Integrated metabolomics and proteomics from voxelated cortical hemispheres of adult rhesus monkeys

Product:

CNS Disease Panel 120

Topic:

Neurology

Disease Area:

Alzheimer's Disease

Sample Type:

NHP-CSF

Topic/Product:

CNS Disease Panel 120

Disease Area:

Alzheimer's Disease

Sample Type:

NHP-CSF

Abstract

The spatial organization of molecular networks across cortex likely contributes to differences in local circuit vulnerability in aging and Alzheimer’s disease; yet many existing molecular datasets sacrifice spatial structure, sampling only a handful of regions per brain. Here, we present a framework for generating spatially registered, paired metabolomic and proteomic maps across an entire cortical hemisphere of an adult rhesus monkey, at millimeter resolution. One hemisphere each from two animals was harvested under controlled conditions, approximately flattened, and hand dissected at different sampling resolutions (roughly 2.5 and 4 mm/side) into tissue voxels. Each voxel was split after homogenization and extraction to provide matched aliquots for targeted metabolomics and deep untargeted proteomics. To handle these high dimensional data, we developed PChclust, a principal component guided feature clustering algorithm. For cross omic integration, we developed a spatially regularized sparse canonical correlation analysis (sr-sCCA), which incorporates spatial neighborhood structure via graph Laplacian smoothing. We recover meaningful biology: Molecular similarity between neighboring voxels decayed with distance in both modalities, confirming that voxelation captures spatially organized biological variance. The sr-sCCA identified joint proteome-metabolome components with coherent cortical gradients that were conserved across animals. Pathway enrichment analysis recovered brain relevant ontologies and reconstructed complete metabolic circuits from single voxels.

Authors & Affiliations

Qiuyi Wu², Alev M. Brigande¹, Michael W. Lutz³, Pixu Shi², and Anita A. Disney¹

¹ Department of Neurobiology, Duke University, Durham, NC 27710, USA
² Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710, USA
³ Department of Neurology, Duke University, Durham, NC 27710, 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.