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, Aβ1–42, total tau (t-tau) and phosphorylated tau (p-tau) in CSF. We stratified the group DLB according to the ratio t-tau/Aβ1–42 (≥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.
Highlights
Epidemiological, pathological and genetic studies support the importance of the innate immunity in the pathophysiology of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD)[1,2]
The main finding of this study is that YKL-40 levels are elevated in cerebrospinal fluid (CSF) in dementia with Lewy bodies (DLB) patients only when there is a CSF profile indicative of concomitant AD pathology
The glial markers YKL-40, soluble fragment of triggering receptor expressed on myeloid cells 2 (TREM2) (sTREM2) and PGRN are not increased in CSF in DLB when comparing with CN
Summary
Epidemiological, pathological and genetic studies support the importance of the innate immunity in the pathophysiology of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD)[1,2]. Astroglia and microglia play an important role in neurodegeneration[3,4] These two cellular types have very different functions in the central nervous system (CNS): microglia, the resident monocytic cells in the CNS, phagocyte cellular debris and protein aggregates, while astrocytes support neuronal and synaptic activities among other key functions[3,4]. Recent studies have shown an elevation in the CSF of the soluble fragment of TREM2 (sTREM2) in early stages of sporadic AD14–16 as well as in autosomal dominant AD17. Another line of evidence that supports the role of inflammation in neurodegenerative conditions implicates the Progranulin protein (PGRN). Genetic variants that modulate GRN expression, such as the GRNrs5848 polymorphism, have been associated with an increased risk of AD24,25
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