Journal of Parkinson's Disease - Volume 12, issue 3

Authors: Hiramatsu, Satoe | Morizane, Asuka | Kikuchi, Tetsuhiro | Doi, Daisuke | Yoshida, Kenji | Takahashi, Jun

Article Type: Research Article

Abstract: Background: Pluripotent stem cell (PSC)-derived dopaminergic (DA) neurons are an expected source of cell therapy for Parkinson’s disease. The transplantation of cell aggregates or neurospheres, instead of a single cell suspension has several advantages, such as keeping the 3D structure of the donor cells and ease of handling. For this PSC-based therapy to become a widely available treatment, cryopreservation of the final product is critical in the manufacturing process. However, cryopreserving cell aggregates is more complicated than cryopreserving single cell suspensions. Previous studies showed poor survival of the DA neurons after the transplantation of cryopreserved fetal ventral-mesencephalic tissues. …Objective: To achieve the cryopreservation of induced pluripotent stem cell (iPSC)-derived DA neurospheres toward clinical application. Methods: We cryopreserved iPSC-derived DA neurospheres in various clinically applicable cryopreservation media and freezing protocols and assessed viability and neurite extension. We evaluated the population and neuronal function of cryopreserved cells by the selected method in vitro . We also injected the cells into 6-hydroxydopamine (6-OHDA) lesioned rats, and assessed their survival, maturation and function in vivo. Results: The iPSC-derived DA neurospheres cryopreserved by Proton Freezer in the cryopreservation medium Bambanker hRM (BBK) showed favorable viability after thawing and had equivalent expression of DA-specific markers, dopamine secretion, and electrophysiological activity as fresh spheres. When transplanted into 6-OHDA-lesioned rats, the cryopreserved cells survived and differentiated into mature DA neurons, resulting in improved abnormal rotational behavior. Conclusion: These results show that the combination of BBK and Proton Freezer is suitable for the cryopreservation of iPSC-derived DA neurospheres. Show more

Keywords: Cryopreservation, cell-based therapy, neurosphere, dopaminergic neuron, induced pluripotent stem cells, Parkinson’s disease

DOI: 10.3233/JPD-212934

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 871-884, 2022

Authors: Leimbach, Friederike | Atkinson-Clement, Cyril | Socorro, Pieter | Jahanshahi, Marjan

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) and subthalamic nucleus deep brain stimulation (STN-DBS) are both known to induce cognitive changes. Objective: The aim of our study was to investigate the impact of STN-DBS on two forms of conditional associative learning (CAL), trial and error or corrective feedback learning, which differed in difficulty to test the load-dependency hypothesis of the cognitive effects of STN-DBS in PD. Methods: We recruited two groups of PD patients, those who had STN-DBS surgery bilaterally (n  = 24) and a second unoperated group (n  = 9) who were assessed on two versions of a task of …visual CAL involving either a more difficult trial and error learning or a relatively easier corrective feedback learning. Each task was completed twice by both groups, On and Off STN-DBS for the operated group and a first and second time by the unoperated group. Results: With STN-DBS Off , corrective feedback learning was superior to trial and error CAL, but not with STN-DBS On . The unoperated PD group had improved performance during the second assessment. To control for the improvement observed with repeated assessment in the PD control group, we split the STN-DBS group into two subgroups based on the condition of the first assessment (Off first vs. On first). While we found no STN-DBS effects for the Off first subgroup (N = 14), we observed improved performance during the second STN-DBS Off session for the On first subgroup (N = 10). Conclusion: The findings suggest that in PD, STN-DBS interferes with use of corrective feedback and its integration in the conditional associative learning process. Also STN stimulation affected the ability of operated patients to resolve proactive interference during learning of the arbitrary visual associations by trial and error or with corrective feedback. Show more

Keywords: Conditional associative learning, deep brain stimulation, Parkinson’s disease, subthalamic nucleus

DOI: 10.3233/JPD-212843

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 885-896, 2022

Authors: Zheng, Zhe | Zhu, Zhoule | Ying, Yuqi | Jiang, Hongjie | Wu, Hemmings | Tian, Jun | Luo, Wei | Zhu, Junming

