Associations Between CSF Markers of Inflammation, White Matter Lesions, and Cognitive Decline in Individuals Without Dementia

Abstract

<h3>Background</h3> and Objectives Small vessel disease (SVD) and neuroinflammation both occur in Alzheimer’s disease (AD), and other neurodegenerative diseases. It is unclear if these processes are related or independent mechanisms in AD, especially in the early stages of disease. We therefore investigated the association between white matter lesions (WML; the most common manifestation of SVD), and CSF biomarkers of neuroinflammation and their effects on cognition in a population without dementia. Methods Individuals without dementia from the Swedish BioFINDER study were included. CSF was analyzed for proinflammatory markers (interleukin [IL]–6, IL-8), cytokines (IL-7, IL-15, IL-16), chemokines (interferon-γ–induced protein 10 [IP-10], monocyte chemoattractant protein 1, markers of vascular injury (soluble intercellular adhesion molecule 1, soluble vascular adhesion molecule 1), and markers of angiogenesis (placental growth factor [PlGF], soluble fms-related tyrosine kinase 1 [sFlt-1], vascular endothelial growth factors [VEGF-A, and VEFG-D]), and Aβ42, Aβ40 and P-tau 217. WML volumes were determined at baseline and longitudinally over six years. Cognition was measured at baseline and follow-up over eight years. Linear regression models were used to test associations. Results 495 cognitively unimpaired (CU) elderly and 247 patients with mild cognitive impairment (MCI) were included. There was significant worsening in cognition over time, measured by MMSE, CDR and mPACC in CU and MCI, with more rapid worsening in MCI for all cognitive tests. At baseline, higher levels of PlGF (β=0.156, p&lt;0.001), lower levels of sFlt-1 (β=-0.086, p=0.003), and higher levels of IL-8 (β=0.07, p=0.030) were associated with more WML in CU. In MCI, higher levels of PlGF (β=0.172, p=0.001), IL-16 (β=0.125, p=0.001), IL-8 (β=0.096, p=0.013), IL-6 (β=0.088, p=0.023), VEGF-A (β=0.068, p=0.028), and VEGF-D (β=0.082, p=0.028) were associated with more WML. PlGF was the only biomarker that was associated with WML independent of Aβ status and cognitive impairment. Longitudinal analyses of cognition showed independent effects of CSF inflammatory markers and WML on longitudinal cognition, especially in people without cognitive impairment at baseline. Discussion Most neuroinflammatory CSF biomarkers were associated with WML in individuals without dementia. Our findings especially highlight a role for PlGF, which was associated with WML independent of Aβ status and cognitive impairment.

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