Plasma biomarkers of neurodegeneration in patients with Parkinson’s disease and dementia with Lewy bodies and at-risk individuals of Lewy body disease in the NaT-PROBE cohort

Abstract

ABSTRACTBackgroundComorbid Alzheimer’s disease (AD) neuropathology is common in Lewy body disease (LBD); however, AD comorbidity in the prodromal phase of LBD remains unclarified. This study investigated AD comorbidity in the prodromal and symptomatic phases of LBD by analysing plasma biomarkers in patients with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) and at-risk individuals of LBD (NaT-PROBE cohort).MethodsPatients 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.Resultsp-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.ConclusionsThe 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 prodromal phase of LBD.What is already known on this topicComorbid Alzheimer’s disease (AD) neuropathology is common in Parkinson’s disease (PD) dementia and dementia with Lewy bodies (DLB); however, AD comorbidity in the prodromal phase of Lewy body disease (LBD) is yet to be clarified.What this study addsFour plasma biomarkers (amyloid-beta (Aβ) composite, phosphorylated tau 181 (p-tau181), neurofilament light chain (NfL), and alpha-synuclein (aSyn)) were measured in patients with PD and DLB and high– and low-risk individuals with ≥2 and without LBD prodromal symptoms. Increased plasma levels of p-tau181 indicated AD comorbidity in patients with PD and DLB, while no elevation of AD-related biomarkers was found in the high-risk individuals. Plasma NfL levels were higher in the high-risk, PD, and DLB groups than in the low-risk group and were associated with a higher rate of abnormalities in metaiodobenzylguanidine (MIBG) scintigraphy in the high-risk group.How this study might affect research, practice or policyThis study demonstrated that comorbid AD neuropathology exists in the symptomatic phase of LBD, though not in its prodromal phase. Plasma p-tau181 may be more sensitive for detecting comorbid AD neuropathology than plasma Aβ composite. Elevated plasma NfL levels may indicate aSyn-induced neurodegeneration in the prodromal phase of LBD.