Quantitative Lipidomic Analysis of Serum Phospholipids Reveals Dissociable Markers of Alzheimer’s Disease and Subcortical Cerebrovascular Disease

Article type: Research Article

Authors: Otoki, Yurika^{a; b; 1} | Yu, Di^{c; d; e; f; 1} | Shen, Qing^a | Sahlas, Demetrios J.^g | Ramirez, Joel^c | Gao, Fuqiang^c | Masellis, Mario^{c; j} | Swartz, Richard H.^{c; h} | Chan, Pak Cheung^{h; i} | Pettersen, Jacqueline A.^j | Kato, Shunji^b | Nakagawa, Kiyotaka^b | Black, Sandra E.^{c; e; f; k} | Swardfager, Walter^{c; d; e; f; l} | Taha, Ameer Y.^{a; m; n; *}

Affiliations: [a] Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California, Davis, CA, USA | [b] Laboratory of Food Function Analysis, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan | [c] Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Canada | [d] Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada | [e] Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Canada | [f] LC Campbell Cognitive Neurology Unit, Sunnybrook Research Institute, Toronto, Canada | [g] Department of Medicine (Neurology Division), McMaster University, Hamilton, Canada | [h] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada | [i] Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Canada | [j] Department of Medicine (Neurology Division) and the Northern Medical Program, University of British Columbia, Vancouver, Canada | [k] Department of Medicine (Neurology Division), University of Toronto, Toronto, Canada | [l] University Health Network Toronto Rehabilitation Institute, Toronto, Canada | [m] West Coast Metabolomics Center, Genome Center, University of California - Davis, Davis, CA, USA | [n] Center for Neuroscience, University of California - Davis, Davis, CA, USA

Correspondence: [*] Correspondence to: Ameer Y. Taha, Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California Davis, One Shields Avenue, Davis, CA 95616, USA. Tel.: +1 530 752 7096; E-mail: ataha@ucdavis.edu.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Circulating phospholipid species have been shown to predict Alzheimer’s disease (AD) prognosis but the link between phospholipid disturbances and subcortical small vessel cerebrovascular disease (CeVD) common in AD patients is not known. Objective:Mass-spectrometry lipidomics was applied to quantify serum diacyl, alkenyl (ether), alkyl, and lyso phospholipid species in individuals with extensive CeVD (n = 29), AD with minimal CeVD (n = 16), and AD with extensive CeVD (n = 14), and compared them to age-matched controls (n = 27). Memory was assessed using the California Verbal Learning Test. 3.0T MRI was used to assess hippocampal volume, atrophy, and white matter hyperintensity (WMH) volumes as manifestations of CeVD. Results:AD was associated with significantly higher concentrations of choline plasmalogen 18:0_18:1 and alkyl-phosphocholine 18:1. CeVD was associated with significantly lower lysophospholipids containing 16:0. Phospholipids containing arachidonic acid (AA) were associated with poorer memory in controls, whereas docosahexaenoic acid (DHA)-containing phospholipids were associated with better memory in individuals with AD+CeVD. In controls, DHA-containing phospholipids were associated with more atrophy, and phospholipids containing linoleic acid and AA were associated with less atrophy. Lysophospholipids containing 16:0, 18:0, and 18:1 were correlated with less atrophy in controls, and of these, alkyl-phosphocholine 18:1 was correlated with smaller WMH volumes. Conversely, 16:0_18:1 choline plasmalogen was correlated with greater WMH volumes in controls. Conclusion:This study demonstrates discernable differences in circulating phospholipids in individuals with AD and CeVD, as well as new associations between phospholipid species with memory and brain structure that were specific to contexts of commonly comorbid vascular and neurodegenerative pathologies.

Keywords: Alkylphospholipids, Alzheimer’s disease, lysophospholipid, plasmalogens, small vessel disease, vascular cognitive impairment, white matter hyperintensity

DOI: 10.3233/JAD-220795

Journal: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 665-682, 2023