (17%) who showed net and congruent leftward trunk and PV tilts. Two of the 18 (11%) had an outstanding clinical picture associating leftward: predominant parkinsonian symptoms, whole-body tilt (head –11°, trunk –8°) and transmodal tilt in verticality perception (PV –10°, VV –8.9°). Trunk orientation or VV were not modulated by STN-DBS, whereas PV tilts were attenuated by unilateral or bilateral stimulations if it was applied on the opposite STN. Conclusion: In most cases of PS, verticality perception is altered by the body deformity. In some cases, PS seems secondary to a biased internal model of verticality, and DBS on the side of the most denervated STN attenuated PV tilts with a quasi-immediate effect. This is an interesting track for further clinical studies. Show more

Keywords: Deep brain stimulation, neuromodulation, Parkinson’s disease, Pisa syndrome, spatial cognition, subthalamic nuclei, verticality perception

DOI: 10.3233/JPD-202388

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Suzuki, Keisuke

Article Type: Research Article

Abstract: Sleep disturbances are among the common nonmotor symptoms in patients with Parkinson’s disease (PD). Sleep can be disrupted by nocturnal motor and nonmotor symptoms and other comorbid sleep disorders. Rapid eye movement sleep behavior disorder (RBD) causes sleep-related injury, has important clinical implications as a harbinger of PD and predicts a progressive clinical phenotype. Restless legs syndrome (RLS) and its related symptoms can impair sleep initiation. Excessive daytime sleepiness (EDS) is a refractory problem affecting patients’ daytime activities. In particular, during the COVID-19 era, special attention should be paid to monitoring sleep problems, as infection-prevention procedures for COVID-19 can affect …patients’ motor symptoms, psychiatric symptoms and sleep. Therefore, screening for and managing sleep problems is important in clinical practice, and the maintenance of good sleep conditions may improve the quality of life of PD patients. This narrative review focused on the literature published in the past 10 years, providing a current update of various sleep disturbances in PD patients and their management, including RBD, RLS, EDS, sleep apnea and circadian abnormalities. Show more

Keywords: Parkinson’s disease, sleep disturbances, excessive daytime sleepiness, REM sleep behavior disorder, restless legs syndrome, sleep apnea syndrome

DOI: 10.3233/JPD-202425

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2021

Authors: Jarrin, Sarah | Hakami, Abrar | Newland, Ben | Dowd, Eilís

Article Type: Review Article

Abstract: Despite decades of research and billions in global investment, there remains no preventative or curative treatment for any neurodegenerative condition, including Parkinson’s disease (PD). Arguably, the most promising approach for neuroprotection and neurorestoration in PD is using growth factors which can promote the growth and survival of degenerating neurons. However, although neurotrophin therapy may seem like the ideal approach for neurodegenerative disease, the use of growth factors as drugs presents major challenges because of their protein structure which creates serious hurdles related to accessing the brain and specific targeting of affected brain regions. To address these challenges, several different delivery …systems have been developed, and two major approaches—direct infusion of the growth factor protein into the target brain region and in vivo gene therapy—have progressed to clinical trials in patients with PD. In addition to these clinically evaluated approaches, a range of other delivery methods are in various degrees of development, each with their own unique potential. This review will give a short overview of some of these alternative delivery systems, with a focus on ex vivo gene therapy and biomaterial-aided protein and gene delivery, and will provide some perspectives on their potential for clinical development and translation. Show more

Keywords: Parkinson’s disease, growth factors, glial cell line-derived neurotrophic factor, gene therapy, biomaterials

DOI: 10.3233/JPD-212662

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Koinuma, Takahiro | Hatano, Taku | Kamagata, Koji | Andica, Christina | Mori, Akio | Ogawa, Takashi | Takeshige-Amano, Haruka | Uchida, Wataru | Saiki, Shinji | Okuzumi, Ayami | Ueno, Shin-Ichi | Oji, Yutaka | Saito, Yuya | Hori, Masaaki | Aoki, Shigeki | Hattori, Nobutaka

Article Type: Research Article

Abstract: Background: Although pathological studies usually indicate pure dopaminergic neuronal degeneration in patients with parkin (PRKN ) mutations, there is no evidence to date regarding white matter (WM) pathology. A previous diffusion MRI study has revealed WM microstructural alterations caused by systemic oxidative stress in idiopathic Parkinson’s disease (PD), and we found that PRKN patients have systemic oxidative stress in serum biomarker studies. Thus, we hypothesized that PRKN mutations might lead to WM abnormalities. Objective: To investigate whether there are WM microstructural abnormalities in early-onset PD patients with PRKN mutations using diffusion tensor imaging (DTI). …Methods: Nine PRKN patients and 19 age- and sex-matched healthy controls were recruited. DTI measures were acquired on a 3T MR scanner using a b value of 1,000 s/mm2 along 32 isotropic diffusion gradients. The DTI measures were compared between groups using tract-based spatial statistics (TBSS) analysis. Correlation analysis was also performed between the DTI parameters and several serum oxidative stress markers obtained in a previously conducted metabolomic analysis. Results: Although the WM volumes were not significantly different, the TBSS analysis revealed a corresponding decrease in fractional anisotropy and an increase in mean diffusivity and radial diffusivity in WM areas, such as the anterior and superior corona radiata and uncinate fasciculus, in PRKN patients compared with controls. Furthermore, 9-hydroxystearate, an oxidative stress marker, and disease duration were positively correlated with several parameters in PRKN patients. Conclusion: This pilot study suggests that WM microstructural impairments occur in PRKN patients and are associated with disease duration and oxidative stress. Show more

Keywords: Diffusion MRI, magnetic resonance imaging (MRI), metabolomics, oxidative stress, Parkinson’s disease

DOI: 10.3233/JPD-202495

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Theodoros, Deborah

Article Type: Review Article

Abstract: Communication and swallowing disorders are highly prevalent in people with Parkinson’s disease (PD). The negative impact of these disorders on the quality of life of the person with PD and their families cannot be underestimated. Despite a demand for speech-language pathology services to support people with PD, many barriers to services exist. Telerehabilitation provides an alternate and complementary approach to in-person therapy that is patient-centered, enables timely assessment and intervention, and facilitates continuity of care throughout the course of the disease. This review explores the telerehabilitation applications designed for the management of the communication and swallowing disorders in PD, addresses …the benefits and challenges of telerehabilitation, identifies future research directions, and highlights the potential of new technologies to enhance the management of communication and swallowing disorders and quality of life for people with PD. Show more

