Mov Disord. 2022 Jan 20. doi: 10.1002/mds.28927. Online ahead of print.
Authors: Alicia Garrido, Enrique Santamaría, Joaquín Fernández-Irigoyen, Marta Soto, Cristina Simonet, Manel Fernández, Donina Obiang, Eduardo Tolosa, María-José Martí, Shalini Padmanabhan, Cristina Malagelada, Mario Ezquerra, Rubén Fernández-Santiago
Background: The clinicopathological phenotype of G2019S LRRK2-associated Parkinson's disease (L2PD) is similar to idiopathic Parkinson's disease (iPD), and G2019S LRRK2 nonmanifesting carriers (L2NMCs) are at increased risk for development of PD. With various therapeutic strategies in the clinical and preclinical pipeline, there is an urgent need to identify biomarkers that can aid early diagnosis and patient enrichment for ongoing and future LRRK2-targeted trials.
Objective: The objective of this work was to investigate differential protein and phospho-protein changes related to G2019S mutant LRRK2 in peripheral blood mononuclear cells from G2019S L2PD patients and G2019S L2NMCs, identify speciﬁc phospho-protein changes associated with the G2019S mutation and with disease status, and compare ﬁndings with patients with iPD.
Methods: We performed an unbiased phospho-proteomic study by isobaric label-based mass spectrometry using peripheral blood mononuclear cell group pools from a LRRK2 cohort from Spain encompassing patients with G2019S L2PD (n = 20), G2019S L2NMCs (n = 20), healthy control subjects (n = 30), patients with iPD (n = 15), patients with R1441G L2PD (n = 5), and R1441G L2NMCs (n = 3) (total N = 93).
Results: Comparing G2019S carriers with healthy controls, we identiﬁed phospho-protein changes associated with the G2019S mutation. Moreover, we uncovered a speciﬁc G2019S phospho-signature that changes with disease status and can discriminate patients with G2019S L2PD, G2019S L2NMCs, and healthy controls. Although patients with iPD showed a differential phospho-proteomic proﬁle, biological enrichment analyses revealed similar changes in deregulated pathways across the three groups.
Conclusions: We found a differential phospho-signature associated with LRRK2 G2019S for which, consistent with disease status, the phospho-proﬁle from PD at-risk G2019S L2NMCs was more similar to healthy controls than patients with G2019S L2PD with the manifested disease
• PMID: 35049090
Mov Disord. 2022 Jan 8. doi: 10.1002/mds.28902. Online ahead of print.
Authors: Cloé Domenighetti, Pierre-Emmanuel Sugier, Ashwin Ashok Kumar Sreelatha, Claudia Schulte, Sandeep Grover, Océane Mohamed, Berta Portugal, Patrick May, Dheeraj R Bobbili, Milena Radivojkov-Blagojevic, Peter Lichtner,
Andrew B Singleton, Dena G Hernandez, Connor Edsall, George D Mellick, Alexander Zimprich, Walter Pirker, Ekaterina Rogaeva, Anthony E Lang, Sulev Koks, Pille Taba, Suzanne Lesage, Alexis Brice, Jean-Christophe Corvol,
Marie-Christine Chartier-Harlin, Eugénie Mutez, Kathrin Brockmann, Angela B Deutschländer, Georges M Hadjigeorgiou, Efthimos Dardiotis, Leonidas Stefanis, Athina Maria Simitsi, Enza Maria Valente, Simona Petrucci, Stefano Duga,
Letizia Straniero, Anna Zecchinelli, Gianni Pezzoli, Laura Brighina, Carlo Ferrarese, Grazia Annesi, Andrea Quattrone, Monica Gagliardi, Hirotaka Matsuo, Yusuke Kawamura, Nobutaka Hattori, Kenya Nishioka, Sun Ju Chung, Yun Joong Kim, Pierre Kolber, Bart P C van de Warrenburg, Bastiaan R Bloem, Jan Aasly , Mathias Toft, Lasse Pihlstrøm,
Leonor Correia Guedes, Joaquim J Ferreira, Soraya Bardien, Jonathan Carr , Eduardo Tolosa, Mario Ezquerra, Pau Pastor, Monica Diez-Fairen, Karin Wirdefeldt , Nancy L Pedersen, Caroline Ran, Andrea C Belin, Andreas Puschmann,
Clara Hellberg, Carl E Clarke, Karen E Morrison, Manuela Tan , Dimitri Krainc, Lena F Burbulla, Matt J Farrer, Rejko Krüger, Thomas Gasser, Manu Sharma, Alexis Elbaz, Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (Courage-PD) Consortium
Background: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding.
Objective: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR).
Methods: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry).
Results: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% conﬁdence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029).
Conclusions: Using MR, our ﬁndings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms.
• PMID: 34997937
Front Neurol. 2021 Dec 23;12:742654. doi: 10.3389/fneur.2021.742654. eCollection 2021.
Authors: Mariana H G Monje, Sergio Domínguez, Javier Vera-Olmos, Angelo Antonini, Tiago A Mestre, Norberto Malpica, Álvaro Sánchez-Ferro
Objective: This study aimed to prove the concept of a new optical video-based system to measure Parkinson's disease (PD) remotely using an accessible standard webcam. Methods: We consecutively enrolled a cohort of 42 patients with PD and healthy subjects (HSs). The participants were recorded performing MDS-UPDRS III bradykinesia upper limb tasks with a computer webcam. The video frames were processed using the artiﬁcial intelligence algorithms tracking the movements of the hands. The video extracted features were correlated with clinical rating using the Movement Disorder Society revision of the Uniﬁed Parkinson's Disease Rating Scale and inertial measurement units (IMUs). The developed classiﬁers were validated on an independent dataset. Results: We found signiﬁcant differences in the motor performance of the patients with PD and HSs in all the bradykinesia upper limb motor tasks. The best performing classiﬁers were unilateral ﬁnger tapping and hand movement speed. The model correlated both with the IMUs for quantitative assessment of motor function and the clinical scales, hence demonstrating concurrent validity with the existing methods. Conclusions: We present here the proof-of-concept of a novel webcam-based technology to remotely detect the parkinsonian features using artiﬁcial intelligence. This method has preliminarily achieved a very high diagnostic accuracy and could be easily expanded to other disease manifestations to support PD management.
• PMID: 35002915
Parkinsons Dis. 2021 Dec 30;2021:8610285. doi: 10.1155/2021/8610285. eCollection 2021.
Authors: A Planas-Ballvé, D Vilas
Cognitive impairment is common in idiopathic Parkinson's disease (PD). Knowledge of the contribution of genetics to cognition in PD is increasing in the last decades. Monogenic forms of genetic PD show distinct cognitive proﬁles and rate of cognitive decline progression. Cognitive impairment is higher in GBA- and SNCA-associated PD, lower in Parkin- and PINK1-PD, and possibly milder in LRRK2-PD. In this review, we summarize data regarding cognitive function on clinical studies, neuroimaging, and biological markers of cognitive decline in autosomal dominant PD linked to mutations in LRRK2 and SNCA, autosomal recessive PD linked to Parkin and PINK1, and also PD linked to GBA mutations.
• PMID: 35003622
J Neurol Sci. 2022 Jan 12;434:120148. doi: 10.1016/j.jns.2022.120148. Online ahead of print.
