Plasma biomarkers of neurodegeneration in patients and high risk subjects with Lewy body disease

Abstract

Comorbid Alzheimer's disease (AD) neuropathology is common in Lewy body disease (LBD); however, AD comorbidity in the prodromal phase of LBD remains unclear. This study investigated AD comorbidity in the prodromal and symptomatic phases of LBD by analyzing plasma biomarkers in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and individuals at risk of LBD (NaT-PROBE cohort). Patients with PD (PD group, n = 84) and DLB (DLB group, n = 16) and individuals with LBD with ≥ 2 (high-risk group, n = 82) and without (low-risk group, n = 37) prodromal symptoms were enrolled. Plasma amyloid-beta (Aβ) composite was measured using immunoprecipitation-mass spectrometry assays. Plasma phosphorylated tau 181 (p-tau181), neurofilament light chain (NfL), and alpha-synuclein (aSyn) were measured using a single-molecule array. Plasma p-tau181 levels were higher in the PD and DLB groups than in the low-risk group. Aβ composite level was higher in the DLB group than in the high-risk group. AD-related biomarker levels were not elevated in the high-risk group. NfL levels were higher in the high-risk, PD, and DLB groups than in the low-risk group. In the PD group, Aβ composite was associated with cognitive function, p-tau181 with motor function and non-motor symptoms, and NfL with cognitive and motor functions and non-motor symptoms. In the high-risk group, NfL was associated with metaiodobenzylguanidine scintigraphy abnormalities. The PD and DLB groups exhibited comorbid AD neuropathology, though not in the prodromal phase. Elevated plasma NfL levels, even without elevated AD-related plasma biomarker levels, may indicate aSyn-induced neurodegeneration in the LBD prodromal phase.

Fig. 1. Levels of plasma biomarkers across diagnostic groups.

Levels of Aβ composite (a), p-tau181 (b), NfL (c), and aSyn/Hb (d) are plotted with individual values and boxplots across diagnostic groups. Analysis of covariance (ANCOVA) adjusted for age and sex is used to determine p values visualized with ***p < 0.001, **p < 0.01, *p < 0.05. Aβ composite, a combination biomarker of amyloid-beta precursor protein (APP)_669-711/amyloid-beta (Aβ)_1-42 and Aβ_1-40/Aβ_1-42 ratios, p-tau181 phosphorylated tau 181, NfL neurofilament light chain, aSyn/Hb alpha-synuclein/hemoglobin ratio, LR low-risk, HR high-risk, PD Parkinson’s disease, DLB dementia with Lewy bodies.

Fig. 2. Age-adjusted partial correlation between plasma biomarkers.

Age-adjusted Pearson’s partial correlation test among the plasma biomarkers in the low-risk group (a–c), high-risk group (d–f), Parkinson’s disease group (g–i), and dementia with Lewy bodies group (j–l). Cut-off values for Aβ composite, log₁₀ (p-tau181), and log₁₀ (NfL) are indicated by dotted lines (Aβ composite, 0.376; log₁₀ [p-tau181], 0.374; log₁₀ [NfL], 1.65). Aβ composite, combination biomarker of amyloid-beta precursor protein (APP)_669-711/amyloid-beta (Aβ)_1-42 and Aβ_1-40/Aβ_1-42 ratios; p-tau181, phosphorylated tau 181; NfL neurofilament light chain, aSyn/Hb alpha-synuclein/hemoglobin ratio.

Fig. 3. Subgroup analysis of plasma biomarkers by cognitive function in the Parkinson’s disease group.

Levels of four plasma biomarkers (Aβ composite (a), p-tau181 (b), NfL (c), and aSyn/Hb (d)) are plotted with individual values and boxplots across diagnostic groups. The patients with PD with MoCA-J ≥ 26 and <26 are classified as cognitively normal (PD-CN) and cognitively impaired (PD-CI), respectively. Analysis of covariance (ANCOVA) adjusted for age and sex is used to determine p values visualized with ***p < 0.001, **p < 0.01, *p < 0.05. Aβ composite combination biomarker of amyloid-beta precursor protein (APP)_669-711/amyloid-beta (Aβ)_1-42 and Aβ_1-40/Aβ_1-42 ratios, p-tau181 phosphorylated tau 181, NfL neurofilament light chain, aSyn/Hb alpha-synuclein/hemoglobin ratio, PD Parkinson’s disease, MoCA-J the Japanese version of the Montreal Cognitive Assessment.