Objective: To estimate the temporal ordering of multimodal biomarker abnormality events leading to cognitive impairment in PD using a Disease Event-Based Model (DEBM), incorporating clinical, cognitive, neuropsychiatric, autonomic, CSF, and plasma biomarkers.

Background: Despite extensive research into individual predictors, the temporal cascade through which multimodal biomarkers sequentially become abnormal before the clinical manifestation of cognitive impairment remains poorly delineated.

Method:

We analyzed 1,873 participants (1,533 PD, 340 healthy controls) from the PPMI. Cognitive impairment was classified using MDS Level 1 and Level 2 criteria. Thirteen biomarkers spanning cognitive (7 domain-specific tests), motor (MDS-UPDRS Part III), autonomic (SCOPA-AUT), sleep (RBDSQ), and neuropsychiatric (apathy, depression, cognitive complaints) domains were modeled using Gaussian mixture modeling with healthy controls as the reference distribution. The maximum likelihood event ordering was estimated via pairwise comparison, with positional uncertainty quantified through 1,000 bootstrap iterations. Secondary analyses incorporated CSF and plasma biomarkers.

Results: The estimated biomarker cascade was: (1) motor dysfunction (MDS-UPDRS III; 70% bootstrap confidence), (2) depressive symptoms, (3) subjective cognitive complaints, (4) apathy, (5) global cognitive decline (MoCA; 74% confidence), followed by domain-specific cognitive deficits in executive function, attention/working memory, processing speed (80% confidence), visuospatial function (74% confidence), and memory. DEBM stages robustly differentiated cognitive impairment groups (Kruskal-Wallis H=742.56, P<0.001). In the CSF subsample, NfL elevation was the earliest biological event, preceding motor and cognitive changes. CSF tau markers occupied intermediate positions, while Aβ-42 and α-Synuclein changes were late events. Plasma NfL preceded domain-specific cognitive decline. Results were robust across sensitivity analyses (baseline-only: Kendall’s τ=0.974, P<0.001).

Conclusion: In PD cognitive impairment cascade, neuropsychiatric symptoms precede objective cognitive decline, with executive deficits appearing before memory impairment. CSF and plasma NfL emerge as the earliest biological signals of this cascade, supporting their role as surrogate biomarkers in neuroprotective trials.

Table 1: DEBM Event Sequence: Primary Analysis

Table 2: DEBM Event Sequence: CSF Subsample

Figure 1: Mean event positions with 95% CI

References: 1. Aarsland D, Batzu L, Halliday GM, et al. Parkinson disease-associated cognitive impairment. Nat Rev Dis Primers. 2021;7(1):47. doi:10.1038/s41572-021-00280-3

2. Yarnall AJ, Breen DP, Duncan GW, et al. Characterizing mild cognitive impairment in incident Parkinson disease: the ICICLE-PD study. Neurology. 2014;82(4):308-316. doi:10.1212/WNL.0000000000000066

3. Venkatraghavan V, Bron EE, Niessen WJ, Klein S. Disease progression timeline estimation for Alzheimer’s disease using discriminative event based modeling. NeuroImage. 2019;186:518-532. doi:10.1016/j.neuroimage.2018.11.024

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MDS Abstracts - https://www.mdsabstracts.org/abstract/temporal-ordering-of-biomarker-abnormality-events-leading-to-cognitive-impairment-in-parkinsons-disease-a-disease-event-based-model-analysis-of-the-ppmi-cohort/