Parkinson's disease psychosis associated with accelerated multi-domain cognitive decline

Cognitive deficits are associated with poor quality of life and increased risk of development of dementia in people with Parkinson's Disease (PD) with psychosis. However, the pattern of progression of cognitive decline within PD psychosis remains unclear. Here, we examined this using data from the Parkinson's Progression Markers Initiative study. We obtained data on drug-naïve PD patients (n=676) and healthy controls (HC, n=187) who underwent baseline and follow-up (year 1 to 5) assessments. We classified PD patients into PD without psychosis (PDnP) and PD with psychosis (PDP) using the MDS-UPDRS part I hallucinations/psychosis item. We examined all cognitive measures assessed at each time point. We used linear mixed-effect models with restricted maximum likelihood. We examined the role of age, sex, ethnicity, education, and neuropsychiatric and PD-specific symptoms as covariates of interest. There were no baseline differences on any cognitive measures between PD patient groups. There were differences in cognitive performance between PD and HC across the majority of the assessments. PDP patients showed a more prominent cognitive decline from baseline to year 5 compared with PDnP across most domains even after controlling for socio-demographics, depression, sleepiness, REM behaviour sleep disorder, and motor symptom severity (immediate recall, b=-0.288, P=0.003; delayed recall, b=-0.146, P=0.003; global cognition, MoCA, b=-0.206, P <0.001; visuo-spatial, b=-0.178, P=0.012; semantic fluency, b=-0.704, P=0.002; processing speed, b=-0.337, P=0.029). Over five years, PD psychosis patients showed worsening of performance in semantic aspects of language, processing speed, global cognition, visuo-spatial abilities, and memory sub-components, regardless of socio-demographic characteristics, neuropsychiatric and motor symptoms. Collectively, these cognitive domains, particularly semantic aspects of language may therefore play an important role in PD psychosis and warrant further investigation. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement PPMI-a public-private partnership-is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson's, AskBio, Avid Radiopharmaceuticals, BIAL, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity Therapeutics. For up-to-date information on the study, visit www.ppmi-info.org. SB, LV, DA, DF, KRC and CB are in receipt of funding from Parkinson's UK for a clinical trial in Parkinson's disease psychosis. SP PhD studentship is funded by Parkinson's UK. The funding source had no involvement in this research. SB is supported by grants from the National Institute of Health Research (NIHR) Efficacy and Mechanism Evaluation scheme and Parkinson's UK. SB has participated in advisory boards for or received honoraria as a speaker from Reckitt Benckiser, EmpowerPharm/SanteCannabis and Britannia Pharmaceuticals. All of these honoraria were received as contributions toward research support through King's College London, and not personally. SB also has collaborated with Beckley Canopy Therapeutics/ Canopy Growth (investigator-initiated research) wherein they supplied study drug for free for charity (Parkinson's UK) and NIHR (BRC) funded research. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. LV has collaborated with Beckley Canopy Therapeutics/ Canopy Growth (investigator-initiated research) wherein they supplied study drug for free for charity (Parkinson's UK) and NIHR (BRC) funded research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The data used in this analysis are openly available from the Parkinson's Progression Marker Initiative (PPMI) study ( at www.ppmi-info.org/access-dataspecimens/download-data). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data used in the preparation of this article were obtained [on February 1st 2023] from the Parkinson's Progression Markers Initiative (PPMI) database (www.ppmi-info.org/access-dataspecimens/download-data), RRID:SCR 006431. For up-to-date information on the study, visit www.ppmi-info.org.