Background: Cognitive deficits have been reported in Parkinson's Disease psychosis (PDP). Reduced dopamine transporter (DAT) binding ratio has also been associated with PDP. However, it remains unclear whether DAT striatal binding ratio (SBR) may contribute to worsening cognitive performance in PDP. Here, we examined this using data from the Parkinson's Progression Markers Initiative study. Methods: We analysed data from 408 PD patients, from baseline to year 4 follow up, and classified patients into PD with (PDP) and without psychosis (PDnP). DAT SBR was available from DaTSCAN imaging with 123 I-FP-CIT-SPECT. We examined all cognitive measures assessed at each time point, socio-demographics, neuropsychiatric and PD-specific symptoms were entered as covariates of interest. Results: PDP patients had lower DAT SBR compared to PDnP patients (b=-0.092, p=0.035) which remained significant after controlling for age, sex, and ethnicity. PDP patients also reported worse trajectory of task performance on MoCA (b=-0.238, p=0.001) and Symbol Digit Modality (b=-0.534, p=0.016) across four years compared to PDnP patients. Worsening of MoCA scores in PDP was independent of DAT SBR decline (interaction group * study years, b=-0.284, p=0.016; three-way interaction group*study years*DAT SBR, b=0.127, p=0.225). However, declining performance in Symbol Digit Modality was significantly associated with the decline in DAT SBR (three-way interaction group*study years*DAT SBR, b=0.683, p=0.028). Conclusion: Overall, longitudinal decline in striatal presynaptic dopamine function may underlie the greater longitudinal decline in performance in the symbol digit modality task that engages processing speed, associative learning and working memory in PD psychosis, whilst declining performance on MoCA seems unrelated to it. Whether striatal presynaptic dopamine changes explain accelerated longitudinal decline in other cognitive domains in people with PDP remains to be tested.

The authors have declared no competing interest.

NCT01141023

Data used in this work were obtained from the Parkinson's Progression Markers Initiative database (http://www.ppmi-info.org/ ). 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.

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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 .