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

Authors: Borghammer, Per

Article Type: Review Article

Abstract: A new model of Parkinson’s disease (PD) pathogenesis is proposed, the α -Synuclein Origin site and Connectome (SOC) model, incorporating two aspects of α -synuclein pathobiology that impact the disease course for each patient: the anatomical location of the initial α -synuclein inclusion, and α -synuclein propagation dependent on the ipsilateral connections that dominate connectivity of the human brain. In some patients, initial α -synuclein pathology occurs within the CNS, leading to a brain-first subtype of PD. In others, pathology begins in the peripheral autonomic nervous system, leading to a body-first subtype. In brain-first cases, it is proposed that the …first pathology appears unilaterally, often in the amygdala. If α -synuclein propagation depends on connection strength, a unilateral focus of pathology will disseminate more to the ipsilateral hemisphere. Thus, α -synuclein spreads mainly to ipsilateral structures including the substantia nigra. The asymmetric distribution of pathology leads to asymmetric dopaminergic degeneration and motor asymmetry. In body-first cases, the α -synuclein pathology ascends via the vagus to both the left and right dorsal motor nuclei of the vagus owing to the overlapping parasympathetic innervation of the gut. Consequently, the initial α -synuclein pathology inside the CNS is more symmetric, which promotes more symmetric propagation in the brainstem, leading to more symmetric dopaminergic degeneration and less motor asymmetry. At diagnosis, body-first patients already have a larger, more symmetric burden of α -synuclein pathology, which in turn promotes faster disease progression and accelerated cognitive decline. The SOC model is supported by a considerable body of existing evidence and may have improved explanatory power. Show more

Keywords: Parkinson’s disease, alpha-synuclein, connectome, autonomic nervous system, pathogenesis, etiology

DOI: 10.3233/JPD-202481

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 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: Braczynski, Anne K. | Ganse, Bergita | Ridwan, Stephanie | Schlenstedt, Christian | Schulz, Jörg B. | Hoog Antink, Christoph

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is the most frequent movement disorder. Patients access YouTube, one of the largest video databases in the World, to retrieve health-related information increasingly often. Objective: We aimed to identify high-quality publishers, so-called “channels” that can be recommended to patients. We hypothesized that the number of views and the number of uploaded videos were indicators for the quality of the information given by a video on PD. Methods: YouTube was searched for 8 combinations of search terms that included “Parkinson” in German. For each term, the first 100 search results were analyzed for …source, date of upload, number of views, numbers of likes and dislikes, and comments. The view ratio (views / day) and the likes ratio (likes * 100 / [likes + dislikes]) were determined to calculate the video popularity index (VPI). The global quality score (GQS) and title - content consistency index (TCCI) were assessed in a subset of videos. Results: Of 800 search results, 251 videos met the inclusion criteria. The number of views or the publisher category were not indicative of higher quality video content. The number of videos uploaded by a channel was the best indicator for the quality of video content. Conclusion: The quality of YouTube videos relevant for PD patients is increased in channels with a high number of videos on the topic. We identified three German channels that can be recommended to PD patients who prefer video over written content. Show more

Keywords: Chronic disease, health information, information retrieval, movement disorder, neurology, social media, video database

DOI: 10.3233/JPD-202513

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

Authors: Fleury, Vanessa | Zekeridou, Alkisti | Lazarevic, Vladimir | Gaïa, Nadia | Giannopoulou, Catherine | Genton, Laurence | Cancela, José | Girard, Myriam | Goldstein, Rachel | Bally, Julien F. | Mombelli, Andrea | Schrenzel, Jacques | Burkhard, Pierre R.

Article Type: Research Article

Abstract: Background: Oral microbiota has largely escaped attention in Parkinson’s disease (PD), despite its pivotal role in maintaining oral and systemic health. Objective: The aim of our study was to examine the composition of the oral microbiota and the degree of oral inflammation in PD. Methods: Twenty PD patients were compared to 20 healthy controls. Neurological, periodontal and dental examinations were performed as well as dental scaling and gingival crevicular fluid sampling for cytokines measurement (interleukine (IL)-1β, IL-6, IL-1 receptor antagonist (RA), interferon-γ and tumor necrosis factor (TNF)-α). Two months later, oral microbiota was sampled from saliva …and subgingival dental plaque. A 16S rRNA gene amplicon sequencing was used to assess bacterial communities. Results: PD patients were in the early and mid-stage phases of their disease (Hoehn & Yahr 2–2.5). Dental and periodontal parameters did not differ between groups. The levels of IL-1β and IL-1RA were significantly increased in patients compared to controls with a trend for an increased level of TNF-α in patients. Both saliva and subgingival dental plaque microbiota differed between patients and controls. Streptococcus mutans , Kingella oralis , Actinomyces AFQC_s, Veillonella AFUJ_s, Scardovia , Lactobacillaceae, Negativicutes and Firmicutes were more abundant in patients, whereas Treponema KE332528_s, Lachnospiraceae AM420052_s, and phylum SR1 were less abundant. Conclusion: Our findings show that the oral microbiome is altered in early and mid-stage PD. Although PD patients had good dental and periodontal status, local inflammation was already present in the oral cavity. The relationship between oral dysbiosis, inflammation and the pathogenesis of PD requires further study. Show more

Keywords: Oral microbiome, inflammation, biomarker, non-motor symptoms, cytokine, Parkinson’s disease, microbiota

DOI: 10.3233/JPD-202459

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 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: Mertsalmi, Tuomas H. | But, Anna | Pekkonen, Eero | Scheperjans, Filip

Article Type: Research Article

Abstract: Background: The gastrointestinal tract is considered as a potential origin of Parkinson’s disease (PD) pathology. Besides constipation, appendectomy and inflammatory bowel disease have also been associated with a higher PD-risk, but findings have been inconsistent. To date, there is only one previous study suggesting that irritable bowel syndrome (IBS) is associated with an increased risk of PD. Objective: To evaluate whether IBS is associated with a higher risk of PD. Methods: In this retrospective registry-based cohort study, we identified 28,150 patients that were diagnosed with IBS (IBS+) during the years 1998–2014, using data from the Finnish …Care Register for Health Care. In addition, 98,789 IBS-free reference subjects (IBS-) of same age and gender and living in the same municipality were included. The study subjects were followed until the end of the year 2014 to analyze the incidence of PD. The association between IBS and PD was assessed by a Cox proportional hazards model. Results: Diagnosis of IBS was associated with a higher hazard of PD with an adjusted hazard ratio (aHR) of 1.70 (95% CI 1.27–2.26). However, the ratio of hazard rates for PD between IBS+ and IBS- subjects was not constant over time. The Cox model with time-varying coefficient for IBS status showed that the hazard of PD was significantly higher in IBS patients only during the first two years of follow-up (aHR 2.96, 95% CI 1.78–4.92). Conclusion: Our findings indicate that the association between IBS and PD is likely explained by reverse causation and detection bias. It remains open whether IBS is an actual risk factor or a prodromal symptom of PD. Show more

Keywords: Parkinson’s disease, irritable bowel syndrome, gastrointestinal tract, epidemiology

DOI: 10.3233/JPD-202330

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

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

Article Type: Research Article

Abstract: Background: Co-occurrence of β-amyloid (Aβ) pathology has been reported in Parkinson’s disease (PD), and Aβ deposition in the brain may contribute to cognitive decline in patients with PD. Whether striatal dopamine uptake and cognitive status differ with amyloid deposition has been reported in only a few studies. Objective: The purpose of this study was to investigate the association among striatal dopaminergic availability, Aβ-positivity, and motor and cognitive status in early and non-demented PD. Methods: A total of 98 newly-diagnosed, non-medicated, and non-demented patients with PD were included in this study. Cognitive status was assessed using neuropsychological …testing. Patients with mild cognitive impairment (MCI) were stratified into two groups: amnestic MCI (aMCI) and non-amnestic MCI (naMCI). Patient motor status was examined using the Unified Parkinson’s Disease Rating Scale (UPDRS) and positron emission tomography (PET) with 18 F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane (18 F-FP-CIT). All patients also underwent 18 F-florbetaben (18 F-FBB) PET and were divided based on the results into Aβ-positive and Aβ-negative groups. Results: Eighteen patients had Aβ-positivity in 18 F-FBB PET and 67 had MCI. Sixteen of 18 with Aβ-positive patients had MCI. The Aβ-positive group had higher frequency of MCI, especially amnestic-type, and lower dopaminergic activities in the left ventral striatum, but not with UPDRS motor score. Conclusion: Amyloid pathology was associated with MCI, especially amnestic-subtype, in early and non-demented PD patients and with low dopaminergic activities in the left ventral striatum. This finding suggests that PD patients with Aβ-positivity have AD-related cognitive pathophysiology in PD and associated impaired dopaminergic availability in the ventral striatum can affect the pathophysiology in various ways. Show more

