Multiplex Proteomics of Lewy Body Dementia Reveals Cerebrospinal Fluid Biomarkers of Disease Pathology and Progression

Product:

CNS Disease Panel 120

Topic:

Neurology

Disease Area:

Lewy Body Dementia, Parkinson's Disease

Sample Type:

CSF

Topic/Product:

CNS Disease Panel 120

Disease Area:

Lewy Body Dementia, Parkinson's Disease

Sample Type:

CSF

Abstract

Lewy body dementia (LBD), which encompasses Parkinson’s disease dementia (PDD) and Dementia with Lewy bodies (DLB), currently lacks established biofluid markers reflective of its complex molecular pathophysiology. Multiplex proteomic tools, such as the recently released NUcleic acid Linked ImmunoSandwich Assay (NULISATM), can simultaneously assess a diverse array of neurodegenerative targets and address this critical biomarker gap. We used the NULISA CNS disease panel to analyze 852 baseline and longitudinal cerebrospinal fluid (CSF) samples from control, PD without cognitive impairment (PD-NCI), PD with cognitive impairment (PDCI), DLB, and Alzheimer’s disease (AD) subjects. A subset of control and DLB cases also had alpha-synuclein seed amplification assay (αSyn-SAA) results. Of the 124 panel markers analyzed, nearly half (n=53) were significantly altered in PD-CI and/or DLB compared to controls. Of these LBD-associated targets, 12 demonstrated divergent abundance trends in AD. Alpha-synuclein (SNCA) as measured by NULISA did not change across clinical LBD diagnoses but was among proteins significantly altered in subgroup comparisons of SAA+ and SAA- cases. Longitudinal analysis revealed five proteins (NEFL, NRGN, CCL26, CRH, PGF) with baseline changes indicative of subsequent cognitive progression. Machine learning identified a series of panels, each comprising only 10 markers, capable of discriminating clinical diagnoses and SAA positivity with high accuracy (AUC > 0.89). Overall, our results highlight the utility of NULISA multiplex proteomic analysis in the identification of diagnostic and prognostic CSF biomarkers of LBD that reflect its diverse molecular pathophysiology.

Authors & Affiliations

Lenora Higginbotham1,2, Anantharaman Shantaraman1,3, Qi Guo1,3, Edward J. Fox1,3, Pritha Bagchi1,3, Fang Wu1,3, James J. Lah1,2, Allan I. Levey1,2, Nicholas T. Seyfried1,2,3*

Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA

Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition. He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.