Authors: Frederic Sampedro, Saul Martínez-Horta, Andrea Horta-Barba, Michel J Grothe, Miguel A Labrador-Espino- sa, Silvia Jesús, Astrid Adarmes-Gómez, Fátima Carrillo, Arnau Puig-Davi, Florinda Roldán Lora, Miquel Aguilar Barberá, Pau Pastor, Sonia Escalante Arroyo, Berta Solano Vila, Anna Cots Foraster, Javier Ruiz Martínez, Francisco Carrillo Padilla, Mercedes Pueyo Morlans, Isabel González Aramburu, Jon Infante Ceberio, Jorge Hernández Vara, Oriol de Fábregues-Boixar, Teresa de Deus Fonticoba, Asunción Ávila, Juan Carlos Martínez-Castrillo, Helena
Bejr-Kasem, Antonia Campolongo, Berta Pascual-Sedano, COPPADIS Study Group; Pablo Martínez-Martín, Diego Santos-García, Pablo Mir, Jaime Kulisevsky
Background: Blood homocysteine appears to be increased in Parkinson's disease (PD) and may play a role in the development and progression of this disorder. However, the speciﬁc contribution of abnormal homocysteine levels to cortical degeneration in PD remains elusive.
Objective: To characterize the cortical structural correlates of homocysteine levels in PD.
Methods: From the COPPADIS cohort, we identiﬁed a subset of PD patients and healthy controls (HC) with available homocysteine and imaging data. Surface-based vertex-wise multiple regression analyses were performed to investigate the cortical macrostructural (cortical thinning) and microstructural (increased intracortical diffusivity) correlates of homocysteine levels in this sample.
Results: A total of 137 PD patients and 43 HC were included. Homocysteine levels were increased in the PD group (t = -2.2, p = 0.03), correlating in turn with cognitive performance (r = -0.2, p = 0.03). Homocysteine in PD was also associated with frontal cortical thinning and, in a subset of patients with available DTI data, with microstructural damage in frontal and posterior-cortical regions (p < 0.05 Monte-Carlo corrected).
Conclusions: Homocysteine in PD appears to be associated with cognitive performance and structural damage in the cerebral cortex. These ﬁndings not only reinforce the presence and importance of cortical degeneration in PD, but also suggest that homocysteine plays a role among the multiple pathological processes thought to be involved in its development.
• PMID: 35085959
PLoS One. 2022 Jan 25;17(1):e0262796. doi: 10.1371/journal.pone.0262796. eCollection 2022.
Authors: Nobutaka Hattori, Atsushi Takeda, Yuki Hanya, Tadayuki Kitagawa, Masaki Arai, Yoshihiko Furusawa, Hideki Mochizuki, Masahiro Nagai, Ryosuke Takahashi
Background: Identifying the factors that inﬂuence health-related quality of life (HRQoL) is of great scientiﬁc interest, but a potential causal relationship between treatment and HRQoL has yet to be fully elucidated. Japanese patients reported better HRQoL outcomes on the Parkinson's Disease Questionnaire (PDQ-39) emotional well-being domain, a 6-question subset of the PDQ-39 which is considered to reﬂect the emotional aspects of the disease-speciﬁc HRQoL, when treated with rasagiline, than placebo, in both a monotherapy clinical trial (NCT02337725) and an adjunctive therapy clinical trial in patients with wearing-off phenomena (NCT02337738).
Objective: To investigate how rasagiline exerts its effect on the PDQ-39 emotional well-being domain in Japanese patients with Parkinson's disease.
Methods: A path analysis was performed to assess the direct treatment effects of rasagiline on the PDQ-39 emotional well-being domain and the effects mediated indirectly through the inﬂuence on items related to motor symptoms by a post-hoc analysis of two clinical trials in Japan.
Results: In the monotherapy trial, the PDQ-39 emotional well-being domain was mainly affected indirectly through items related to motor symptoms (80.7%) composed of the Movement Disorder Society-Uniﬁed Parkinson's Disease Rating Scale (MDS-UPDRS) Part II (67.2%) and Part III (13.5%). In the adjunctive therapy trial, the PDQ-39 emotional well-being domain was also mainly inﬂuenced indirectly through effects on items related to motor symptoms (1 mg/day: 54.7%, 0.5 mg/day: 57.6%) composed of MDS-UPDRS Part II (1 mg/day: 35.6%,
0.5 mg/day: 40.9%), Part III (1 mg/day: 8.0%, 0.5 mg/day: 8.3%) and mean daily OFF-time (1 mg/day: 11.1%, 0.5 mg/day: 8.4%).
Conclusions: The effects of rasagiline on the PDQ-39 emotional well-being domain were mediated primarily by inﬂuence on the subjective aspects of motor experiences of daily living.
• PMID: 35077474
Brain. 2022 Jan 28;awac026. doi: 10.1093/brain/awac026. Online ahead of print.
Authors: Marta Francisca Corrà, Nuno Vila-Chã, Ana Sardoeira, Clint Hansen, Ana Paula Sousa, Inês Reis, Firmina Sambayeta, Joana Damásio, Margarida Calejo, Andreas Schicketmueller, Inês Laranjinha, Paula Salgado, Ricardo Taipa, Rui Magalhães, Manuel Correia, Walter Maetzler, Luís F Maia
Peripheral neuropathy is a common problem in patients with Parkinson's disease. Peripheral neuropathy's prevalence in Parkinson's disease varies between 4.8% - 55%, compared to 9% in the general population. It remains unclear whether peripheral neuropathy leads to decreased motor performance in Parkinson's disease, resulting in impaired mobility and increased balance deﬁcits. We aimed to determine the prevalence and type of peripheral neuropathy in Parkinson's disease patients, and evaluate its functional impact on gait and balance. A cohort of consecutive Parkinson's disease patients assessed by Movement Disorders' specialists based on the UK Brain Bank criteria underwent clinical, neurophysiological (nerve conduction studies and Quantitative Sensory Testing) and neuropathological (Intraepidermal nerve ﬁber density in skin biopsies' punches) evaluation, to characterize peripheral neuropathy's type and etiology with a cross-sectional design. Gait and balance were characterized using wearable health-technology at OFF and ON medication states and the main parameters were extracted using validated algorithms. A total of 99 Parkinson's disease participants with a mean age of 67.2 (±10) years-old and mean disease duration of 6.5 (±5) years were assessed. Based on a comprehensive clinical, neurophysiological and neuropathological evaluation we found that 40.4% of Parkinson's disease patients presented peripheral neuropathy, with a predominance of small ﬁber neuropathy (70% of the group). At OFF state, the presence of peripheral neuropathy was signiﬁcantly associated with shorter stride length (P = 0.029), slower gait speed (P = 0.005) and smaller toe-off angles (P = 0.002) during straight walking; signiﬁcantly slower speed (P = 0.019) and smaller toe-off angles (P = 0.007) were also observed during circular walking. At ON state, the above effects remained, albeit moderately reduced. With regard to balance, signiﬁcant differences between Parkinson's disease patients with and without peripheral neuropathy were observed at OFF medication state during stance with closed eyes on a foam surface. At ON states, these differences were no longer observable. We showed that peripheral neuropathy is common in Parkinson's disease, and inﬂuences gait and balance parameters, as measured with mobile health-technology. Our study supports that peripheral neuropathy recognition and directed treatment should be pursued in order to improve Parkinson's disease patient's gait and minimize balance related disability, targeting individualized medical care.
• PMID: 35088837
Sci Rep. 2022 Jan 27;12(1):1532. doi: 10.1038/s41598-022-05587-z.