Keywords: Parkinson’s disease, mild cognitive impairment, dopamine transporter, amyloid, motor, positron emission tomography

DOI: 10.3233/JPD-202496

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

Authors: Senkevich, Konstantin | Bandres-Ciga, Sara | Yu, Eric | Liyanage, Upekha E. | International Parkinson Disease Genomics Consortium (IPDGC) | Noyce, Alastair J | Gan-Or, Ziv

Article Type: Research Article

Abstract: Background: Epidemiological data suggest that cancer patients have a reduced risk of subsequent Parkinson’s disease (PD) development, but the prevalence of PD in melanoma patients is often reported to be increased. Causal relationships between cancers and PD have not been fully explored. Objective: To study causal relationship between different cancers and PD. Methods: We used GWAS summary statistics of 15 different types of cancers and two-sample Mendelian randomization to study the causal relationship with PD. Results: There was no evidence to support a causal relationship between the studied cancers and PD. We also performed …reverse analyses between PD and cancers with available full summary statistics (melanoma, breast, prostate, endometrial and keratinocyte cancers) and did not find evidence of causal relationship. Conclusion: We found no evidence to support a causal relationship between cancer and PD and the previously reported associations could be a result of genetic pleiotropy, shared biology or biases. Show more

Keywords: Parkinson’s disease, mendelian randomization, cancer, melanoma

DOI: 10.3233/JPD-202474

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 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: Camarda, Cecilia | Torelli, Paola | Pipia, Carmela | Bataglini, Iacopo | Sottile, Gianluca | Cilluffo, Giovanna | Camarda, Rosolino

Article Type: Research Article

Abstract: Background: Rigidity is a key clinical feature of Parkinson’s disease (PD), but in a very early phase of the disease, it may be absent and can be enhanced through active movements of the arm contralateral to the one being tested. Objective: To evaluate in a large cohort of neurologically and cognitively healthy (NCH) subjects aged 18–90 years if activation-induced rigidity (AR) is present in all age classes, and if there are biological differences between subjects showing AR (AR+) and not showing AR (AR-). Methods: 2,228 NCH subjects categorized as young adult (18–44 years), adult (45–64 years), …elderly (65–74 years), and old/oldest-old (75–90 years) were included in the analysis, and underwent brain MRI. White matter hyperintensities were assessed through two visual rating scales. Lacunes were also rated. Atrophy of the caudate nuclei and ventricular enlargement were assessed through the bicaudate ratio and the lateral ventricles to brain ratio. To elicit AR, the Froment’s maneuver (FM) and the instructions of the UPDRS-ME were used. Results: Among the sample, 1,689 (75.81%) subjects showed AR, of which 1,270 (57.00%) subjects showed AR by using FM, and 419 (18.81%) showed AR by using UPDRS-ME instructions. The latter subjects also showed AR by using FM. The number of AR+ subjects significantly increased with increasing age, regardless of the activation maneuver used. In each age class, the number of AR+ subjects was significantly higher by using the FM than the UPDRS-ME instructions. Conclusion: Our findings suggest that AR is likely to be one of the signs of the prodromal phase of PD. Show more

Keywords: Activation-induced rigidity, healthy aging subjects, white matter hyperintensities, lacunes, caudate atrophy, global cerebral atrophy

DOI: 10.3233/JPD-202488

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

Authors: Dinur, Tama | Becker-Cohen, Michal | Revel-Vilk, Shoshana | Zimran, Ari | Arkadir, David

Article Type: Short Communication

Abstract: Low penetrance of Parkinson’s disease (PD) associated with GBA pathogenic variants indicates the presence of modifiers genes. Clusters of PD cases in certain families with GBA variants would serve as a strong evidence for the clinical relevance of such modifiers. We studied eight family trees of non-Parkinsonian, GBA -N370S homozygote, Gaucher probands, with multiple cases of PD. Differences in PD risk associated with different GBA variants were balanced by variant homozygosity. In these families, all PD cases stemmed from only one of the proband’s parents. This observation provides a direct epidemiological evidence for genetic modifiers determining PD …risk in GBA variant carriers. Show more

Keywords: Parkinson’s disease, Gaucher disease, allele penetrance, pedigrees

DOI: 10.3233/JPD-202422

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 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: Tsitsi, Panagiota | Benfatto, Mattias Nilsson | Seimyr, Gustaf Öqvist | Larsson, Olof | Svenningsson, Prof Per | Markaki, Ioanna

Article Type: Research Article

Abstract: Background: Visual and oculomotor problems are very common in Parkinson’s disease (PD) and by using eye-tracking such problems could be characterized in more detail. However, eye-tracking is not part of the routine clinical investigation of parkinsonism. Objective: To evaluate gaze stability and pupil size in stable light conditions, as well as eye movements during sustained fixation in a population of PD patients and healthy controls (HC). Methods: In total, 50 PD patients (66% males) with unilateral to mild-to-moderate disease (Hoehn & Yahr 1– 3, Schwab and England 70– 90% ) and 43 HC (37% males) were …included in the study. Eye movements were recorded with Tobii Pro Spectrum, a screen-based eye tracker with a sampling rate of 1200 Hz. Logistic regression analysis was applied to investigate the strength of association of eye-movement measures with diagnosis. Results: Median pupil size (OR 0.811; 95% CI 0.666– 0.987; p  = 0.037) and longest fixation period (OR 0.798; 95% CI 0.691-0.921; p  = 0.002), were the eye-movement parameters that were independently associated with diagnosis, after adjustment for sex (OR 4.35; 95% CI 1.516– 12.483; p  = 0.006) and visuospatial/executive score in Montreal Cognitive Assessment (OR 0.422; 95% CI 0.233– 0.764; p  = 0.004). The area under the ROC curve was determined to 0.817; 95% (CI) 0.732– 0.901. Conclusion: Eye-tracking based measurements of gaze fixation and pupil reaction may be useful biomarkers of PD diagnosis. However, larger studies of eye-tracking parameters integrated into the screening of patients with suspected PD are necessary, to further investigate and confirm their diagnostic value. Show more

Keywords: Parkinson’s disease, eye-tracking, fixation, pupil size, eye movements

DOI: 10.3233/JPD-202427

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 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: George, Sonia | Tyson, Trevor | Rey, Nolwen L. | Sheridan, Rachael | Peelaerts, Wouter | Becker, Katelyn | Schulz, Emily | Meyerdirk, Lindsay | Burmeister, Amanda R. | von Linstow, Christian U. | Steiner, Jennifer A. | Escobar Galvis, Martha L. | Ma, Jiyan | Pospisilik, Andrew | Labrie, Viviane | Brundin, Lena | Brundin, Patrik

Article Type: Research Article

Abstract: Background: α -Synuclein (α -syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of α - synucleinopathies, such as Parkinson’s disease (PD) and multiple system atrophy (MSA). Other hallmarks include activation of microglia, elevation of pro-inflammatory cytokines, as well as the activation of T and B cells. These immune changes point towards a dysregulation of both the innate and the adaptive immune system. T cells have been shown to recognize epitopes derived from α -syn and altered populations of T cells have been found in PD and MSA patients, providing evidence that these cells can be key …to the pathogenesis of the disease. Objective To study the role of the adaptive immune system with respect to α -syn pathology. Methods: We injected human α -syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated α -syn pathology, proteinase K-resistant α -syn pathology and microgliosis in the striatum, substantia nigra and frontal cortex. We also assessed the impact of adoptive transfer of naïve T and B cells into PFF-injected immunocompromised mice. Results: Compared to wildtype mice, NSG mice had an 8-fold increase in phosphorylated α -syn pathology in the substantia nigra. Reconstituting the T cell population decreased the accumulation of phosphorylated α -syn pathology and resulted in persistent microgliosis in the striatum when compared to non-transplanted mice. Conclusion: Our work provides evidence that T cells play a role in the pathogenesis of experimental α -synucleinopathy. Show more

Keywords: Parkinson’s disease, multiple system atrophy, alpha-synuclein, phosphorylated alpha-synuclein, T lymphocytes, microglia

DOI: 10.3233/JPD-202351

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2021

Authors: Ashraf-ganjouei, Amir | Moradi, Kamyar | Aarabi, Mohammadhadi | Abdolalizadeh, AmirHussein | Kazemi, Seyedeh Zahra | Kasaeian, Amir | Vahabi, Zahra

