Journal of Parkinson's Disease - Volume 11, issue 4

Authors: Manna, Ida | Quattrone, Andrea | De Benedittis, Selene | Iaccino, Enrico | Quattrone, Aldo

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting 5%of the elderly population. Currently, the diagnosis of PD is mainly based on clinical features and no definitive diagnostic biomarkers have been identified. The discovery of biomarkers at the earliest stages of PD is of extreme interest. This review focuses on the current findings in the field of circulating non-coding RNAs in PD. We briefly describe the more established circulating biomarkers in PD and provide a more thorough review of non-coding RNAs, in particular microRNAs, long non-coding RNAs and circular RNAs, differentially expressed in PD, highlighting their potential for …being considered as biomarkers for diagnosis. Together, these studies hold promise for the use of peripheral biomarkers for the diagnosis of PD. Show more

Keywords: Biomarkers, circular RNAs, long non-coding RNAs, microRNAs, noncoding RNAs, Parkinson’s disease

DOI: 10.3233/JPD-212726

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1475-1489, 2021

Authors: Yemula, Nehal | Dietrich, Celina | Dostal, Vaclav | Hornberger, Michael

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, characterized by symptoms of bradykinesia, rigidity, postural instability, and tremor. Recently, there has been a growing focus on the relationship between the gut and the development of PD. Emerging to the forefront, an interesting concept has developed suggesting that the initial pathophysiological changes occur in the gastrointestinal tract before changes are seen within the brain. This review is aimed at highlighting the relationship between PD and the gastrointestinal tract, along with the supporting evidence for this. Firstly, we will focus on the gastrointestinal conditions and symptoms which commonly affects …patients, including both upper and lower gastrointestinal issues. Secondly, the impact of nutrition and diet on neurological health and PD physiology, with particular emphasis on commonly consumed items including macronutrients and micronutrients. Finally, variability of the gut microbiome will also be discussed and its link with both the symptoms and signs of PD. The evidence presented in this review highly suggests that the initial pathogenesis in the gut may proceed the development of prodromal PD subtypes, and therefore building on this further could be imperative and lead to earlier diagnosis with new and improved therapeutics. Show more

Keywords: Gut, microbiota, nutrition, Parkinson’s disease

DOI: 10.3233/JPD-212707

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1491-1505, 2021

Authors: Auffret, Manon | Meuric, Vincent | Boyer, Emile | Bonnaure-Mallet, Martine | Vérin, Marc

Article Type: Review Article

Abstract: Despite clinical evidence of poor oral health and hygiene in Parkinson’s disease (PD) patients, the mouth is often overlooked by both patients and the medical community, who generally focus on motor or psychiatric disorders considered more burdensome. Yet, oral health is in a two-way relationship with overall health—a weakened status triggering a decline in the quality of life. Here, we aim at giving a comprehensive overview of oral health disorders in PD, while identifying their etiologies and consequences. The physical (abnormal posture, muscle tone, tremor, and dyskinesia), behavioral (cognitive and neuropsychiatric disorders), and iatrogenic patterns associated with PD have an …overall detrimental effect on patients’ oral health, putting them at risk for other disorders (infections, aspiration, pain, malnutrition), reducing their quality of life and increasing their isolation (anxiety, depression, communication issues). Interdisciplinary cooperation for prevention, management and follow-up strategies need to be implemented at an early stage to maintain and improve patients’ overall comfort and condition. Recommendations for practice, including (non-)pharmacological management strategies are discussed, with an emphasis on the neurologists’ role. Of interest, the oral cavity may become a valuable tool for diagnosis and prognosis in the near future (biomarkers). This overlooked but critical issue requires further attention and interdisciplinary research. Show more

Keywords: Parkinson’s disease, oral health, stomatognathic diseases, dentistry, microbiota, interdisciplinary research

DOI: 10.3233/JPD-212605

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1507-1535, 2021

Authors: Zaman, Muhammed Shahriar | Ghahari, Setareh | McColl, Mary Ann

Article Type: Review Article

Abstract: Parkinson’s disease is a complex condition that affects many different aspects of a person’s health. Because of its complexity, people with Parkinson’s disease require access to a variety of healthcare services. The aim of the present study was to identify the barriers to access healthcare services for people with Parkinson’s disease. We conducted a scoping review according to guidelines posed by Arksey & O’Malley (2005). A search of MEDLINE, Embase, CINHAL, and PsycINFO databases was conducted, and 38 articles were selected based on the inclusion criteria. The review findings identified person-level and system-level barriers. The person-level barriers included skills required …to seek healthcare services, ability to engage in healthcare and cost for services. The system-level barriers included the availability of appropriate healthcare resources. Based on the existing barriers elucidated in the scope review, we have discussed potential areas in healthcare that require improvement for people with Parkinson’s disease to manage their healthcare needs more equitably. Show more

Keywords: Parkinson’s disease, access barriers, healthcare services

DOI: 10.3233/JPD-212735

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1537-1553, 2021

Authors: Polinski, Nicole K.

Article Type: Review Article

Abstract: The use of wildtype recombinant alpha-synuclein preformed fibrils (aSyn PFFs) to induce endogenous alpha-synuclein to form pathological phosphorylation and trigger neurodegeneration is a popular model for studying Parkinson’s disease (PD) biology and testing therapeutic strategies. The strengths of this model lie in its ability to recapitulate the phosphorylation/aggregation of aSyn and nigrostriatal degeneration seen in PD, as well as its suitability for studying the progressive nature of PD and the spread of aSyn pathology. Although the model is commonly used and has been adopted by many labs, variability in observed phenotypes exists. Here we provide summaries of the study design …and reported phenotypes from published reports characterizing the aSyn PFF in vivo model in rodents following injection into the brain, gut, muscle, vein, peritoneum, and eye. These summaries are designed to facilitate an introduction to the use of aSyn PFFs to generate a rodent model of PD—highlighting phenotypes observed in papers that set out to thoroughly characterize the model. This information will hopefully improve the understanding of this model and clarify when the aSyn PFF model may be an appropriate choice for one’s research. Show more

Keywords: Alpha-synuclein, Parkinson disease, preformed fibril, model

DOI: 10.3233/JPD-212847

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1555-1567, 2021

Authors: Maple-Grødem, Jodi | Paul, Kimberly C. | Dalen, Ingvild | Ngo, Kathie J. | Wong, Darice | Macleod, Angus D. | Counsell, Carl E. | Bäckström, David | Forsgren, Lars | Tysnes, Ole-Bjørn | Kusters, Cynthia D.J. | Fogel, Brent L. | Bronstein, Jeff M. | Ritz, Beate | Alves, Guido

Article Type: Position Paper

Abstract: Background: Motor complications are a consequence of the chronic dopaminergic treatment of Parkinson’s disease (PD) and include levodopa-induced dyskinesia (LIDs) and motor fluctuations (MF). Currently, evidence is on lacking whether patients with GBA -associated PD differ in their risk of developing motor complications compared to the general PD population. Objective: To evaluate the association of GBA carrier status with the development of LIDS and MFs from early PD. Methods: Motor complications were recorded prospectively in 884 patients with PD from four longitudinal cohorts using part IV of the UPDRS or MDS-UPDRS. Subjects were followed for …up to 11 years and the associations of GBA mutations with the development of motor complications were assessed using parametric accelerated failure time models. Results: In 439 patients from Europe, GBA mutations were detected in 53 (12.1%) patients and a total of 168 cases of LIDs and 258 cases of MF were observed. GBA carrier status was not associated with the time to develop LIDs (HR 0.78, 95%CI 0.47 to 1.26, p  = 0.30) or MF (HR 1.19, 95%CI 0.84 to 1.70, p  = 0.33). In the American cohorts, GBA mutations were detected in 36 (8.1%) patients and GBA carrier status was also not associated with the progression to LIDs (HR 1.08, 95%CI 0.55 to 2.14, p  = 0.82) or MF (HR 1.22, 95%CI 0.74 to 2.04, p  = 0.43). Conclusion: This study does not provide evidence that GBA -carrier status is associated with a higher risk of developing motor complications. Publication of studies with null results is vital to develop an accurate summary of the clinical features that impact patients with GBA -associated PD. Show more

Keywords: GBA, Parkinson’s disease, motor complications, dyskinesias, motor fluctuations

DOI: 10.3233/JPD-212657

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1569-1578, 2021

Authors: Ineichen, Christian | Baumann-Vogel, Heide | Sitzler, Matthias | Waldvogel, Daniel | Baumann, Christian R.