Article Type: Research Article

Abstract: Background: Accurate electrode targeting was essential for the efficacy of deep brain stimulation (DBS). There is ongoing debate about the necessary of microelectrode recording (MER) in subthalamic nucleus (STN)-DBS surgery for accurate targeting. Objective: This study aimed to analyze the accuracy of imaging-guided awake DBS with MER in STN for Parkinson’s disease in a single center. Methods: The authors performed a retrospective analysis of 161 Parkinson’s disease patients undergoing STN-DBS at our center from March 2013 to June 2021. The implantation was performed by preoperative magnetic resonance imaging (MRI)-based direct targeting with intraoperative MER and macrostimulation …testing. 285 electrode tracks with preoperative and postoperative coordinates were included to calculate the placement error in STN targeting. Results: 85.9% of electrodes guided by preoperative MRI were implanted without intraoperative adjustment. 31 (10.2%) and 12 (3.9%) electrodes underwent intraoperative adjustment due to MER and intraoperative testing, respectively. We found 86.2% (245/285) of electrodes with trajectory error ≤2 mm. The MER physiological signals length < 4 mm and ≥4 mm group showed trajectory error > 2 mm in 38.0% and 8.8% of electrodes, respectively. Compared to non-adjustment electrodes, the final positioning of MER-adjusted electrodes deviated from the center of STN. Conclusion: The preoperative MRI guided STN targeting results in approximately 14% cases that require electrode repositioning. MER physiological signals length < 4 mm at first penetration implied deviation off planned target. MER combined with intraoperative awake testing served to rescue such deviation based on MRI alone. Show more

Keywords: Accuracy, deep brain stimulation, microelectrode recording, Parkinson’s disease, subthalamic nucleus

DOI: 10.3233/JPD-213095

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 897-903, 2022

Authors: Michels, Jennifer | van der Wurp, Hendrik | Kalbe, Elke | Rehberg, Sarah | Storch, Alexander | Linse, Katharina | Schneider, Christine | Gräber, Susanne | Berg, Daniela | Dams, Judith | Balzer-Geldsetzer, Monika | Hilker-Roggendorf, Rüdiger | Oberschmidt, Carola | Baudrexel, Simon | Witt, Karsten | Schmidt, Nele | Deuschl, Günther | Mollenhauer, Brit | Trenkwalder, Claudia | Liepelt-Scarfone, Inga | Spottke, Annika | Roeske, Sandra | Wüllner, Ullrich | Wittchen, Hans-Ulrich | Riedel, Oliver | Kassubek, Jan | Dodel, Richard | Schulz, Jörg Bernhard | Costa, Ana Sofia | Reetz, Kathrin

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is associated with various non-motor symptoms, including cognitive deterioration. Objective: Here, we used data from the DEMPARK/LANDSCAPE cohort to describe the association between progression of cognitive profiles and the PD motor phenotypes: postural instability and gait disorder (PIGD), tremor-dominant (TR-D), and not-determined (ND). Methods: Demographic, clinical, and neuropsychological six-year longitudinal data of 711 PD-patients were included (age: M  = 67.57; 67.4% males). We computed z-transformed composite scores for a priori defined cognitive domains. Analyses were controlled for age, gender, education, and disease duration. To minimize missing data and drop-outs, three-year follow-up data …of 442 PD-patients was assessed with regard to the specific role of motor phenotype on cognitive decline using linear mixed modelling (age: M  = 66.10; 68.6% males). Results: Our study showed that in the course of the disease motor symptoms increased while MMSE and PANDA remained stable in all subgroups. After three-year follow-up, significant decline of overall cognitive performance for PIGD-patients were present and we found differences for motor phenotypes in attention (β = –0.08, SE = 0.003, p  < 0.006) and memory functions showing that PIGD-patients deteriorate per months by –0.006 compared to the ND-group (SE = 0.003, p  = 0.046). Furthermore, PIGD-patients experienced more often difficulties in daily living. Conclusion: Over a period of three years, we identified distinct neuropsychological progression patterns with respect to different PD motor phenotypes, with early executive deficits yielding to a more amnestic profile in the later course. Here, in particular PIGD-patients worsened over time compared to TR-D and ND-patients, highlighting the greater risk of dementia for this motor phenotype. Show more

