Presymptomatic Dutch-type hereditary cerebral amyloid angiopathy related blood metabolite alterations

Pratishtha Chatterjee, Anne M. Fagan, Chengjie Xiong, Matthew McKay, Atul Bhatnagar, Yunqi Wu, Abhay K. Singh, Kevin Taddei, Ian Martins, Samantha L. Gardener, Mark P. Molloy, Gerhard Multhaup, Colin L. Masters, Peter R. Schofield, Tammie L. S. Benzinger, John C. Morris, Randall J. Bateman, Steven M. Greenberg, Marieke J. H. Wermer, Mark A. van Buchem & 3 others Hamid Sohrabi, Ralph N. Martins*, Dominantly Inherited Alzheimer Network (DIAN)

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Background: Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers.

Objective: Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs).

Methods: Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n = 9) and non-carriers (D-CAA NCs, n = 8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults).

Results: 275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in theD-CAAMCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ε4 (p < 00.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in th eD-CAAMCs compared to the D-CAA NCs (p < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidine was also observed to correlate with CSF Aβ40 (rs = 0.621, p = 0.024), CSF Aβ42 (rs = 0.714, p = 0.006), and brain Aβ load (rs = -0.527, p = 0.030).

Conclusion: The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aβ neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia.

Original languageEnglish
Article number20-1267
Pages (from-to)895-903
Number of pages9
JournalJournal of Alzheimer's Disease
Volume79
Issue number2
Early online date24 Dec 2020
DOIs
Publication statusPublished - 19 Jan 2021

Keywords

  • Blood biomarkers
  • cerebral amyloid angiopathy
  • early diagnosis
  • hereditary cerebral hemorrhage with amyloidosis - Dutch type
  • intracerebral hemorrhage
  • metabolomics
  • vascular dementia

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