Article Type: Short Communication

Abstract: Whilst some studies investigated the impact of viral infection or reduced access to medication during the COVID-19 pandemic in patients with Parkinson’s disease (PD), data on the effects of pandemic restrictions are still scarce. We retrospectively analyzed motor symptoms of longitudinally followed PD patients (n  = 264) and compared motor disease progression before and during the COVID-19 pandemic. Additionally, we performed a trend analysis of the yearly evolution of motor symptoms in 755 patients from 2016 until 2021. We observed a worsening of motor symptoms and a significantly increased motor disease progression during pandemic-related restrictions as compared to before the COVID-19 …outbreak. Show more

Keywords: Parkinson’s disease, COVID-19, confinement, motor disease progression, MDS-UPDRS part III

DOI: 10.3233/JPD-212779

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1579-1583, 2021

Authors: Komici, Klara | Femminella, Grazia Daniela | Bencivenga, Leonardo | Rengo, Giuseppe | Pagano, Gennaro

Article Type: Research Article

Abstract: Background: A link between diabetes mellitus (DM) and Parkinson’s disease (PD) have been proposed but evidence are sparse and inconsistent. Objective: Perform a systematic review of all evidence that link DM and PD characterising the prevalence of DM in PD patients, the risk of developing PD in DM patients and the influence of DM on PD severity and progression. Methods: MEDLINE, Scopus, and Cochrane Library from inception to June 30, 2021 were searched. Studies reporting prevalence, incidence, severity and disease progression of DM and PD were included. Prevalence of DM in PD and incidence of PD …in DM patients, and characteristics of PD. Results: A total of 21 studies (n  = 11,396) included data on DM prevalence in PD patients, 12 studies (n  = 17,797,221) included data on incidence of PD in DM patients, and 10 studies (n  = 2,482) included data on DM impact on PD severity and disease progression. The prevalence of DM in PD patients was 10.02 %, (95%C.I. 7.88 –12.16), DM patients showed a higher risk of developing PD (OR: 1.34 95%CI 1.26–1.43 p  < 0.0001) compared to non-DM, and PD patients with DM showed a greater severity of motor symptoms, with higher Hoehn and Yahr stage (SMD: 0.36 95%CI 0.12–0.60; p  < 0.001) and higher UPDRS (SMD 0.60 95%CI 0.28–0.92; p  < 0.001) compared with PD patients without DM. Conclusion: Although the prevalence of DM in PD patients is similar to the general population, patients with DM have a higher risk of developing PD, and the presence of DM is associated with greater PD severity and faster progression, which suggests that DM may be a facilitating factor of neurodegeneration. Show more

Keywords: Parkinson’s disease, diabetes mellitus, hyperglycaemia, insulin sensitivity, neurodegeneration

DOI: 10.3233/JPD-212725

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1585-1596, 2021

Authors: Tan, Qian Yue | Cox, Natalie J. | Lim, Stephen E.R. | Coutts, Laura | Fraser, Simon D.S. | Roberts, Helen C. | Ibrahim, Kinda

Article Type: Research Article

Abstract: Background High treatment burden is associated with poor adherence, wasted resources, poor quality of life and poor health outcomes. Identifying factors that impact treatment burden in Parkinson’s disease can offer insights into strategies to mitigate them. Objective To explore the experiences of treatment burden among people with Parkinson’s disease (PwP) and their caregivers. Methods A systematic review of studies published from year 2006 was conducted. Qualitative and mixed-method studies with a qualitative component that relate to usual care in Parkinson’s disease were included. Quantitative studies and grey literature were excluded. Data synthesis was conducted using framework …synthesis. Results 1757 articles were screened, and 39 articles included. Understanding treatment burden in PwP and caregivers was not the primary aim in any of the included studies. The main issues of treatment burden in Parkinson’s disease are: 1) work and challenges of taking medication; 2) healthcare provider obstacles including lack of patient-centered care, poor patient-provider relationships, lack of care coordination, inflexible organizational structures, lack of access to services and issues in care home or hospital settings; and 3) learning about health and challenges with information provision. The treatment burden led to physical and mental exhaustion of self-care and limitations on the role and social activities of PwP and caregivers. Conclusion: There are potential strategies to improve the treatment burden in Parkinson’s disease at an individual level such as patient-centered approach to care, and at system level by improving access and care coordination between services. Future research is needed to determine the modifiable factors of treatment burden in Parkinson’s disease. Show more

Keywords: Treatment burden, burden of treatment, Parkinson’s disease, caregivers, review, qualitative, experience

DOI: 10.3233/JPD-212612

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1597-1617, 2021

Authors: Okada, Yohei | Ohtsuka, Hiroyuki | Kamata, Noriyuki | Yamamoto, Satoshi | Sawada, Makoto | Nakamura, Junji | Okamoto, Masayuki | Narita, Masaru | Nikaido, Yasutaka | Urakami, Hideyuki | Kawasaki, Tsubasa | Morioka, Shu | Shomoto, Koji | Hattori, Nobutaka

Article Type: Research Article

Abstract: Background: Long-term physiotherapy is acknowledged to be crucial to manage motor symptoms for Parkinson’s disease (PD) patients, but its effectiveness is not well understood. Objective: This systematic review and meta-analysis aimed to assess the evidence regarding the effectiveness of long-term physiotherapy to improve motor symptoms and reduce antiparkinsonian medication dose in PD patients. Methods: Pubmed, Cochrane, PEDro, and CINAHL were searched for randomized controlled trials before August 31, 2020 that investigated the effectiveness of physiotherapy for 6 months or longer on motor symptoms and levodopa-equivalent dose (LED) in PD patients with Hoehn and Yahr stage 1– …3. We performed random effects meta-analyses for long-term physiotherapy versus no/control intervention and estimated standard mean differences with 95% confidence intervals (CIs). Levels of evidence were rated by the Grading of Recommendation Assessment, Development and Evaluation approach. Results: From 2,940 studies, 10 studies involving 663 PD patients were assessed. Long-term physiotherapy had favorable effects on motor symptoms in off medication state [– 0.65, 95% CI – 1.04 to – 0.26, p  = 0.001] and LED [– 0.49, 95% CI – 0.89 to – 0.09, p  = 0.02]. Subgroup analyses demonstrated favorable effects on motor symptoms in off medication state by aerobic exercise [– 0.42, 95% CI – 0.64 to – 0.20, p  < 0.001] and LED by multidisciplinary rehabilitation of primarily physiotherapy [– 1.00, 95% CI – 1.44 to – 0.56, p  < 0.001]. Quality of evidence for aerobic exercise and multidisciplinary rehabilitation were low and very low. Conclusion: This review provided evidence that long-term physiotherapy has beneficial impact on motor symptoms and antiparkinsonian medication dose in PD patients and could motivate implementation of long-term physiotherapy. Show more

Keywords: Physiotherapy, Parkinson’s disease, motor symptoms, randomized controlled trial, systematic review, meta-analysis

DOI: 10.3233/JPD-212782

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1619-1630, 2021

Authors: Zhou, Cheng | Guo, Tao | Wu, JingJing | Wang, Linbo | Bai, Xueqin | Gao, Ting | Guan, Xiaojun | Gu, Luyan | Huang, Peiyu | Xuan, Min | Gu, Quanquan | Xu, Xiaojun | Zhang, Baorong | Cheng, Wei | Feng, Jianfeng | Zhang, Minming

Article Type: Research Article

Abstract: Background: The widely divergent responsiveness of Parkinson’s disease (PD) patients to levodopa is an important clinical issue because of its relationship with quality of life and disease prognosis. Preliminary animal experiments have suggested that degeneration of the locus coeruleus (LC) attenuates the efficacy of levodopa treatment. Objective: To explore the relationship between LC degeneration and levodopa responsiveness in PD patients in vivo . Methods: Neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a good indicator of LC and substantia nigra (SN) degeneration, and levodopa challenge tests were conducted in 57 PD patients. Responsiveness to levodopa was …evaluated by the rates of change of the Unified Parkinson’s Disease Rating Scale Part III score and somatomotor network synchronization calculated from resting-state functional MRI before and after levodopa administration. Next, we assessed the relationship between the contrast-to-noise ratio of LC (CNRLC ) and levodopa responsiveness. Multiple linear regression analysis was conducted to rule out the potential influence of SN degeneration on levodopa responsiveness. Results: A significant positive correlation was found between CNRLC and the motor improvement after levodopa administration (R  = 0.421, p  = 0.004). CNRLC also correlated with improvement in somatomotor network synchronization (R  = –0.323, p  = 0.029). Furthermore, the relationship between CNRLC and levodopa responsiveness was independent of SN degeneration. Conclusion: LC degeneration might be an essential factor for levodopa resistance. LC evaluation using NM-MRI might be an alternative tool for predicting levodopa responsiveness and for helping to stratify patients into clinical trials aimed at improving the efficacy of levodopa. Show more

Keywords: Parkinson’s disease, locus coeruleus, levodopa, magnetic resonance imaging, network

DOI: 10.3233/JPD-212720

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1631-1640, 2021

Authors: Tilley, Bension S. | Patel, Shivani R. | Goldfinger, Marc H. | Pearce, Ronald K.B. | Gentleman, Steve M.