Keywords: Cognitive decline, dementia, longitudinal, mild cognitive impairment, Parkinson’s disease, postural instability and gait disorder, progression, tremor-dominant

DOI: 10.3233/JPD-212787

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 905-916, 2022

Authors: Kovács, Norbert | Bergmann, Lars | Anca-Herschkovitsch, Marieta | Cubo, Esther | Davis, Thomas L. | Iansek, Robert | Siddiqui, Mustafa S. | Simu, Mihaela | Standaert, David G. | Chaudhuri, K. Ray | Bourgeois, Paul | Gao, Tianming | Kukreja, Pavnit | Pontieri, Francesco E. | Aldred, Jason

Article Type: Research Article

Abstract: Background: It is believed that motor symptoms, including dyskinesia, and non-motor symptoms impact health-related quality of life (HRQoL) in patients with Parkinson’s disease (PD), and that improvements in these metrics are correlated. Objective: Investigate the relationship between HRQoL and measures of PD severity and treatment efficacy, including motor and non-motor symptoms. Methods: This was a planned investigation of an international, prospective, single-arm, post-marketing observational study of the long-term effectiveness of levodopa-carbidopa intestinal gel (LCIG) in patients with advanced PD. Pearson correlation coefficients (PCC) were calculated for baseline and change from baseline at 12 months between HRQoL …and motor and non-motor symptoms. Results: A total of 195 patients were included. At baseline, HRQoL was moderately positively correlated with Activities of Daily Living (UPDRS II, PCC = 0.44), non-motor symptoms (0.48), and measures of sleep (0.50 and 0.40); all p  < 0.001. After 12 months of treatment with LCIG, improvements in HRQoL were moderately positively correlated with improvement from baseline in non-motor symptoms (PCC = 0.42), sleep (0.54), and daytime sleepiness (0.40; all p  < 0.001), and weakly correlated with improvement in dyskinesia signs and symptoms (PCC = 0.23; p  = 0.011). Improvement in HRQoL was not correlated with improvements in OFF time or dyskinesia time. Conclusion: Both at baseline and for change from baseline at 12 months, HRQoL was correlated with baseline and change from baseline in dyskinesia, Activities of Daily Living, and non-motor symptoms, including sleep; but not with baseline or change in OFF time. Show more

Keywords: Dyskinesia, health-related quality of life, levodopa-carbidopa intestinal gel, non-motor symptoms, Parkinson’s disease

DOI: 10.3233/JPD-212979

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 917-926, 2022

Authors: Zolfaghari, Sheida | Lewandowski, Natalia | Pelletier, Amelie | Naeimi, Seyed Ali | Gagnon, Jean-François | Brillon-Corbeil, Marina | Montplaisir, Jacques Y. | Postuma, Ronald B.

Article Type: Short Communication

Abstract: Several studies have suggested that atherosclerotic diseases and diabetes may be risk factors for α -synucleinopathies. This prospective cohort study evaluated whether cardiovascular diseases and metabolic risk factors alter the rate or type of phenoconversion from idiopathic/isolated REM sleep behavior disorder (iRBD) to parkinsonism or dementia. Polysomnography-confirmed iRBD patients recruited between 2004 and 2020 were followed annually. Baseline history of cardiovascular disorders, hypertension, hypercholesterolemia, and diabetes were compared among patients who developed outcomes versus those who remained outcome-free. No atherosclerotic risk factors were associated with development of α -synucleinopathies. Patients with hypercholesterolemia were somewhat more likely to develop dementia with …Lewy bodies rather than Parkinson’s disease. Show more

Keywords: REM sleep behavior disorder, cardiovascular disease, hypertension, diabetes, hypercholesterolemia, α-synucleinopathies, Parkinson’s disease, dementia with Lewy bodies, cohort

