Disease Progression, Resilience, and Inflammation Markers During the Coronavirus Disease 2019 Pandemic in Parkinson's Disease

During the coronavirus disease 2019 (COVID-19) pandemic, complete lockdown periods, slowly installed vaccination programs, and appearances of new virus variants led to increased stress in the population. In patients with Parkinson's disease (PD), the stress impact also included cancellations of outpatient visits, temporary abandonment of multidisciplinary treatment, and reduced physical activity. We analyzed the stress impact on PD during the first phase of the COVID-19 pandemic, characterized by longest lockdown and highest uncertainty. We hypothesized on a negative stress modulation on the disease trajectories during this period.1 By using data from the Luxembourg Parkinson's Study,2 we compared a pandemic PD group without infection (n = 79), but with exposure to COVID-19 restrictions between two visits (V2 and V3) with a prepandemic PD control group (n = 117; Fig. 1A, Fig. S1). Motor and cognitive status were established through in-person examinations between September 2020 and March 2021 for the pandemic PD group and between 2018 and 2019 for the prepandemic PD control group. The pandemic PD group self-rated their resilience and risk for posttraumatic stress disorder (PTSD) by using the Brief Resilience Scale and the Revised Impact of Event Scale (Table S2). In this group, 92 serological inflammation markers of the Olink panel were measured at V2 and V3. Motor progression rated by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score was the primary outcome. Secondary outcomes were other progression scores (MDS-UPDRS Parts I and II), cognitive performance (Montreal Cognitive Assessment), depressive symptoms (Beck Depression Inventory [BDI]), resilience (Brief Resilience Scale), and risk for PTSD (Revised Impact of Event Scale). A multiple linear regression approach with adjustments for confounder variables was used. The pandemic PD group did not show a more pronounced deterioration in motor and cognitive scores from V1 to V3 than the prepandemic control group (Fig. 1B,C, Table S1), but they experienced higher depressive symptoms. Remarkably, 74.7% of the pandemic PD patients had normal or high resilience scores. About 20.3% of the pandemic PD patients with an increased risk for PTSD had higher BDI scores, but not higher MDS-UPDRS Part III scores. Regarding the inflammatory markers, only the tumor suppressor Axin-1 (AXIN1) increased in the pandemic PD patients at V3 compared with V2 (Figs. S1 and S2) after adjustments for multiple hypothesis testing. In our study, the stress impact of the COVID-19 pandemic's initial phase did not produce any major modulation on the PD motor and cognitive trajectories. These counterintuitive results refute the initial hypothesis of a negative stress impact on the disease course.3 However, while the motor and cognitive trajectories remained unimpacted, the depression score increased during this period, although patients with higher resilience maintained lower BDI scores.4 Apart from AXIN1, there was no increase in inflammatory markers (Fig. S4). The study's small cohort and short observation period are some of its limitations. However, we assumed that longer intervals between visits might have diluted any negative stress impact. In contrast with other studies,1, 5 in-person examinations shortly after the first lockdown, concomitant analysis of inflammatory markers, and the availability of a prepandemic PD control group are considered specific strengths of this study. This work was supported by the Luxembourg National Research Fund (FNR) within the National Centre for Excellence in Research on Parkinson's disease (FNR/NCER13/BM/11264123) and within the PEARL Excellence Program (FNR/P13/6682797) to R.K. E.G. received funding support from the Fonds National de la Recherche Luxembourg as part of the COVID-19 Fast-Track research project CovScreen (COVID-19/2020-1/14715687) and from the European Union's Horizon 2020 research and innovation program under grant ERAPERMED 2020–314 for the project DIGI-PD. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant 863664). Data used in the preparation of this manuscript were obtained from the National Centre of Excellence in Research on Parkinson's Disease (NCER-PD). We would like to thank all participants of the Luxembourg Parkinson's Study for their important support on our research. Furthermore, we acknowledge the joint effort of the NCER-PD Consortium members from the partner institutions Luxembourg Centre for Systems Biomedicine, Luxembourg Institute of Health, Centre Hospitalier de Luxembourg and Laboratoire National de Santé generally contributing to the Luxembourg Parkinson's Study as listed here: Geeta Acharya (6), Gloria Aguayo (6), Myriam Alexandre (6), Muhammad Ali (1), Wim Ammerlann (6), Rudi Balling (1), Michele Bassis (1), Katy Beaumont (6), Regina Becker (1), Camille Bellora (6), Guy Berchem (5), Daniela Berg (15), Alexandre Bisdorff (8), Kathrin Brockmann (15), Jessica Calmes (6), Lorieza Castillo (6), Gessica Contesotto (6), Rene Dondelinger (8), Daniela Esteves (6), Guy Fagherazzi (6), Jean-Yves Ferrand (6), Manon Gantenbein (6), Thomas Gasser (15), Piotr Gawron (1), Soumyabrata Ghosch (1), Marijus Giraitis (2,5), Clarissa Gomes (1), Elisa Gomes de Lope (1), Jérôme Graas (6), Mariela Graziano (21), Valentin Groues (1), Anne Grünewald (1), Wei Gu (1), Gaël Hammot (6), Anne-Marie Hanff (2), Linda Hansen (1,3), Michael Heneka (1), Estelle Henry (6), Sylvia Herbrink (9), Sascha Herzinger (1), Michael Heymann (6), Michele Hu (11), Alexander Hundt (6), Nadine Jacoby (22), Jacek Jaroslaw Lebioda (1), Yohan Jaroz (1), Quentin Klopfenstein (1), Jochen Klucken (2,5), Pauline Lambert (2), Zied Landoulsi (1), Roseline Lentz (10), Inga Liepelt (15), Robert Liszka (18), Laura Longhino (5), Victoria Lorentz (6), Paula Cristina Lupu (6), Clare Mackay (18), Walter Maetzler (19), Katrin Marcus (17), Guilherme Marques (6), Patricia Martins Conde (1), Patrick May (1), Deborah Mcintyre (2), Chouaib Mediouni (6), Francoise Meisch (1), Myriam Menster (6), Maura Minelli (6), Michel Mittelbronn (1,7), Brit Mollenhauer (16), Carlos Moreno (1), Friedrich Mühlschlegel (7), Romain Nati (5), Ulf Nehrbass (6), Sarah Nickels (1), Beatrice Nicolai (5), Jean-Paul Nicolay (23), Jean-Paul Nicolay (23), Fozia Noor (6), Marek Ostaszewski (1), Sinthuja Pachchek (1), Laure Pauly (1), Lukas Pavelka (1,2,5), Magali Perquin (6), Rosalina Ramos Lima (6), Armin Rauschenberger (1), Rajesh Rawal, Dheeraj Reddy Bobbili (1), Eduardo Rosales (6), Isabel Rosety (6), Kirsten Roomp (1), Estelle Sandt (6), Stefano Sapienza (1), Venkata Satagopam (1), Margaux Schmitt (6), Sabine Schmitz (1), Reinhard Schneider (1), Jens Schwamborn (1), Jean-Edouard Schweitzer (1), Amir Sharify (6), Ekaterina Soboleva (1,2,5), Kate Sokolowska (6), Olivier Terwindt (1,2,5), Hermann Thien (6), Elodie Thiry (5), Rebecca Ting Jiin Loo (1), Christophe Trefois (1), Johanna Trouet (6), Olena Tsurkalenko (3), Michel Vaillant (6), Mesele Valenti (6), Liliana Vilas Boas (5), Maharshi Vyas (1), Richard Wade-Martins (13), Evi Wollscheid-Lengeling (1), Gelani Zelimkhanov (5). We thank Prof. Jochen Klucken for valuable feedback. (1) Luxembourg Centre for Systems Biomedicine, University of Luxembourg. (6) Luxembourg Institute of Health, Strassen, Luxembourg. (5) Centre Hospitalier de Luxembourg, Strassen. Luxembourg. (7) Laboratoire National de Santé, Dudelange, Luxembourg. (8) Centre Hospitalier Emile Mayrisch, Esch-sur-Alzette, Luxembourg. (9) Centre