Article Type: Research Article

Abstract: Background: Lewy body dementia (LBD) has two main phenotypes: Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), separated by the ‘one-year-rule’. They also show different symptom profiles: core DLB features include fluctuating cognition, REM-sleep behaviur disorder, and visual hallucinations. These symptoms are sometimes present in PDD, representing an intermediate ‘PDD-DLB’ phenotype. Objective: DLB-like features may reflect deficits in the functions of the noradrenergic nucleus locus coeruleus (LC). Therefore, we compared the LC in the LBD phenotypes, PD, and controls. Methods: 38 PD, 56 PDD, 22 DLB, and 11 age-matched control cases from the Parkinson’s …UK tissue bank were included. LC tissue sections were immunostained for tyrosine-hydroxylase (TH), α-synuclein, tau, and amyloid-β. TH-neurons were quantified and pathologic burden calculated by %-coverage method. Results: The LC shows a stepwise reduction in neuron count from controls, PD, PDD, to DLB. PDD-DLB cases showed an intermediate clinical phenotype that was reflected pathologically. Cell counts were significantly reduced in DLB compared to PDD after correction for demographic factors. LC degeneration contributed significantly to the onset of all DLB symptoms. While α-synuclein was not significantly different between PDD and DLB cases, DLB exhibited significantly less tau pathology. Conclusion: DLB and DLB-like symptoms represent noradrenergic deficits resulting from neuronal loss in the LC. PDD and DLB are likely to represent a clinical continuum based on the presence or absence of DLB-like symptoms mirrored by a pathological continuum in the LC. Show more

Keywords: Alpha-synuclein, Lewy body disease, locus coeruleus, neuropathology, Parkinson’s disease, tau proteins

DOI: 10.3233/JPD-212748

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1641-1650, 2021

Authors: Palermo, Giovanni | Giannoni, Sara | Giuntini, Martina | Belli, Elisabetta | Frosini, Daniela | Siciliano, Gabriele | Ceravolo, Roberto

Article Type: Research Article

Abstract: Background: It has been speculated that stains are neuroprotective and are associated with a reduced risk of Parkinson’s disease (PD), but only a few studies have investigated the influence of statins on the progression of PD. Objective: To evaluate whether long-term statin use may affect motor progression in a large cohort of de novo patients with PD. Methods: We conducted a 4-year retrospective observational cohort study to assess patients with PD. The patients were consecutively recruited from a single tertiary center between January 2015 and January 2017. Information on motor function was obtained using the …MDS-Unified Parkinson Disease Rating Scale (UPDRS)-III and all subjects were extensively characterized, including information about lifestyle habits, cardiovascular risk factors and cholesterol blood levels. Results: Of the 181 participants included in the study, 104 patients were evaluated for eligibility (42 patients were exposed to statin therapies and 62 were not treated with statins). They presented similar scores in UPDRS III at baseline but the statin users had a lower motor impairment at 4 years compared to non-user PD patients. Additionally, statin treatment resulted in slower progression of the rigidity score of UPDRS over 4 years. No other significant differences were observed between PD patients with and without statins. Conclusion: Early PD patients with long-term statin usage showed lower motor deterioration after 4 years of disease duration compared with patients not taking statins at diagnosis, suggesting a possible influence of statins on disease progression in PD. Further investigation is warranted to understand the potential beneficial effects of statin treatment on clinical symptoms in PD. Show more

Keywords: Cholesterol, disease progression, Parkinson’s disease, statin

DOI: 10.3233/JPD-212655

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1651-1662, 2021

Authors: Hauser, Robert A. | Hattori, Nobutaka | Fernandez, Hubert | Isaacson, Stuart H. | Mochizuki, Hideki | Rascol, Olivier | Stocchi, Fabrizio | Li, June | Mori, Akihisa | Nakajima, Yu | Ristuccia, Robert | LeWitt, Peter

Article Type: Research Article

Abstract: Background: Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with Parkinson’s disease (PD) experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Objective: This pooled analysis of eight randomized, placebo-controlled, double-blind phase 2b/3 studies evaluated the efficacy and safety of istradefylline. Methods: Istradefylline was evaluated in PD patients receiving levodopa with carbidopa/benserazide and experiencing motor fluctuations. Eight 12- or 16-week trials were conducted (n  = 3,245); four of these studies were the basis for istradefylline’s FDA approval. Change in OFF time as assessed in patient-completed 24-h PD diaries at Week 12 was the …primary endpoint. All studies were designed with common methodology, thereby permitting pooling of data. Pooled analysis results from once-daily oral istradefylline (20 and 40 mg/day) and placebo were evaluated using a mixed-model repeated-measures approach including study as a factor. Results: Among 2,719 patients (placebo, n  = 992; 20 mg/day, n  = 848; 40 mg/day, n  = 879), OFF hours/day were reduced at Week 12 at istradefylline dosages of 20 mg/day (least-squares mean difference [LSMD] from placebo in reduction from baseline [95%CI], –0.38 h [–0.61, –0.15]) and 40 mg/day (–0.45 h [–0.68, –0.22], p  < 0.0001); ON time without troublesome dyskinesia (ON-WoTD) significantly increased. Similar results were found in the four-study pool (OFF hours/day, 20 mg/day, –0.75 h [–1.10, –0.40]; 40 mg/day, –0.82 h [–1.17, –0.47]). Istradefylline was generally well-tolerated; the average study completion rate among istradefylline-treated patients across all studies was 89.2%. Dyskinesia was the most frequent adverse event (placebo, 9.6%; 20 mg/day, 16.1%; 40 mg/day, 17.7%). Conclusion: In this pooled analysis, istradefylline significantly improved OFF time and ON-WoTD relative to placebo and was well-tolerated. Show more

Keywords: Adenosine 2A receptor antagonist, istradefylline, Parkinson’s disease, treatment

DOI: 10.3233/JPD-212672

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1663-1675, 2021

Authors: Knudsen, Karoline | Fedorova, Tatyana D. | Horsager, Jacob | Andersen, Katrine B. | Skjærbæk, Casper | Berg, Daniela | Schaeffer, Eva | Brooks, David J. | Pavese, Nicola | Van Den Berge, Nathalie | Borghammer, Per

Article Type: Research Article

Abstract: Background: We have hypothesized that Parkinson’s disease (PD) comprises two subtypes. Brain-first , where pathogenic α-synuclein initially forms unilaterally in one hemisphere leading to asymmetric nigrostriatal degeneration, and body-first with initial enteric pathology, which spreads through overlapping vagal innervation leading to more symmetric brainstem involvement and hence more symmetric nigrostriatal degeneration. Isolated REM sleep behaviour disorder has been identified as a strong marker of the body-first type. Objective: To analyse striatal asymmetry in [18 F]FDOPA PET and [123 I]FP-CIT DaT SPECT data from iRBD patients, de novo PD patients with RBD (PD+RBD ) and de novo …PD patients without RBD (PD-RBD ). These groups were defined as prodromal body-first , de novo body-first , and de novo brain-first , respectively. Methods: We included [18 F]FDOPA PET scans from 21 iRBD patients, 11 de novo PD+RBD , 22 de novo PD-RBD , and 18 controls subjects. Also, [123 I]FP-CIT DaT SPECT data from iRBD and de novo PD patients with unknown RBD status from the PPPMI dataset was analysed. Lowest putamen specific binding ratio and putamen asymmetry index (AI) was defined. Results: Nigrostriatal degeneration was significantly more symmetric in patients with RBD versus patients without RBD or with unknown RBD status in both FDOPA (p  = 0.001) and DaT SPECT (p  = 0.001) datasets. Conclusion: iRBD subjects and de novo PD+RBD patients present with significantly more symmetric nigrostriatal dopaminergic degeneration compared to de novo PD-RBD patients. The results support the hypothesis that body-first PD is characterized by more symmetric distribution most likely due to more symmetric propagation of pathogenic α-synuclein compared to brain-first PD. Show more

Keywords: Parkinson’s disease, asymmetry, dopaminergic dysfunction, brain- and body-first