Article Type: Research Article

Abstract: Background: REM behavior disorder (RBD) can occur in the context of neurodegenerative alpha-synucleinopathies, such as Parkinson’s disease (PD). PD patients with RBD (PD-pRBD) represent more severe symptoms and signs compared with those without RBD (PD-nRBD). On another note, autonomic dysfunction in PD patients is categorized as one of the most prominent non-motor symptoms and has been lately the field of interest in research. Objective: In the current study, we longitudinally studied autonomic dysfunction in PD-pRBD and PD-nRBD groups. Method: This study was conducted on 420 drug-naïve PD patients selected from the Parkinson’s Progression Markers Initiative database. …The RBD Screening Questionnaire was used to define the presence of probable RBD. SCOPA-AUT was used to assess autonomic dysfunction. Additionally, dopamine transporter deficits on [123 I] FP-CIT SPECT imaging was performed for all of the patients. Results: Out of 420 PD patients, 158 individuals (37.6%) were considered to have probable RBD (PD-pRBD) and others without RBD (PD-nRBD). Except for pupillomotor function, all the autonomic symptoms were significantly more severe in PD-pRBD group. In PD-nRBD group, caudate striatal binding ratio was negatively correlated with SCOPA-AUT scores, while no significant correlation was observed in PD-pRBD group. Finally, there was a significant difference considering the longitudinal changes of SCOPA-AUT total between PD-pRBD and PD-nRBD groups, suggesting a more severe autonomic decline in PD-pRBD patients. Conclusion: Our results indicate that PD-pRBD patients have more severe autonomic dysfunction. These results support the theory that PD patients can be categorized based on the clinical presentation, possibly representing differences in the disease pathophysiology. Show more

Keywords: Autonomic dysfunction, Parkinson’s disease, REM behavior disorder

DOI: 10.3233/JPD-202134

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

Authors: Gupta, Ankita | LaFaver, Kathrin | Duque, Kevin R. | Lingaiah, Anushree | Meriwether, Kate V. | Gaskins, Jeremy | Gomes, Josephine | Espay, Alberto J. | Mahajan, Abhimanyu

Article Type: Research Article

Abstract: Background: Urinary dysfunction and constipation, manifestations of pelvic floor dysfunction are common sources of disability and impaired quality of life in women with Parkinson’s disease (PD). Objective: We sought to evaluate the pelvic floor health amongst women with PD and their reporting of bladder and bowel symptoms. Methods: We surveyed women with PD and age-matched controls about pelvic floor health using validated questionnaires. All participants completed the Pelvic Floor Disability Index (PFDI-20), the Pelvic Floor Impact Questionnaire (PFIQ-7) and the Patient-Reported Outcomes Measurement Information System (PROMIS) short form version 2.0 Cognitive Function 8a. Additionally, PD patients …underwent the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) scale and the Montreal Cognition Assessment (MoCA). Results: Women with PD (n  = 59; age, 70.4±8.6 years, PROMIS cognitive score, 52.0±7.8) self-reported urinary symptoms to a greater extent than controls (n  = 59; age, 70.2±8.7 years, PROMIS cognitive score, 51.0±10) (68% vs 43%, p  <  0.01). The difference was mirrored by higher (worse) scores on both PFDI-20 (35.4 vs 15.6; p  = 0.01) and PFIQ-7 (4.8 vs 0; p  <  0.01) for PD women compared to controls. Only 63% of all participants with self-reported pelvic floor symptoms had previously reported these symptoms to a health care provider. There was no difference in utilization of specialty care between the two groups (30% vs 46%, p  = 0.2). Conclusion: Pelvic floor dysfunction, more common amongst women with PD, is underreported and undertreated. Our study identifies a key gap in care of women with PD. Show more

Keywords: Parkinson’s disease, pelvic floor disease, urinary incontinence, urinary dysfunction, prolapse, health care utilization, women’s health

DOI: 10.3233/JPD-202491

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 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: Jones, Jolynn | Nielson, Spencer A. | Trout, Jonathan | Swenson, Mckaella | Reiley, Joseph | Tanner, Jared | Bowers, Dawn | Kay, Daniel B.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is associated with sleep disturbance (SD) and sleep-related impairment (SRI). Validation of self-report measures of these problems is needed in PD. The Patient-Reported Outcomes Measurement Information System (PROMIS) includes tools that assess these problems (PROMIS-SD and PROMIS-SRI, respectively). Objective: This study aimed to further validate these measures in individuals with PD and matched controls. Methods: Individuals with early-stage PD (n =50) and matched controls (n =48) completed measures of SD including the PROMIS-SD, Pittsburgh Sleep Quality Index (PSQI), and Insomnia Severity Index (ISI). They also completed measures of daytime impairment including the …PROMIS-SRI, Epworth Sleepiness Scale, State-Trait Anxiety Inventory, Beck Depression Inventory 2nd edition, and Parkinson’s Disease Questionnaire-39. Internal consistency for the PROMIS measures were assessed using Cronbach’s α coefficient and item-total correlations in the total sample. Convergent and divergent validity of the PROMIS item banks were assessed using Spearman correlations. Results: The PROMIS item banks had excellent internal consistency (α >0.94). Supporting convergent validity, the PROMIS-SD had strong correlations with other measures of SD (ρ >0.70, for PSQI and ISI) and the PROMIS-SRI had moderate to strong correlations with all measures of daytime impairment (ρ =0.41–0.72). Supporting divergent validity within the PD group, the PROMIS-SD correlated more strongly with SRI than with the Parkinson’s Disease Questionnaire total score, a metric of PD related impairment. Conclusion: In middle-aged and older adults, with and without early-stage PD, the PROMIS-SD and PROMIS-SRI are reliable and valid measures of SD and SRI, respectively. Show more

Keywords: Parkinson’s disease, sleep, validation study, patient-reported outcome measures

DOI: 10.3233/JPD-202429

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

Authors: Rodríguez, Miguel Ángel | Crespo, Irene | del Valle, Miguel | Olmedillas, Hugo

Article Type: Article Commentary

DOI: 10.3233/JPD-212541

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-2, 2021

Authors: Contin, Manuela | Lopane, Giovanna | Cortelli, Pietro | Sambati, Luisa | Mohamed, Susan | Calandra-Buonaura, Giovanna

Article Type: Research Article

Abstract: Background: Differential diagnosis between Parkinson’s disease (PD) and atypical parkinsonisms (APs) may be difficult at disease onset. The response to levodopa (LD) is a key supportive feature but its definition is largely empirical. Studies evaluating this issue by quantitative tests are scanty. Objective: We aimed to assess the utility of a subacute low LD dose kinetic-dynamic test in the differential diagnosis between PD and APs. It was applied at the baseline of a prospective follow-up in patients with parkinsonian signs within three years of disease motor onset (“BoProPark” cohort) and eventually diagnosed as PD or APs according to …consensus criteria. Methods: Patients under at least 3-month LD therapy received a first morning fasting dose of LD/benserazide or carbidopa (100/25 mg) and underwent simultaneous serial assessments of plasma LD concentration and alternate finger tapping frequency up to 3 h. The main outcome was the extent of LD motor response, calculated by the area under the 3 h tapping effect–time curve (AUC_ETap). A receiver operating characteristic (ROC) curve analysis was performed to establish the optimal AUC_ETap cut-off to differentiate PD and APs. Results: The first 100 consecutive “BoProPark” patients were analyzed. Forty-seven patients were classified as possible, 37 as probable PD and 16 as APs. AUC_ETap medians were similar in the PD subgroups but reduced to a third in APs (p  <  0.001). The optimal AUC_ETap cut-off value was >2186 [(tap/min) x min], with a sensitivity of 92% and a specificity of 75%. Accuracy of the test was 0.85 (95% CI 0.74–0.95), p  <  0.0001. Conclusion: The estimation of 3 h AUC_ETap after a subacute low LD dose proved a reliable, objective tool to assess LD motor response in our cohort of patients. AUC_ETap value rounded to ≥2200 supports PD diagnosis, while lower values may alert to AP diagnoses. Show more

Keywords: Keywords: Levodopa, Parkinson’s disease, atypical parkinsonisms, alternate finger tapping test, kinetics-dynamics

DOI: 10.3233/JPD-202262

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

Authors: Isaacson, Jonathan R. | Brillman, Salima | Chhabria, Nisha | Isaacson, Stuart H.