Authors: Kyohei Mikami, Makoto Shiraishi, Tsutomu Kamo
In a retrospective study we tested our hypothesis that the subjective postural vertical ratio (SPV ratio), i.e., the subjective postural vertical measured in relation to the lateral ﬂexion axis, is predictive of lateral trunk ﬂexion in patients with Parkinson's disease (PD). Twenty-ﬁve patients were included. The SPV angle, i.e., the subjective perception of a vertical position with reference to the vertical axis, and the SPV ratio, i.e., the SPV angle with reference to the axis of lateral ﬂexion, were calculated. The SPV ratio (r = 0.698, P = 0.001) and LTF angle (r = - 0.601, P = 0.001) correlated with change in the LTF angle at 1 year. The SPV ratio was signiﬁcantly smaller in patients for whom lateral trunk ﬂexion improved (n = 12) than in those for whom it did not improve (n = 13) (0.99
± 0.78 vs 1.66 ± 0.71, P = 0.011). The AUC under the ROC curve of the SPV ratio for discrimination of improvement was 0.795 (95% conﬁdence interval: 0.61-0.98). We found that the SPV ratio is associated with change in the LTF and that it can conceivably be used to predict the likelihood of improvement in PD-associated lateral trunk ﬂexion.
• PMID: 35087194
Front Neurol. 2022 Jan 10;12:794784. doi: 10.3389/fneur.2021.794784. eCollection 2021.
Authors: Paloma Cristina Alves de Oliveira, Thiago Anderson Brito de Araújo, Daniel Gomes da Silva Machado, Abner Cardoso Rodrigues, Marom Bikson, Suellen Marinho Andrade, Alexandre Hideki Okano, Hougelle Simplicio, Rodrigo Pegado, Edgard Morya
Background: Clinical impact of transcranial direct current stimulation (tDCS) alone for Parkinson's disease (PD) is still a challenge. Thus, there is a need to synthesize available results, analyze methodologically and statistically, and provide evidence to guide tDCS in PD.
Objective: Investigate isolated tDCS effect in different brain areas and number of stimulated targets on PD motor symptoms.
Methods: A systematic review was carried out up to February 2021, in databases: Cochrane Library, EMBASE, PubMed/MEDLINE, Scopus, and Web of science. Full text articles evaluating effect of active tDCS (anodic or cathodic) vs. sham or control on motor symptoms of PD were included.
Results: Ten studies (n = 236) were included in meta-analysis and 25 studies (n = 405) in qualitative synthesis. The most frequently stimulated targets were dorsolateral prefrontal cortex and primary motor cortex. No signiﬁcant effect was found among single targets on motor outcomes: Uniﬁed Parkinson's Disease Rating Scale (UPDRS) III - motor aspects (MD = -0.98%, 95% CI = -10.03 to 8.07, p = 0.83, I2 = 0%), UPDRS IV - dyskinesias (MD = -0.89%, CI 95% = -3.82
to 2.03, p = 0.55, I2 = 0%) and motor ﬂuctuations (MD = -0.67%, CI 95% = -2.45 to 1.11, p = 0.46, I2 = 0%), timed up and go - gait (MD = 0.14%, CI 95% = -0.72 to 0.99, p = 0.75, I2 = 0%), Berg Balance Scale - balance (MD = 0.73%, CI 95% = -1.01 to 2.47, p = 0.41, I2 = 0%). There was no signiﬁcant effect of single vs. multiple targets in: UPDRS III - motor aspects (MD = 2.05%, CI 95% = -1.96 to 6.06, p = 0.32, I2 = 0%) and gait (SMD = -0.05%, 95% CI = -0.28 to 0.17, p =
0.64, I2 = 0%). Simple univariate meta-regression analysis between treatment dosage and effect size revealed that number of sessions (estimate = -1.7, SE = 1.51, z-score = -1.18, p = 0.2, IC = -4.75 to 1.17) and cumulative time (estimate = -0.07, SE = 0.07, z-score = -0.99, p = 0.31, IC = -0.21 to 0.07) had no signiﬁcant association. Conclusion: There was no signiﬁcant tDCS alone short-term effect on motor function, balance, gait, dyskinesias or motor ﬂuctuations in Parkinson's disease, regardless of brain area or targets stimulated.
• PMID: 35082749
Front Neurol. 2022 Jan 10;12:628388. doi: 10.3389/fneur.2021.628388. eCollection 2021.
Authors: Daphne J Geerse, Bert Coolen, Jacobus J van Hilten, Melvyn Roerdink
External visual cueing is a well-known means to target freezing of gait (FOG) in Parkinson's disease patients. Holocue is a wearable visual cueing application that allows the HoloLens 1 mixed-reality headset to present on-demand patient-tailored action-relevant 2D and 3D holographic visual cues in free-living environments. The aim of this study involving 24 Parkinson's disease patients with dopaminergic "ON state" FOG was two-fold. First, to explore unfamiliarity and habituation effects associated with wearing the HoloLens on FOG. Second, to evaluate the potential immediate effect of Holocue on alleviating FOG in the home environment. Three sessions were conducted to examine (1) the effect of wearing the unfamiliar HoloLens on FOG by comparing walking with and without the HoloLens, (2) habituation effects to wearing the HoloLens by comparing FOG while walking with HoloLens over sessions, and (3) the potential immediate effect of Holocue on FOG by comparing walking with HoloLens with and without Holocue. Wearing the HoloLens (without Holocue) did signiﬁcantly increase the number and duration of FOG episodes, but this unfamiliarity effect disappeared with habituation over sessions. This not only emphasizes the need for sufﬁcient habituation to unfamiliar devices, but also testiﬁes to the need for research designs with appropriate control conditions when examining effects of unfamiliar wearable cueing devices. Holocue had overall no immediate effect on FOG, although objective and subjective beneﬁts were observed for some individuals, most notably those with long and/or many FOG episodes. Our participants raised valuable opportunities to improve Holocue and conﬁrmed our assumptions about current and anticipated future design choices, which supports ongoing Holocue development for and with end users.
• PMID: 35082741
Sci Rep. 2022 Jan 25;12(1):1330. doi: 10.1038/s41598-022-05227-6.
Authors: Elisa Zago, Alessandra Dal Molin, Giovanna Maria Dimitri, Luciano Xumerle, Chiara Pirazzini, Maria Giulia Bacalini, Maria Giovanna Maturo, Tiago Azevedo, Simeon Spasov, Pilar Gómez-Garre, María Teresa Periñán, Silvia Jesús, Luca Baldelli, Luisa Sambati, Giovanna Calandra-Buonaura, Paolo Garagnani, Federica Provini, Pietro Cortelli, Pablo Mir, Claudia Trenkwalder, Brit Mollenhauer, Claudio Franceschi, Pietro Liò, Christine Nardini, PROPAG-AGEING Consortium
Advanced age represents one of the major risk factors for Parkinson's Disease. Recent biomedical studies posit a role for microRNAs, also known to be remodelled during ageing. However, the relationship between microRNA remodelling and ageing in Parkinson's Disease, has not been fully elucidated. Therefore, the aim of the present study is to unravel the relevance of microRNAs as biomarkers of Parkinson's Disease within the ageing framework. We employed Next Generation Sequencing to proﬁle serum microRNAs from samples informative for Parkinson's Disease (recently diagnosed, drug-naïve) and healthy ageing (centenarians) plus healthy controls, age-matched with Parkinson's Disease patients. Potential microRNA candidates markers, emerging from the combination of differential expression and network analyses, were further validated in an independent cohort including both drug-naïve and advanced Parkinson's Disease patients, and healthy siblings of Parkinson's Disease patients at higher genetic risk for developing the disease. While we did not ﬁnd evidences of microRNAs co-regulated in Parkinson's Disease and ageing, we report that hsa-miR-144-3p is consistently down-regulated in early Parkinson's Disease patients. Moreover, interestingly, functional analysis revealed that hsa-miR-144-3p is involved in the regulation of coagulation, a process known to be altered in Parkinson's Disease. Our results consistently show the down-regulation of hsa-mir144-3p in early Parkinson's Disease, robustly conﬁrmed across a variety of analytical and experimental analyses. These promising results ask for further research to unveil the functional details of the involvement of hsa-mir144-3p in Parkinson's Disease.