Hospitalier du Nord, Ettelbrück, Luxembourg. (10) Parkinson Luxembourg Association, Leudelange, Luxembourg. (11) Oxford Parkinson's Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. (12) Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. (13) Oxford Centre for Human Brain Activity, Welcome Centre for Integrative Neuroimaging, Department of Psychiatry, University of Oxford, Oxford. (14) Centre of Neurology and Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University Hospital of Tübingen, Tübingen, Germany. (15) Paracelsus-Elena Klinik, Kassel, Germany. (16) Ruhr University of Bochum, Bochum, Germany. (17) Westpfalz- Klinikum GmbH, Kaiserlautern, Germany. (18) Department of Neurology, University Medical Centre Schleswig-Holstein, Kiel, Germany. (19) Department of Neurology Philipps, University of Marburg, Marburg, Germany. (20) Association of Physiotherapists in Parkinson's Disease Europe, Esch-sur-Alzette, Luxembourg. (21) Private Practice Ettelbruck, Luxembourg. (22) Private Practice, Luxembourg, Luxembourg. C.P. and E.G. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: N.J.D., C.P., M.H. Acquisition of data: C.P., M.H., C.M.-G., T.M. Interpretation of data: N.J.D., C.P., M.H., C.M.-G., E.G. Drafting of the manuscript: N.J.D., C.P., E.G. Critical revision of the manuscript for intellectual content: all authors. Statistical analysis: E.G., M.L., M.H. Administrative and technical support: T.M., P.W., R.K. Supervision: N.J.D. The datasets for this manuscript are not publicly available as they are linked to the Luxembourg Parkinson's Study and its internal regulations. Requests to access the datasets should be directed to Prof. Rejko Krueger, mean of contact via email: request.ncer-pd@uni.lu. The datasets for this manuscript are not publicly available as they are linked to the Luxembourg Parkinson's Study and its internal regulations. Requests to access the datasets should be directed to Prof. Rejko Krueger, mean of contact via email: request.ncer-pd@uni.lu. Appendix S1. Supporting Information. Figure S1. The filtering procedure (A) of the PD patients of the pandemic group, (B) of the PD patients of the pre-pandemic group. Figure S2. Violin plot of normalized protein expression levels for AXIN1 (left) and LAP TGF-beta-1 (right) in the pandemic PD group at visit V2 (before the pandemic) and visit V3 (during the pandemic). Table S1. Overview of characteristics for the pandemic and pre-pandemic PD group, including P-value significance scores for the difference between means (two-sided T-test for continuous data, Fisher's Exact test for categorical data, P-values below 0.05 are highlighted in red). By coincidence, the mean value for LEDD at visit 1 was identical for the pandemic and the pre-pandemic group. Table S2. Comparison of disease characteristics between PD patients of the pandemic group and dropouts including P-value significance scores for the difference between means (two-sided T-test for continuous data, Fisher's Exact test for categorical data, P-values below 0.05 are highlighted in red). Table S3. Differential abundance statistics for the protein inflammatory markers (Olink panel) obtained using the empirical Bayes moderated t-statistic (the column headers are defined as follows: Protein name = the protein name identifier for the inflammatory markers from the Olink panel; logFC = the fold-change difference between the protein expression before and after the pandemic; AveExpr = average measured protein expression across all samples; t = the t-statistic, P-value = the nominal P-value significance for the empirical Bayes moderated t-statistic; ad. P-value = the P-value significance after adjustment for multiple hypothesis testing using the Benjamini-Hochberg method). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.