Article Type: Other

Abstract: Background: The diagnosis of Parkinson’s disease (PD) is primarily clinical, but in cases of diagnostic uncertainty, evaluation of nigrostriatal dopaminergic degeneration (NSDD) by imaging of the dopamine transporter using DaTscan with single-photon emission computed tomography (SPECT) brain imaging may be helpful. Objective/Methods: In the current paper, we describe clinical scenarios for which DaTscan imaging was used in a prospective case series of 201 consecutive patients in whom a movement disorder specialist ordered DaTscan imaging to clarify NSDD. We describe the impact of DaTscan results on changing or confirming pre-DaTscan clinical diagnosis and on post-DaTscan treatment changes. …Results/Conclusion: DaTscan imaging can be useful in several clinical scenarios to determine if NSDD is present. These include in patients with early subtle symptoms, suboptimal response to levodopa, prominent action tremor, drug-induced parkinsonism, and in patients with lower extremity or other less common parkinsonism clinical presentations. We also found DaTscan imaging to be useful to determine underlying NSDD in patients with PD diagnosis for 3-5 years but without apparent clinical progression or development of motor fluctuations. Overall, in 201 consecutive patients with clinically questionable NSDD, DaTscan was abnormal in 58.7% of patients, normal in 37.8%, and inconclusive in 3.5%. DaTscan imaging changed clinical diagnosis in 39.8% of patients and led to medication therapy changes in 70.1% of patients. Show more

DOI: 10.3233/JPD-202506

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

Authors: Zhang, Zijuan | Hao, Li | Shi, Ming | Yu, Ziyang | Shao, Simai | Yuan, Ye | Zhang, Zhenqiang | Hölscher, Christian

Article Type: Research Article

Abstract: Background: Glucagon-like peptide 2 (GLP-2) is a peptide hormone derived from the proglucagon gene expressed in the intestines, pancreas and brain. Some previous studies showed that GLP-2 improved aging and Alzheimer’s disease related memory impairments. Parkinson’s disease (PD) is a progressive neurodegenerative disorder, and to date, there is no particular medicine reversed PD symptoms effectively. Objective: The aim of this study was to evaluate neuroprotective effects of a GLP-2 analogue in the 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) PD mouse model. Methods: In the present study, the protease resistant Gly(2)-GLP-2 (50 nmol/kg ip.) analogue has been tested for …14 days by behavioral assessment, transmission electron microscope, immunofluorescence histochemistry, enzyme-linked immunosorbent assay and western blot in an acute PD mouse model induced by MPTP. For comparison, the incretin receptor dual agonist DA5-CH was tested in a separate group. Results: The GLP-2 analogue treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement imbalance of mice. Gly(2)-GLP-2 treatment also protected dopaminergic neurons and restored tyrosine hydroxylase expression levels in the substantia nigra. Gly(2)-GLP-2 furthermore reduced the inflammation response as seen in lower microglia activation, and decreased NLRP3 and interleukin-1β pro-inflammatory cytokine expression levels. In addition, the GLP-2 analogue improved MPTP-induced mitochondrial dysfunction in the substantia nigra. The protective effects were comparable to those of the dual agonist DA5-CH. Conclusion: The present results demonstrate that Gly(2)-GLP-2 can attenuate NLRP3 inflammasome-mediated inflammation and mitochondrial damage in the substantia nigra induced by MPTP, and Gly(2)-GLP-2 shows neuroprotective effects in this PD animal model. Show more

Keywords: GLP-1, growth factor, inflammation, insulin, mitochondria, Parkinson’s disease

DOI: 10.3233/JPD-202318

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

Authors: Mazza, Melissa Conti | Nguyen, Victoria | Beilina, Alexandra | Karakoleva, Ema | Coyle, Michael | Ding, Jinhui | Bishop, Christopher | Cookson, Mark R.

Article Type: Research Article

Abstract: Background: Coding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson’s disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, suggesting that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Objective: Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, we set out to determine whether there are …any consequences on brain function with aging after deletion of both genes. Methods: We generated a double knockout mouse model and performed a battery of motor and non-motor behavioral tests. We then investigated postmortem assays to determine the presence of PD-like pathology, including nigral dopamine cell count, astrogliosis, microgliosis, and striatal monoamine content. Results: Behaviorally, we noted only that 18–24-month Rab29 -/-  and double (Lrrk2 -/-  /Rab29 -/-  ) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in the outcomes that represented PD-like pathology. Conclusion: These results suggest that depletion of both LRRK2 and RAB29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans. Show more

Keywords: LRRK2, RAB29, dopamine, Parkinson’s disease, behavior

DOI: 10.3233/JPD-202172

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 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: Amundsen Huffmaster, Sommer L. | Petrucci, Matthew N. | Linn-Evans, Maria E. | Chung, Jae Woo | Howell, Michael J. | Videnovic, Aleksandar | Tuite, Paul J. | Cooper, Scott E. | MacKinnon, Colum D.

Article Type: Research Article

Abstract: Background: Subtle gait deficits can be seen in people with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD), a prodromal stage of Parkinson’s disease (PD) and related alpha-synucleinopathies. It is unknown if the presence and level of REM sleep without atonia (RSWA, the electromyographic hallmark of RBD) is related to the severity of gait disturbances in people with PD. Objective: We hypothesized that gait disturbances in people with mild to moderate PD would be greater in participants with RSWA compared to those without RSWA and matched controls, and that gait impairment would correlate with measures of RSWA. …Methods: Spatiotemporal characteristics of gait were obtained from 41 people with PD and 21 age-matched controls. Overnight sleep studies were used to quantify muscle activity during REM sleep and group participants with PD into those with RSWA (PD-RSWA+, n  = 22) and normal REM sleep muscle tone (PD-RSWA-, n  = 19). Gait characteristics were compared between groups and correlated to RSWA. Results: The PD-RSWA+ group demonstrated significantly reduced gait speed and step lengths and increased stance and double support times compared to controls, and decreased speed and cadence and increased stride velocity variability compared to PD-RSWA- group. Larger RSWA scores were correlated with worse gait impairment in the PD group. Conclusion: The presence and level of muscle tone during REM sleep is associated with the severity of gait disturbances in PD. Pathophysiological processes contributing to disordered gait may occur earlier and/or progress more rapidly in people with PD and RBD. Show more

Keywords: Parkinson’s disease, REM sleep without atonia, gait

DOI: 10.3233/JPD-202098

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

Authors: van Wamelen, Daniel J. | Urso, Daniele | Chaudhuri, Kallol Ray

Article Type: Research Article

Abstract: Background: Several smaller-scale studies have shown that motor performance in Parkinson’s disease (PD) fluctuates throughout the day. Studies focusing on de novo patients are, however, lacking. Objective: To evaluate the effect of clock time on motor performance in de novo drug-naïve patients with PD. Methods: We retrieved MDS-UPDRS III scores for 421 de novo PD patients from the PPMI cohort and stratified them into three groups based on time of assessment: group 1) 7:00–10:00; group 2) 10:00–13:00, and group 3) 13:00–18:00. Groups were compared using Kruskal-Wallis test and results corrected for multiple testing. …In addition, we obtained 27 wearable sensor reports, objectively capturing bradykinesia scores in a home setting over a 6-day continuous period, in 12 drug-naïve patients from the Parkinson’s Kinetigraph Registry held at King’s College Hospital London. Time spent in severe bradykinesia scores were broken down into five daytime (06:00–21:00) three-hourly epochs and scores compared using the Friedman test. Results: There were no group differences in demographic or other clinical variables for the cross-sectional analysis. MDS-UPDRS III total scores worsened significantly during the course of the day (median 18 (group 1); 20 (group 2); and 23 (group 3); p  = 0.001). In the longitudinal wearable sensor cohort, diurnal variations were present in percentage of time spent in severe bradykinesia (p  <  0.001) with the lowest percentage during the 09:00–12:00 epoch (69.56±16.68%), when most patients are awake and start daily activity, and the highest percentage during the 18:00–21:00 epoch (73.58±16.35%). Conclusion: This exploratory study shows the existence of a diurnal pattern of motor function in patients with de novo PD. The results obtained were corroborated by objective measurements in a small longitudinal cohort confirming a similar diurnal motor score variation. Show more

Keywords: Parkinson’s disease, circadian rhythm, diurnal rhythm, bradykinesia, motor

DOI: 10.3233/JPD-202352

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

Authors: Deischinger, Carola | Dervic, Elma | Kaleta, Michaela | Klimek, Peter | Kautzky-Willer, Alexandra

Article Type: Research Article

Abstract: Background: In general, the risk to develop Parkinson’s disease (PD) is higher in men compared to women. Besides male sex and genetics, research suggests diabetes mellitus (DM) is a risk factor for PD as well. Objective: In this population-level study, we aimed at investigating the sex-specific impact of DM on new diagnoses of PD. Methods: Medical claims data were analyzed in a cross-sectional study in the Austrian population between 1997 and 2014. In the age group of 40–79 and 80+, 235,268 patients (46.6%females, 53.4%males) with DM were extracted and compared to 1,938,173 non-diabetic controls (51.9%females, 48.1%males) …in terms of risk of developing PD. Results: Men with DM had a 1.46 times increased odds ratio (OR) to be diagnosed with PD compared to non-diabetic men (95%CI 1.38–1.54, p  <  0.001). The association of DM with newly diagnosed PD was significantly greater in women (OR = 1.71, 95%CI 1.60–1.82, p  <  0.001) resulting in a relative risk increase of 1.17 (95%CI 1.11–1.30) in the age group 40 to 79 years. In 80+-year-olds the relative risk increase is 1.09 (95%CI 1.01–1.18). Conclusion: Although men are more prone to develop PD, women see a higher risk increase in PD than men amongst DM patients. Show more

