Elevated Soluble TNF-Receptor 1 in the Serum of Predementia Subjects with Cerebral Small Vessel Disease

Kaung H T Salai; Liu-Yun Wu; Joyce R Chong; Yuek Ling Chai; Bibek Gyanwali; Caroline Robert; Saima Hilal; Narayanaswamy Venketasubramanian; Gavin S Dawe; Christopher P Chen; Mitchell K P Lai

doi:10.3390/biom13030525

Elevated Soluble TNF-Receptor 1 in the Serum of Predementia Subjects with Cerebral Small Vessel Disease

Biomolecules. 2023 Mar 13;13(3):525. doi: 10.3390/biom13030525.

Authors

Kaung H T Salai^{1

2}, Liu-Yun Wu^{1

3}, Joyce R Chong^{1

3}, Yuek Ling Chai^{1

3}, Bibek Gyanwali^{1

3}, Caroline Robert¹, Saima Hilal^{1

3

4

5}, Narayanaswamy Venketasubramanian⁶, Gavin S Dawe^{1

2

7

8}, Christopher P Chen^{1

2

3}, Mitchell K P Lai^{1

2

3}

Affiliations

¹ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
² Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore.
³ Memory Aging and Cognition Centre, National University Health System, Singapore 117600, Singapore.
⁴ Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore.
⁵ Departments of Epidemiology and Radiology & Nuclear Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.
⁶ Raffles Neuroscience Centre, Raffles Hospital, Singapore 188770, Singapore.
⁷ Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore.
⁸ Neurobiology Programme, Life Sciences Institute, Centre for Life Sciences, National University of Singapore, Singapore 117456, Singapore.

Abstract

Tumor necrosis factor-receptor 1 (TNF-R1)-mediated signaling is critical to the regulation of inflammatory responses. TNF-R1 can be proteolytically released into systemic blood circulation in a soluble form (sTNF-R1), where it binds to circulating TNF and functions to attenuate TNF-mediated inflammation. Increases of peripheral sTNF-R1 have been reported in both Alzheimer's disease (AD) dementia and vascular dementia (VaD). However, the status of sTNF-R1 in predementia subjects (cognitive impairment, no dementia, CIND) is unknown, and putative associations with cerebral small vessel disease (CSVD), as well as with longitudinal changes in cognitive functions are unclear. We measured baseline serum sTNF-R1 in a longitudinally assessed cohort of 93 controls and 103 CIND, along with neuropsychological evaluations and neuroimaging assessments. Serum sTNF-R1 levels were increased in CIND compared with controls (p < 0.001). Higher baseline sTNF-R1 levels were specifically associated with lacunar infarcts (rate ratio = 6.91, 95% CI 3.19-14.96, p < 0.001), as well as lower rates of cognitive decline in the CIND subgroup. Our data suggest that sTNF-R1 interacts with vascular cognitive impairment in a complex manner at predementia stages, with elevated levels associated with more severe CSVD at baseline, but which may subsequently be protective against cognitive decline.

Keywords: Alzheimer’s disease; TNF-receptor 1; biomarker; cerebral small vessel diseases; predementia; serum; tumor necrosis factor; vascular cognitive impairment.

Publication types

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

MeSH terms

Cerebral Small Vessel Diseases*
Humans
Receptors, Tumor Necrosis Factor
Receptors, Tumor Necrosis Factor, Type I*
Tumor Necrosis Factor-alpha / metabolism

Substances

Receptors, Tumor Necrosis Factor, Type I
Receptors, Tumor Necrosis Factor
Tumor Necrosis Factor-alpha

Grants and funding

This work was funded by the Singapore National Medical Research Council (grants MOH-000500-01, MOH-000707-01 and MOH-001086-00), the Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine (grant HLTRP/2022/PS-01) and the National University Health System (grant A-0006090-00-00). Y.L.C. is a recipient of a post-doctoral fellowship award from the Yong Loo Lin School of Medicine (NUSMED/2021/PDF/05). Research in the laboratory of G.S.D. is supported by the Singapore Ministry of Education (grant MOE2017-T3-1-002).