• PMID: 35079043
J Parkinsons Dis. 2022 Jan 21. doi: 10.3233/JPD-213113. Online ahead of print.
Authors: Yue Hui Lau, Aleksandra Podlewska, Josephine Ocloo, Atul Gupta, Christopher Gonde, Bastiaan R Bloem, K Ray Chaudhuri
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.
• PMID: 35068418
J Parkinsons Dis. 2022 Jan 21. doi: 10.3233/JPD-212787. Online ahead of print.
Authors: Jennifer Michels, Hendrick van der Wurp, Elke Kalbe, Sarah Petra Rehberg, Alexander Storch, Katharina Linse, Christine Schneider, Susanne Gräber, Daniela Berg, Judith Dams, Monika Balzer-Geldsetzer, Rüdiger Hilker-Roggendorf, Carola Oberschmidt, Simon Baudrexel, Karsten Witt, Nele Schmidt, Günther Deuschl, Brit Mollenhauer, Claudia Trenk- walder, Inga Liepelt-Scarfone, Annika Spottke, Sandra Roeske , Ullrich Wüllner, Hans-Ulrich Wittchen, Oliver Riedel,
Jan Kassubek, Richard Dodel, Jörg Bernhard Schulz, Ana Soﬁa Costa, Kathrin Reetz
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.
• PMID: 35068416
Ann Neurol. 2022 Jan 24. doi: 10.1002/ana.26306. Online ahead of print.
Authors: Anouk Tosserams, Vivian Weerdesteyn, Tess Bal, Bastiaan R Bloem, Teodoro Solis-Escalante, Jorik Nonnekes
Objective: Gait impairment in persons with Parkinson's disease is common and debilitating. Compensation strategies (e.g. external cues) are an essential part of rehabilitation, but their underlying mechanisms remain unclear. Using EEG, we explored the cortical correlates of three categories of strategies: external cueing, internal cueing, and action observation.
Methods: Eighteen participants with Parkinson's disease and gait impairment were included. We recorded 126-channel EEG both during stance and gait on a treadmill under four conditions: (1) uncued; (2) external cueing (listening to a metronome); (3) internal cueing (silent rhythmic counting); and (4) action observation (observing another person walking). To control for the effects of sensory processing of the cues, we computed relative power changes as the difference in power spectral density between walking and standing for each condition.
Results: Relative to uncued gait, the use of all three compensation strategies induced a decrease of beta band activity in sensorimotor areas, indicative of increased cortical activation. Parieto-occipital alpha band activity decreased with external and internal cueing, and increased with action observation. Only internal cueing induced a change in frontal cortical activation, showing a decrease of beta band activity compared to uncued gait.
Interpretation: The application of compensation strategies resulted in changed cortical activity compared to uncued gait, which could not be solely attributed to sensory processing of the cueing modality. Our ﬁndings suggest there are multiple routes to control gait, and different compensation strategies seem to rely on different cortical mechanisms to achieve enhanced central motor activation in persons with Parkinson's disease. This article is protected by copyright. All rights reserved.
• PMID: 35067999
Neurology. 2022 Jan 21;10.1212/WNL.0000000000013303. doi: 10.1212/WNL.0000000000013303. Online ahead of print.
Authors: Anne Paakinaho, Marjaana Koponen, Miia Tiihonen, Markku Kauppi, Sirpa Hartikainen, Anna-Maija Tolppanen
Background: Epidemiological studies have suggested a link between rheumatoid arthritis and Parkinson's disease (PD). Disease-modifying anti-rheumatic drugs (DMARDs) might explain this association.
Objective: To evaluate the association between DMARDs and risk of PD in persons with rheumatoid arthritis.
Methods: Nested nationwide case-control study was conducted within the Finnish Parkinson's disease (FINPARK) cohort that includes 22,189 Finnish persons with clinically veriﬁed PD diagnosed in 1996-2015. The cases had recorded diagnosis of PD in the Special Reimbursement Register and had no exclusion diagnoses whose symptoms may be confused with PD within two years of PD diagnosis. This study included cases with PD diagnosed during 1999-2015 and rheumatoid arthritis diagnosed >3 years before PD. Rheumatoid arthritis was identiﬁed using Finnish Care Register for Health Care and Special Reimbursement Register. Cases were matched with up to seven control persons by age, sex, duration of rheumatoid arthritis and region. DMARDs were categorised into ﬁve classes and data on purchased prescriptions was identiﬁed from the Prescription Register since 1995. Associations were studied with conditional logistic regression adjusted for confounders.
Results: Altogether 315 cases with PD and 1,571 matched controls were included. Majority (> 60%) were women and median duration of rheumatoid arthritis on matching date was 11.6 years for controls and 12.6 years for cases. Use of DMARDs was not associated with risk of PD with three-year lag period applied between exposure and outcome, except chloroquine/hydroxychloroquine which associated with decreased risk (adjusted odds ratio 0.74; 95% conﬁdence interval 0.56-0.97). Other DMARDs, including sulfasalazine, methotrexate, gold preparations and immunosuppressants, were not associated with PD.
Discussion: Our results suggest that the lower risk of PD in people with rheumatoid arthritis is not explained by DMARD use as these drugs in general did not modify the risk of PD among persons with rheumatoid arthritis. Association between chloroquine/hydroxychloroquine and lower risk of PD as well as the possible underlying mechanisms should be further investigated.
Classiﬁcation of evidence: This study provides Class II evidence that in individuals with rheumatoid arthritis using DMARDs, only chloroquine/hydroxychloroquine was associated with a potentially decreased risk of developing PD (adjusted OR 0.74, 95% CI 0.56-0.97).
• PMID: 35064025
Brain Res. 2022 Jan 19;1780:147798. doi: 10.1016/j.brainres.2022.147798. Online ahead of print.
Authors: Laetitia Francelle, Joseph R Mazzulli
Lysosomal storage diseases (LSDs) are rare genetic disorders caused by a disruption in cellular clearance, resulting in pathological storage of undegraded lysosomal substrates. Recent clinical and genetic studies have uncovered links between multiple LSDs and common neurodegenerative diseases such as Parkinson's disease (PD). Here, we review recent literature describing the role of glia cells and neuroinﬂammation in PD and LSDs, including Gaucher disease (GD) and neuronal ceroid lipofuscinosis (NCL), and highlight converging inﬂammation pathways that lead to neuron loss. Recent data indicates that lysosomal dysfunction and accumulation of storage materials can initiate the activation of glial cells, through interaction with cell surface or cytosolic pattern recognition receptors that detect pathogenic aggregates of cellular debris. Activated glia cells could act to protect neurons through the elimination of toxic protein or lipid aggregates early in the disease process. However prolonged glial activation that occurs over several decades in chronic-age related neurodegeneration could induce the inappropriate elimination of synapses, leading to neuron loss. These studies provide mechanistic insight into the relationship between lysosomal dysfunction and glial activation, and offer novel therapeutic pathways for the treatment of PD and LSDs focused on reducing neuroinﬂammation and mitigating cell loss.
• PMID: 35063468
Mov Disord. 2022 Jan 20. doi: 10.1002/mds.28921. Online ahead of print. .
