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

• 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 aphasia [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 inGRN(n= 3),MAPT(n= 4), orC9orf72(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 beta-amyloid 1-42 (A beta 42), with each other, and with age and disease du-ration.Results:CSF YKL-40 and chitotriosidase levels were higher in FTD, particularly lvPPA (both) and nfvPPA (YKL-40), compared with controls.GRNmutation carriers had higher levels of both proteins than controls andC9orf72expansion carriers, and YKL-40 was higher inMAPTmutation 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 A beta 42, and with each other, depending on clinical syndrome and underlying pathology. CSF YKL-40 but not chitotriosidase was associated with age, but not disease duration.Conclusion:CSF YKL-40 and chitotriosidase levels are increased in individuals with clinical FTD syndromes, particularly due to AD pathology. In a preliminary analysis of genetic groups, levels of both proteins are found to be highly elevated in FTD due toGRNmutations, while YKL-40 is increased in individuals withMAPTmutations. As glia-derived protein levels generally correlate with T-tau and P-tau levels, they may reflect the glial response to neurodegeneration in FTLD.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Geriatrik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Geriatrics (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Psykiatri (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Psychiatry (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

Astrocytes

Biomarkers

Cerebrospinal fluid

Chitotriosidase

Frontotemporal dementia

Microglia

Neuroinflammation

Progranulin

YKL-40

primary progressive aphasia

fibrillary acidic protein

alzheimers-disease

lobar degeneration

microglial activation

potential

biomarker

csf

tau

inflammation

macrophage

Geriatrics & Gerontology

Neurosciences & Neurology

Psychiatry

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