Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer's disease and relationship to amyloid-β and tau

Kelly R Jacobs; Chai K Lim; Kaj Blennow; Henrik Zetterberg; Pratishtha Chatterjee; Ralph N Martins; Bruce J Brew; Gilles J Guillemin; David B Lovejoy

doi:10.1016/j.neurobiolaging.2019.03.015

Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer's disease and relationship to amyloid-β and tau

Neurobiol Aging. 2019 Aug:80:11-20. doi: 10.1016/j.neurobiolaging.2019.03.015. Epub 2019 Apr 1.

Authors

Kelly R Jacobs¹, Chai K Lim¹, Kaj Blennow², Henrik Zetterberg³, Pratishtha Chatterjee⁴, Ralph N Martins⁵, Bruce J Brew⁶, Gilles J Guillemin⁷, David B Lovejoy⁸

Affiliations

¹ Department of Biomedical Sciences, Neuroinflammation Group, Centre for Motor Neuron Disease Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
² Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
³ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; UK Dementia Research Institute at University College London, London, UK; Department of Neurodegenerative Disease, University College London Institute of Neurology, Queen Square, London, UK.
⁴ Department of Biomedical Sciences, Macquarie University, North Ryde, New South Wales, Australia; School of Medical Health and Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.
⁵ Department of Biomedical Sciences, Macquarie University, North Ryde, New South Wales, Australia; School of Medical Health and Sciences, Edith Cowan University, Joondalup, Western Australia, Australia; KaRa Institute of Neurological Disease, Sydney, Macquarie Park, Australia; School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, Western Australia, Australia; Australian Alzheimer's Research Foundation, Nedlands, Western Australia, Australia; The Cooperative Research Centre for Mental Health, Carlton South, Australia.
⁶ Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent's Centre for Applied Medical Research Sydney, New South Wales, Australia; Faculty of Medicine, St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia; Departments of Neurology and Immunology, St. Vincent's Hospital, Sydney, New South Wales, Australia.
⁷ Department of Biomedical Sciences, Neuroinflammation Group, Centre for Motor Neuron Disease Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia. Electronic address: gilles.guillemin@mq.edu.au.
⁸ Department of Biomedical Sciences, Neuroinflammation Group, Centre for Motor Neuron Disease Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia. Electronic address: david.lovejoy@mq.edu.au.

PMID: 31055163
DOI: 10.1016/j.neurobiolaging.2019.03.015

Abstract

Chronic kynurenine pathway (KP) activation is implicated in Alzheimer's disease (AD) pathophysiology and results in quinolinic acid-induced excitotoxic stimulation of the N-methyl-D-aspartate receptor. However, most studies focus on plasma and it is unclear if peripheral concentrations reflect brain concentrations and how these may correlate to the AD biomarkers amyloid-β, total-tau (t-tau), or phosphorylated-tau (p-tau). We characterized the KP in matched plasma and cerebrospinal fluid (CSF) samples from 20 AD patients and 18 age-matched control subjects. Plasma concentrations of kynurenine (KYN), 3-hydroxykynurenine, anthranilic acid, picolinic acid, and neopterin significantly correlated with their respective CSF levels. In patients with AD, plasma KYN (r = -0.48, p = 0.033) and picolinic acid (r = -0.57, p = 0.009) inversely correlated with CSF p-tau and t-tau, respectively. Furthermore, in AD CSF, increased 3-hydroxykynurenine/KYN ratio correlated with t-tau (r = 0.58, p = 0.009) and p-tau (r = 0.52, p = 0.020). These data support KP involvement in AD pathogenesis and add to the case for the therapeutic modulation of the KP in AD.

Keywords: Alzheimer's disease; Amyloid-β; Cerebrospinal fluid; Disease biomarkers; Kynurenine pathway; Tau protein.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / etiology
Alzheimer Disease / metabolism*
Amyloid beta-Peptides / cerebrospinal fluid*
Female
Humans
Kynurenine / blood*
Kynurenine / cerebrospinal fluid*
Male
Signal Transduction
tau Proteins / cerebrospinal fluid*

Substances

Amyloid beta-Peptides
tau Proteins
Kynurenine