Authors: Indu Subramanian, Soania Mathur, Annelien Oosterbaan, Richelle Flanagan, Adrienne M Keener, Elena Moro
Personalized medicine considering sex, gender, and cultural context has become the vanguard of delivery of care. However, women's issues in Parkinson disease (PD), especially from a psychosocial standpoint, have been an overlooked ﬁeld. The key research areas include women-inclusive drug and device studies and genetic and hormonal considerations. Moreover, women with PD need to be educated and empowered on how to communicate their symptoms and needs, get engaged in research, get organized as a community, and support one another. Women with PD need tools to help track and convey their unique motor and nonmotor symptoms and psychological and social support needs. The management of PD needs to be customized to include the unique stages of women's lives, including menstrual cycles, pregnancy, perimenopause, menopause, and postmenopause. Speciﬁc guidelines for the use of hormonal treatments and customized dopamine replacement dosing need to be developed. Women need guidance on culturally sensitive wellness and self-care strategies that are customized for them. Basic core competencies in knowledge for all clinicians treating women with PD need to be established, including how to accurately diagnose, proactively identify, and treat the symptoms of PD in women and to ensure timely referral for specialty care, advanced therapies, and research studies. Caregivers and families need guidance on holistically supporting women with PD. The voices of women living with PD must be ampliﬁed to catalyze real change in this neglected ﬁeld. This paper provides an overview of the current knowledge, gaps, and possible strategies to deal with the unmet needs of women living with PD with a focus on the clinical and psychosocial aspects. © 2022 International Parkinson and Movement Disorder Society.
• PMID: 35060180
Front Neurol. 2022 Jan 3;12:716126. doi: 10.3389/fneur.2021.716126. eCollection 2021.
Authors: Eduard Linetsky, Suaad Abd Elhadi, Max Bauer, Akiva Gallant, Montaser Namnah, Sagit Weiss, Daniel Segal, Ronit Sharon, David Arkadir
Mannitol, a natural alcoholic-sugar, was recently suggested as a potential disease-modifying agent in Parkinson's disease. In animal models of the disease, mannitol interferes with the formation of α-synuclein ﬁbrils, inhibits the formation of α-synuclein oligomers and leads to phenotypic recovery of impaired motor functions. Parkinson's patients who consume mannitol report improvements of both motor and non-motor symptoms. Safety of long-term use of oral mannitol, tolerable dose and possible beneﬁt, however, were never clinically studied. We studied the safety of oral mannitol in Parkinson's disease and assessed the maximal tolerable oral dose by conducting a phase IIa, randomized, double-blind, placebo-controlled, single-center, dose-escalating study (ClinicalTrials.gov Identiﬁer: NCT03823638). The study lasted 36 weeks and included four dose escalations of oral mannitol or dextrose to a maximal dose of 18 g per day. The primary outcome was the safety of oral mannitol, as assessed by the number of adverse events and abnormal laboratory results. Clinical and biochemical efﬁcacy measures were collected but were not statistically-powered. Fourteen patients receiving mannitol completed the trial (in addition to eight patients on placebo). Mannitol-related severe adverse events were not observed. Gastrointestinal symptoms limited dose escalation in 6/14 participants on mannitol. None of the clinical or biochemical efﬁcacy secondary outcome measures signiﬁcantly differed between groups. We concluded that long-term use of 18 g per day of oral mannitol is safe in Parkinson's disease patients but only two third of patients tolerate this maximal dose. These ﬁndings should be considered in the design of future efﬁcacy trials.
• PMID: 35046880
Neurol Sci. 2022 Jan 19. doi: 10.1007/s10072-021-05833-8. Online ahead of print.
Authors: Eleonora Del Prete, Emmanuelle Schmitt, Sara Meoni, Valerie Fraix, Anna Castrioto, Pierre Pelissier, Roberto Ceravolo, Elena Moro
Introduction: In Parkinson's disease (PD), non-motor ﬂuctuations (NMFs), especially neuropsychiatric ﬂuctuations, often coexist with motor ﬂuctuations (MFs) but are often under-recognized by physicians and patients.
Objective: To investigate the relationship between MFs and neuropsychiatric ﬂuctuations in PD.
Methods: PD patients with MFs and NMFs were enrolled. The Parkinson's Kinetigraph (PKG), a wearable device to detect MFs and dyskinesia, was used to conﬁrm and measure MFs. The Neuropsychiatric Fluctuation Scale (NFS), a scale composed by subscores for both the ON and OFF neuropsychiatric states, was used to identify and quantify neuropsychiatric ﬂuctuations. Patients were asked to wear the PKG for six consecutive days to identify the ON and OFF motor periods, and then to ﬁll the NFS during the ON and OFF motor periods for three consecutive days wearing the PKG. The PKG system provided a bradykinesia score (BKS) and a dyskinesia score (DKS). Relations between BKS, DKS, and ON and OFF NFS subscores were analyzed.
Results: In 18 PD patients, anxiety, apathy, and depression characterized the OFF condition, whereas self-conﬁdence, competency, and interest in doing things were typically in the ON condition. There was a positive correlation between the BKS and the OFF NFS subscores (p = 0.036, r = 0.51), whereas no correlation was found between the DKS and the ON NFS subscores (p = 0.38, r = 0.22).
Conclusion: Neuropsychiatric ﬂuctuations temporarily matched the OFF MFs only in the OFF condition. These ﬁndings are useful to better manage OFF NMSs and support the need to further investigate associations between non-motor and motor symptoms in PD patients.
• PMID: 35043355
Neuropsychologia. 2022 Jan 15;167:108161. doi: 10.1016/j.neuropsychologia.2022.108161. Online ahead of print.
Authors: Soraya Lahlou, Ella Gabitov, Lucy Owen, Daphna Shohamy, Madeleine Sharp
Patients with Parkinson's disease, who lose the dopaminergic projections to the striatum, are impaired in certain aspects of motor learning. Recent evidence suggests that, in addition to its role in motor performance, the striatum plays a key role in the memory of motor learning. Whether Parkinson's patients have impaired motor memory and whether motor memory is modulated by dopamine at the time of initial learning is unknown. To address these questions, we measured memory of a learned motor sequence in Parkinson's patients who were either On or Off their dopaminergic medications at the time of initial learning. We compared them to a group of older and younger controls. Contrary to our predictions, motor memory was not impaired in patients compared to older controls, and was not inﬂuenced by dopamine state at the time of initial learning. To probe post-learning consolidation processes, we also tested whether learning a new sequence shortly after learning the initial sequence would interfere with later memory. We found that, in contrast to younger adults, neither older adults nor patients were susceptible to this interference. These ﬁndings suggest that motor memory is preserved in Parkinson's patients and raise the possibility that motor memory in patients is supported by compensatory non-dopamine sensitive mechanisms. Furthermore, given the similar performance characteristics observed in the patients and older adults and the absence of an effect of dopamine, these results raise the possibility that aging and Parkinson's disease affect motor memory in similar ways.
• PMID: 35041839
Mov Disord. 2022 Jan 17. doi: 10.1002/mds.28913. Online ahead of print.
Authors: Sygrid van der Zee, Prabesh Kanel, Marleen J J Gerritsen, Jeffrey M Boertien, Anne C Slomp, Martijn L T M Müller, Nicolaas I Bohnen, Jacoba M Spikman, Teus van Laar
Background: Altered cholinergic innervation plays a putative role in cognitive impairment in Parkinson's disease (PD) at least in advanced stages. Identiﬁcation of the relationship between cognitive impairment and cholinergic innervation early in the disease will provide better insight into disease prognosis and possible early intervention.
Objective: The aim was to assess regional cholinergic innervation status in de novo patients with PD, with and without cognitive impairment.
