Journal of Parkinson's Disease - Volume 11, issue 3

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-212604

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1167-1176, 2021

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

Article Type: Research Article

Abstract: Background: Literature shows an inverse association of circulating cholesterol level with the risk of Parkinson’s disease (PD); this finding has important ramifications, but its interpretation has been debated. Objective: To longitudinally examine how blood total cholesterol changes during the development of PD. Methods: In the Health, Aging and Body Composition study (n  = 3,053, 73.6±2.9 years), blood total cholesterol was measured at clinic visit years 1, 2, 4, 6, 8, 10, and 11. We first examined baseline cholesterol in relation to PD risk, adjusting for potential confounders and competing risk of death. Then, by contrasting the observed …with expected cholesterol levels, we examined the trajectory of changes in total cholesterol before and after disease diagnosis. Results: Compared to the lowest tertile of baseline total cholesterol, the cumulative incidence ratio of PD and 95% confidence interval was 0.41 (0.20, 0.86) for the second tertile, and 0.69 (0.35, 1.35) for the third tertile. In the analysis that examined change of total cholesterol level before and after PD diagnosis, we found that its level began to decrease in the prodromal stage of PD and became statistically lower than the expected values ∼4 years before disease diagnosis (observed-expected difference, –6.68 mg/dL (95% confidence interval: –13.14, –0.22)). The decreasing trend persisted thereafter; by year-6 post-diagnosis, the difference increased to –13.59 mg/dL (95% confidence interval: –22.12, –5.06), although the linear trend did not reach statistical significance (p  = 0.10). Conclusion: Circulating total cholesterol began to decrease in the prodromal stage of PD, which may in part explain its reported inverse association with PD. Show more

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

DOI: 10.3233/JPD-212670

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1177-1186, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-212562

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1187-1196, 2021

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

Article Type: Research Article

Abstract: Background: Early-onset Parkinson’s disease (EOPD), occurring between ages 40 and 55, carries social, societal, and personal consequences and may progress, with fewer comorbidities than typical, later-onset disease. Objective: To examine the incidence and survival of EOPD and other Parkinsonism occurring before age 55 in the population-based cohort of residents in seven Minnesota counties. Methods: A movement-disorder specialist reviewed all the medical records in a 2010–2015 Parkinsonism-incident cohort to confirm diagnosis and subtypes. Results: We identified 27 patients diagnosed at ≤ 50 years with incident Parkinsonism 2010–15:11 (41%) cases of EOPD, 13 (48%) drug-induced Parkinsonism, and …3 (11%) other Parkinsonism; we also identified 69 incident cases of Parkinsonism ≤ 55 years, of which 28 (41%) were EOPD, 28 (41%) DIP, and 13 (19%) other Parkinsonism. Overall incidence for Parkinsonism ≤ 50 years was 1.98/100,000 person-years, and for EOPD was 0.81/100,000 person-years. In patients ≤ 55 years, Parkinsonism incidence was 5.05/100,000 person-years: in EOPD, 2.05/100,000 person-years. Levodopa-induced dyskinesia was present in 45%of EOPD (both ≤ 50 years and ≤ 55 years). Onset of cardinal motor symptoms was proximate to the diagnosis of EOPD, except for impaired postural reflexes, which occurred later in the course of EOPD. Among the 69 Parkinsonism cases ≤ 55 years, 9 (13%; all male) were deceased (only 1 case of EOPD). Men had a higher mortality risk compared to women (p  = 0.049). Conclusion: The incidence of EOPD ≤ 50 years was 0.81/100,000 person-years (1.98 in Parkinsonism all type); prior to ≤ 55 years was 2.05/100,000 person-years (5.05 in Parkinsonism all type) with higher incidence in men than women. Men with Parkinsonism, all type, had higher mortality compared to women. Show more

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

DOI: 10.3233/JPD-202464

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1197-1207, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-212570

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1209-1219, 2021

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

Article Type: Research Article

Abstract: Background: Although pathological studies usually indicate pure dopaminergic neuronal degeneration in patients with parkin (PRKN ) mutations, there is no evidence to date regarding white matter (WM) pathology. A previous diffusion MRI study has revealed WM microstructural alterations caused by systemic oxidative stress in idiopathic Parkinson’s disease (PD), and we found that PRKN patients have systemic oxidative stress in serum biomarker studies. Thus, we hypothesized that PRKN mutations might lead to WM abnormalities. Objective: To investigate whether there are WM microstructural abnormalities in early-onset PD patients with PRKN mutations using diffusion tensor imaging (DTI). …Methods: Nine PRKN patients and 15 age- and sex-matched healthy controls were recruited. DTI measures were acquired on a 3T MR scanner using a b value of 1,000 s/mm2 along 32 isotropic diffusion gradients. The DTI measures were compared between groups using tract-based spatial statistics (TBSS) analysis. Correlation analysis was also performed between the DTI parameters and several serum oxidative stress markers obtained in a previously conducted metabolomic analysis. Results: Although the WM volumes were not significantly different, the TBSS analysis revealed a corresponding decrease in fractional anisotropy and an increase in mean diffusivity and radial diffusivity in WM areas, such as the anterior and superior corona radiata and uncinate fasciculus, in PRKN patients compared with controls. Furthermore, 9-hydroxystearate, an oxidative stress marker, and disease duration were positively correlated with several parameters in PRKN patients. Conclusion: This pilot study suggests that WM microstructural impairments occur in PRKN patients and are associated with disease duration and oxidative stress. Show more

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

DOI: 10.3233/JPD-202495

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1221-1235, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-202409

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1237-1246, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-202524

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1247-1256, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-212580

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1257-1269, 2021

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

Article Type: Research Article

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

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

DOI: 10.3233/JPD-212544

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1271-1283, 2021