Keywords: Diabetes mellitus, Parkinson’s disease, women’s health, sex differences

DOI: 10.3233/JPD-202486

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

Authors: Pérez-Soriano, Alexandra | Giraldo, Darly M. | Ríos, Jose | Muñoz, Esteban | Compta, Yaroslau | Martí, María José | Catalán MSA Registry (CMSAR)

Collaborators: Pagonabarraga, Javier | Valldeoriola, Francesc | Hernández-Vara, Jorge | Classen, Serge Jauma | Puente, Victor | Pont, Claustre | Caballol, Núria | Tolosa, Eduardo | Bayes, Angels | Campdelacreu, Jaume | de Fábregues, Oriol | Ávila, Asunción | Calopa, Matilde | Gaig, Carles | Pastor, Pau | Pujol, Montserrat | Garrido, Alicia | Painous, Celia | Planellás, Lluís | Cámara, Ana

Article Type: Research Article

Abstract: Background/Objective: Multiple system atrophy (MSA) is a highly debilitating, rare neurodegenerative disorder with two clinical motor variants (parkinsonian or MSA-P and cerebellar or MSA-C). There is a wide span of motor and non-motor symptoms (NMS) that progress over time. We studied the cohort from the Catalan Multiple System Atrophy Registry (CMSAR) to determine which symptoms are most likely to progress throughout a 2-year follow-up. Methods: We analyzed baseline, 12-month, and 24-month follow-up evaluations from the 80 cases recruited by the CMSAR. Evaluations included the UMSARS assessment, cognitive and neuropsychiatric evaluations, and a non-motor scale (NMSS-PD). Statistical analysis was …done using a Generalized Estimated Equations (GEE) model. Results: Both UMSARS I and II sub-scores significantly increased at 12- and 24-month follow-ups (p  <  0.001), with a median total score increase of 11 and 12.5 points, respectively. Items on UMSARS I that significantly worsened were mostly motor affecting daily activities. NMS, including urinary and sexual dysfunction, as well as sleep difficulties showed a significant progression on the NMSS-PD; however, other NMS such as postural hypotension, gastrointestinal, and mood dysfunction, although prevalent, did not show a clear progression on clinical scales. Conclusion: Within 24 months and as early as 12 months, MSA cases may experience significant motor worsening, affecting basic daily activities. NMS are prevalent; however, not all clinical scales register a clear progression of symptoms, perhaps suggesting that they are not sensitive enough for non-motor evaluation. Show more

Keywords: MSA, prospective changes, motor symptoms, non-motor symptoms

DOI: 10.3233/JPD-202332

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 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: Tropea, Thomas F. | Amari, Noor | Han, Noah | Rick, Jacqueline | Suh, EunRan | Akhtar, Rizwan S. | Dahodwala, Nabila | Deik, Andres | Gonzalez-Alegre, Pedro | Hurtig, Howard | Siderowf, Andrew | Spindler, Meredith | Stern, Matthew | Thenganatt, Mary Ann | Weintraub, Daniel | Willis, Allison W. | Van Deerlin, Vivianna | Chen-Plotkin, Alice

Article Type: Research Article

Abstract: Background: Observational studies in Parkinson’s disease (PD) have focused on relatively small numbers of research participants who are studied extensively. The Molecular Integration in Neurological Diagnosis Initiative at the University of Pennsylvania aims to characterize molecular and clinical features of PD in every patient in a large academic center. Objective: To determine the feasibility and interest in a global-capture biomarker research protocol. Additionally, to describe the clinical characteristics and GBA and LRRK2 variant carrier status among participants. Methods: All patients at UPenn with a clinical diagnosis of PD were eligible. Informed consent included options …for access to the medical record, future recontact, and use of biosamples for additional studies. A blood sample and a completed questionnaire were obtained from participants. Targeted genotyping for four GBA and eight LRRK2 variants was performed, with plasma and DNA banked for future research. Results: Between September 2018 and December 2019, 704 PD patients were approached for enrollment; 652 (92.6%) enrolled, 28 (3.97%) declined, and 24 (3.41%) did not meet eligibility criteria. Median age was 69 (IQR 63_75) years, disease duration was 5.41 (IQR 2.49_9.95) years, and 11.10%of the cohort was non-white. Disease risk-associated variants in GBA were identified in 39 participants (5.98%) and in LRRK2 in 16 participants (2.45%). Conclusions: We report the clinical and genetic characteristics of PD patients in an all-comers, global capture protocol from an academic center. Patient interest in participation and yield for identification of GBA and LRRK2 mutation carriers is high, demonstrating feasibility of PD clinic-wide molecular characterization. Show more

Keywords: Parkinson’s disease, LRRK2, GBA, clinical protocols

DOI: 10.3233/JPD-202406

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

Authors: Sezgin, Mine | Kicik, Ani | Bilgic, Basar | Kurt, Elif | Bayram, Ali | Hanagası, Hasmet | Tepgec, Fatih | Toksoy, Guven | Gurvit, Hakan | Uyguner, Oya | Gokcay, Gulden | Demiralp, Tamer | Emre, Murat

Article Type: Research Article

Abstract: Background: There is evidence that alterations in functional connectivity (FC) of the striatocortical circuits may appear before the onset of clinical symptoms of Parkinson’s disease (PD). Objective: The aim of this study was to investigate FC of the striatocortical circuitry in asymptomatic carriers of heterozygous glucocerebrosidase (GBA ) mutations, which pose a significant risk for developing PD. Methods: Twenty-one parents of confirmed Gaucher disease patients who were carrying heterozygous GBA mutations and 18 healthy individuals matched for age and gender were included. GBA mutation analysis was performed in all participants. Clinical evaluation included neurological …examination, Mini Mental State Examination, and UPDRS Part III. Structural and functional MRI data of 18 asymptomatic GBA mutation carriers (asGBA mc) and 17 healthy controls (HC) were available. FC was analyzed with seed-based approach. Results: Eleven asymptomatic mutation carriers had heterozygous p.L483P mutation, 6 subjects heterozygous p.N409S mutation and 1 subject heterozygous p.R392G mutation in GBA gene. Mini-Mental State Examination mean score was 28.77 (±1.16) and 29.64 (±0.70) in asGBA mc and HC groups, respectively (p  = 0.012). Significant increased connectivity Conclusion: Our results suggest that alterations in striatocortical FC can be detected in asymptomatic heterozygous GBA mutation carriers who are at risk of developing PD. These findings may provide insight into network changes during the asymptomatic phase of PD. Show more

Keywords: Parkinson’s disease, glucoserobrosidase, GBA, functional connectivity, resting state fMRI

DOI: 10.3233/JPD-202295

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

Authors: Fearon, Conor | Fasano, Alfonso

Article Type: Research Article

Abstract: Studies focusing on the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19), and Parkinson’s disease (PD) have provided conflicting results. We review the literature to investigate: 1) Are PD patients at higher risk for contracting COVID-19 and are there specific contributing factors to that risk? 2) How does COVID-19 affect PD symptoms? 3) How does COVID-19 present in PD patients? 4) What are the outcomes in PD patients who contract COVID-19? 5) What is the impact of COVID-19 on PD care? 6) Does COVID-19 increase the risk of developing PD? A literature search was performed …from 1979 to 2020 using the terms: ‘Parkinson’s disease’ and ‘parkinsonism’ combined with: ‘COVID-19’; ‘SARS-CoV-2’ and ‘coronavirus’. It does not appear that PD is a specific risk factor for COVID-19. There is evidence for direct/indirect effects of SARS-CoV-2 on motor/non-motor symptoms of PD. Although many PD patients present with typical COVID-19 symptoms, some present atypically with isolated worsening of parkinsonian symptoms, requiring increased anti-PD therapy and having worse outcomes. Mortality data on PD patients with COVID-19 is inconclusive (ranging from 5.2%to 100%). Patients with advanced PD appear to be particularly vulnerable. Single cases of acute hypokinetic-rigid syndrome have been described but no other convincing data has been reported. The rapidity with which COVID-19 has swept across the globe has favored the proliferation of studies which lack scientific rigor and the PD literature has not been immune. A coordinated effort is required to assimilate data and answer these questions in larger PD cohorts. Show more