Methods: Fifty-seven newly diagnosed, treatment-naive, PD patients (32 men, mean age 64.6 ± 8.2 years) and 10 healthy controls (5 men, mean age 54.6 ± 6.0 years) were included. All participants underwent cholinergic [18 F]ﬂuoroethoxybenzovesamicol positron emission tomography and detailed neuropsychological assessment. PD patients were classiﬁed as either cognitively normal (PD-NC) or mild cognitive impairment (PD-MCI). Whole brain voxel-based group comparisons were performed.
Results: Results show bidirectional cholinergic innervation changes in PD. Both PD-NC and PD-MCI groups showed signiﬁcant cortical cholinergic denervation compared to controls (P < 0.05, false discovery rate corrected), primarily in the posterior cortical regions. Higher-than-normal binding was most prominent in PD-NC in both cortical and subcortical regions, including the cerebellum, cingulate cortex, putamen, gyrus rectus, hippocampus, and amygdala.
Conclusion: Altered cholinergic innervation is already present in de novo patients with PD. Posterior cortical cholinergic losses were present in all patients independent of cognitive status. Higher-than-normal binding in cerebellar, frontal, and subcortical regions in cognitively intact patients may reﬂect compensatory cholinergic upregulation in early-stage PD. Limited or failing cholinergic upregulation may play an important role in early, clinically evident cognitive impairment in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
• PMID: 35037719
Neurol Sci. 2022 Jan 15. doi: 10.1007/s10072-022-05885-4. Online ahead of print.
Authors: Rita Nisticò, Andrea Quattrone, Marianna Crasà, Marida De Maria, Basilio Vescio, Aldo Quattrone
Background: Rest tremor (RT) can be observed in several positions (seated, standing, lying down) but it is unknown whether the tremor features may vary across them. This study aimed to compare the RT electrophysiological features across different positions in tremor-dominant Parkinson's disease (PD) and essential tremor plus (ET with RT, rET).
Methods: We consecutively enrolled 90 tremor-dominant PD and 24 rET patients. The RT presence was evaluated in three positions: with the patient seated, the arm ﬂexed at 90°, the forearm supported against gravity, and the hand hanging down from the chair armrest (hand-hanging position), in lying down supine and in standing position. RT electrophysiological features (amplitude, frequency, burst duration, pattern) were compared between the two patient groups and across the different positions.
Results: All PD and rET patients showed RT in hand-hanging position. Supine and standing RT were signiﬁcantly more common in PD (67.8% and 75.6%, respectively) than in rET patients (37.5% and 45.8%, respectively). RT amplitude, frequency and pattern were signiﬁcantly different between groups in hand-hanging position whereas only pattern was signiﬁcantly different between PD and rET in both standing and supine positions. In each patient group, all RT electrophysiological features did not signiﬁcantly vary across different recording positions (p > 0.05).
Discussion: In our study, PD and rET showed RT in hand-hanging, supine, and standing positions. RT pattern was the only electrophysiological feature signiﬁcantly different between PD and rET patients in all these positions, enabling clinicians to perform the RT analysis for diagnostic purposes in different tremor positions.
• PMID: 35034234
Neurobiol Dis. 2022 Jan 11;164:105626. doi: 10.1016/j.nbd.2022.105626. Online ahead of print.
Authors: Jacob Horsager, Karoline Knudsen, Michael Sommerauer
Braak's hypothesis has been extremely inﬂuential over the last two decades. However, neuropathological and clinical evidence suggest that the model does not conform to all patients with Parkinson's disease (PD). To resolve this controversy, a new model was recently proposed; in brain-ﬁrst PD, the initial α-synuclein pathology arise inside the central nervous system, likely rostral to the substantia nigra pars compacta, and spread via interconnected structures
- eventually affecting the autonomic nervous system; in body-ﬁrst PD, the initial pathological α-synuclein originates in the enteric nervous system with subsequent caudo-rostral propagation to the autonomic and central nervous system. By using REM-sleep behavior disorder (RBD) as a clinical identiﬁer to distinguish between body-ﬁrst PD (RBD-positive at motor symptom onset) and brain-ﬁrst PD (RBD-negative at motor symptom onset), we explored the literature to evaluate clinical and imaging differences between these proposed subtypes. Body-ﬁrst PD patients display: 1) a larger burden of autonomic symptoms - in particular orthostatic hypotension and constipation, 2) more frequent pathological α-synuclein in peripheral tissues, 3) more brainstem and autonomic nervous system involvement in imaging studies, 4) more symmetric striatal dopaminergic loss and motor symptoms, and 5) slightly more olfactory dysfunction. In contrast, only minor cortical metabolic alterations emerge before motor symptoms in body-ﬁrst. Brain-ﬁrst PD is characterized by the opposite clinical and imaging patterns. Patients with pathological LRRK2 genetic variants mostly resemble a brain-ﬁrst PD proﬁle whereas patients with GBA variants typically conform to a body-ﬁrst proﬁle. SNCA-variant carriers are equally distributed between both subtypes. Overall, the literature indicates that body-ﬁrst and brain-ﬁrst PD might be two distinguishable entities on some clinical and imaging markers.
• PMID: 35031485
Neurobiol Dis. 2022 Jan 10;164:105625. doi: 10.1016/j.nbd.2022.105625. Online ahead of print. .
Authors: Neurobiol Dis. 2022 Jan 10;164:105625. doi: 10.1016/j.nbd.2022.105625. Online ahead of print.
In several neurodegenerative disorders, proteins that typically exhibit an α-helical structure misfold into an amyloid conformation rich in β-sheet content. Through a self-templating mechanism, these amyloids are able to induce additional protein misfolding, facilitating their propagation throughout the central nervous system. This disease mechanism was originally identiﬁed for the prion protein (PrP), which misfolds into PrPSc in a number of disorders, including variant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE). More recently, the prion mechanism of disease was expanded to include other proteins that rely on this self-templating mechanism to cause progressive degeneration, including α-synuclein misfolding in Parkinson's disease (PD). Several studies now suggest that PD patients can be subcategorized based on where in the body misfolded α-synuclein originates, either the brain or the gut, similar to patients developing sporadic CJD or vCJD. In this review, we discuss the human and animal model data indicating that α-synuclein and PrPSc misfolding originates in the gut in body-ﬁrst PD and vCJD, and summarize the data identifying the role of the autonomic nervous system in the gut-brain axis of both diseases.
• PMID: 35026401
Neurosci Lett. 2022 Jan 10;772:136449. doi: 10.1016/j.neulet.2022.136449. Online ahead of print.
Authors: Daryoush Afshari, Jalal Shakeri, Mehdi Khodamoradi, Reza Nejad Shahrokh Abadi, Jaza Rahkan, Leila Afshar Hezarkhani
Motor and psychiatric symptoms in patients with Parkinson's disease (PD) constitute some of the most problematic issues for both the patients and their caregivers. This study evaluated the short- and long-term efﬁcacy of electroconvulsive therapy (ECT) in PD patients whose psychiatric symptoms had been exacerbated due to drug therapy. Fifteen PD patients were treated using an electroshock device at a range of 25-100 Joules over a period of 6 weeks, during 12 sessions. Motor and psychiatric symptoms of all patients were evaluated before conducting ECT as baseline, after 12 sessions of ECT at the 6th week, and one month after completion of the treatment at the 10th week. The results showed that the variables mentation, behavior, mood, performance of daily activities, and severity of motor and psychiatric symptoms, were signiﬁcantly improved at the end of the 6th and 10th weeks when compared with the baseline. Moreover, the results revealed that the mean values were signiﬁcantly different only for motor symptoms at the end of the study (10th week) compared with the second time point. The current trial may indicate that ECT could potentially serve as a viable treatment for PD patients with refractory psychiatric symptoms. However, due to waning efﬁcacy of ECT, it is recommended that PD patients undergo a conventional treatment in conjunction with periodic ECT sessions to ensure an optimal medical outcome.