Keywords: Dysarthria, language disorders, Parkinson’s disease, speech-language pathology, swallowing disorders, telerehabilitation

DOI: 10.3233/JPD-202414

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Templeton, John Michael | Poellabauer, Christian | Schneider, Sandra

Article Type: Research Article

Abstract: Background: Due to the COVID-19 pandemic, beneficial physical intervention classes for individuals with Parkinson’s disease (PD) were cancelled. Objective: To understand effects of the COVID-19 stay-at-home mandate and the inability to participate in recommended and structured physical interventions as a consequence of these mandates, specifically designed mobile assessments were used that collected both self-reporting information and objective task-based metrics of neurocognitive functions to assess symptom changes for individuals with PD. Methods: Self-reporting questionnaires focusing on overall quality of life (e.g., when individuals typically feel at their best, changes in activity levels, and symptom progression) were given …to all individuals (n  = 28). In addition, mobile-based neurocognitive assessments were administered to a subset of the population (n  = 8) to quantitatively assess changes due to COVID-19 restrictions. Results: The highest self-reported factors in which individuals denoted feeling their best were after exercise (67.86%) and being in a comfortable and supportive environment (60.71%). Objective measures found overall duration of physical activity during the stay-at-home mandate decreased significantly (p  = 0.022). With the lack of overall activity, 82.14%of individuals self-reported having at least one symptom that worsened moderately or higher. Further testing, using mobile-based assessments, showed average completion times of functional tasks increased, taking about 2.1 times longer, while accuracy metrics showed overall degradation. Conclusion: Although the COVID-19 stay-at-home mandate was intended to help protect individuals at high risk from coming into contact with the virus, it also prevented individuals from receiving recommended supervised exercise interventions resulting in significant negative effects in social well-being and across motor and speech neurocognitive tasks for individuals with PD. Show more

Keywords: COVID-19, Parkinson’s disease, physical interventions, neurocognitive assessment, quality of life

DOI: 10.3233/JPD-212553

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Santos García, Diego | de Deus Fonticoba, Teresa | Cores, Carlos | Castro, Ester Suárez | Hernández Vara, Jorge | Jesús, Silvia | Mir, Pablo | Cosgaya, Marina | Martí, Maria José | Pastor, Pau | Cabo, Iria | Seijo, Manuel | Legarda, Inés | Vives, Bárbara | Caballol, Nuria | Rúiz Martínez, Javier | Croitoru, Ioana | Cubo, Esther | Miranda, Javier | Alonso Losada, Maria Gema | Labandeira, Carmen | López Ariztegui, Nuria | Morales-Casado, Mabel | González Aramburu, Isabel | Infante, Jon | Escalante, Sonia | Bernardo, Noemí | Blázquez Estrada, Marta | Menéndez González, Manuel | Caldentey, Juan García | Borrué, Carmen | Vela, Lydia | Catalán, Maria José | Gómez Mayordomo, Víctor | Kurtis, Mónica | Prieto, Cristina | Ordás, Carlos | Nogueira, Víctor | López Manzanares, Lydia | Ávila Rivera, Maria Asunción | Puente, Victor | García Moreno, Jose Manuel | Solano Vila, Berta | Álvarez Sauco, María | Carrillo Padilla, Francisco | Carlos Martínez Castrillo, Juan | Sánchez Alonso, Pilar | Gastón, Itziar | Kulisevsky, Jaime | Valero, Caridad | de Fábregues, Oriol | González Ardura, Jessica | López Díaz, Luis Manuel | Martinez-Martin, Pablo | COPPADIS Study Group

Article Type: Research Article

Abstract: Background: There is a need for identifying risk factors for hospitalization in Parkinson’s disease (PD) and also interventions to reduce acute hospital admission. Objective: To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort. Methods: PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed …on time to hospital encounter 1-year after the baseline visit. Results: Thirty-five out of 605 (5.8%) PD patients (62.5±8.9 years old; 59.8% males) presented an AH during the 1-year follow-up after the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065–5.678; p = 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319–6.063; p = 0.008), falls (HR 3.966; 95% CI 1.757–8.470; p = 0.001), and dysphagia (HR 2.356; 95% CI 1.124–4.941; p = 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080–8.322; p = 0.035) was an independent predictor of AH. Conclusion: Falls is an independent predictor of AH in PD patients. Show more

DOI: 10.3233/JPD-212539

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2021

Authors: Siddiqi, Bernadette | Koemeter-Cox, Andrew

Article Type: Position Paper

Abstract: The current base of knowledge around Parkinson’s disease has been assembled in partnership with a cohort of participants that does not resemble the diversity of people with the disease. This poor representation in research results in an incomplete picture of the disease and disparities in care. The Michael J. Fox Foundation has defined four major areas of action: 1) identifying barriers and solutions to research participation; 2) funding inclusive research with greater participant diversity; 3) building a clinician/researcher workforce committed to health equity; and 4) supporting a more holistic understanding of PD. While factors driving disparities, including broader societal challenges, …are complex, it is imperative that the PD research, care, and patient communities move in a decisive and coordinated fashion to identify and implement strategies that advance treatments for everyone with PD and eliminate care inequities. Show more

Keywords: Health disparities, minority health, The Michael J. Fox Foundation, research diversity, health equity, Parkinson’s research, clinical research, research participation, research Inclusivity, Parkinson’s disease