Keywords: Parkinson’s disease, COVID-19, review

DOI: 10.3233/JPD-202320

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

Authors: Colón-Semenza, Cristina | Fulford, Daniel | Ellis, Terry

Article Type: Research Article

Abstract: Background: People with Parkinson’s disease (PwPD) are less active than their age-matched peers. Non-motor symptoms, specifically, deficient motivation, may influence decision-making for exercise due to the impaired mesolimbic dopaminergic pathway. Objective: The purpose of this study was to determine if effort-based decision-making for physical effort was different in PwPD compared to healthy controls. We sought to determine the relationship between effort-based decision making for exercise and a discrete motor task as well as the impact of components of motivation on decision-making for physical effort in PwPD. Methods: An effort-based decision-making paradigm using a discrete motor task …(button pressing) and a continuous exercise task (cycling) was implemented in 32 PwPD and 23 healthy controls. Components of motivation were measured using the Apathy Scale and the Temporal Experience of Pleasure Scale- Anticipatory Pleasure scale. Results: The presence of Parkinson’s disease (PD) did not moderate decisions for either physical effort task. There was a moderate correlation between decisions for both tasks, within each group. The anticipation of pleasure and apathy were predictors of decisions for both physical effort tasks in PwPD, but not in healthy controls. Conclusion: PwPD responded similarly to effort and reward valuations compared to those without PD. Individuals were consistent in their decisions, regardless of the physical effort task. The anticipation of pleasure and apathy were significant predictors of decisions for exercise in PwPD only. Increased anticipation of pleasure, reduction of apathy, and the use of rewards may enhance engagement in high effort exercise among PwPD. Show more

Keywords: Decision-making, effort, rewards, Parkinson’s disease, exercise, motivation

DOI: 10.3233/JPD-202353

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

Authors: HØrmann Thomsen, Trine | Wallerstedt, Susanna M. | Winge, Kristian | Bergquist, Filip

Article Type: Research Article

Abstract: People with Parkinson’s disease (PwP) have been suggested to be more vulnerable to negative psychological and psycho-social effects of the COVID-19 pandemic. Our aim was to assess the potential impact of the COVID-19 pandemic in PwP. A Danish/Swedish cohort of 67 PwP was analysed. Health-related quality of life (HRQL), depression, anxiety, apathy, sleep and motor symptom-scores were included in the analysis. Additionally, the Danish participants provided free-text descriptions of life during the pandemic. Overall, the participants reported significantly better HRQL during the COVID-19 period compared with before. Reduced social pressure may be part of the explanation. Despite worsened anxiety, night …sleep improved. Show more

DOI: 10.3233/JPD-202342

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

Authors: Port, Rebecca J. | Rumsby, Martin | Brown, Graham | Harrison, Ian F. | Amjad, Anneesa | Bale, Claire J.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a neurodegenerative condition with a diverse and complex pattern of motor and non-motor symptoms which change over time with disease duration. Objective: The aims of the present study were to discover what symptoms matter most to people with the condition and to examine how these priorities change with disease duration. Methods: A simple free-text online survey (using SmartSurvey) was developed by Parkinson’s UK, which asked participants to identify up to three aspects of the condition they would most like to see improvement in. Results: 790 people participated reporting 2,295 …issues related to PD which were grouped into 24 broad symptom domains. Of these, 1,358 (59.1%) were categorised as motor symptoms, 859 (37.4%) as non-motor issues and 78 (3.4%) as medication problems. This study reveals how certain features of PD become more or less important to patients as the condition progresses. Non-motor symptoms were highly cited from the very earliest stages of PD. Problems with walking, balance and falls, speech problems, freezing and dyskinesia become increasingly important as the condition progresses whereas tremor, stiffness and psychological health become decreasingly important as the condition progresses. Conclusions: The data suggest that the priorities of people affected by PD for improving life are personal and change with duration of the condition. These findings have implications for developing person-centred management and care, as well as for directing future research to improve quality of life. Show more

Keywords: Parkinson’s disease, quality of life, symptoms, patient priorities, progression

DOI: 10.3233/JPD-202346

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

Authors: Boucherie, Deirdre M. | Duarte, Gonçalo S. | Machado, Tiago | Faustino, Patrícia R. | Sampaio, Cristina | Rascol, Olivier | Ferreira, Joaquim J.

Article Type: Research Article

Abstract: Background: A global overview of drug development programs in Parkinson’s disease over the last few decades is lacking, while such programs are challenging given the multifaceted and heterogeneous nature of the disease. Objective: To indirectly assess drug development programs in Parkinson’s disease, exploring some factors associated with compound attrition at different trial phases. Methods: We assessed all Parkinson’s disease trials in the WHO trials portal, from inception (1999) to September 2019. Independent authors selected trials and extracted data. The success rate was the number of compounds that progressed to the next drug development phase divided by …the number of compounds in that phase. Results: Overall, 357 trials (studying 152 compounds) fulfilled our inclusion criteria, with 62 (17.3%) phase 1 trials, 135 (37.8%) phase 2 trials, 85 (23.8%) phase 3 trials, and 53 (14.8%) phase 4 trials. The success rate was 42.4% from phase 2 to 3. Original compounds received regulatory approval by the FDA in 21.4% of cases, compared with 6.7% of repurposed compounds, representing an overall success rate of 14.9%. We found 172 trials (48.2%) conducted for repurposing previously licensed compounds. These figures were approximately the same regarding approval by the EMA. Most compounds were approved to treat parkinsonism and motor fluctuations. Conclusion: We found a moderate-to-high success rate in all phases of drug development. This was largely based on the success of original compounds, despite almost half of the identified trials attempting compound repurposing. Show more

Keywords: Clinical development, drug development, clinical trials, parkinson’s disease

DOI: 10.3233/JPD-202184

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

Authors: Siebner, Thomas Hartwig | Fugl Madelung, Christopher | Bendtsen, Flemming | Løkkegaard, Annemette | Hove, Jens Dahlgaard | Siebner, Hartwig Roman

Article Type: Research Article

Abstract: Background: Gastrointestinal dysfunction and related clinical symptoms are common in Parkinson’s disease (PD), but the underlying mechanisms are still poorly understood. Objective: In this study, we investigated how PD affects the postprandial vascular response in the splanchnic circulation. Methods: 23 patients with PD in the “ON-medication state” and 23 age- and sex-matched healthy control participants underwent serial phase-contrast magnetic resonance imaging (PC-MRI) to measure the postprandial blood flow response in the superior mesenteric artery (SMA). Participants ingested a standardized liquid test meal (∼400 kcal) and underwent four PC-MRI runs within the following hour. Each PC-MRI run …consisted of six consecutive measurements of SMA blood flow. Results: In both groups, standardized food intake triggered an increase of blood flow in the SMA, but absolute and relative increases in blood flow were attenuated in patients compared to the control group (p  <  0.001). While baseline blood flow in the SMA was comparable in both groups, the postprandial maximum blood flow was attenuated in patients (p  = 0.03). The temporal dynamics of the postprandial blood flow did not differ between groups. Postprandial SMA blood flow increase in patients correlated neither with subjective reports of non-motor symptoms or upper gastrointestinal complaints, nor with levodopa equivalent daily dose or disease duration. Blood glucose measurements in between the PC-MRI runs showed a smaller postprandial increase in blood glucose in the patient group (p  = 0.006). Conclusion: This study provides first-time evidence that patients with PD have an attenuated postprandial blood flow response in the SMA, indicating an impaired functional regulation of gastrointestinal perfusion in response to food intake in PD. Show more

Keywords: Parkinson’s disease, non-motor symptoms, postprandial blood flow, magnetic resonance imaging, gastrointestinal dysfunction

DOI: 10.3233/JPD-202341

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

Authors: Gallagher, Julia | Rick, Jacqueline | Xie, Sharon X. | Martinez-Martin, Pablo | Mamikonyan, Eugenia | Chen-Plotkin, Alice | Dahodwala, Nabila | Morley, James | Duda, John E. | Trojanowski, John Q. | Siderowf, Andrew | Weintraub, Daniel

Article Type: Research Article

Abstract: Background: A composite measure that assesses both cognitive and functional abilities in Parkinson’s disease (PD) would be useful for diagnosing mild cognitive impairment (MCI) and PD dementia (PDD) and as an outcome measure in randomized controlled trials. The Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) was designed to assess both cognition and basic-instrumental activities of daily living in Alzheimer’s disease but has not yet been validated in PD. Objective: To validate the CDR-SOB as a composite cognitive-functional measure for PD patients, as well as to assess its sensitivity to change. Methods: The CDR-SOB and a …comprehensive cognitive and functional battery was administered to 101 PD patients at baseline (39 normal cognition [NC], 41 MCI and 21 PDD by expert consensus panel), and re-administered to 64 patients after 1-2 years follow-up (32 NC and 32 cognitive impairment [CI] at baseline). Results: Cross-sectionally, CDR-SOB and domain scores were correlated with corresponding neuropsychological or functional measures and were significantly different between cognitive subgroups both at baseline and at follow-up. In addition, CDR-SOB ROC curves distinguished between normal cognition and dementia with high sensitivity, but did not distinguish well between NC and MCI. Longitudinal changes in the CDR-SOB and domain scores were not significant and were inconsistent in predicting change in commonly-used cognitive and functional tests. Conclusion: The CDR-SOB detects dementia-level cognitive impairment in PD but may not be appropriate for predicting longitudinal combined cognitive-functional changes in patients without significant cognitive impairment at baseline. Show more

Keywords: Cognition, dementia, Parkinson’s disease, rating scale

DOI: 10.3233/JPD-202390

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

Authors: Vitorio, Rodrigo | Hasegawa, Naoya | Carlson-Kuhta, Patricia | Nutt, John G. | Horak, Fay B. | Mancini, Martina | Shah, Vrutangkumar V.