DOI: 10.3233/JPD-212761

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1677-1687, 2021

Authors: Cotogni, Marco | Sacchi, Lucia | Sadikov, Aleksander | Georgiev, Dejan

Article Type: Research Article

Abstract: Background: Even though a significant fraction of Parkinson’s disease (PD) patients presents with only minor or no motor asymmetry, the motor symptoms in PD typically start on one side of the body and worse symptoms on the side of the disease onset usually persist long after the disease has become clinically bilateral. The asymmetric presentation of PD has been studied over the years, with some studies showing slower progression in PD subjects with asymmetric disease presentation. In other studies, however, it was not possible to relate the asymmetry to disease progression. Objective: The main objective of the present …study was to assess the effect of asymmetry at disease onset on disease progression. Methods: Using the data available in the Parkinson’s Progression Markers Initiative (PPMI) database, at baseline, 423 subjects with de-novo PD were included in the study. Instead of dichotomizing the subjects in asymmetric and symmetric, we kept the asymmetry index and the non-motor, disability, and motor progression at one-, three-, and five-year follow-up continuous. Pearson’s r correlational analysis and the coefficient of determination R 2 were used to correlate asymmetry indices and disease progression. Results: There was no correlation between neither clinically, nor DatSCAN defined asymmetry and non-motor, motor, and disability progression in the de-novo PD subjects with a 5-year follow-up. Conclusion: Asymmetry at disease onset does not predict progression of PD. Further studies are needed to investigate whether early detection of asymmetry on clinical grounds could successfully distinguish between PD and symmetric types of atypical parkinsonism in the early stages of the disease. Show more

Keywords: Asymmetry index, DatSCAN, disease progression, Parkinson’s disease

DOI: 10.3233/JPD-202525

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1689-1694, 2021

Authors: Rosebraugh, Matthew | Liu, Wei | Neenan, Melina | Facheris, Maurizio F.

Article Type: Research Article

Abstract: Background: Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is in development for the treatment of motor complications for patients with advanced Parkinson’s disease (aPD). Objective: The current work characterizes the levodopa (LD) and carbidopa (CD) pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients. Methods: This was a Phase 1, single ascending dose, single-blind study conducted in 28 adult male and female subjects at seven sites in the United States. Foslevodopa/foscarbidopa was administered via abdominal SC …infusion in PD patients over 72 hours. Patients were stratified in 4 groups and received a fixed dose of foslevodopa/foscarbidopa based on their oral daily LD intake. Serial plasma PK samples were collected to assay for LD and CD concentrations. Safety and tolerability were assessed throughout the study. Results: LD exposure quickly reached steady state and remained stable with minimal fluctuations. Foslevodopa/foscarbidopa infusion provides stable LD and CD exposures compared to oral LD/CD dosing with the average steady-state exposure ranging from 747-4660 ng/mL for the different groups. Conclusion: Foslevodopa/foscarbidopa was able to provide stable LD and CD exposures in PD patients over 72 hours via SC route of delivery with very low fluctuation in LD concentration level across a wide range of clinically relevant exposures. Foslevodopa/foscarbidopa had a favorable safety profile. The low PK fluctuation following foslevodopa/foscarbidopa infusion is expected to maintain LD exposure to treat aPD patients within a narrow therapeutic window. Show more

Keywords: Levodopa, carbidopa, Parkinson’s disease, pharmacokinetics, NCT03033498

DOI: 10.3233/JPD-212813

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1695-1702, 2021

Authors: Yoo, Han Soo | Lee, Sangwon | Jeong, Seong Ho | Ye, Byoung Seok | Sohn, Young H. | Yun, Mijin | Lee, Phil Hyu

Article Type: Research Article

Abstract: Background: Olfactory or autonomic dysfunction is one of the earliest prodromal symptoms of Parkinson’s disease (PD). It has not been investigated whether PD patients have different phenotypes depending on the presence of these prodromal symptoms. Objective: To investigate whether hyposmia-dominant and dysautonomia-dominant patients with early PD have different clinical manifestations and nigrostriatal degeneration. Methods: This cross-sectional study recruited 168 drug-naive PD patients and 34 control subjects. PD patients were classified as patients without hyposmia and dysautonomia (PD–H–D–, n  = 51), hyposmia-dominant patients (PD–H+D–, n  = 36), dysautonomia-dominant patients (PD–H–D+, n  = 33), and patients with hyposmia and dysautonomia (PD–H+D+, …n  = 48). We then compared the baseline clinical characteristics, striatal specific to non-specific binding ratio (SNBR), neuropsychological performance, and neuropsychiatric symptoms among the groups. Results: The PD–H+D–group had a lower SNBR in the ventral striatum (p  = 0.013), a greater asymmetric index of striatal SNBRs, and higher prevalence of apathy (p  = 0.021) than the PD–H–D+ group. The PD–H–D+ group had older age at onset (p  = 0.043) and a higher prevalence of REM sleep behavior disorder (p  = 0.041) than the PD–H+D–group. The PD–H+D+ group had higher motor deficits, lower cognitive function, and lower SNBRs in all striatal subregions than the PD–H–D–group. Decreased SNBRs in the anterior caudate, posterior caudate, and ventral striatum were associated with the presence of apathy. Conclusion: The present study suggests that hyposmia-dominant and dysautonomia-dominant PD have different clinical characteristics and patterns of striatal dopamine depletion. Show more

Keywords: Olfaction, hyposmia, autonomic function, dysautonomia, Parkinson’s disease

DOI: 10.3233/JPD-212747

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1703-1713, 2021

Authors: Chung, Seok Jong | Lee, Phil Hyu | Sohn, Young H. | Kim, Yun Joong

Article Type: Research Article

Abstract: Background: The concept of motor reserve explains the individual differences in motor deficits despite similar degrees of nigrostriatal dopamine depletion in Parkinson’s disease (PD). Objective: To investigate glucocerebrosidase (GBA) variants as potential determinants of motor reserve for exploratory purposes. Methods: A total of 408 patients with drug-naïve PD were enrolled from the Parkinson’s Progression Markers Initiative cohort database. All patients underwent SPECT dopamine transporter (DAT) scans and had results for Sanger sequencing of GBA . Parkinsonian motor deficits were assessed using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III). We compared MDS-UPDRS-III …scores while adjusting for DAT availability in the putamen (i.e., motor reserve) between the PD groups according to the presence of GBA mutations. Results: Fifty-four (13.2%) patients carried GBA mutations. PD patients with GBA mutations were younger than those without mutations. There were no significant differences in sex, disease duration, years of education, and striatal DAT availability between the PD groups. PD patients with GBA mutations had higher MDS-UPDRS-III scores for the less affected side than those without mutations, despite similar levels of DAT availability in the contralateral putamen. The MDS-UPDRS-III sub-scores of the more affected side did not differ between the two PD groups. Conclusion: The results of this study demonstrated the detrimental effect of GBA variants on individual capacity to cope with PD-related pathologies, with different impacts depending on the motor laterality. Show more

Keywords: β-Glucocerebrosidase (GBA), laterality, motor reserve, Parkinson’s disease, Parkinson’s progression markers initiative (PPMI)

DOI: 10.3233/JPD-212758

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1715-1724, 2021

Authors: Schechter, Meir | Sharon, Ronit

Article Type: Review Article

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

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

DOI: 10.3233/JPD-212684

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1725-1750, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-212589

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1751-1759, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-212694

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1761-1772, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-212554

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1773-1790, 2021

Authors: Folke, Jonas | Arkan, Sertan | Martinsson, Isak | Aznar, Susana | Gouras, Gunnar | Brudek, Tomasz | Hansen, Christian

Article Type: Research Article

Abstract: Background: α-synuclein (α-syn) aggregation contributes to the progression of multiple neurodegenerative diseases. We recently found that the isoform b of the co-chaperone DNAJB6 is a strong suppressor of α-syn aggregation in vivo and in vitro . However, nothing is known about the role of the endogenous isoform b of DNAJB6 (DNAJB6b) in health and disease, due to lack of specific antibodies. Objective: Here we generated a novel anti-DNAJB6b antibody to analyze the localization and expression of this isoform in cells, in tissue and in clinical material. Methods: To address this we used immunocytochemistry, immunohistochemistry, as …well as a novel quantitative DNAJB6 specific ELISA method. Results: The endogenous protein is mainly expressed in the cytoplasm and in neurites in vitro , where it is found more in dendrites than in axons. We further verified in vivo that DNAJB6b is expressed in the dopaminergic neurons of the substantia nigra pars compacta (SNpc ), which is a neuronal subpopulation highly sensitive to α-syn aggregation, that degenerate to a large extend in patients with Parkinson’s disease (PD) and multiple system atrophy (MSA). When we analyzed the expression levels of DNAJB6b in brain material from PD and MSA patients, we found a downregulation of DNAJB6b by use of ELISA based quantification. Interestingly, this was also true when analyzing tissue from patients with progressive supranuclear palsy, a taupathic atypical parkinsonian disorder. However, the total level of DNAJB6 was upregulated in these three diseases, which may indicate an upregulation of the other major isoform of DNAJB6, DNAJB6a. Conclusion: This study shows that DNAJB6b is downregulated in several different neurodegenerative diseases, which makes it an interesting target to further investigate in relation to amyloid protein aggregation and disease progression. Show more

Keywords: Alpha-synuclein, clinical samples, DNAJB6, neurodegeneration, synucleinopathy

DOI: 10.3233/JPD-202512

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1791-1803, 2021

Authors: Fellgett, Alison | Middleton, C. Adam | Munns, Jack | Ugbode, Chris | Jaciuch, David | Wilson, Laurence G. | Chawla, Sangeeta | Elliott, Christopher J.H.