DOI: 10.3233/JPD-212984

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 927-933, 2022

Authors: Santos García, Diego | Canfield, Hector | de Deus Fonticoba, Teresa | Cores Bartolomé, Carlos | Naya Ríos, Lucía | García Roca, Lucía | Martínez Miró, Cristina | Jesús, Silvia | Aguilar, Miquel | Pastor, Pau | Cosgaya, Marina | García Caldentey, Juan | Caballol, Nuria | Legarda, Inés | Hernández Vara, Jorge | Cabo, Iria | López Manzanares, Lydia | González Aramburu, Isabel | Ávila Rivera, María A. | Gómez Mayordomo, Víctor | Nogueira, Víctor | Puente, Víctor | Dotor, Julio | Borrué, Carmen | Solano Vila, Berta | Álvarez Sauco, María | Vela, Lydia | Escalante, Sonia | Cubo, Esther | Carrillo Padilla, Francisco | Martínez Castrillo, Juan C. | Sánchez Alonso, Pilar | Alonso Losada, Maria G. | López Ariztegui, Nuria | Gastón, Itziar | Kulisevsky, Jaime | Blázquez Estrada, Marta | Seijo, Manuel | Rúiz Martínez, Javier | Valero, Caridad | Kurtis, Mónica | de Fábregues, Oriol | González Ardura, Jessica | Alonso Redondo, Ruben | Ordás, Carlos | López Díaz, Luis M. | McAfee, Darrian | Martinez-Martin, Pablo | Mir, Pablo | COPPADIS Study Group

Article Type: Research Article

Abstract: Background: Motor phenotype (MP) can be associated with a different prognosis in Parkinson’s disease (PD), but it is not fixed and can change over time. Objective: Our aim was to analyze how the MP changed over time and to identify factors associated with the changes in PD patients from a multicenter Spanish PD cohort. Methods: PD patients who were recruited from January-2016 to November-2017 (baseline visit; V0) and evaluated again at a 2-year±30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort, were included in this study.MP was calculated at both visits based …on Jankovic classification in TD (tremor dominant), IND (indeterminate), or PIGD (postural instability and gait difficulty). Sociodemographic and clinical data were collected, including serum biomarkers. Results: Five hundred eleven patients (62.57±8.59 years old; 59.2%males) were included in the study. At V0, MP was: 47.4%(242/511) TD; 36.6%(187/511) PIGD; 16%(82/511) IND. Up to 38%(194/511) of the patients changed their phenotype from V0 to V2, being the most frequent from TD to IND (8.4%) and from TD to PIGD (6.7%). A worse cognitive status (OR = 0.966) and less autonomy for activities of daily living (OR  =  0.937) at V0 and a greater increase in the globalNMS burden (OR  =  1.011) from V0 to V2 were associated with changing from TD to another phenotype after 2-year follow-up. Conclusion: The MP in PD can change over time. With disease progression, the percentage of cases with non-tremoric MP increases. PD patients who changed from TD to postural instability and gait difficulty increased NMS burden significantly. Show more

Keywords: Changes, motor, Parkinson’s disease, phenotype, postural instability, gait difficulty, tremor

DOI: 10.3233/JPD-213004

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 935-955, 2022

Authors: Soh, Emily Ming Li | Neo, Shermyn | Saffari, Seyed Ehsan | Wong, Aidan Sheng Yong | Ganesan, Ganga | Li, Wei | Ng, Hwee Lan | Xu, Zheyu | Tay, Kay Yaw | Au, Wing Lok | Tan, Kelvin Bryan | Tan, Louis Chew Seng

Article Type: Research Article

Abstract: Background: There is currently insufficient long-term data on costs of treatment in patients with Parkinson’s disease (PD), which is chronic and progressive, and associated with substantial healthcare costs. Identifying patterns in healthcare utilization and cost may illuminate further discussion on early intervention. Objective: To characterize long-term healthcare utilization and costs of PD in newly diagnosed patients managed by movement disorder specialists. Methods: Using a longitudinal matched-cohort study of linked data from the National Neuroscience Institute Parkinson’s disease and Movement Disorder and healthcare administrative databases in Singapore from 2008–2017, we compared healthcare utilization and costs between patients …and controls matched on age, sex, race, and Charlson Comorbidity Index score. Results: 1,162 patients met study inclusion criteria and 1,157 matched controls were identified. The total mean annual healthcare cost (at 2017 costs) was significantly increased in patients compared to controls from years 1–9 post-diagnosis. The increased cost was observed 2 years before diagnosis (USD2322 vs. 2052; p  < 0.001). Mean annual cost attributable to PD increased from USD1854 at 1-year post-diagnosis to USD2652 at 9 years. Over 9 years, average costs were significantly higher across all domains of healthcare utilization except primary care—cost of intermediate and long-term care was increased by a factor of 2.5, specialist care by 2.3, emergency department visits by 1.6, and hospital admissions by 1.3. Conclusion: PD results in higher healthcare utilization and costs. Pre-diagnosis increase in healthcare utilization observed in patients supports the presence of prodromal PD symptoms and may present an opportunity for early diagnosis. Show more