DOI: 10.3233/JPD-212593

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2021

Authors: Oh, Byeong Ho | Park, Yoon Young | Park, Ji Kang | Park, Young Seok

Article Type: Research Article

Abstract: Background: Scalp erosion is not an uncommon complication of deep brain stimulation (DBS) surgery. Although various methods have been proposed to prevent and manage complications, there are still challenges. We introduce a case of recurrent scalp erosion after DBS surgery treated with vacuum-assisted closure. Case description: This article reports the case of a patient who underwent DBS for advanced Parkinson’s disease and suffered from recurrent scalp erosion with device extrusion through the skin. Scalp erosion occurred 2 years after DBS and repeated improvement and deterioration despite scalp reconstruction using a skin flap. We opened the wound and performed …temporal muscle reconstruction to cover the burr hole site, and we changed the exposed cable and applied vacuum-assisted closure. During the follow-up period, no signs of erosion or infection occurred, and DBS efficacy was preserved. Conclusion: To date, the available management strategies for scalp erosion after DBS are revision with debridement and scalp reconstruction using skin flaps or skin grafts. However, if erosion occurs repeatedly despite the above management strategies, vacuum-assisted closure with temporalis muscle reconstruction could be a suitable option. We suggest that if the condition of the scalp is weakened, it is worth considering this approach preferentially. Show more

Keywords: DBS, scalp erosion, vacuum-assisted closure

DOI: 10.3233/JPD-212651

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2021

Authors: Leta, Valentina | Urso, Daniele | Batzu, Lucia | Weintraub, Daniel | Titova, Nataliya | Aarsland, Dag | Martinez-Martin, Pablo | Borghammer, Per | van Wamelen, Daniel J. | Yousaf, Tayyabah | Rizos, Alexandra | Rodriguez-Blazquez, Carmen | Chung-Faye, Guy | Ray Chaudhuri, K.

Article Type: Research Article

Abstract: Background: Constipation is regarded as one of the prodromal features of Parkinson’s disease (PD) and there is emerging evidence linking gastrointestinal dysfunction and cognitive impairment (CI) in PD. Objective: We explored whether constipation is associated with development of CI in two independent cohorts of de novo PD patients (n  = 196 from the Non-motor International Longitudinal Study [NILS] and n  = 423 from the Parkinson’s Progression Markers Initiative [PPMI] study). Methods: Constipation was clinically defined using the Non-Motor Symptoms Scale (NMSS) item-21 [NILS] and Scales for Outcomes in PD-Autonomic (SCOPA-AUT) item-5 [PPMI]. We assessed baseline group differences …(PD with or without constipation) in CI, global non-motor symptoms burden, motor dysfunction, and striatal dopaminergic denervation. Kaplan-Meier method estimated group differences in cumulative proportion of patients with incident CI over three years. In PPMI, we subsequently performed univariate and multivariate Cox survival analyses to evaluate whether constipation predicts incident mild cognitive impairment or dementia over a 6-year period, including constipation and other known predictors of CI as covariates. Results: Patients with constipation had greater motor and global non-motor burden in both cohorts at baseline (p  <  0.05). Kaplan-Meier plots showed faster conversion to CI in patients with constipation in both cohorts (p  <  0.05). In PPMI, 37 subjects developed dementia during a mean follow-up of 4.9 years, and constipation was an independent predictor of dementia onset (hazard ratio = 2.311; p  = 0.02). Conclusion: Constipation in de novo PD patients is associated with development of cognitive decline and may serve as a clinical biomarker for identification of patients at risk for cognitive impairment. Show more

Keywords: Parkinson’s disease, constipation, cognition, mild cognitive impairment, dementia

DOI: 10.3233/JPD-212570

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Barker, Roger A. | Cutting, Emma V. | Daft, Danielle M.

Article Type: Research Article

Abstract: There is much excitement around the use of advanced therapy medicinal products (ATMPs), including cell and gene treatments, in Parkinson’s disease (PD). However, taking an ATMP to clinical trials in patients with PD is complex. As such it is important from an investigator’s perspective that they ask themselves two key questions before embarking on such work: firstly, why are you doing it, and, secondly, do you understand what is needed to conduct a clinical trial with that product. In this article, we briefly discuss these two questions.

Keywords: Parkinson’s disease, ATMP, stem cells, gene therapy, clinical trial, regulations

DOI: 10.3233/JPD-212563

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Little, Max A.

Article Type: Research Article

Abstract: Parkinson’s disease is a complex and heterogeneous condition, and there are many gaps in the medical community’s scientific and practical understanding of the disease. Closing these gaps relies on objective data about symptoms and signs, collected over long durations. Smartphones contain sensor devices which can be used to remotely capture behavioral signals. From these signals, computational algorithms can distill metrics of symptom severity and progression. This brief review introduces the main concepts of the discipline, addressing the experimental, hardware and software logistics, and computational analysis. The article finishes with an exploration of future prospects for the technology.

Keywords: Wearables, sensors, smartphones, algorithms, digital signals

DOI: 10.3233/JPD-202453

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2021

Authors: Björklund, Anders | Parmar, Malin

Article Type: Review Article

Abstract: Cell therapy for Parkinson’s disease (PD) is aimed to replace the degenerated midbrain dopamine (mDA) neurons and restore DA neurotransmission in the denervated forebrain targets. A limitation of the intrastriatal grafting approach, which is currently used in clinical trials, is that the mDA neurons are implanted into the target area, in most cases the putamen, and not in the ventral midbrain where they normally reside. This ectopic location of the cells may limit their functionality due to the lack of appropriate afferent regulation from the host. Homotopic transplantation, into the substantia nigra, is now being pursued in rodent …PD models as a way to achieve more complete circuitry repair. Intranigral grafts of mDA neurons, derived from human embryonic stem cells, have the capacity to re-establish the nigrostriatal and mesolimbic pathways in their entirety and restore dense functional innervations in striatal, limbic and cortical areas. Tracing of host afferent inputs using the rabies tracing technique shows that the afferent connectivity of grafts implanted in the nigra matches closely that of the intrinsic mDA system, suggesting a degree of circuitry reconstruction that exceeds what has been achieved before. This approach holds great promise, but to match the larger size of the human brain, and the 10 times greater distance between substantia nigra and its forebrain targets, it may be necessary to find ways to improve the growth capacity of the grafted mDA neurons, pointing to a combined approach where growth promoting factors are used to enhance the performance of mDA neuron grafts. Show more

Keywords: Parkinson’s disease, embryonic stem cells, transplantation, connectivity

DOI: 10.3233/JPD-212609

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Avisar, Hila | Guardia-Laguarta, Cristina | Area-Gomez, Estela | Surface, Matthew | Chan, Amanda K. | Alcalay, Roy N. | Lerner, Boaz