Article Type: Research Article

Abstract: Background: There is a lack of recommendations for selecting the most appropriate gait measures of Parkinson’s disease (PD)-specific dual-task costs to use in clinical practice and research. Objective: We aimed to identify measures of dual-task costs of gait and turning that best discriminate performance in people with PD from healthy individuals. We also investigated the relationship between the most discriminative measures of dual-task costs of gait and turning with disease severity and disease duration. Methods: People with mild-to-moderate PD (n  = 144) and age-matched healthy individuals (n  = 79) wore 8 inertial sensors while walking under single and …dual-task (reciting every other letter of the alphabet) conditions. Outcome measures included 26 objective measures within four gait domains (upper/lower body, turning and variability). The area under the curve (AUC) from the receiver-operator characteristic plot was calculated to compare discriminative ability of dual-task costs on gait across outcome measures. Results: PD-specific, dual-task interference was identified for arm range of motion, foot strike angle, turn velocity and turn duration. Arm range of motion (AUC = 0.73) and foot strike angle (AUC = 0.68) had the largest AUCs across dual-task costs measures and they were associated with disease severity and/or disease duration. In contrast, the most commonly used dual-task gait measure, gait speed, showed an AUC of only 0.54. Conclusion: Findings suggest that people with PD rely more than healthy individuals on executive-attentional resources to control arm swing, foot strike, and turning, but not gait speed. The dual-task costs of arm range of motion best discriminated people with PD from healthy individuals. Show more

Keywords: Cognition, gait, locomotion, Parkinson’s disease

DOI: 10.3233/JPD-202289

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

Authors: Smilowska, Katarzyna | van Wamelen, Daniel J. | Pietrzykowski, Tomasz | Calvano, Alexander | Rodriguez-Blazquez, Carmen | Martinez-Martin, Pablo | Odin, Per | Chaudhuri, K. Ray

Article Type: Review Article

Abstract: Background: Despite optimal dopaminergic treatment most patients in moderate to advanced stages of Parkinson’s disease (PD) experience progressively increasing disabilities, necessitating a shift from oral medication to device-aided therapies, including deep brain stimulation (DBS), intrajejunal levodopa-carbidopa infusion (IJLI), and continuous subcutaneous apomorphine infusion (CSAI). However, these therapies are costly, limiting their implementation. Objectives: To perform a systematic review on cost-effectiveness analyses for device-aided therapies in PD. Methods: References were identified by performing a systematic search in the PubMed and Web of Science databases in accordance with the PRISMA statement. In the absence of universal cost-effectiveness definitions, …the gross domestic product per capita (GDP) in the country where a study was performed was used as a cut-off for cost-effectiveness based on cost per quality adjusted life year (QALY) gained. Results: In total 30 studies were retrieved. All device-aided therapies improved quality of life compared to best medical treatment, with improvements in QALYs between 0.88 and 1.26 in the studies with long temporal horizons. For DBS, nearly all studies showed that cost per QALY was below the GDP threshold. For infusion therapies only three studies showed a cost per QALY below this threshold, with several studies with long temporal horizons showing costs below or near the GDP threshold. Conclusion: Of the device-aided therapies, DBS can be considered cost-effective, but the majority of infusion therapy studies showed that these were less cost-effective. However, long-term use of the infusion therapies appears to improve their cost-effectiveness and in addition, several strategies are underway to reduce these high costs. Show more

Keywords: Parkinson’s disease, cost-effectiveness, deep brain stimulation, quality adjusted life year, levodopa-carbidopa intestinal gel, continuous subcutaneous apomorphine infusion

DOI: 10.3233/JPD-202348

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

Authors: Contaldi, Elena | Magistrelli, Luca | Milner, Anna Vera | Cosentino, Marco | Marino, Franca | Comi, Cristoforo

Article Type: Research Article

Abstract: Background: Management of motor complications (MC) represents a major challenge in the long-term treatment of Parkinson’s disease (PD) patients. In this context, the role of peripheral adaptive immunity may provide new insights, since neuroinflammatory mechanisms have been proved crucial in the disease. Objective: The aim of this study was to analyze the transcription factors genes involved in CD4 + T cells development to uncover specific molecular signatures in patients with (PMC) and without (WMC) motor complications. Methods: mRNA levels of CD4 + T lymphocytes transcription factor genes TBX21 , STAT1 , STAT3 , STAT4 , STAT6 , RORC , GATA3 …, FOXP3 , and NR4A2 were measured from 40 PD patients, divided into two groups according to motor complications. Also, 40 age- and sex-matched healthy controls were enrolled. Results: WMC patients had higher levels of STAT1 and NR4A2 (p  = 0.004; p  = 0.003), whereas in PMC we found higher levels of STAT6 (p  = 0.04). Also, a ROC curve analysis confirmed STAT1 and NR4A2 as feasible biomarkers to discriminate WMC (AUC = 0.76, 95%CI 0.59–0.92, p  = 0.005; AUC = 0.75, 95%CI 0.58–0.90, p  = 0.007). Similarly, STAT6 detected PMC patients (AUC = 0.69, 95%CI 0.52–0.86, p  = 0.037). Conclusion: These results provide evidence of different molecular signatures in CD 4 + T cells of PD patients with and without MC, thus suggesting their potential as biomarkers of MC development. Show more

Keywords: Parkinson’s disease, motor complications, CD4 + T lymphocytes transcription factors, peripheral immune system

DOI: 10.3233/JPD-202417

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

Authors: Dahodwala, Nabila | Jahnke, Jordan | Pettit, Amy R. | Li, Pengxiang | Ladage, Vrushabh P. | Kandukuri, Prasanna L. | Bao, Yanjun | Zamudio, Jorge | Jalundhwala, Yash J. | Doshi, Jalpa A.

Article Type: Research Article

Abstract: Background: Increasing doses of oral antiparkinson medications are indicated in advanced Parkinson’s disease (PD), but little is known about sustainment of high-dose regimens. Objective: To investigate sustainment of high-dose oral medication regimens in Medicare beneficiaries with incident advanced PD. Methods: This retrospective cohort study utilized 100%fee-for-service Medicare claims from 2011–2013. We identified advanced PD using a pharmacy claims-based proxy and selected patients who initiated a new high-dose oral medication regimen (daily levodopa equivalent dose [LED] >1000 mg/day for ≥30 days) in 2012. In the following 12 months, we examined: 1) annual proportion of days covered (PDC)≥0.80 and …2) presence of a ≥90 day continuous gap at varying dosage thresholds: the initial >1000 mg/day, >800 mg/day, >500 mg/day, or >0 mg/day. Results: We identified 9,405 patients with advanced PD (mean age 77.4 [SD 6.8] years; 53%men). Only 5%maintained a regimen of >1000 mg/day at PDC ≥0.80; 75%had a ≥90-day gap in that dosage level. At a dosage threshold of >800 mg/day, 20%had a PDC ≥0.80 and 53%had a ≥90-day gap; at >500 mg/day, 56%had a PDC ≥0.80 and 19%had a ≥90-day gap; and at >0 mg/day (any dose), 76%had a PDC ≥0.80 and only 10%had a ≥90-day gap. Conclusion: Few patients with advanced PD sustained a high-dose oral medication regimen in the year following initiation, but most sustained a substantially lower-dose regimen. Strategies to improve advanced PD treatment are needed. Show more

Keywords: Advanced Parkinson’s disease, prescribing patterns, discontinuation, medicare, administrative claims

DOI: 10.3233/JPD-202147

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

Authors: Shrigley, Shelby | Nilsson, Fredrik | Mattsson, Bengt | Fiorenzano, Alessandro | Mudannayake, Janitha | Bruzelius, Andreas | Ottosson, Daniella Rylander | Björklund, Anders | Hoban, Deirdre B. | Parmar, Malin

Article Type: Research Article

Abstract: Background: Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson’s disease (PD) and they provide the option of using the patient’s own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD. Objective: To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α -synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line …(RC17) as a reference control. Methods: Cells were differentiated into ventral mesencephalic (VM)-patterned DA progenitors using an established GMP protocol. The progenitors were then either terminally differentiated to mature DA neurons in vitro or transplanted into 6-hydroxydopamine (6-OHDA) lesioned rats and their survival, maturation, function, and propensity to develop α -synuclein related pathology, were assessed in vivo . Results: Both cell lines generated functional neurons with DA properties in vitro . AST18-derived VM progenitor cells survived transplantation and matured into neuron-rich grafts similar to the RC17 cells. After 24 weeks, both cell lines produced DA-rich grafts that mediated full functional recovery; however, pathological changes were only observed in grafts derived from the α -synuclein triplication patient line. Conclusion: This data shows proof-of-principle for survival and functional recovery with familial PD patient-derived cells in the 6-OHDA model of PD. However, signs of slowly developing pathology warrants further investigation before use of autologous grafts in patients. Show more

Keywords: Parkinson’s disease, alpha-synuclein, cell transplantation, dopaminergic neurons

DOI: 10.3233/JPD-202366

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

Authors: Salvatore, Michael F. | Soto, Isabel | Alphonso, Helene | Cunningham, Rebecca | James, Rachael | Nejtek, Vicki A.