Article Type: Research Article

Abstract: Background: Inherited mutations in the LRRK2 protein are common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S . An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. Objective: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian …activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. Methods: LRRK2 -G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. Results: Rab10 loss-of-function rescued LRRK2 -G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2 -G2019S . Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. Conclusion: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease. Show more

Keywords: Bradykinesia, circadian rhythms, courtship memory, dopamine, Drosophila, Leucine-rich-repeat-kinase2, sleep, vision

DOI: 10.3233/JPD-202421

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1805-1820, 2021

Authors: Diwakarla, Shanti | McQuade, Rachel M. | Constable, Remy | Artaiz, Olivia | Lei, Enie | Barnham, Kevin J. | Adlard, Paul A. | Cherny, Robert A. | Di Natale, Madeleine R. | Wu, Hongyi | Chai, Xin-yi | Lawson, Victoria A. | Finkelstein, David I. | Furness, John B.

Article Type: Research Article

Abstract: Background: Gastrointestinal (GI) complications, that severely impact patient quality of life, are a common occurrence in patients with Parkinson’s disease (PD). Damage to enteric neurons and the accumulation of alpha-synuclein in the enteric nervous system (ENS) are thought to contribute to this phenotype. Copper or iron chelators, that bind excess or labile metal ions, can prevent aggregation of alpha-synuclein in the brain and alleviate motor-symptoms in preclinical models of PD. Objective: We investigated the effect of ATH434 (formally PBT434), a small molecule, orally bioavailable, moderate-affinity iron chelator, on colonic propulsion and whole gut transit in A53T alpha-synuclein transgenic …mice. Methods: Mice were fed ATH434 (30 mg/kg/day) for either 4 months (beginning at ∼15 months of age), after the onset of slowed propulsion (“treatment group”), or for 3 months (beginning at ∼12 months of age), prior to slowed propulsion (“prevention group”). Results: ATH434, given after dysfunction was established, resulted in a reversal of slowed colonic propulsion and gut transit deficits in A53T mice to WT levels. In addition, ATH434 administered from 12 months prevented the slowed bead expulsion at 15 months but did not alter deficits in gut transit time when compared to vehicle-treated A53T mice. The proportion of neurons with nuclear Hu+ translocation, an indicator of neuronal stress in the ENS, was significantly greater in A53T than WT mice, and was reduced in both groups when ATH434 was administered. Conclusion: ATH434 can reverse some of the GI deficits and enteric neuropathy that occur in a mouse model of PD, and thus may have potential clinical benefit in alleviating the GI dysfunctions associated with PD. Show more

Keywords: Parkinson’s disease, colonic propulsion, gut dysfunction, alpha-synuclein, ATH434, enteric neuropathy

DOI: 10.3233/JPD-212731

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1821-1832, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-212733

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1833-1843, 2021

Authors: Chen, Yong-Ping | Gu, Xiao-Jing | Song, Wei | Hou, Yan-Bing | Ou, Ru-Wei | Zhang, Ling-Yu | Liu, Kun-Cheng | Su, Wei-Ming | Cao, Bei | Wei, Qian-Qian | Zhao, Bi | Wu, Ying | Shang, Hui-Fang

Article Type: Research Article

Abstract: Background: Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson’s disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown. Objective: This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD. Methods: In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal …function-related genes and 52 lysosomal storage disorder genes. Results: Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2 , MCOLN1 , LYST , VPS16 , and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs. Conclusion: Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence. Show more

Keywords: Parkinson’s disease, lysosomal genes, rare variants, burden analysis, genotype-phenotype correction

DOI: 10.3233/JPD-212658

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1845-1855, 2021

Authors: Brown, Gregory L. | Camacci, Mona L. | Kim, Sean D. | Grillo, Stephanie | Nguyen, James V. | Brown, Douglas A. | Ullah, Sarah P. | Lewis, Mechelle M. | Du, Guangwei | Kong, Lan | Sundstrom, Jeffrey M. | Huang, Xuemei | Bowie, Esther M.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is marked clinically by motor symptoms and pathologically by Lewy bodies and dopamine neuron loss in the substantia nigra pars compacta (SNc). Higher iron accumulation, assessed by susceptibility MRI, also is observed as PD progresses. Recently, evidence has suggested that PD affects the retina. Objective: To better understand retinal alterations in PD and their association to clinical and SNc iron-related imaging metrics. Methods: Ten PD and 12 control participants (2 eyes each) from an ongoing PD imaging biomarker study underwent enhanced depth imaging optical coherence tomography evaluation. Choroidal (vascular) thickness and nerve …layers were measured in 4 subregions [superior, temporal, inferior, and nasal] and at 3 foveal distances (1, 1.5, and 3 mm). These metrics were compared between PD and control groups. For significantly different metrics, their associations with clinical [levodopa equivalent daily dosage (LEDD), motor and visuospatial function] and SNc susceptibility MRI metrics [R2* and quantitative susceptibility mapping (QSM)] were explored. Results: Compared to control participants, PD participants had a thicker choroid (p  = 0.005), but no changes in nerve layers. Higher mean choroidal thickness was associated with lower LEDD (p  < 0.01) and better visuospatial function (p  < 0.05). Subregion analyses revealed higher choroidal thickness correlated with lower LEDD and better motor and visuospatial measures. Higher mean choroidal thickness also was associated with lower nigral iron MRI (p  < 0.05). Conclusion: A small cohort of PD research participants displayed higher choroidal thickness that was related to better clinical performance and less nigral pathology. These intriguing findings warrant further investigation. Show more

Keywords: Choroid, optical coherence tomography, Parkinson’s disease, retina, susceptibility MRI, visuospatial function

DOI: 10.3233/JPD-212676

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1857-1868, 2021

Authors: Ye, Zheng | Hanssen, Henrike | Steinhardt, Julia | Tronnier, Volker | Rasche, Dirk | Brüggemann, Norbert | Münte, Thomas F.

Article Type: Research Article

Abstract: Background: Maintaining and manipulating sequences online is essential for language and memory. In Parkinson’s disease (PD), poor performance in sequencing tasks has been associated with basal ganglia dysfunction, especially subthalamic hyperactivity. Objective: This study is aimed to investigate the impact of high-frequency subthalamic nucleus (STN) deep brain stimulation (DBS) on sequence processing in PD. Methods: Twenty-nine patients with PD (17 women) completed a ‘before/after’ sentence task and a digit ordering task with STN DBS ON and OFF. In the sentence task, patients read a sequence of events expressed in the actual order of occurrence (‘after’ sentences) …or reversed order (‘before’ sentences) for comprehension. In the digit task, patients recalled a sequence of ordered digits (ordered trials) or reordered and recalled random digits in ascending order (random trials). Volumes of tissue activated (VTAs) were estimated for the motor and associative STN. Results: Patients were slower with STN DBS ON versus OFF in both tasks, although their motor symptoms were significantly improved under DBS. In the sentence task, patients showed higher ordering-related reaction time costs (‘before’ > ‘after’) with DBS ON versus OFF. Moreover, patients with larger left associative VTAs, smaller total motor VTAs, and more daily exposure to dopaminergic drugs tended to show larger reaction time cost increases under DBS. In the digit ordering task, patients with too large or too small right associative VTAs tended to show larger reaction time cost increases under DBS. Conclusion: Stimulating the STN, especially its associative part, might impair sequence processing in language and memory. Show more

Keywords: Parkinson’s disease, subthalamic nucleus, deep brain stimulation, sentence comprehension, temporal connectives, sequential working memory

DOI: 10.3233/JPD-212778

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1869-1879, 2021

Authors: Wong, Joshua K. | Hilliard, Justin D. | Holanda, Vanessa M. | Gunduz, Aysegul | Wagle Shukla, Aparna | Foote, Kelly D. | Okun, Michael S.

Article Type: Short Communication

Abstract: Deep brain stimulation (DBS) is an effective neuromodulatory therapy for Parkinson’s disease (PD). Early studies using globus pallidus internus (GPi) DBS for PD profiled the nucleus as having two functional zones. This concept disseminated throughout the neuromodulation community as the “GPi triangle”. Although our understanding of the pallidum has greatly evolved over the past 20 years, we continue to reference the triangle in our clinical decision-making process. We propose a new direction, termed the spatial boundary hypothesis, to build upon the 2-dimensional outlook on GPi DBS. We believe an updated 3-D GPi model can produce more consistent, positive patient outcomes.