Article Type: Research Article

Abstract: Background: The role of the lipidome as a biomarker for Parkinson’s disease (PD) is a relatively new field that currently only focuses on PD diagnosis. Objective: To identify a relevant lipidome signature for PD severity markers. Methods: Disease severity of 149 PD patients was assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Montreal Cognitive Assessment (MoCA). The lipid composition of whole blood samples was analyzed, consisting of 517 lipid species from 37 classes; these included all major classes of glycerophospholipids, sphingolipids, glycerolipids, and sterols. To handle the high number of lipids, the selection …of lipid species and classes was consolidated via analysis of interrelations between lipidomics and disease severity prediction using the random forest machine-learning algorithm aided by conventional statistical methods. Results: Specific lipid classes dihydrosphingomyelin (dhSM), plasmalogen phosphatidylethanolamine (PEp), glucosylceramide (GlcCer), dihydro globotriaosylceramide (dhGB3), and to a lesser degree dihydro GM3 ganglioside (dhGM3), as well as species dhSM(20:0), PEp(38:6), PEp(42:7), GlcCer(16:0), GlcCer(24:1), dhGM3(22:0), dhGM3(16:0), and dhGB3(16:0) contribute to PD severity prediction of UPDRS III score. These, together with age, age at onset, and disease duration, also contribute to prediction of UPDRS total score. We demonstrate that certain lipid classes and species interrelate differently with the degree of severity of motor symptoms between men and women, and that predicting intermediate disease stages is more accurate than predicting less or more severe stages. Conclusion: Using machine-learning algorithms and methodologies, we identified lipid signatures that enable prediction of motor severity in PD. Future studies should focus on identifying the biological mechanisms linking GlcCer, dhGB3, dhSM, and PEp with PD severity. Show more

Keywords: Parkinson’s disease (PD), PD severity, lipidomics, lipidome, UPDRS, machine learning

DOI: 10.3233/JPD-202476

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Chen, Yancong | Sun, Xuemei | Lin, Yali | Zhang, Zixuan | Gao, Yinyan | Wu, Irene X.Y.

Article Type: Research Article

Abstract: Background: Numerous systematic reviews (SRs) and meta-analyses on non-genetic risk factors for Parkinson’s disease (PD) development have been published with inconsistent conclusions. Objective: This overview of SRs aimed to summarize evidence on non-genetic factors for the development of PD from the published SRs, and explore the reasons behind the conflicting results. Methods: Three international databases were searched for SRs with meta-analyses summarized evidence on non-genetic factors for PD development. The Assessing the Methodological Quality of Systematic Reviews 2 tool was used to appraise the methodological quality of included SRs. Pooled effect estimations were extracted from each …meta-analysis. Results: Forty-six SRs covered six categories, and more than 80 factors were included in this overview. Thirty-nine SRs (84.7%) were judged to be of critically low methodological quality. Evidence from prospective studies showed that physical activity, smoking, coffee, caffeine, tea, fat intake, ibuprofen use, calcium channel blocker use, statin use, thiazolidinediones, and high serum urate levels significantly reduced the risk of PD, while dairy intake, diabetes, hormone replacement therapy, depression, mood disorder, bipolar disorder, and aspirin use significantly increased the risk of PD. Differences in study designs (e.g., cohort studies, case-control studies) accounted for the conflicting results among included SRs. Conclusion: Modifiable lifestyle factors such as physical activity and tea and coffee drinking may reduce the risk of PD, which may offer PD prevention strategies and hypotheses for future research. However, the designs of primary studies on PD risk factors and related SRs need to be improved and harmonized. Show more

Keywords: Risk factors, Parkinson’s disease, systematic review, meta-analysis

DOI: 10.3233/JPD-202521

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Doppler, Kathrin

Article Type: Research Article

Abstract: Alpha-synuclein deposits are detectable in skin biopsies of patients with Parkinson’s disease and other synucleinopathies like multiple system atrophy by immunohistochemical staining. As they are easily to obtain, they appear a promising tool for the pre-mortem histopathological confirmation of the disease and as a potential outcome measure in studies targeting alpha-synuclein aggregates. Good sensitivity, specificity, and practicability are the most important requirements of a biomarker. The review gives an overview on all three aspects, addresses methodological problems and the lack of standardized procedures as a major problem and gives an outlook on the future of skin biopsy as a potential …diagnostic tool in synucleinopathies. Show more

Keywords: Parkinson’s disease, synucleinopathy, skin, alpha-synuclein

DOI: 10.3233/JPD-202489

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Suzuki, Keisuke | Numao, Ayaka | Komagamine, Tomoko | Haruyama, Yasuo | Kawasaki, Akiko | Funakoshi, Kei | Fujita, Hiroaki | Suzuki, Shiho | Okamura, Madoka | Shiina, Tomohiko | Hirata, Koichi

Article Type: Research Article

Abstract: Background: The coronavirus disease 2019 (COVID-19) pandemic has negatively affected the mental health of the general population. Objective: We investigated the determinants of quality of life (QOL) in Parkinson’s disease (PD) patients during the COVID-19 pandemic. Methods: Impacts of lifestyle changes due to the COVID-19 pandemic on 100 patients with PD and their caregivers/spouses were assessed. The Hospital Anxiety and Depression Scale was used to assess anxiety and depression. The physical component summary (PCS) and mental component summary (MCS) scores of the short form (SF)-8 were used to evaluate health-related QOL. Results: Regarding health-related …QOL, physical function, role physical, general health, vitality and the PCS score were significantly worse in PD patients than in caregivers. Worsening of PD-related symptoms, increased stress, and decreased physical activity were observed in 29.0%, 37.0% and 44.0% of PD patients, respectively. Sixteen patients (16.0%) experienced problems with hospital access, but none reported medication shortages. Strong concerns about COVID-19 were reported by 47.0% of caregivers and 50.0% of PD patients. In PD patients, increased gait disturbance and rigidity, disease severity, smoking, the levodopa equivalent dose and decreased body weight predicted a worse PCS score; anxiety, depression, female sex, stress and long disease duration predicted a worse MCS score. In caregivers, age and smoking contributed to a worse PCS score; depression, stress and worsening patient mood contributed to a worse MCS score. Conclusion: We report the negative impacts of the COVID-19 pandemic on health-related QOL and its determinants in PD patients and their caregivers. Show more

Keywords: Caregivers, COVID-19, Parkinson’s disease, quality of life, SARS-CoV-2

DOI: 10.3233/JPD-212560

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Guilherme, Evelyn M. | Padovez, Roberta de Fátima C.M. | de Oliveira, Adriele | Ferro, Alyne Montero | di Lorenzo, Valéria A. P. | Gianlorenço, Anna Carolyna L.

