Elevated YKL-40 and low sAPPβ:YKL-40 ratio in antemortem cerebrospinal fluid of patients with pathologically confirmed FTLD

Abstract

ObjectivesThe combination of high YKL-40 (a glial inflammatory marker) and low sAPPβ (a soluble β fragment of amyloid precursor protein) in cerebrospinal fluid (CSF) has been associated with frontotemporal lobar degeneration (FTLD) in clinical series. We investigate these biomarkers in a neuropathologically confirmed cohort of patients with FTLD.MethodsCSF samples were selected from the Penn FTD Center (University of Pennsylvania). Participants were followed to autopsy and had a neuropathological diagnosis of FTLD-Tau (n=24), transactive response DNA-binding protein with 43 kDa (FTLD-TDP) (n=25) or Alzheimer’s disease (AD, n=97). We compared levels of YKL-40 and sAPPβ between groups and with cognitively normal controls (n=77), and assessed their diagnostic utility using receiver operating characteristic curves. We also investigated the effect of AD copathology and the correlation between these CSF markers and tau burden at autopsy.ResultsBoth FTLD groups had lower levels of sAPPβ, higher levels of YKL-40 and lower sAPPβ:YKL-40 ratio in CSF compared with controls. The group of pure FTLD-Tau (without AD copathology) showed higher levels of YKL-40 than AD and than pure FTLD-TDP. YKL-40 levels correlated with pathological tau burden. The sAPPβ:YKL-40 ratio had an area under the curve (AUC) of 0.91 (95% CI 0.86 to 0.96) to distinguish subjects with FTLD from controls, but lower values to distinguish FTLD from AD (AUC 0.70; 95% CI 0.61 to 0.79) and to discriminate FTLD-Tau from FTLD-TDP (AUC 0.67; 95% CI 0.51 to 0.82).ConclusionsOur study provides pathological confirmation that the combination of low sAPPβ and high YKL-40 in CSF is associated with FTLD. These biomarkers could be useful in particular clinical settings when FTLD is suspected.

Novel P397S MAPT variant associated with late onset and slow progressive frontotemporal dementia

“…Surprisingly, levels of p‐tau ant t‐tau were increased in all three, with decreased levels of Aβ42 only in one of them. Several previous reports have described diminished CSF Aβ levels in sporadic or/and genetic FTLD . It is discussed whether this finding is related to an increased deposition of Aβ spices or to a reduction of Aβ production, as it is associated with a reduction in soluble APP levels.…”

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

“…Raised CSF YKL-40 levels have previously been demonstrated in several FTD cohorts versus controls [33,[42][43][44][45][46][47][48][49], including in familial FTD [48], and compared with individuals with primary psychiatric diagnoses [50]. In contrast, few studies have examined CSF chitotriosidase levels in FTD.…”

“…There was also significant intra-group variability in protein levels, particularly for chitotriosidase, suggesting glial activation may vary considerably according to the FTLD subtype or disease mechanism. Other studies have explored this by stratifying pathologically confirmed FTLD groups and found higher CSF YKL-40 levels in both FTLD-tau and FTLD-TDP than in individuals with subjective memory impairment, and in FTLD-tau compared with AD [43,44,49]. One study found higher YKL-40 levels in "pure" FTLD-tau (excluding AD pathology) than in patients with FTLD-TDP or AD [44], although others have found higher levels in FTLD-TDP (but not FTLD-tau) compared with controls [43,45].…”

Synaptic, axonal damage and inflammatory cerebrospinal fluid biomarkers in neurodegenerative dementias

“…YKL‐40 is a glycoprotein produced by inflammatory cells, mostly astrocytes. Its physiological role is not completely understood but YKL‐40 is increased in the brain and CSF in several neurologic and neurodegenerative diseases associated with inflammatory processes …”

“…Its physiological role is not completely understood but YKL-40 is increased in the brain and CSF in several neurologic and neurodegenerative diseases associated with inflammatory processes. 15,[28][29][30] In this study, we aimed to analyze and compare the diagnostic accuracy and discriminatory properties of four noncore biomarkers that reflect different aspects of the neurodegeneration process: axonal damage, presynapsis and postsynapsis loss, and neuroinflammation (NF-L, 143-3, Ng and YKL-40, respectively) in an unicentric cohort with a broad spectrum of clinical diagnoses: the Alzheimer's continuum (including preclinical phase and genetic cases), FTD (sporadic and genetic), and sporadic CJD. In addition, we investigated the performance of each of these markers as a potential neurodegenerative (N) marker in the recently proposed AT(N) system in AD.…”