• PMID: 35026333
Neurology. 2022 Jan 12;10.1212/WNL.0000000000013218. doi: 10.1212/WNL.0000000000013218. Online ahead of print.
Authors: Kazuto Tsukita, Haruhi Sakamaki-Tsukita, Ryosuke Takahashi
Objective: Owing to the lack of long-term observations and/or comprehensive adjustment for confounding factors, reliable conclusions regarding long-term effects of exercise and regular physical activity in Parkinson's disease (PD) have yet to be drawn. Here, using data from the Parkinson's Progression Markers Initiative study that includes longitudinal and comprehensive evaluations of many clinical parameters, we examined the long-term effects of regular physical activity and exercise habits on the course of PD.
Methods: In this observational cohort study, we primarily used the multivariate linear mixed-effects models to analyze the interaction effects of their regular physical activity and moderate-to-vigorous exercise levels, measured through the Physical Activity Scale for the Elderly questionnaire, on the progression of clinical parameters, after adjusting for age, sex, levodopa-equivalent dose, and disease duration. We also calculated bootstrapping 95% conﬁdence intervals (CIs), and conducted sensitivity analyses using the multiple imputation method and subgroup analyses using the propensity score matching to match for all baseline background factors.
Results: 237 early PD patients [median (interquartile range); age, 63.0 (56.0-70.0) years; Male, 69.2%; follow-up duration, 5.0 (4.0-6.0) years] were included. Regular physical activity and moderate-to-vigorous exercise levels at the baseline did not signiﬁcantly affect the subsequent clinical progression of PD. However, average regular overall physical activity levels over time were signiﬁcantly associated with slower deterioration of postural and
gait stability [standardized ﬁxed-effects coefﬁcients of the interaction term (βinteraction) = -0.10 (95% CI, -0.14 to
-0.06)], activities of daily living [βinteraction = 0.08 (95% CI, 0.04 to 0.12)], and processing speed [βinteraction = 0.05 (95% CI, 0.03 to 0.08)] in PD patients. Moderate-to-vigorous exercise levels were preferentially associated with slower decline of postural and gait stability [βinteraction = -0.09 (95% CI, -0.13 to -0.05)] and work-related activity levels were primarily associated with slower deterioration of processing speed [βinteraction = 0.07 (95% CI, 0.04 to 0.09)]. Multiple imputation and propensity score matching conﬁrmed the robustness of our results.
Conclusions: In the long-term, the maintenance of high regular physical activity levels and exercise habits was robustly associated with better clinical course of PD, with each type of physical activity having different effects.
Trial registration information: Clinicaltrials.gov (NCT01176565). A link to trial registry page is https://clinicaltrials.gov/ct2/show/NCT01141023.
Classiﬁcation of evidence: This study provides Class II evidence that sustained increase in overall regular physical activity levels in patients with early Parkinson disease was associated with slower decline of several clinical parameters.
• PMID: 35022304
Sci Rep. 2022 Jan 10;12(1):351. doi: 10.1038/s41598-021-04131-9.
Authors: Makoto Hideshima, Yasuyoshi Kimura, César Aguirre, Keita Kakuda, Toshihide Takeuchi, Chi-Jing Choong, Junko Doi, Kei Nabekura, Keiichi Yamaguchi, Kichitaro Nakajima, Kousuke Baba, Seiichi Nagano, Yuji Goto, Yoshitaka Nagai, Hideki Mochizuki , Kensuke Ikenaka
Parkinson's disease is a neurodegenerative disease characterized by the formation of neuronal inclusions of α-synuclein in patient brains. As the disease progresses, toxic α-synuclein aggregates transmit throughout the nervous system. No effective disease-modifying therapy has been established, and preventing α-synuclein aggregation is thought to be one of the most promising approaches to ameliorate the disease. In this study, we performed a two-step screening using the thioﬂavin T assay and a cell-based assay to identify α-synuclein aggregation inhibitors. The ﬁrst screening, thioﬂavin T assay, allowed the identiﬁcation of 30 molecules, among a total of 1262 FDA-approved small compounds, which showed inhibitory effects on α-synuclein ﬁbrilization. In the second screening, a cell-based aggregation assay, seven out of these 30 candidates were found to prevent α-synuclein aggregation without causing substantial toxicity. Of the seven ﬁnal candidates, tannic acid was the most promising compound. The robustness of our screening method was validated by a primary neuronal cell model and a Caenorhabditis elegans model, which demonstrated the effect of tannic acid against α-synuclein aggregation. In conclusion, our two-step screening system is a powerful method for the identiﬁcation of α-synuclein aggregation inhibitors, and tannic acid is a promising candidate as a disease-modifying drug for Parkinson's disease.
• PMID: 35013421
Sci Rep. 2022 Jan 10;12(1):386. doi: 10.1038/s41598-021-03563-7.
Authors: Noreen Akram, Haoxuan Li, Aaron Ben-Joseph, Caroline Budu, David A Gallagher, Jonathan P Bestwick, Anette Schrag, Alastair J Noyce, Cristina Simonet
Disability in Parkinson's disease (PD) is measured by standardised scales including the MDS-UPDRS, which are subject to high inter and intra-rater variability and fail to capture subtle motor impairment. The BRadykinesia Akinesia INcoordination (BRAIN) test is a validated keyboard tapping test, evaluating proximal upper-limb motor impairment. Here, a new Distal Finger Tapping (DFT) test was developed to assess distal upper-limb function. Kinetic parameters of the test include kinesia score (KS20, key taps over 20 s), akinesia time (AT20, mean dwell-time on each key) and incoordination score (IS20, variance of travelling time between key taps). To develop and evaluate a new keyboard-tapping test for objective and remote distal motor function in PD patients. The DFT and BRAIN tests were assessed in 55 PD patients and 65 controls. Test scores were compared between groups and correlated with the MDS-UPDRS-III ﬁnger tapping sub-scores. Nine additional PD patients were recruited for monitoring motor ﬂuctuations. All three parameters discriminated effectively between PD patients and controls, with KS20 performing best, yielding 79% sensitivity for 85% speciﬁcity; area under the receiver operating characteristic curve (AUC) = 0.90. A combination of DFT and BRAIN tests improved discrimination (AUC = 0.95). Among three parameters, KS20 showed a moderate correlation with the MDS-UPDRS ﬁnger-tapping sub-score (Pearson's r = - 0.40, p = 0.002). Further, the DFT test detected subtle changes in motor ﬂuctuation states which were not reﬂected clearly by the MDS-UPDRS-III ﬁnger tapping sub-scores. The DFT test is an online tool for assessing distal movements in PD, with future scope for longitudinal monitoring of motor complications.
• PMID: 35013372
Front Neurol. 2021 Dec 23;12:794640. doi: 10.3389/fneur.2021.794640. eCollection 2021.
Authors: Carley Rusch, Matthew Beke, Lily Tucciarone, Carmelo Nieves Jr, Maria Ukhanova, Massimiliano S Tagliamonte, Volker Mai, Joon Hyuk Suh, Yu Wang, Shannon Chiu, Bhavana Patel, Adolfo Ramirez-Zamora, Bobbi Langkamp-Henken
Introduction: Non-motor symptoms of Parkinson's disease (PD) such as gastrointestinal (GI) dysfunction are common, yet little is known about how modifying dietary intake impacts PD symptoms. The aim of this study in individuals with PD was to determine whether a Mediterranean diet intervention is feasible and affects GI function, intestinal permeability and fecal microbial communities.
