Cerebrospinal Fluid YKL-40 and Chitotriosidase Levels in Frontotemporal Dementia Vary by Clinical, Genetic and Pathological Subtype

Abstract

Background: Chronic glial dysfunction may contribute to the pathogenesis of frontotemporal dementia (FTD). Cerebrospinal fluid (CSF) levels of glia-derived proteins YKL-40 and chitotriosidase are increased in Alzheimer's disease (AD) but have not been explored in detail across the spectrum of FTD. Methods: We investigated whether CSF YKL-40 and chitotriosidase levels differed between FTD patients and controls, across different clinical and genetic subtypes of FTD, and between individuals with a clinical FTD syndrome due to AD versus non-AD (frontotemporal lobar degeneration, FTLD) pathology (based on CSF neurodegenerative biomarkers). Eighteen healthy controls and 64 people with FTD (behavioural variant FTD, n = 20; primary progressive apha-sia [PPA], n = 44: nfvPPA, n = 16, svPPA, n = 11, lvPPA, n = 14, PPA-NOS, n = 3) were included. 10/64 had familial FTD, with mutations in GRN (n = 3), MAPT (n = 4), or C9orf72 (n = 3). 15/64 had neurodegenerative biomarkers consistent with AD pathology. Levels were measured by immunoassay and compared using multiple linear regressions. We also examined relationships of YKL-40 and chitotriosidase with CSF total tau (T-tau), phosphorylated tau 181 (P-tau) and β-amyloid 1-42 (Aβ42), with each other, and with age and disease duration. Results: CSF YKL-40 and chitotriosidase levels were higher in FTD, particularly lvPPA (both) and nfvPPA (YKL-40), compared with controls. GRN mutation carriers had higher levels of both proteins than controls and C9orf72 expansion carriers, and YKL-40 was higher in MAPT mutation carriers than controls. Individuals with underlying AD pathology had higher YKL-40 and chitotriosidase levels than both controls and those with likely FTLD pathology. CSF YKL-40 and chitotriosidase levels were variably associated with levels of T-tau, P-tau and Aβ42, and with each other, depending on clinical syndrome and underlying pathology. CSF YKL-40 but not

Differential Lipid Mediator Involvement in the Different Forms of Genetic Frontotemporal Dementia: Novel Insights into Neuroinflammation

“…The finding of abnormal proinflammatory eicosanoids in GRN mutation carriers is consistent with previous studies showing that inflammation plays a major role in this form of FTD [5,20]. In CSF, abnormalities have previously been shown in microglial activation markers [21][22][23][24], chemokines and cytokines [20,25], and complement proteins [26]. Here, we add to these findings, suggesting a further biomarker that may be useful in disease modifying trials -lowering of the concentrations of the proinflammatory eicosanoids may help to show a therapeutic effect in GRN-related FTD with improvement of chronic neuroinflammation, although more validation work would need to be done in the first instance.…”

Fluid biomarkers in frontotemporal dementia: past, present and future

“…Similarly to TREM2, the chitinase proteins have been shown to be increased in the CSF of some cohorts but not others 29,30,79,83,84,85 , with some forms of FTD more likely to show increases than others (e.g. those with associated ALS).…”

The role of inflammation in neurodegeneration: novel insights into the role of the immune system in C9orf72 HRE-mediated ALS/FTD

“…In C9-ALS/FTD patients, relatively few studies of neuroinflammatory CSF biomarkers have been performed. A recent comparison between low numbers of FTD patients with different mutations did no identify increased CSF levels of chitotriosidase (CHIT1) and YKL-40 in C9orf72 HRE patients [ 239 ].…”