Keywords: Parkinson’s disease, cost-of-illness, healthcare, utilization

DOI: 10.3233/JPD-212982

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 957-966, 2022

Authors: Roos, Dareia S. | Klein, Martin | Deeg, Dorly J.H. | Doty, Richard L. | Berendse, Henk W.

Article Type: Research Article

Abstract: Background: The prodromal phase of Parkinson’s disease (PD) can last up to 20 years and is characterized by a variety of non-motor symptoms. Objective: To determine the prevalence of a selection of non-motor symptoms known to be associated with an increased risk of developing PD in a late middle-aged population-based sample and to determine their association with motor function. Methods: At a mean age of 60.3 years, 775 subjects were recruited from the Longitudinal Aging Study Amsterdam (LASA). Hyposmia, cognitive impairment, patient-reported constipation, possible REM-sleep behavior disorder, depression, and anxiety were indexed as known PD risk …factors. Additionally, 1) the PD screening questionnaire, 2) four physical performance tests, and 3) a functional limitations questionnaire, were used to determine whether the presence of two or more PD risk factors was associated with reduced motor function. Results: The prevalence of single risk factors ranged between 3 and 13%. Approximately 11% of subjects had two or more PD risk factors. Motor functioning of subjects with two or more PD risk factors was significantly worse than performance of subjects without or with a single risk factor (all p values≤0.001). Conclusion: Approximately 11% of the late middle-aged population has two or more known PD risk factors. Among these subjects self-perceived PD symptoms and reduced physical performance are more prevalent, suggesting that at least some of these subjects may be in the prodromal phase of PD. Show more

Keywords: Parkinson’s disease, prodromal symptoms, hyposmia, risk factors

DOI: 10.3233/JPD-213007

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 967-974, 2022

Authors: Lau, Yue Hui | Podlewska, Aleksandra | Ocloo, Josephine | Gupta, Atul | Gonde, Christopher | Bloem, Bastiaan R. | Chaudhuri, K. Ray

Article Type: Research Article

Abstract: Background: Lack of participation of black and minority ethnic communities (BAME) in registered clinical trials is a concern as data emerging from these studies are used to licence new drugs or other interventions, even though findings made in such selected study populations have limited external validity in the aforesaid ethnic groups. Objective: We used Parkinson’s disease (PD), the fastest rising neurodegenerative disorder in the world, as an exemplar condition to test our hypothesis that participants from BAME communities are underrepresented in clinical trials. Methods: A systematic search of clinical trials registered on a Clinicaltrials.gov database which …queried for PD with racial distribution data from 2017 to 2021. Results: Out of 266 trials considered, 54 trials were published in peer reviewed journals. Among these, only 23 (42.65%) publications reported data regarding the racial distribution of the participants. Out of these, five studies involved mixed racial participation and two trials included black subjects. Conclusion: We found that inclusion of under-represented BAME groups in recently published clinical trials is low, at only 21.57%, and is not even considered in most studies. Out of the reviewed trials, only 5 (21.75%) studies reported detailed demographic categories with black minorities enrolment. This constitutes a severe under-representation when compared to the proportion of Black or African American in the UK population (3%). Results of this study identified the need for better reporting of racial composition in clinical trials. We strongly recommend that future studies should consider ethnicity and other issues around diversity when designing and implementing the clinical trials, not only in the PD field but also beyond. Show more

Keywords: Clinical trials, diversity, ethnicity, Parkinson’s disease

DOI: 10.3233/JPD-213113

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 975-981, 2022