Constipation is Associated with Development of Cognitive Impairment in de novo Parkinson’s Disease: A Longitudinal Analysis of Two International Cohorts

Article type: Research Article

Authors: Leta, Valentina^{a; b; 1} | Urso, Daniele^{a; b; c; 1} | Batzu, Lucia^{a; b} | Weintraub, Daniel^d | Titova, Nataliya^{e; f} | Aarsland, Dag^{a; g} | Martinez-Martin, Pablo^h | Borghammer, Per^{i; j} | van Wamelen, Daniel J.^{a; b; k} | Yousaf, Tayyabah^a | Rizos, Alexandra^{a; b} | Rodriguez-Blazquez, Carmen^l | Chung-Faye, Guy^m | Chaudhuri, K. Ray^{a; b; *}

Affiliations: [a] Institute of Psychiatry, Psychology & Neuroscience, Department of Neurosciences, King’s College London, London, United Kingdom | [b] Parkinson’s Foundation Centre of Excellence, King’s College Hospital, London, United Kingdom | [c] Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari ‘Aldo Moro’, Tricase, Lecce, Italy | [d] University of Pennsylvania, Philadelphia, PA, USA | [e] Federal State Autonomous Educational Institution of Higher Education “N.I. Pirogov Russian National Research Medical University” of the Ministry of Health of the Russian Federation, Department of Neurology, Neurosurgery and Medical Genetics, Moscow, Russia | [f] Federal State Budgetary Institution “Federal Center of Brain and Neurotechnologies” of the Ministry of Health of the Russian Federation, Department of Neurodegenerative Diseases, Moscow, Russia | [g] Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway | [h] Centre for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Carlos III Institute of Health, Madrid, Spain | [i] Institute for Clinical Medicine, Aarhus University, Aarhus, Denmark | [j] Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark | [k] Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands | [l] National Centre of Epidemiology, Carlos III Institute of Health, Madrid, Spain | [m] Department of Gastroenterology, King’s College Hospital Foundation NHS Trust, London, United Kingdom

Correspondence: [*] Professor K. Ray Chaudhuri, MD, FRCP, DSc, Department of Basic and Clinical Neuroscience, The Maurice Wohl Clinical Neuroscience Institute, King’s College London, Cutcombe Road, London, SE5 9RT, United Kingdom. Tel.: +44 0203299 8807; [email protected].

Note: [1] These authors contributed equally to this work.

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

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

DOI: 10.3233/JPD-212570

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