Keywords: Deep brain stimulation, DBS, globus pallidus, GPi, Parkinson’s disease, targeting, neuromodulation

DOI: 10.3233/JPD-212820

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1881-1885, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-202480

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1887-1899, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-212683

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1901-1915, 2021

Authors: Turner, Travis H. | Atkins, Alexandra | Keefe, Richard S.E.

Article Type: Research Article

Abstract: Background: Cognitive impairment is common in Parkinson’s disease (PD) and highly associated with loss of independence, caregiver burden, and assisted living placement. The need for cognitive functional capacity tools validated for use in PD clinical and research applications has thus been emphasized in the literature. The Virtual Reality Functional Capacity Assessment Tool (VRFCAT-SL) is a tablet-based instrument that assesses proficiency for performing real world tasks in a highly realistic environment. Objective: The present study explored application of the VRFCAT-SL in clinical assessments of patients with PD. Specifically, we examined associations between VRFCAT-SL performance and measures of cognition, motor …severity, and self-reported cognitive functioning. Methods: The VRFCAT-SL was completed by a sample of 29 PD patients seen in clinic for a comprehensive neuropsychological evaluation. Fifteen patients met Movement Disorders Society Task Force criteria for mild cognitive impairment (PD-MCI); no patients were diagnosed with dementia. Non-parametric correlations between VRFCAT-SL performance and standardized neuropsychological tests and clinical measures were examined. Results: VRFCAT-SL performance was moderately associated with global rank on neuropsychological testing and discriminated PD-MCI. Follow-up analyses found completion time was associated with visual memory, sustained attention, and set-switching, while errors were associated with psychomotor inhibition. No clinical or motor measures were associated with VRFCAT-SL performance. Self-report was not associated with VRFCAT-SL or neuropsychological test performance. Conclusion: The VRFCAT-SL appears to provide a useful measure of cognitive functional capacity that is not confounded by PD motor symptoms. Future studies will examine utility in PD dementia. Show more

Keywords: Assessment, cognitive capacity, functional capacity, functional outcome, mild cognitive impairment, neuropsychology, Parkinson’s disease, virtual reality

DOI: 10.3233/JPD-212688

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1917-1925, 2021

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

Article Type: Article Commentary

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

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

DOI: 10.3233/JPD-212647

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1927-1933, 2021

Authors: Fearn, Sarah | Bartolomeu Pires, Sandra | Agarwal, Veena | Roberts, Helen C. | Spreadbury, John | Kipps, Christopher

Article Type: Research Article

Abstract: Background: The reasons for acute hospital admissions among people with Parkinson’s disease are well documented. However, understanding of crises that are managed in the community is comparatively lacking. Most existing literature on the causes of crisis for people with Parkinson’s disease (PwP) uses hospital data and excludes the individual’s own perspective on the crisis trigger and the impact of the crisis on their care needs. Objective: To identify the causes and impact of crises in both community and hospital settings, from a patient and carer perspective. Methods: A total of 550 UK-based PwP and carers completed …a survey on (a) their own personal experiences of crisis, and (b) their general awareness of potential crisis triggers for PwP. Results: In addition to well-recognised causes of crisis such as falls, events less widely associated with crisis were identified, including difficulties with activities of daily living and carer absence. The less-recognised crisis triggers tended to be managed more frequently in the community. Many of these community-based crises had a greater impact on care needs than the better-known causes of crisis that more frequently required hospital care. PwP and carer responses indicated a good general knowledge of potential crisis triggers. PwP were more aware of mental health issues and carers were more aware of cognitive impairment and issues with medications. Conclusion: These findings could improve care of Parkinson’s by increasing understanding of crisis events from the patient and carer perspective, identifying under-recognised crisis triggers, and informing strategies for best recording symptoms from PwP and carers. Show more

Keywords: Parkinson’s disease, hospital admissions, care needs, crisis, patient perspective, resource use, activities of daily living, caregivers, surveys and questionnaires, content analysis

DOI: 10.3233/JPD-212641

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1935-1945, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-212660

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1947-1956, 2021

Authors: Javidnia, Monica | Arbatti, Lakshmi | Hosamath, Abhishek | Eberly, Shirley W. | Oakes, David | Shoulson, Ira

Article Type: Research Article

Abstract: Background: Postural instability is an intractable sign of Parkinson’s disease, associated with poor disease prognosis, fall risk, and decreased quality of life. Objective: 1) Characterize verbatim reports of postural instability and associated symptoms (gait disorder, balance, falling, freezing, and posture), 2) compare reports with responses to three pre-specified questions from Part II of the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS), and 3) examine postural instability symptoms and MDS-UPDRS responses as predictors of future falls. Methods: Fox Insight research participants reported their problems attributed to PD in their own words using the Parkinson Disease …Patient Reports of Problems (PD-PROP). Natural language processing, clinical curation, and data mining techniques were applied to classify text into problem domains and clinically-curated symptoms. Baseline postural instability symptoms were mapped to MDS-UPDRS questions 2.11–2.13. T -tests and chi-square tests were used to compare postural instability reporters and non-reporters, and Cochran-Armitage trend tests were used to evaluate associations between PD-PROP and MDS-UPDRS responses; survival methods were utilized to evaluate the predictive utility of PD-PROP and MDS-UPDRS responses in time-to-fall analyses. Results: Of participants within 10 years of PD diagnosis, 9,692 (56.0%) reported postural instability symptoms referable to gait unsteadiness, balance, falling, freezing, or posture at baseline. Postural instability symptoms were significantly associated with patient-reported measures from the MDS-UPDRS questions. Balance problems reported on PD-PROP and MDS-UPDRS 2.11–2.13 measures were predictive of future falls. Conclusion: Verbatim-reported problems captured by the PD-PROP and categorized by natural language processing and clinical curation and MDS-UPDRS responses predicted falls. The PD-PROP output was more granular than, and as informative as, the categorical responses. Show more

Keywords: Clinical trials, disease progression, falling, observational research, patient-reported outcomes

DOI: 10.3233/JPD-212636

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1957-1964, 2021

Authors: Di Luca, Daniel G. | McArthur, Eric W. | Willis, Allison | Martino, Rosemary | Marras, Connie

Article Type: Research Article

Abstract: Background: Dysphagia is a frequent complication that may increase morbidity and mortality in Parkinson’s disease (PD). Nevertheless, there is limited data on its objective impact on healthcare outcomes. Objective: To investigate the outcomes associated with dysphagia in hospitalized patients with PD and associated healthcare costs and utilization. Methods: We performed a retrospective cohort study using the National Inpatient Sample (NIS) data from 2004 to 2014. A multivariable regression analysis was adjusted for demographic, and comorbidity variables to examine the association between dysphagia and associated outcomes. Logistic and negative binomial regressions were used to estimate odds or …incidence rate ratios for binary and continuous outcomes, respectively. Results: We identified 334,395 non-elective hospitalizations of individuals with PD, being 21,288 (6.36%) associated with dysphagia. Patients with dysphagia had significantly higher odds of negative outcomes, including aspiration pneumonia (AOR 7.55, 95%CI 7.29–7.82), sepsis (AOR 1.91, 95%CI 1.82–2.01), and mechanical ventilation (AOR 2.00, 95%CI 1.86–2.15). For hospitalizations with a dysphagia code, the length of stay was 44%(95%CI 1.43–1.45) longer and inpatient costs 46%higher (95%CI 1.44–1.47) compared to those without dysphagia. Mortality was also substantially increased in individuals with PD and dysphagia (AOR 1.37, 95%CI 1.29–1.46). Conclusion: In hospitalized patients with PD, dysphagia was a strong predictor of adverse clinical outcomes, and associated with substantially prolonged length of stay, higher mortality, and care costs. These results highlight the need for interventions focused on early recognition and prevention of dysphagia to avoid complications and lower costs in PD patients. Show more

Keywords: Dysphagia, Parkinson’s disease, neurodegenerative diseases, healthcare costs

DOI: 10.3233/JPD-212798

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1965-1971, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-212716

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1973-1980, 2021

Authors: Heilbron, Karl | Jensen, Melanie P. | Bandres-Ciga, Sara | Fontanillas, Pierre | Blauwendraat, Cornelis | Nalls, Mike A. | Singleton, Andrew B. | Smith, George Davey | Cannon, Paul | Noyce, Alastair J. | The 23andMe Research Team

