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. 2018 Aug 28;91(9):e867-e877.
doi: 10.1212/WNL.0000000000006082. Epub 2018 Jul 27.

CSF Biomarkers of Neuroinflammation and Cerebrovascular Dysfunction in Early Alzheimer Disease

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Free PMC article

CSF Biomarkers of Neuroinflammation and Cerebrovascular Dysfunction in Early Alzheimer Disease

Shorena Janelidze et al. Neurology. .
Free PMC article

Abstract

Objective: To measure CSF levels of biomarkers reflecting microglia and astrocytes activation, neuroinflammation, and cerebrovascular changes and study their associations with the core biomarkers of Alzheimer disease (AD) pathology (β-amyloid [Aβ] and tau), structural imaging correlates, and clinical disease progression over time.

Methods: The study included cognitively unimpaired elderly (n = 508), patients with mild cognitive impairment (MCI, n = 256), and patients with AD dementia (n = 57) from the longitudinal Swedish BioFINDER cohort. CSF samples were analyzed for YKL-40, interleukin (IL)-6, IL-7, IL-8, IL-15, IP-10, monocyte chemoattractant protein 1, intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), placental growth factor, and fms-related tyrosine kinase 1 (Flt-1). MRI data were available from 677 study participants. Longitudinal clinical assessments were conducted in control individuals and patients with MCI (mean follow-up 3 years, range 1-6 years).

Results: CSF levels of YKL-40, ICAM-1, VCAM-1, IL-15, and Flt-1 were increased during the preclinical, prodromal, and dementia stages of AD. High levels of these biomarkers were associated with increased CSF levels of total tau, with the associations, especially for YKL-40, being stronger in Aβ-positive individuals. The results were similar for associations between phosphorylated tau and YKL-40, ICAM-1, and VCAM-1. High levels of the biomarkers were also associated with cortical thinning (primarily in the precuneus and superior parietal regions) and with subsequent cognitive deterioration in patients without dementia as measured with Mini-Mental State Examination (YKL-40) and Clinical Dementia Rating Sum of Boxes (YKL-40, ICAM-1, VCAM-1 and IL-15). Finally, higher levels of CSF YKL-40, ICAM-1, and Flt-1 increased risk of development of AD dementia in patients without dementia.

Conclusions: Neuroinflammation and cerebrovascular dysfunction are early events occurring already at presymptomatic stages of AD and contribute to disease progression.

Figures

Figure 1
Figure 1. CSF biomarkers of neuroinflammation and cerebrovascular changes in diagnostic groups
CSF levels of YKL-40 (A), intercellular adhesion molecule 1 (ICAM-1) (B), vascular adhesion molecule 1 (VCAM-1) (C), interleukin-15 (IL-15) (D), and fms-related tyrosine kinase 1 (Flt-1) (E) in cognitively unimpaired controls and patients with mild cognitive impairment (MCI) with normal (Ctrl–β-amyloid (Aβ)−, MCI–Aβ−, Aβ42/Aβ40 >0.1) and pathologic (Ctrl–Aβ+, MCI–Aβ+, Aβ42/Aβ40 ≤0.1) CSF Aβ status and patients with Alzheimer disease (AD) dementia. For comparison, CSF levels of total tau in the same diagnostic groups are shown in (F). The dotted lines indicate median levels in the Ctrl-Aβ− group. p Values are from one-way analysis of variance; statistical significance was set to p < 0.0071 (0.05/7) to account for Bonferroni correction. The significant findings were very similar when adjusting for the covariates (age, sex, APOE ε4 genotype, and anti-inflammatory medications), with the exception of ICAM-1, for which there were no differences between the groups with pathologic CSF Aβ status (Ctrl–Aβ+, MCI–Aβ+, and AD dementia).
Figure 2
Figure 2. CSF biomarkers of neuroinflammation and cerebrovascular changes, CSF tau, and cortical atrophy
(A, B) Association between CSF YKL-40 and total tau (t-tau) and CSF YKL-40 and phosphorylated tau (p-tau), respectively, in study participants with normal (β-amyloid [Aβ]−) and pathologic (Aβ+) CSF status. Unstandardized B coefficients and p values for slopes are from linear regression models. The results were very similar when adjusting for the covariates (age, sex, APOE ε4 genotype, and anti-inflammatory medications). (C) Associations between YKL-40 and cortical thickness. Voxel-wise regression analysis corrected for age, sex, and APOE ε4.
Figure 3
Figure 3. CSF biomarkers of neuroinflammation and cerebrovascular changes and progression to Alzheimer disease (AD)
Kaplan-Meier curves of progression from cognitively normal and mild cognitive impairment (MCI) to AD for tertiles of YKL-40 (A), intercellular adhesion molecule 1 (ICAM-1) (B), and fms-related tyrosine kinase 1 (Flt-1) (C).

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