Article Type: Systematic Review

Abstract: Background: Parkinson’s disease (PD) non motor symptoms may present early in the disease course and worsen with advancing disease. Respiratory changes can affect individuals to remain physically active, contributing to a reductionof functionality and quality of life. Objective: The aim of this systematic review is to synthesize evidence of respiratory disorders in patients with PD. Methods: An electronic search was performed up to November 2020 on PubMed-MEDLINE, Embase, Web of Science, Lilacs, Cinahl, and Cochrane using the following keyword combination: [(“Parkinson disease”) AND (“respiratory function tests” OR “evaluation”) AND (“respiratory system” OR “respiration disorders” OR “respiratory …muscles”)]. Results: The electronic search resulted in 601 references in English or Portuguese. The selection process and data extraction were made by two independent reviewers. We selected 19 studies including cross-sectional studies that investigated the respiratory disorders in patients with PD through pulmonary function, respiratory muscle strength, or physical capacity evaluation. We excluded studies that considered patients with other diseases. Eighteen studies evaluated the pulmonary function in patients with PD, eleven studies verified the influence of PD on respiratory muscle strength, and three studies assessed the physical capacity through functional tests. Conclusion: The evidence showed that PD patients have higher chances to present a pulmonary dysfunction, either obstructive or restrictive, when compared to healthy subjects. In addition, these patients present lower respiratory muscle strength and a consequent decrease in physical capacity in endurance exercises. The respiratory impairment in PD seems to be directly related to the progression of the disease. Show more

Keywords: Disability evaluation, Parkinson’s disease, respiration disorders, respiratory function tests, respiratory muscle, respiratory system, spirometry

DOI: 10.3233/JPD-212565

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: Dijkstra, Bauke Wybren | Gilat, Moran | Cofré Lizama, L. Eduardo | Mancini, Martina | Bergmans, Bruno | Verschueren, Sabine M.P. | Nieuwboer, Alice

Article Type: Research Article

Abstract: Background: People with Parkinson’s disease and freezing of gait (FOG; freezers) suffer from pronounced postural instability. However, the relationship between these phenomena remains unclear and has mostly been tested in paradigms requiring step generation. Objective: To determine if freezing-related dynamic balance deficits are present during a task without stepping and determine the influence of dopaminergic medication on dynamic balance control. Methods: Twenty-two freezers, 16 non-freezers, and 20 healthy age-matched controls performed mediolateral weight-shifts at increasing frequencies when following a visual target projected on a screen (MELBA task). The amplitude and phase shift differences between center of …mass and target motion were measured. Balance scores (Mini-BESTest), 360° turning speed and the freezing ratio were also measured. Subjects with Parkinson’s disease were tested ON and partial OFF (overnight withdrawal) dopaminergic medication. Results: Freezers had comparable turning speed and balance scores to non-freezers and took more levodopa. Freezers produced hypokinetic weight-shift amplitudes throughout the MELBA task compared to non-freezers (p  = 0.002), which were already present at task onset (p  < 0.001). Freezers also displayed an earlier weight-shift breakdown than controls when OFF-medication (p  = 0.008). Medication improved mediolateral weight-shifting in freezers and non-freezers. Freezers decreased their freezing ratio in response to medication. Conclusion: Hypokinetic weight-shifting proved a marked postural control deficit in freezers, while balance scores and turning speed were similar to non-freezers. Both weight-shift amplitudes and the freezing ratio were responsive to medication in freezers, suggesting axial motor vigor is levodopa-responsive. Future work needs to test whether weight-shifting and freezing severity can be further ameliorated through training. Show more

Keywords: Parkinson disease, freezing of gait, levodopa, postural balance

DOI: 10.3233/JPD-202370

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Chen, Szu-Ju | Chi, Yu-Chiao | Ho, Chang-Han | Yang, Wei-Shiung | Lin, Chin-Hsien

Article Type: Research Article

Abstract: Background: Lipopolysaccharide-binding protein (LBP) presents bacterial endotoxin, lipopolysaccharides, to cellular surface pattern receptors for immune responses in the gut-brain axis of Parkinson’s disease (PD). Objective: We investigated whether plasma LBP levels were associated with PD severity and progression. Methods: This study included 397 participants (248 PD patients and 149 controls). We measured participants’ plasma levels of LBP and pro-inflammatory cytokines, including TNF-α , IL-6, andIL-17A. PD patients underwent motor and cognition evaluations at baseline and at a mean follow-up interval of 4.7±2.3 years. We assessed the progression of motor and cognition symptoms based on changes in …the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III motor score and Mini-Mental State Examination (MMSE) score, respectively. Results: Plasma LBP levels were lower in PD patients than controls (9.08±2.91 vs. 10.10±3.00μ g/ml, p  <  0.01). A multiple logistic regression model with adjustment for age, sex, and plasma cytokine levels revealed that reduced plasma LBP levels were associated with increased PD risk (odds ratio 0.816, [95% CI 0.717–0.929], p  = 0.002). Among PD patients, LBP levels were correlated with MDS-UPDRS part III motor score after adjustment for confounders (coefficient = 0.636, p  = 0.017), but not with MMSE score. Adjusted Cox regression analysis showed that higher plasma LBP levels associated with faster motor progression (adjusted hazard ratio 1.084 [95% CI 1.011–1.163], p  = 0.024) during follow-up. Conclusion: Our results demonstrated that plasma LBP levels reflect risk, motor symptom severity and progression in patients with PD. Show more

Keywords: Parkinson’s disease, lipopolysaccharide-binding protein (LBP), lipopolysaccharide, endotoxin, neuroinflammation, gut-brain axis

