The utility of a composite endpoint for tracking disease progression in Lewy body dementia

Abstract

Abstract INTRODUCTION Dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD), collectively termed Lewy body dementia (LBD), show heterogenous progression across cognitive, motor, and neuropsychiatric symptom domains, yet disease‐specific endpoints are lacking. We evaluated whether a composite clinical endpoint using validated scales across different symptom domains could sensitively track disease progression and align with functional and caregiver outcomes. METHODS One hundred sixteen participants (DLB = 72; PDD = 44) were assessed at baseline, 3, and 6 months in a cluster‐randomized trial comparing usual care versus management informed by an evidence‐based toolkit. The Lewy Body Symptom Severity (LBSS) index was constructed by summing rescaled Mini‐Mental State Examination, Movement Disorder Society Unified Parkinson's Disease Rating Scale (Part III), Dementia Cognitive Fluctuations Scale, and Neuropsychiatric Inventory 4‐item subscore (including hallucinations). Linear mixed‐effects models tested change over time. Validity was examined against caregiver Clinical Rating of Change (CRC), Bristol Activities of Daily Living (ADL) Scale, and caregiver Zarit Burden Interview. RESULTS Over 6 months, LBSS increased significantly ( β = 0.0307; P = 0.0006). Simulation‐based power analyses indicated greater statistical efficiency for LBSS than for any individual component. LBSS also detected a significant intervention effect ( P = 0.0365) not observed with single‐domain measures. LBSS correlated with caregiver burden (Zarit; ρ = 0.53, P < 0.001), functional dependence (Bristol ADL; ρ = 0.57, P < 0.001), and CRC ( ρ = −0.33, P = 0.002), permitting derivation of a minimal clinically important difference. DISCUSSION A simple composite spanning cognition, parkinsonism, cognitive fluctuations, and neuropsychiatric symptoms sensitively detected short‐interval progression, with improved statistical efficiency over single‐domain measures, and was aligned with functional/caregiver outcomes. These findings support composite endpoints for LBD trials and can inform the design of disease‐specific scales. Highlights A multidomain composite index detects 6‐month progression in Lewy body dementia. The composite shows greater statistical efficiency than individual domain measures. Composite change correlates with functional dependence and caregiver burden. Simulation‐based analyses estimate reduced sample sizes for longitudinal trials. A pragmatic framework is presented for multidomain endpoints in heterogeneous Lewy body dementia.