Article Type: Research Article

Abstract: Background: Tobacco smoking and alcohol intake have been identified in observational studies as potentially protective factors against developing Parkinson’s disease (PD); the impact of body mass index (BMI) on PD risk is debated. Whether such epidemiological associations are causal remains unclear. Mendelian randomsation (MR) uses genetic variants to explore the effects of exposures on outcomes; potentially reducing bias from residual confounding and reverse causation. Objective: Using MR, we examined relationships between PD risk and three unhealthy behaviours: tobacco smoking, alcohol intake, and higher BMI. Methods: 19,924 PD cases and 2,413,087 controls were included in the analysis. …We performed genome-wide association studies to identify single nucleotide polymorphisms associated with tobacco smoking, alcohol intake, and BMI. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design. Results: Ever-smoking reduced the risk of PD (OR 0.955; 95%confidence interval [CI] 0.921–0.991; p  = 0.013). Higher daily alcohol intake increased the risk of PD (OR 1.125, 95%CI 1.025–1.235; p  = 0.013) and a 1 kg/m2 higher BMI reduced the risk of PD (OR 0.988, 95%CI 0.979–0.997; p  = 0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments. Conclusion: Using split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD. In contrast to observational data, alcohol consumption appeared to increase the risk of PD. Higher BMI had a protective effect on PD, but the effect was small. Show more

Keywords: Parkinson’s disease, 23andMe, smoking, alcohol, BMI

DOI: 10.3233/JPD-202487

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1981-1993, 2021

Authors: Snyder, Allison | Gruber-Baldini, Ann L. | Rainer von Coelln, F. | Savitt, Joseph M. | Reich, Stephen G. | Armstrong, Melissa J. | Shulman, Lisa M.

Article Type: Research Article

Abstract: Background: Cognitive impairment (CI) is common in Parkinson’s disease (PD) and an important cause of disability. Screening facilitates early detection of CI and has implications for management. Preclinical disability is when patients have functional limitations but maintain independence through compensatory measures. Objective: The objective of this study was to investigate the relationship between scores on the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) with levels of PD severity and disability. Methods: PD patients (n  = 2,234) in a large observational study were stratified by disease severity, based on Total Unified Parkinson’s Disease Rating Scale (Total …UPDRS) and Hoehn and Yahr (HY) stage. Using MMSE (n  = 1,184) or MoCA (n  = 1,050) and basic (ADL) and instrumental activities of daily living (IADL) scales for disability, linear regression analysis examined associations between cognitive status and disability. Results: Cognition and disability were highly correlated, with the strongest correlation between IADL and MoCA. Only 16.0% of mean MMSE scores were below threshold for CI (28) and only in advanced PD (Total UPDRS 60+, HY≥3). MoCA scores fell below CI threshold (26) in 66.2% of the sample and earlier in disease (Total UPDRS 30+, HY≥2), corresponding with impairments in ADLs. Conclusion: In a large clinical dataset, a small fraction of MMSE scores fell below cutoff for CI, reinforcing that MMSE is an insensitive screening tool in PD. MoCA scores indicated CI earlier in disease and coincided with disability. This study shows that MoCA, but not MMSE is sensitive to the emergence of early cognitive impairment in PD and correlates with the concomitant onset of disability. Show more

Keywords: Parkinson’s disease, cognitive impairment, cognitive screening, disability

DOI: 10.3233/JPD-212705

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1995-2003, 2021

Authors: Hamada, Tomoya | Higashiyama, Yuichi | Saito, Asami | Morihara, Keisuke | Landin-Romero, Ramon | Okamoto, Mitsuo | Kimura, Katsuo | Miyaji, Yousuke | Joki, Hideto | Kishida, Hitaru | Doi, Hiroshi | Ueda, Naohisa | Takeuchi, Hideyuki | Tanaka, Fumiaki

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) in Parkinson’s disease (PD) is considered a risk factor for PD with dementia (PDD). Verbal fluency tasks are widely used to assess executive function in PDD. However, in cases of PD with MCI (PD-MCI), the relative diagnostic accuracy of different qualitative verbal fluency measures and their related neural mechanisms remain unknown. Objective: This study aimed to investigate the relative diagnostic accuracy of qualitative (clustering and switching) verbal fluency strategies and their correlates with functional imaging in PD-MCI. Methods: Forty-five patients with PD (26 with MCI and 19 without MCI) and 25 …healthy controls underwent comprehensive neurocognitive testing and resting-state functional magnetic resonance imaging. MCI in patients with PD was diagnosed according to established clinical criteria. The diagnostic accuracy of verbal fluency measures was determined via receiver operating characteristic analysis. Changes in brain functional connectivity between groups and across clinical measures were assessed using seed-to-voxel analyses. Results: Patients with PD-MCI generated fewer words and switched less frequently in semantic and phonemic fluency tasks compared to other groups. Switching in semantic fluency showed high diagnostic accuracy for PD-MCI and was associated with reduced functional connectivity in the salience network. Conclusion: Our results indicate that reduced switching in semantic fluency tasks is a sensitive and specific marker for PD-MCI. Qualitative verbal fluency deficits and salience network dysfunction represent early clinical changes observed in PD-MCI. Show more

Keywords: Brain connectivity, mild cognitive impairment, Parkinson’s disease, salience network, verbal fluency

DOI: 10.3233/JPD-202473

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2005-2016, 2021

Authors: Loftus, Andrea M. | Nielsen, Chloe | Corti, Emily J. | Starkstein, Sergio | Gasson, Natalie | Egan, Sarah J.

Article Type: Research Article

Abstract: Background: Recent research suggests that a significant number of those who receive advanced treatments for Parkinson’s disease (PD) do not report improvements for some symptoms, which may relate to their pre-treatment expectations. It is important that expectations of treatment are measured and discussed prior to advanced treatment. Objective: The primary aim of this study was to develop a measure of treatment expectations of two advanced-stage treatments in PD, deep brain stimulation (DBS), and Levodopa/Carbidopa Intestinal Gel (LCIG). A secondary aim was to explore potential predictors of treatment expectations. Methods: The questionnaire-based measure was developed by researchers …in conjunction with a highly experienced clinician, and evaluated treatment expectations in 189 people aged 46–91 years (M  = 71.35, SD  = 8.73; 61% male) with idiopathic PD. Results: The overall measure demonstrated excellent internal consistency (α = 0.96). Exploratory factor analysis suggested the scale was unidimensional for both DBS and LCIG. Participant expectations of the two treatments differed significantly, with expectations being higher for DBS. Perceived symptom severity was the strongest predictor of treatment expectations. Conclusion: This scale has potential to inform clinicians about client expectations prior to advanced stage therapy for PD, with a view to the management of these expectations. Further evaluation of the scale is required across different treatment contexts. Show more

Keywords: Parkinson’s disease, treatment expectations, deep brain stimulation, Levodopa/carbidopa intestinal gel, quality of life, psychological

DOI: 10.3233/JPD-212777

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2017-2026, 2021

Authors: Silbergleit, Alice K. | Schultz, Lonni | Hamilton, Kendra | LeWitt, Peter A. | Sidiropoulos, Christos

Article Type: Research Article

Abstract: Background: Hypokinetic dysarthria and dysphagia are known features of Parkinson’s disease; however, self-perception of their handicapping effects on emotional, physical, and functional aspects of quality of life over disease duration is less understood. Objective: 1) Based upon patient self-perception, to determine the relationship of the handicapping effects of dysphagia and dysphonia with time since diagnosis in individuals with Parkinson’s disease; 2)To determine if there is a relationship between voice and swallowing handicap throughout the course of Parkinson’s disease. Method: 277 subjects completed the Dysphagia Handicap Index and the Voice Handicap Index. Subjects were divided into three …groups based on disease duration: 0–4 years, 5–9 years, and 10 + years. Results: Subjects in the longer duration group identified significantly greater perceptions of voice and swallowing handicap compared to the shorter duration groups. There was a significant positive correlation between the DHI and VHI. Conclusion: Self-perception of swallowing and voice handicap in Parkinson’s disease are associated with later stages of disease and progress in a linear fashion. Self-perception of voice and swallowing handicap parallel each other throughout disease progression in Parkinson’s disease. Individuals may be able to compensate for changes in voice and swallowing early while sensory perceptual feedback is intact. Results support early targeted questioning of patient self-perception of voice and swallowing handicap as identification of one problem indicates awareness of the other, thus creating an opportunity for early treatment and maintenance of swallowing and communication quality of life for as long as possible. Show more

Keywords: Disease duration, dysarthria, dysphagia, handicapping effects, self-perception

DOI: 10.3233/JPD-212621

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2027-2034, 2021

Authors: Utz, Kathrin S. | Martini, Max | Mrochen, Anne | Lambrecht, Vera | Süß, Patrick | Renner, Bertold | Freiherr, Jessica | Schenk, Thomas | Winkler, Jürgen | Marxreiter, Franz