DOI: 10.3233/JPD-212574

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Chandler, Julie | Nair, Radhika | Biglan, Kevin | Ferries, Erin A. | Munsie, Leanne | Changamire, Tich | Patel, Nick

Article Type: Research Article

Abstract: Background: Characterizing patients with Parkinson’s disease (PD) and cognitive impairment is important toward understanding their natural history. Objective: Understand clinical, treatment, and cost characteristics of patients with PD pre- and post-cognitive impairment (memory loss/mild cognitive impairment/dementia or dementia treatment) recognition. Methods: 2,711 patients with PD newly diagnosed with cognitive impairment (index) were identified using administrative claims data. They were matched (1:1) on age and gender to patients with PD and no cognitive impairment (controls). These two cohorts were compared on patient characteristics, healthcare resource utilization, and total median costs for 3 years pre- and post-index using …Chi-square tests, t -tests, and Wilcoxon rank-sum tests. Logistic regression was used to identify factors predicting cognitive impairment. Results: Comorbidity indices for patients with cognitive impairment increased during the 6-year study period, especially after the index. Enrollment in Medicare Advantage Prescription Drug plans vs. commercial (OR = 1.60), dual Medicare/Medicaid eligibility (OR = 1.36), cerebrovascular disease (OR = 1.24), and PD medication use (OR = 1.46) were associated with a new cognitive impairment diagnosis (all p  <  0.05). A greater proportion of patients with cognitive impairment had hospitalizations and emergency department visits and higher median total healthcare costs than controls for each year pre- and post-index. Conclusion: In patients with PD newly diagnosed with cognitive impairment, comorbidity burden, hospitalizations, emergency department visits, and total costs peaked 1-year pre- and post-identification. These data coupled with recommendations for annual screening for cognitive impairment in PD support the early diagnosis and management of cognitive impairment in order to optimize care for patients and their caregivers. Show more

Keywords: Parkinson’s disease, mild cognitive impairment, dementia, cost

DOI: 10.3233/JPD-202190

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Camerucci, Emanuele | Stang, Cole D. | Hajeb, Mania | Turcano, Pierpaolo | Mullan, Aidan F. | Martin, Peter | Ross, Owen A. | Bower, James H. | Mielke, Michelle M. | Savica, Rodolfo

Article Type: Research Article

Abstract: Background: Early-onset Parkinson’s disease (EOPD), occurring between ages 40 and 55, carries social, societal, and personal consequences and may progress, with fewer comorbidities than typical, later-onset disease. Objective: To examine the incidence and survival of EOPD and other Parkinsonism occurring before age 55 in the population-based cohort of residents in seven Minnesota counties. Methods: A movement-disorder specialist reviewed all the medical records in a 2010–2015 Parkinsonism-incident cohort to confirm diagnosis and subtypes. Results: We identified 27 patients diagnosed at <  50 years with incident Parkinsonism 2010–15:11 (41%) cases of EOPD, 13 (48%) drug-induced Parkinsonism, and …3 (11%) other Parkinsonism and 69 incident cases of Parkinsonism <  55 years of age. Overall incidence for Parkinsonism <  50 years was 1.98/100,000 person-years, and for EOPD was 0.81/100,000 person-years. In patients <  55 years, Parkinsonism incidence was 5.05/100,000 person-years: in EOPD, 2.05/100,000 person-years. Levodopa-induced dyskinesia was present in 45%of EOPD (both <  50 years and <  55 years). Onset of cardinal motor symptoms was proximate to the diagnosis of EOPD, except for impaired postural reflexes, which occurred later in the course of EOPD. Among the 69 Parkinsonism cases <  55 years, 9 (13%; all male) were deceased (only 1 case of EOPD). Men had a higher mortality risk compared to women (p  = 0.049). Conclusion: The incidence of EOPD <  50 years was 0.81/100,000 person-years (1.98 in Parkinsonism all type); prior to 55 years was 2.05/100,000 person-years (5.05 in Parkinsonism all type) with higher incidence in men than women. Men with Parkinsonism, all type, had higher mortality compared to women. Show more

Keywords: Early-onset Parkinson’s disease (EOPD), incident cohort, rochester epidemiology project (REP), prevalence

DOI: 10.3233/JPD-202464

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Henderson, Michael X. | Changolkar, Lakshmi | Trojanowski, John Q. | Lee, Virginia M.Y.

Article Type: Research Article

Abstract: Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD) and are also associated with genetic risk in idiopathic PD. Mutations in LRRK2, including the most common p.G2019S lead to elevated kinase activity, making LRRK2 kinase inhibitors prime targets for therapeutic development. However, the role of LRRK2 kinase activity in PD pathogenesis has remained unclear. While essentially all LRRK2-PD patients exhibit dopaminergic neuron loss, many of these patients do not have α-synuclein Lewy bodies in their brains. So, what is the neuropathological substrate of LRRK2-PD? Tau has emerged as a possible candidate …due to the presence of tau pathology in the majority of LRRK2 mutation carriers and reports of hyperphosphorylated tau in LRRK2 animal models. Objective: In the current study, we aim to address whether a mutation in LRRK2 changes the cell-autonomous seeding of tau pathology in primary neurons. We also aim to assess whether LRRK2 kinase inhibitors are able to modulate tau pathology. Methods/Results: Treatment of primary neurons with LRRK2 kinase inhibitors leads to prolonged kinase inhibition but does not alter tau pathology induction. The lack of an effect of LRRK2 kinase activity was further confirmed in primary neurons expressing LRRK2G2019S and with two different forms of pathogenic tau. In no case was there more than a minor change in tau pathology induction. Conclusion: Together, our results indicate that LRRK2 kinase activity is not playing a major role in the induction of tau pathology in individual neurons. Understanding the impact of LRRK2 kinase inhibitors on pathology generation is important as kinase inhibitors move forward in clinical trials. Show more

Keywords: Leucine-rich repeat kinase 2, G2019S, genetic risk, kinase inhibition, Mapt

DOI: 10.3233/JPD-212562

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Hanein, Yael | Mirelman, Anat