Article Type: Research Article

Abstract: Up to 23% of newly diagnosed, non-demented, Parkinson’s disease (PD) patients experience deficits in executive functioning (EF). In fact, EF deficits may occur up to 39-months prior to the onset of motor decline. Optimal EF requires working memory, attention, cognitive flexibility, and response inhibition underlying appropriate decision-making. The capacity for making strategic decisions requires inhibiting imprudent decisions and are associated with noradrenergic and dopaminergic signaling in prefrontal and orbitofrontal cortex. Catecholaminergic dysfunction and the loss of noradrenergic and dopaminergic cell bodies early in PD progression in the aforementioned cortical areas likely contribute to EF deficits resulting in non-strategic decision-making. Thus, …detecting these deficits early in the disease process could help identify a significant portion of individuals with PD pathology (14–60%) before frank motor impairment. A task to evaluate EF in the domain of non-strategic decision-making might be useful to indicate the moderate loss of catecholamines that occurs early in PD pathology prior to motor decline and cognitive impairment. In this review, we focus on the potential utility of the Iowa Gambling Task (IGT) for this purpose, given significant overlap between in loss of dopaminergic and noradrenergic cells bodies in early PD and the deficits in catecholamine function associated with decreased EF. As such, given the loss of catecholamines already well-underway after PD diagnosis, we evaluate the potential utility of the IGT to identify the risk of therapeutic non-compliance and a potential companion approach to detect PD in premotor stages. Show more

Keywords: Iowa gambling task, Parkinson’s disease, therapeutic compliance, decision-making

DOI: 10.3233/JPD-202449

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

Authors: Wood, Kimberly H. | Memon, Adeel A. | Memon, Raima A. | Joop, Allen | Pilkington, Jennifer | Catiul, Corina | Gerstenecker, Adam | Triebel, Kristen | Cutter, Gary | Bamman, Marcas M. | Miocinovic, Svjetlana | Amara, Amy W.

Article Type: Research Article

Abstract: Background: Cognitive and sleep dysfunction are common non-motor symptoms in Parkinson’s disease (PD). Objective: Determine the relationship between slow wave sleep (SWS) and cognitive performance in PD. Methods: Thirty-two PD participants were evaluated with polysomnography and a comprehensive level II neurocognitive battery, as defined by the Movement Disorders Society Task Force for diagnosis of PD-mild cognitive impairment. Raw scores for each test were transformed into z -scores using normative data. Z-scores were averaged to obtain domain scores, and domain scores were averaged to determine the Composite Cognitive Score (CCS), the primary outcome. Participants were grouped by …percent of SWS into High SWS and Low SWS groups and compared on CCS and other outcomes using 2-sided t -tests or Mann-Whitney U . Correlations of cognitive outcomes with sleep architecture and EEG spectral power were performed. Results: Participants in the High SWS group demonstrated better global cognitive function (CCS) (p  = 0.01, effect size: r  = 0.45). In exploratory analyses, the High SWS group showed better performance in domains of executive function (effect size: Cohen’s d  = 1.05), language (d  = 0.95), and processing speed (d  = 1.12). Percentage of SWS was correlated with global cognition and executive function, language, and processing speed. Frontal EEG delta power during N3 was correlated with the CCS and executive function. Cognition was not correlated with subjective sleep quality. Conclusion: Increased SWS and higher delta spectral power are associated with better cognitive performance in PD. This demonstrates the significant relationship between sleep and cognitive function and suggests that interventions to improve sleep might improve cognition in individuals with PD. Show more

Keywords: Parkinson’s disease, slow wave sleep, sleep, cognition

DOI: 10.3233/JPD-202215

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

Authors: Umehara, Tadashi | Oka, Hisayoshi | Nakahara, Atsuo | Shiraishi, Tomotaka | Sato, Takeo | Matsuno, Hiromasa | Komatsu, Teppei | Omoto, Shusaku | Murakami, Hidetomo | Iguchi, Yasuyuki

Article Type: Research Article

Abstract: Background: Orthostatic hypotension (OH) at an early stage of Parkinson’s disease (PD) predicts poor prognosis, which may suggest degeneration of dopaminergic neurons affects sympathetic function, causing OH. Objective: We tested the hypothesis that striatal dopaminergic depletion is associated with OH in PD. Methods: Out of 99 patients with newly diagnosed untreated PD, 81 patients were enrolled according to our selection criteria. All patients underwent head-up tilt-table testing and striatal 123 I-2β-carbomethoxy-3β-(4-iodophenyl)-N -(3-fluoropropyl) nortropane (123 I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT-SPECT). DaTQUANT software (GE Healthcare) was used as a semi-quantitative tool to analyze DAT-SPECT …data. The association between hemodynamic changes and 123 I-FP-CIT uptake was examined. Results: 123 I-FP-CIT uptake in the putamen, especially the anterior part and left side, was related not only to motor severity but also to OH. Change in systolic blood pressure correlated negatively with 123 I-FP-CIT uptake in bilateral anterior putamen (left: p  <  0.01, right: p  <  0.05) and left posterior putamen (p  <  0.05). Patients with OH had more severe dopamine depletion in left anterior (p  = 0.008) and posterior (p  = 0.007) putamen at a similar motor severity than did patients without OH even though both groups have similar baseline characteristics. An analysis of asymmetry index showed patients with OH had symmetrically decreased dopamine levels in anterior putamen when compared to those without OH (p  = 0.024). Conclusion: OH is closely related to striatal dopamine depletion in PD. This relation may help to account for the prognostic value of OH. Show more

Keywords: Autonomic nervous system, Parkinson’s disease, single photon emission tomography (SPECT), orthostatic hypotension, striatal dopamine depletion

DOI: 10.3233/JPD-202239

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

Authors: Kim, Ryul | Park, Sangmin | Yoo, Dallah | Ju Suh, Young | Jun, Jin-Sun | Jeon, Beomseok

Article Type: Research Article

Abstract: Background/Objective: To compare the longitudinal trajectories of cognition according to the presence of the apolipoprotein E (APOE ) ɛ 4 allele in male and female Parkinson’s disease (PD) patients. Methods: This study included a total of 361 patients with recently diagnosed de novo PD (mean age [standard deviation], 61.4 [9.8 ] years). The patients were classified into the following groups: APOE ɛ 4 + /M (n  = 65), APOE ɛ 4-/M (n  = 173), APOE ɛ 4 + /F (n  = 25), and APOE ɛ 4-/F (n  = 98). Cognitive decline was assessed annually over 5 years of follow-up using the …Montreal Cognitive Assessment (MoCA). To assess the sex-specific impacts of the APOE ɛ 4 status on cognitive decline, we used generalized linear mixed effects (GLME) models separately for men, women, and the two sexes combined. Results: In the sex-stratified GLME models adjusted for covariates, the interaction results showed that the males with APOE ɛ 4 had a steeper rate of cognitive decline than those without APOE ɛ 4. In contrast, there was no significant interaction between APOE ɛ 4 and time on longitudinal MoCA performance in the females. The main effect of APOE ɛ 4 on the change in the MoCA score was not significant for either men or women. When the data from both men and women were used, the APOE ɛ 4 + /M group exhibited a steeper rate of cognitive decline than did the APOE ɛ 4 + /F and APOE ɛ 4-/F groups. These results were consistent with those of sensitivity analyses. Conclusion: Sex may be considered when APOE ɛ 4-related vulnerability to early cognitive decline is evaluated in PD patients. Show more

Keywords: APOE , apolipoprotein, cognition, Parkinson’s disease, sex

DOI: 10.3233/JPD-202288

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