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

Abstract

Backgroundand ObjectivesSmall 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.MethodsIndividuals 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.Results495 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<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.DiscussionMost 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.

Hope for vascular cognitive impairment: Ac-YVAD-cmk as a novel treatment against white matter rarefaction

“…Previous studies showed that inflammation is significantly associated with white matter dysfunction before [ 78 ] and during VCI [ 79 ], suggesting that inflammation plays an early important role in the etiology of white matter dysfunction [ 80 ]. Indeed, the NLRP3 and AIM2 inflammasomes were found to be activated in the brains of BCAS-operated mice [ 47 , 81 ], but it remained unclear whether modulating the activity of their common mediator caspase-1 may be beneficial.…”

Soluble Biomarkers of Cerebrovascular Pathologies

“…Another study also showed that increased levels of plasma PLGF indicated increased white matter lesions, regardless of cognitive status or Aβ presence. 88 It is thought that PLGF could not only serve as a sensitive and specific biomarker of cerebrovascular injury but also provide us with mechanistic avenues to explore for VCID. This is being explored by several groups currently.…”

“…Another study also showed that increased levels of plasma PLGF indicated increased white matter lesions, regardless of cognitive status or Aβ presence. 88…”

Implications of Inflammatory Processes on a Developing Central Nervous System in Childhood‐Onset Systemic Lupus Erythematosus

“…Outside of cSLE, prior work has revealed that inflammatory states are associated with cognitive dysfunction and depressed mood. 10 Therefore, bidirectional interactions between disease activity or inflammatory status with neurocognitive deficits or potent emotional states should be expected in cSLE. Although a greater genetic susceptibility may independently yield an overall more progressive disease status in cSLE versus adult-onset SLE patient populations, what remains largely unclear are the neuropathological mechanisms associated with more severe presentation of neuropsychiatric symptoms and the poorer long-term prognosis in patients with cSLE.…”

“…Outside of cSLE, prior work has revealed that inflammatory states are associated with cognitive dysfunction and depressed mood 10 . Therefore, bidirectional interactions between disease activity or inflammatory status with neurocognitive deficits or potent emotional states should be expected in cSLE.…”