Article Type: Review Article

Abstract: Sleep disturbances are prevalent in neurodegenerative diseases in general, and in Parkinson’s disease (PD) in particular. Recent evidence points to the clinical value of sleep in disease progression and improving quality of life. Therefore, monitoring sleep quality in an ongoing manner at the convenience of one’s home has the potential to improve clinical research and to contribute to significantly better personalized treatment. Further, precise mapping of sleep patterns of each patient can contribute to a better understanding of the disease, its progression and the appropriate medical treatment. Here we review selective, state-of-the-art, home-based devices for assessing sleep and sleep related …disorders. We highlight the large potential as well as the main challenges. In particular, we discuss medical validity, standardization and regulatory concerns that currently impede widespread clinical adoption of existing devices. Finally, we propose a roadmap with the technological and scientific steps that are required to impact PD research and treatment. Show more

Keywords: Movement disorders, sleep disorders, wearable electrophysiology, skin electronics, flexible electronics, smart skin

DOI: 10.3233/JPD-202412

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Sibley, Krista G. | Girges, Christine | Hoque, Ehsan | Foltynie, Thomas

Article Type: Review Article

Abstract: Remote and objective assessment of the motor symptoms of Parkinson’s disease is an area of great interest particularly since the COVID-19 crisis emerged. In this paper, we focus on a) the challenges of assessing motor severity via videos and b) the use of emerging video-based Artificial Intelligence (AI)/Machine Learning techniques to quantitate human movement and its potential utility in assessing motor severity in patients with Parkinson’s disease. While we conclude that video-based assessment may be an accessible and useful way of monitoring motor severity of Parkinson’s disease, the potential of video-based AI to diagnose and quantify disease severity in the …clinical context is dependent on research with large, diverse samples, and further validation using carefully considered performance standards. Show more

Keywords: Parkinson’s disease, video, artificial intelligence, machine learning

DOI: 10.3233/JPD-202402

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Riggare, Sara | Stamford, Jon | Hägglund, Maria

Article Type: Research Article

Abstract: Digital health promises to improve healthcare, health, and wellness through the use of digital technologies. The purpose of this commentary is to review and discuss the field of digital health for Parkinson’s disease (PD) focusing on the needs, expectations, and wishes of people with PD (PwP). Our analysis show that PwP want to use digital technologies to actively manage the full complexity of living with PD on an individual level, including the unpredictability and variability of the condition. Current digital health projects focusing on PD, however, does not live up to the expectations of PwP. We conclude that for digital …health to reach its full potential, the right of PwP to access their own data needs to be recognised, PwP should routinely receive personalised feedback based on their data, and active involvement of PwP as an equal partner in digital health development needs to be the norm. Show more

Keywords: Digital health, patient perspectives, digital technology, patient empowerment

DOI: 10.3233/JPD-202408

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Ellis, Terry D. | Earhart, Gammon M.

Article Type: Research Article

Abstract: Digital therapeutics, treatments delivered remotely and enabled by modern technology, facilitate the provision of personalized, evidence-based, interdisciplinary interventions to manage the complexities associated with Parkinson’s disease. In the context of the COVID-19 pandemic, the need for digital therapeutics has arguably never been greater. However, despite new advances in technology and a heightened interest due to the pandemic, digital therapeutics remain underdeveloped and underutilized. In this paper, we briefly review practical applications and emerging advances in digital therapeutic platforms that target motor and non-motor signs and healthy lifestyle behaviors such as regular exercise, a healthy diet and optimal sleep hygiene habits. …Future applications which could transform personalized self-management and patient care are presented. Opportunities, drawbacks and barriers to access are discussed. Show more

Keywords: Parkinson’s disease, digital therapeutics, virtual coach, mobile health

DOI: 10.3233/JPD-202407

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Cristina Simonet, Alastair | Noyce, Alastair J.

Article Type: Research Article

Abstract: Technology has an increasing presence and role in the management of Parkinson’s disease. Whether embraced or rebuffed by patients and clinicians, this is an undoubtedly growing area. Wearable sensors have received most of the attention so far. This review will focus on technology integrated into the home setting; from fixed sensors to automated appliances, which are able to capture information and have the potential to respond in an unsupervised manner. Domotics also have the potential to provide ‘real world’ context to kinematic data and therapeutic opportunities to tackle challenging motor and non-motor symptoms. Together with wearable technology, domotics have the …ability to gather long-term data and record discrete events, changing the model of the cross-sectional outpatient assessment. As clinicians, our ultimate goal is to maximise quality of life, promote autonomy, and personalisation of care. In these respects, domotics may play an essential role in the coming years. Show more

Keywords: Domotics, smart home, technology, unsupervised monitoring, Parkinson’s disease

DOI: 10.3233/JPD-202398

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Mirelman, Anat | Ray Dorsey, E. | Brundin, Patrik | Bloem, Bastiaan R.

Article Type: Editorial

Keywords: Neurological examination, expertise, clinical skills, Parkinson’s disease, movement disorders

DOI: 10.3233/JPD-219002

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2021

Authors: Stephenson, Diane | Badawy, Reham | Mathur, Soania | Tome, Maria | Rochester, Lynn

Article Type: Review Article

Abstract: The burden of Parkinson’s disease (PD) continues to grow at an unsustainable pace particularly given that it now represents the fastest growing brain disease. Despite seminal discoveries in genetics and pathogenesis, people living with PD oftentimes wait years to obtain an accurate diagnosis and have no way to know their own prognostic fate once they do learn they have the disease. Currently, there is no objective biomarker to measure the onset, progression, and severity of PD along the disease continuum. Without such tools, the effectiveness of any given treatment, experimental or conventional cannot be measured. Such tools are urgently needed …now more than ever given the rich number of new candidate therapies in the pipeline. Over the last decade, millions of dollars have been directed to identify biomarkers to inform progression of PD typically using molecular, fluid or imaging modalities. These efforts have produced novel insights in our understanding of PD including mechanistic targets, disease subtypes and imaging biomarkers. While we have learned a lot along the way, implementation of robust disease progression biomarkers as tools for quantifying changes in disease status or severity remains elusive. Biomarkers have improved health outcomes and led to accelerated drug approvals in key areas of unmet need such as oncology. Quantitative biomarker measures such as HbA1c a standard test for the monitoring of diabetes has impacted patient care and management, both for the healthcare professionals and the patient community. Such advances accelerate opportunities for early intervention including prevention of disease in high-risk individuals. In PD, progression markers are needed at all stages of the disease in order to catalyze drug development—this allows interventions aimed to halt or slow disease progression (very early) but also facilitates symptomatic treatments at moderate stages of the disease. Recently, attention has turned to the role of digital health technologies to complement the traditional modalities as they are relatively low cost, objective and scalable. Success in this endeavor would be transformative for clinical research and therapeutic development. Consequently, significant investment has led to a number of collaborative efforts to identify and validate suitable digital biomarkers of disease progression. Show more