Methods: A single-arm, 5-week Mediterranean diet intervention study was conducted in eight people with PD. Daily and weekly questionnaires were administered to determine changes in GI symptoms. Urine and stool samples were collected at baseline and after 5 weeks to assess intestinal permeability and fecal microbial communities. Additionally, live-in partners of the participants with PD were matched as controls (n = 8) for baseline urine and stool samples.
Results: Participants with PD increased intake of Mediterranean diet based on adherence scores from baseline to week 5 (4.4 ± 0.6 vs. 11.9 ± 0.7; P < 0.01 with >10 representing good adherence), which was linked with weight loss (77.4 kg vs. 74.9 kg, P = 0.01). Constipation syndrome scores decreased after 5 weeks (2.3 ± 0.5 vs.
1.5 ± 0.3; P = 0.04). Bilophila, was higher at baseline in PD (0.6 ± 0.1% vs. 0.2 ± 0.1% P = 0.02) and slightly decreased after the diet intervention (0.5 ± 0.1%; P = 0.01). Interestingly, the proportion of Roseburia was signiﬁcantly lower in PD compared to controls (0.6 ± 0.2% vs. 1.6 ± 0.3%; P = 0.02) and increased at week 5 (0.9
± 0.2%; P < 0.01). No differences were observed for markers of intestinal permeability between the control and PD groups or post-intervention.
Conclusions: Short-term Mediterranean diet adherence is feasible in participants with PD; correlated with weight loss, improved constipation, and modiﬁed gut microbiota. Clinical Trial Registration: ClinicalTrials.gov, identiﬁer: NCT03851861.
• PMID: 35002935
J Parkinsons Dis. 2022 Jan 4. doi: 10.3233/JPD-202324. Online ahead of print.
Authors: Iris van der Lijn, Gera A de Haan, Famke Huizinga, Fleur E van der Feen, A Wijnand F Rutgers, Catherina Stellingwerf, Teus van Laar, Joost Heutink
Background: Scientiﬁc research increasingly focuses on visual symptoms of people with Parkinson's disease (PD). However, this mostly involves functional measures, whereas self-reported data are equally important for guiding clinical care.
Objective: This review provides an overview of the nature and prevalence of self-reported visual complaints by people with PD, compared to healthy controls.
Methods: A systematic literature search was performed. Studies from three databases (PubMed, PsycInfo, and Web of Science) were screened for eligibility. Only studies that reported results of visual self-reports in people with idiopathic PD were included.
Results: One hundred and thirty-nine eligible articles were analyzed. Visual complaints ranged from function-related complaints (e.g., blurred vision, double vision, increased sensitivity to light or changes in contrast sensitivity) to activity-related complaints (e.g., difﬁculty reading, reaching, or driving). Visual complaints were more prevalent in people with PD compared to healthy controls. The presence of visual complaints leads to a reduced quality of life (QoL). Increased prevalence and severity of visual complaints in people with PD are related to longer disease duration, higher disease severity, and off-state.
Conclusion: A large proportion of people with PD have visual complaints, which negatively affect QoL. Complaints are diverse in nature, and speciﬁc and active questioning by clinicians is advised to foster timely recognition, acknowledgement, and management of these complaints.
• PMID: 35001897
Mov Disord. 2022 Jan 8. doi: 10.1002/mds.28917. Online ahead of print.
Authors: Nora Vanegas-Arroyave, Denise F Chen, Peter M Lauro, Gina Norato, Codrin Lungu, Mark Hallett
Background: Parkinson's disease (PD) is associated with gait and visuomotor abnormalities, but it is not clear where PD patients look during ambulation.
Objective: We sought to characterize the visual areas of interest explored by PD patients, with and without freezing of gait (FOG), compared to healthy volunteers (HVs).
Methods: Using an eye-tracking device, we compared visual ﬁxation patterns in 17 HVs and 18 PD patients, with and without FOG, during an ambulatory and a nonambulatory, computer-based task.
Results: During ambulation, PD patients with FOG ﬁxated more on proximal areas of the ground and less on the target destination. PD patients without FOG displayed a ﬁxation pattern more similar to that of HVs. Similar patterns were observed during the nonambulatory, computer-based task.
Conclusions: Our ﬁndings suggest increased dependence on visual feedback from nearby areas in the environment in PD patients with FOG, even in the absence of motor demands. © 2022 International Parkinson and Movement Disorder Society.
• PMID: 34997620
Eur J Neurosci. 2022 Jan 5. doi: 10.1111/ejn.15594. Online ahead of print.
Authors: Sara Ekraminasab, Mahsa Dolatshahi, Mohammadmahdi Sabahi, Mahta Mardani, Sina Rashedi
Leptin is a hormone that regulates appetite by acting on receptors in the hypothalamus, where it modiﬁes food intake to maintain equilibrium with the body energy resources. Leptin and its receptors are widely distributed in the central nervous system, suggesting that they may give neuronal survival signals. The potential of leptin to decrease/increase neuronal damage and neuronal plasticity in Parkinson's diseases (PD) is the subject of this review, which outlines our current knowledge of how leptin acts in the brain. Although leptin-mediated neuroprotective signalling results in neuronal death prevention, it can affect neuroinﬂammatory cascades and also neuronal plasticity which contribute to PD pathology. Other neuroprotective molecules, such as insulin and erythropoietin, share leptin-related signalling cascades, and therefore constitute a component of the neurotrophic effects mediated by endogenous hormones. With the evidence that leptin dysregulation causes increased neuronal vulnerability to damage in PD, using leptin as a target for therapeutic modiﬁcation is an appealing and realistic option. .
• PMID: 34989050
Neurol Sci. 2022 Jan 4. doi: 10.1007/s10072-021-05730-0. Online ahead of print.
Authors: Mario Giorgio Rizzone, Francesca Mancini, Carlo Alberto Artusi, Roberta Balestrino, Salvatore Bonvegna, Margherita Fabbri, Gabriele Imbalzano, Elisa Montanaro, Alberto Romagnolo, Maurizio Zibetti, Leonardo Lopiano
Background: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective surgical treatment for advanced Parkinson's disease (PD). However, some patients still experience motor ﬂuctuations or dyskinesia after STN-DBS. Saﬁnamide is approved as add-on treatment to levodopa in ﬂuctuating PD patients. In this study, we evaluated the effect of saﬁnamide as adjunctive therapy in PD patients still experiencing motor ﬂuctuations and dyskinesias after STN-DBS.
Methods: PD patients treated for at least 2 years with bilateral STN-DBST and with troublesome motor ﬂuctuation and/or dyskinesias were examined by means of the Movement Disorders Society-Uniﬁed Parkinson's Disease Rating Scale (MDS-UPDRS), the quality of life questionnaire Parkinson's Disease Questionnaire-8 (PDQ-8) and the Non-Motor Symptoms Scale (NMSS) at baseline (T0), after 1 month of treatment with saﬁnamide 50 mg daily (T1) and after another month of treatment with saﬁnamide 100 mg daily (T2).
Results: Twenty-nine PD patients were examined. An improvement of the MDS-UPDRS IV score (motor complications) was observed between T0 and T1, T0 and T2, and T1 and T2. The time spent in the OFF state, the functional impact and the complexity of motor ﬂuctuations signiﬁcantly improved between T0 and T1 and T0 and T2. The mean levodopa equivalent daily dose signiﬁcantly decreased from T0 to T1 and from T0 to T2. Regarding non-motor symptoms, an improvement on mood and pain was observed.
Conclusions: Saﬁnamide seems to be an effective adjunctive treatment in PD patients treated with bilateral STN-DBS, leading to an improvement of motor complications, mood and pain.
• PMID: 34982297