Objective: To assess the synergy between neuroimaging deficits and plasma biomarkers in predicting longitudinal cognitive and motor progression in individuals at high risk for prodromal Lewy body disease (LBD).

Background: Identifying “fast progressors” is vital for prodromal LBD trials. While imaging (dopamine transporter [DaT] imaging and cardiac metaiodobenzylguanidine [MIBG] scintigraphy) and plasma biomarkers (neurofilament light chain [NfL], amyloid/tau) are individual predictors, their combined impact on longitudinal progression remains unclear.

Method: NaT-PROBE enrolled community-dwelling adults (≥50 years). High-risk status was determined by multiple prodromal symptoms (dysautonomia, hyposmia, or REM sleep behavior disorder) via questionnaires. We analyzed longitudinal data from 88 high-risk individuals (mean age 64.5 [7.5] years, follow-up: 4.0 [1.8] years) with baseline DaT and MIBG imaging. Plasma amyloid-beta composite, phosphorylated tau 181 (p-tau181), and NfL were measured using immunoprecipitation-mass spectrometry and single-molecule array platforms. Imaging-positive (Im+) status was defined as a deficit on DaT or MIBG. The main clinical measures were longitudinal MoCA-J and MDS-UPDRS III changes. Linear mixed-effects models tested the three-way interaction between imaging status, plasma biomarkers, and time, adjusting for age and sex.

Results: Thirty-five participants (39.8%) were Im+. A significant three-way interaction was found for MoCA-J decline (β = -0.684, p = 0.006); within the Im+ group, high NfL (n = 20) showed markedly accelerated deterioration compared to low NfL (n = 15). In the dual-positive subgroup (n = 7; both DaT and MIBG deficits), 85.7% (n = 6) had high NfL and exhibited the steepest decline. Exploratory analyses for Alzheimer’s disease pathology suggested a further synergistic impact, particularly in individuals with high p-tau181 levels, despite limited sample size. No significant synergy was observed for MDS-UPDRS III, suggesting plasma NfL is more closely linked to cognitive than motor progression in this pre-diagnostic phase.

Conclusion: Plasma NfL significantly amplifies cognitive decline in the presence of neuroimaging deficits in prodromal LBD. This multimodal approach provides a robust framework for identifying fast progressors in pre-diagnostic clinical trials.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/synergistic-impact-of-plasma-neurofilament-light-chain-and-neuroimaging-deficits-on-cognitive-decline-in-prodromal-lewy-body-disease/