Keywords: Parkinson’s disease, digital health technologies, biomarkers, regulatory science, drug development, clinical research, collaborations

DOI: 10.3233/JPD-202428

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Shalash, Ali | Spindler, Meredith | Cubo, Esther

Article Type: Review Article

Abstract: Telemedicine programs are particularly suited to evaluating patients with Parkinson’s disease (PD) and other movement disorders, primarily because much of the physical exam findings are visual. Telemedicine uses information and communication technologist to overcome geographical barriers and increase access to healthcare services, and it is particularly beneficial for rural and underserved communities, groups that traditionally suffer from lack of access to healthcare. There is a growing evidence of the feasibility of telemedicine, cost and time savings, patients’ and physicians’ satisfaction, and its outcome and impact on patients’ morbidity and quality of life. In addition, given the unusual current situation with …the COVID-19 pandemic, telemedicine has offered the opportunity to address the ongoing healthcare needs of patients with PD, to reduce in-person clinic visits, and human exposures (among healthcare workers and patients) to a range of infectious diseases including COVID-19. However, there are still several challenges to widespread implementation of telemedicine including the limited performance of parts of the neurological exam, limited technological savvy, fear of loss of a personal connection, or uneasiness about communicating sensitive information. On the other hand, while we are facing the new wave of COVID-19 pandemic, patients and clinicians are gaining increasing experience with telemedicine, facilitating equity of access to specialized multidisciplinary care for PD. This article summarizes and reviews the current state and future directions of telemedicine from a global perspective. Show more

Keywords: Telemedicine, telehealth, movement disorders, Parkinson’s disease

DOI: 10.3233/JPD-202411

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Del Din, Silvia | Kirk, Cameron | Yarnall, Alison J. | Rochester, Lynn | Hausdorff, Jeffrey M.

Article Type: Review Article

Abstract: The increasing prevalence of neurodegenerative conditions such as Parkinson’s disease (PD) and related mobility issues places a serious burden on healthcare systems. The COVID-19 pandemic has reinforced the urgent need for better tools to manage chronic conditions remotely, as regular access to clinics may be problematic. Digital health technology in the form of remote monitoring with body-worn sensors offers significant opportunities for transforming research and revolutionizing the clinical management of PD. Significant efforts are being invested in the development and validation of digital outcomes to support diagnosis and track motor and mobility impairments “off-line”. Imagine being able to remotely assess …your patient, understand how well they are functioning, evaluate the impact of any recent medication/intervention, and identify the need for urgent follow-up because things are changing? This could offer new pragmatic solutions for personalized care and clinical research. So the question remains: how close are we to achieving this? Here, we describe the state-of-the-art based on representative papers published between 2017 and 2020. We focus on remote (i.e., real-world, daily-living) monitoring of PD using body-worn sensors (e.g., accelerometers, inertial measurement units) for assessing motor symptoms and their complications. Despite the tremendous potential, existing challenges exist (e.g., validity, regulatory) that are preventing the widespread clinical adoption of body-worn sensors as a digital outcome. We propose a roadmap with clear recommendations for addressing these challenges and future directions to bring us closer to the implementation and widespread adoption of this important way of improving the clinical care, evaluation, and monitoring of PD. Show more

Keywords: Parkinson’s disease, remote monitoring, real-world, wearables, motor symptoms, accelerometer

DOI: 10.3233/JPD-202471

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Larson, Danielle N. | Schneider, Ruth B. | Simuni, Tanya

Article Type: Research Article

Abstract: The COVID-19 pandemic forced the abrupt and rapid expansion of an alternative care model that embraces the use of video-based visits in the care of persons with Parkinson’s disease. Video-based visits not only eliminate the risk of infection but also reduce geography- and disability-related barriers to accessing specialist care. Research has established that they are feasible, acceptable to persons with Parkinson’s disease and patient-centered. In the Unites States, the relaxation of licensure requirements, adoption of reimbursement parity and investment in telemedicine infrastructure has enabled the rapid growth of video-based visits during the COVID-19 pandemic. Now, we must turn our attention …to ensuring that progress made in expanding access to video-based care is not lost and expanded worldwide. More work is needed to identify the optimal video-based care model, establish best practices, and ensure equitable access to care. Show more

Keywords: Parkinson’s disease, telemedicine, remote consultation, coronavirus

DOI: 10.3233/JPD-202381

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Sacks, Leonard | Kunkoski, Elizabeth

Article Type: Research Article

Abstract: Digital health technology (DHT), including wearable and environmental sensors, video cameras and other electronic tools, has provided new opportunities for the measurement of movement and functionality in Parkinson’s disease. Compared to current standards for evaluation of the disease (MDS-UPDRS), DHT may offer new possibilities for more frequent objective measurements of the duration, severity and frequency of disease manifestations over time, that may provide more information than periodic clinic visits. However, DHT measurement are only scientifically and medically useful if they are accurate, reliable and clinically meaningful. Verification and validation, also known as analytical validation and clinical validation, of DHT performance …is important to ensure the accuracy and precision of measurements, and the specificity of findings. Given the wide range of clinical manifestations associated with Parkinson’s disease and the many tools and metrics to assess them, the challenge is to identify those that may represent a standard for use in clinical trials, and to confirm when digital measurements succeed or fall short of capturing meaningful benefits during drug development. Show more

Keywords: Parkinson’s disease, digital health technology, wearable, mobile technology, drug development, FDA, regulatory

DOI: 10.3233/JPD-202416

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2021