Plasma neurofilament light chain and amyloid-β are associated with the kynurenine pathway metabolites in preclinical Alzheimer's disease.

Chatterjee P1,2, Zetterberg H3,4,5,6, Goozee K1,2,7,8,9, Lim CK1, Jacobs KR1, Ashton NJ3,10,11,12, Hye A10,11, Pedrini S2, Sohrabi HR1,2,7,13, Shah T1,2,13, Asih PR1, Dave P1,8, Shen K14, Taddei K2,13, Lovejoy DB1, Guillemin GJ1, Blennow K3,4, Martins RN15,16,17,18,19,20,21.

Author information

1: Department of Biomedical Sciences, Macquarie University, North Ryde, NSW, Australia.
2: School of Medical Health and Sciences, Edith Cowan University, Joondalup, WA, Australia.
3: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden.
4: Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
5: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
6: UK Dementia Research Institute at UCL, London, UK.
7: KaRa Institute of Neurological Disease, Sydney, Macquarie Park, NSW, Australia.
8: Clinical Research Department, Anglicare, Sydney, Castle Hill, NSW, Australia.
9: School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia.
10: Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, King's College London, London, UK.
11: NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia, South London and Maudsley NHS Foundation, London, UK.
12: Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
13: Australian Alzheimer's Research Foundation, Nedlands, WA, Australia.
14: Australian eHealth Research Centre, CSIRO, Floreat, WA, Australia.
15: Department of Biomedical Sciences, Macquarie University, North Ryde, NSW, Australia. r.martins@ecu.edu.au.
16: School of Medical Health and Sciences, Edith Cowan University, Joondalup, WA, Australia. r.martins@ecu.edu.au.
17: KaRa Institute of Neurological Disease, Sydney, Macquarie Park, NSW, Australia. r.martins@ecu.edu.au.
18: School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia. r.martins@ecu.edu.au.
19: Australian Alzheimer's Research Foundation, Nedlands, WA, Australia. r.martins@ecu.edu.au.
20: The Cooperative Research Centre for Mental Health, Carlton South, VIC, Australia. r.martins@ecu.edu.au.
21: School of Medical and Health Sciences, Edith Cowan University, Ralph & Patricia Sarich Neuroscience Research Institute, 8 Verdun Street, Nedlands, WA, 6009, Australia. r.martins@ecu.edu.au.

Abstract

BACKGROUND:

Blood markers indicative of neurodegeneration (neurofilament light chain; NFL), Alzheimer's disease amyloid pathology (amyloid-β; Aβ), and neuroinflammation (kynurenine pathway; KP metabolites) have been investigated independently in neurodegenerative diseases. However, the association of these markers of neurodegeneration and AD pathology with neuroinflammation has not been investigated previously. Therefore, the current study examined whether NFL and Aβ correlate with KP metabolites in elderly individuals to provide insight on the association between blood indicators of neurodegeneration and neuroinflammation.

METHODS:

Correlations between KP metabolites, measured using liquid chromatography and gas chromatography coupled with mass spectrometry, and plasma NFL and Aβ concentrations, measured using single molecule array (Simoa) assays, were investigated in elderly individuals aged 65-90 years, with normal global cognition (Mini-Mental State Examination Score ≥ 26) from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort.

RESULTS:

A positive correlation between NFL and the kynurenine to tryptophan ratio (K/T) reflecting indoleamine 2,3-dioxygenase activity was observed (r = .451, p < .0001). Positive correlations were also observed between NFL and kynurenine (r = .364, p < .0005), kynurenic acid (r = .384, p < .0001), 3-hydroxykynurenine (r = .246, p = .014), anthranilic acid (r = .311, p = .002), and quinolinic acid (r = .296, p = .003). Further, significant associations were observed between plasma Aβ40 and the K/T (r = .375, p < .0005), kynurenine (r = .374, p < .0005), kynurenic acid (r = .352, p < .0005), anthranilic acid (r = .381, p < .0005), and quinolinic acid (r = .352, p < .0005). Significant associations were also observed between plasma Aβ42 and the K/T ratio (r = .215, p = .034), kynurenic acid (r = .214, p = .035), anthranilic acid (r = .278, p = .006), and quinolinic acid (r = .224, p = .027) in the cohort. On stratifying participants based on their neocortical Aβ load (NAL) status, NFL correlated with KP metabolites irrespective of NAL status; however, associations between plasma Aβ and KP metabolites were only pronounced in individuals with high NAL while associations in individuals with low NAL were nearly absent.

CONCLUSIONS:

The current study shows that KP metabolite changes are associated with biomarker evidence of neurodegeneration. Additionally, the association between KP metabolites and plasma Aβ seems to be NAL status dependent. Finally, the current study suggests that an association between neurodegeneration and neuroinflammation manifests in the periphery, suggesting that preventing cytoskeleton cytotoxicity by KP metabolites may have therapeutic potential.

KEYWORDS:

Alzheimer’s disease; Amyloid-beta; Blood amyloid-beta; Blood markers; Brain amyloid-beta; Kynurenine pathway; Neurodegeneration; Neurofilament light chain; Neuroinflammation