Article Type: Research Article

Abstract: Background: There is growing interest in non-motor symptoms in Parkinson’s disease (PD), due to the impact on quality of life. Anhedonia, the inability to experience joy and lust, has a prevalence of up to 46% in PD. The perception of pleasantness of an odor is reduced in anhedonia without PD. We previously showed a reduced hedonic olfactory perception in PD, i.e., patients evaluated odors as less pleasant or unpleasant compared to controls. This deficit correlated with anhedonia. Objective: We aimed to confirm these findings. Moreover, we hypothesized that the perception of pleasantness in PD is affected on a …multisensory level and correlates with anhedonia. Therefore, we assessed olfactory, visual and acoustic evaluation of pleasantness in PD and healthy individuals. Methods: Participants had to rate the pleasantness of 22 odors, pictures, and sounds on a nine-point Likert scale. Depression, anhedonia, and apathy were assessed by means of questionnaires. Results of the pleasantness-rating were compared between groups and correlated to scores of the questionnaires. Results: In particular pleasant and unpleasant stimuli across all three modalities are perceived less intense in PD, suggesting that a reduced range of perception of pleasantness is a multisensory phenomenon. However, only a reduction of visual hedonic perception correlated with anhedonia in PD. A correlation of reduced perception of pleasantness with apathy or depression was not present. Conclusion: We provide evidence for a multisensory deficit in the perception of pleasantness. Further studies should delineate the underlying neural circuity and the diagnostic value to detect neuropsychiatric symptoms in PD. Show more

Keywords: Parkinson’s disease, anhedonia, hyposmia, non-motor symptoms, depression, apathy, Sniffin’ Sticks, affective pictures

DOI: 10.3233/JPD-212812

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2035-2045, 2021

Authors: Luque-Casado, Antonio | Novo-Ponte, Sabela | Sánchez-Molina, José Andrés | Sevilla-Sánchez, Marta | Santos-García, Diego | Fernández-del-Olmo, Miguel

Article Type: Research Article

Abstract: Background: Despite the frequent use of the Timed Up and Go (TUG) test in clinical trials, evaluation of longitudinal test-retest reliability is generally lacking and still inconclusive for patients with Parkinson’s disease (PD). Objective: We aimed to further investigate long-term reliability and sensitivity of the TUG test among this population. Furthermore, we explored alternative assessment strategies of the test aimed at elucidating whether the inclusion or combination of timed trials may have potential implications on outcome measure. Methods: Relative and absolute reliability of the TUG performance were obtained in forty-three subjects with PD over three timed …trials in two different testing sessions separated by a two-months period. Results: Our results reported excellent intra-session and moderate inter-session reliability coefficients. The use of different assessment strategies of the TUG was found to have an important impact on outcome measure, highlighting the averaging of several timed trials in each testing session as a recommended alternative to minimize measurement error and increase reliability in longitudinal assessments. Nevertheless, beyond acceptable reliability, poor trial-to-trial stability of the measure appears to exist, since the ranges of expected variability upon retesting were wide and the incidence of spurious statistical effects was not negligible, especially in longitudinal repeated testing. Conclusion: Limitations may exist in the interpretation of the TUG outputs as part of longitudinal assessments aimed at evaluating treatment effectiveness in PD population. Researchers and practitioners should be aware of these concerns to prevent possible misrepresentations of functional ability in patients for a particular intervention. Show more

Keywords: Absolute reliability, intervention, learning effects, long-term, measurement error, minimal detectable change, relative reliability

DOI: 10.3233/JPD-212687

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2047-2055, 2021

Authors: Albrecht, Franziska | Pereira, Joana B. | Mijalkov, Mite | Freidle, Malin | Johansson, Hanna | Ekman, Urban | Westman, Eric | Franzén, Erika

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is characterized by motor deficits and brain alterations having a detrimental impact on balance, gait, and cognition. Intensive physical exercise can induce changes in the neural system, potentially counteracting neurodegeneration in PD and improving clinical symptoms. Objective: This randomized controlled trial investigated effects of a highly challenging, cognitively demanding, balance and gait training (HiBalance) program in participants with PD on brain structure. Methods: 95 participants were assigned to either the HiBalance or an active control speech training program. The group-based interventions were performed in 1-hour sessions, twice per week over a 10-week …period. Participants underwent balance, gait, cognitive function, and structural magnetic resonance imaging assessments before and after the interventions. Voxel-based morphometry was analyzed in 34 HiBalance and 31 active controls. Additionally, structural covariance networks were assessed. Results: There was no significant time by group interaction between the HiBalance and control training in balance, gait, or brain volume. Within-HiBalance-group analyses showed higher left putamen volumes post-training. In repeated measures correlation a positive linear, non-significant relationship between gait speed and putamen volume was revealed. In the HiBalance group we found community structure changes and stronger thalamic-cerebellar connectivity in structural covariance networks. Neither brain volume changes nor topology changes were found for the active controls after the training. Conclusion: Thus, subtle structural brain changes occur after balance and gait training. Future studies need to determine whether training modifications or other assessment methods lead to stronger effects. Show more

Keywords: Randomized controlled trial, magnetic resonance imaging, idiopathic Parkinson’s disease, gait, physical exercise, putamen, gray matter

DOI: 10.3233/JPD-212801

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2057-2071, 2021

Authors: Padmanabhan, Purnima | Sreekanth Rao, Keerthana | Gonzalez, Anthony J. | Pantelyat, Alexander Y. | Chib, Vikram S. | Roemmich, Ryan T.

Article Type: Research Article

Abstract: Background: Gait slowing is a common feature of Parkinson’s disease (PD). Many therapies aim to improve gait speed in persons with PD, but goals are often imprecise. How fast should each patient walk? And how do persons with PD benefit from walking faster? There is an important need to understand how walking speed affects fundamental aspects of gait—including energy cost and stability—that could guide individualized therapy decisions in persons with PD. Objective: We investigated how changes in walking speed affected energy cost and spatiotemporal gait parameters in persons with PD. We compared these effects between dopaminergic medication states …and to those observed in age-matched control participants. Methods: Twelve persons with PD and twelve control participants performed treadmill walking trials spanning at least five different speeds (seven speeds were desired, but not all participants could walk at the fastest speeds). Persons with PD participated in two walking sessions on separate days (once while optimally medicated, once after 12-hour withdrawal from dopaminergic medication). We measured kinematic and metabolic data across all trials. Results: Persons with PD significantly reduced energy cost by walking faster than their preferred speeds. This held true across medication conditions and was not observed in control participants. The patient-specific walking speeds that reduced energy cost did not significantly affect gait variability metrics (used as proxies for gait stability). Conclusion: The gait slowing that occurs with PD results in energetically suboptimal walking. Rehabilitation strategies that target patient-specific increases in walking speed could result in a less effortful gait. Show more

Keywords: Gait, Parkinson’s disease, rehabilitation, energy, dopamine

DOI: 10.3233/JPD-212613

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2073-2084, 2021

Authors: Kumar, Srishti | Shen, Julia W. | Grimes, David | Mestre, Tiago | Thavorn, Kednapa

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a complex and debilitating condition that requires care from a multispecialty team. The Integrated Parkinson Care Network (IPCN) is an innovative pragmatic care model that focuses on integrated care, self-management support and technology-enabled care. Objective: This study aims to estimate the costs of the IPCN and assess whether benefits gained from the intervention offset its costs based on a single center experience. Methods: We conducted a return on investment (ROI) analysis of the IPCN from a societal perspective. The ROI for the IPCN was estimated as a ratio …of the net savings and the intervention cost. The intervention cost was calculated as a sum of set-up and implementation costs. Cost savings was measured as the absolute reduction in the societal costs realized by PD patients. A positive ROI indicated that savings generated from the intervention offset its cost. Results: The total cost of the IPCN for 100 PD patients was C$135,669, or C$226 per patient per month. IPCN was associated with the reduction in societal cost of C$915 per patient per month (95%CI: –2,782, 951). The ROI per PD patient per month for the IPCN was 3.08 (95%CI: –0.60, 22.93), suggesting that for every C$1 invested in the IPCN, C$4.08 is gained through reduction in societal costs. The returns were greater among advanced PD patients. Conclusion: The IPCN has the potential to offer a good return on investment for PD patients, and its value for money is higher among advanced PD patients. Show more

Keywords: Economic evaluation, Parkinson’s disease, integrated care, self-management support, technology-enabled care

DOI: 10.3233/JPD-212578

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2085-2091, 2021

Authors: Nonnekes, Jorik | Koehler, Peter | Bloem, Bastiaan R.

Article Type: Article Commentary

DOI: 10.3233/JPD-212933

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2093-2094, 2021