Different pattern of CSF glial markers between dementia with Lewy bodies and Alzheimer's disease

Abstract

The role of innate immunity in dementia with Lewy bodies (DLB) has been little studied. We investigated the levels in cerebrospinal fluid (CSF) of glial proteins YKL-40, soluble TREM2 (sTREM2) and progranulin in DLB and their relationship with Alzheimer's disease (AD) biomarkers. We included patients with DLB (n = 37), prodromal DLB (prodDLB, n = 23), AD dementia (n = 50), prodromal AD (prodAD, n = 53), and cognitively normal subjects (CN, n = 44). We measured levels of YKL-40, sTREM2, progranulin, Aβ_1-42, total tau (t-tau) and phosphorylated tau (p-tau) in CSF. We stratified the group DLB according to the ratio t-tau/Aβ_1-42 (≥0.52, indicative of AD pathology) and the A/T classification. YKL-40, sTREM2 and progranulin levels did not differ between DLB groups and CN. YKL-40 levels were higher in AD and prodAD compared to CN and to DLB and prodDLB. Patients with DLB with a CSF profile suggestive of AD copathology had higher levels of YKL-40, but not sTREM2 or PGRN, than those without. T+ DLB patients had also higher YKL-40 levels than T-. Of these glial markers, only YKL-40 correlated with t-tau and p-tau in DLB and in prodDLB. In contrast, in prodAD, sTREM2 and PGRN also correlated with t-tau and p-tau. In conclusion, sTREM2 and PGRN are not increased in the CSF of DLB patients. YKL-40 is only increased in DLB patients with an AD biomarker profile, suggesting that the increase is driven by AD-related neurodegeneration. These data suggest a differential glial activation between DLB and AD.

Figure 1

Inflammation-related biomarkers across clinical diagnoses. *p < 0,05, **p < 0.01. The group-wise comparisons were analyzed by ANCOVA adjusting by age for all biomarkers and additionally for sex in the case of sTREM2. The p-values were adjusted by Bonferroni correction for multiple comparisons (10 comparisons). Thicker horizontal bars represent the mean while whiskers represent the standard deviation. CN: cognitively normal controls, DLB: Dementia with Lewy Bodies, prodDLB: prodromal DLB, AD: Alzheimer’s disease, prodAD: prodromal AD. (a) CSF YKL-40 levels in the different clinical groups. (b) CSF sTREM2 levels in the different clinical groups. (c) CSF PGRN levels in the different clinical groups.

Figure 2

Correlations between glial biomarkers. CN: cognitively normal controls, DLB: Dementia with Lewy Bodies, prodDLB: prodromal DLB, AD: Alzheimer’s disease, prodAD: prodromal AD. (a–c) Correlations between CSF sTREM2 and YKL-40, PGRN and YKL-40, and sTREM2 and PGRN levels in the different diagnostic groups, r and p-values of the partial correlation are shown in brackets (adjusted by age for all the biomarkers and additionally for sex in sTREM2).

Figure 3

Influence of AD copathology on CSF glial markers in DLB patients. *p-value < 0.05. **p-value = 0.009. Thicker horizontal bars represent the mean while whiskers represent the SD. CN: cognitively normal controls, DLB: Dementia with Lewy Bodies, Non AD-Sg: DLB patients with core CSF biomarkers non-suggestive of concomitant AD copathology (t-tau/Aβ_1–42 ratio < 0.52). AD-Sg: DLB patients with core CSF biomarkers suggestive of concomitant AD copathology (t-tau/Aβ_1–42 ratio > 0.52). (a–c) CSF YKL-40, sTREM2 and PGRN levels in CN and DLB patients with and without AD copathology according to the t-tau/Aβ_1–42 ratio.

Figure 4

CSF glial markers in DLB patients according to A/T classification. *p-value < 0.05. Thicker horizontal bars represent the mean while whiskers represent the SD. DLB patients were stratified by levels of Aβ_1–42 and t-tau in CSF: A+: decreased CSF levels of Aβ_1–42, A−: normal CSF levels of Aβ_1–42, T+ increased CSF levels of p-tau, T− normal CSF levels of p-tau.