Plasma metabolites distinguish dementia with Lewy bodies from Alzheimer's disease: a cross-sectional metabolomic analysis

Xiaobei Pan; Paul C Donaghy; Gemma Roberts; Leonidas Chouliaras; John T O'Brien; Alan J Thomas; Amanda J Heslegrave; Henrik Zetterberg; Bernadette McGuinness; Anthony P Passmore; Brian D Green; Joseph P M Kane

doi:10.3389/fnagi.2023.1326780

Plasma metabolites distinguish dementia with Lewy bodies from Alzheimer's disease: a cross-sectional metabolomic analysis

Front Aging Neurosci. 2024 Jan 4:15:1326780. doi: 10.3389/fnagi.2023.1326780. eCollection 2023.

Authors

Xiaobei Pan¹, Paul C Donaghy², Gemma Roberts², Leonidas Chouliaras³, John T O'Brien³, Alan J Thomas², Amanda J Heslegrave^{4

5}, Henrik Zetterberg^{4

5

6

7

8

9}, Bernadette McGuinness¹⁰, Anthony P Passmore¹⁰, Brian D Green¹, Joseph P M Kane¹⁰

Affiliations

¹ School of Biological Sciences, Queen's University Belfast, Belfast, United Kingdom.
² Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
³ Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.
⁴ Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, United Kingdom.
⁵ Dementia Research Institute, UCL, London, United Kingdom.
⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁷ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁸ Hong Kong Center for Neurodegenerative Diseases, Kowloon, Hong Kong SAR, China.
⁹ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.
¹⁰ Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom.

Abstract

Background: In multifactorial diseases, alterations in the concentration of metabolites can identify novel pathological mechanisms at the intersection between genetic and environmental influences. This study aimed to profile the plasma metabolome of patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), two neurodegenerative disorders for which our understanding of the pathophysiology is incomplete. In the clinical setting, DLB is often mistaken for AD, highlighting a need for accurate diagnostic biomarkers. We therefore also aimed to determine the overlapping and differentiating metabolite patterns associated with each and establish whether identification of these patterns could be leveraged as biomarkers to support clinical diagnosis.

Methods: A panel of 630 metabolites (Biocrates MxP Quant 500) and a further 232 metabolism indicators (biologically informative sums and ratios calculated from measured metabolites, each indicative for a specific pathway or synthesis; MetaboINDICATOR) were analyzed in plasma from patients with probable DLB (n = 15; age 77.6 ± 8.2 years), probable AD (n = 15; 76.1 ± 6.4 years), and age-matched cognitively healthy controls (HC; n = 15; 75.2 ± 6.9 years). Metabolites were quantified using a reversed-phase ultra-performance liquid chromatography column and triple-quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode, or by using flow injection analysis in MRM mode. Data underwent multivariate (PCA analysis), univariate and receiving operator characteristic (ROC) analysis. Metabolite data were also correlated (Spearman r) with the collected clinical neuroimaging and protein biomarker data.

Results: The PCA plot separated DLB, AD and HC groups (R2 = 0.518, Q2 = 0.348). Significant alterations in 17 detected metabolite parameters were identified (q ≤ 0.05), including neurotransmitters, amino acids and glycerophospholipids. Glutamine (Glu; q = 0.045) concentrations and indicators of sphingomyelin hydroxylation (q = 0.039) distinguished AD and DLB, and these significantly correlated with semi-quantitative measurement of cardiac sympathetic denervation. The most promising biomarker differentiating AD from DLB was Glu:lysophosphatidylcholine (lysoPC a 24:0) ratio (AUC = 0.92; 95%CI 0.809-0.996; sensitivity = 0.90; specificity = 0.90).

Discussion: Several plasma metabolomic aberrations are shared by both DLB and AD, but a rise in plasma glutamine was specific to DLB. When measured against plasma lysoPC a C24:0, glutamine could differentiate DLB from AD, and the reproducibility of this biomarker should be investigated in larger cohorts.

Keywords: Alzheimer’s disease; Lewy body dementia; biomarkers; dementia; metabolomic analyses.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by an Alzheimer’s Research UK Northern Ireland Network grant and supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre. PD is supported by the Medical Research Council [grant number MR/W000229/1]. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022–01018 and #2019–02397), the European Union’s Horizon Europe research and innovation program under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809–2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Program – Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003).