Abstract
BackgroundReliable biomarkers of frontotemporal dementia (FTD) are currently lacking. FTD may be associated with chronic immune dysfunction, microglial activation and raised inflammatory markers, particularly in progranulin (GRN) mutation carriers. Levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) are elevated in Alzheimer’s disease (AD), but they have not been fully explored in FTD.MethodsWe investigated whether cerebrospinal fluid (CSF) sTREM2 levels differ between FTD and controls, across different clinical and genetic subtypes of FTD, or between individuals with FTD due to AD versus non-AD pathology (based on CSF neurodegenerative biomarkers). We also assessed relationships between CSF sTREM2 and other CSF biomarkers (total tau [T-tau], tau phosphorylated at position threonine-181 [P-tau] and β-amyloid 1–42 [Aβ42]) and age and disease duration. Biomarker levels were measured using immunoassays in 17 healthy controls and 64 patients with FTD (behavioural variant FTD, n = 20; primary progressive aphasia, n = 44). Ten of 64 had familial FTD, with mutations in GRN (n = 3), MAPT (n = 4), or C9orf72 (n = 3). Fifteen of 64 had neurodegenerative biomarkers consistent with AD pathology (11 of whom had logopenic variant PPA). Levels were compared using multivariable linear regressions.ResultsCSF sTREM2 levels did not differ between FTD and controls or between clinical subgroups. However, GRN mutation carriers had higher levels than controls (mean ([SD] = 9.7 [2.9] vs. 6.8 [1.6] ng/ml; P = 0.028) and MAPT (3.9 [1.5] ng/ml; P = 0.003] or C9orf72 [4.6 [1.8] ng/ml; P = 0.006) mutation carriers. Individuals with AD-like CSF had higher sTREM2 levels than those with non-AD-like CSF (9.0 [3.6] vs. 6.9 [3.0] ng/ml; P = 0.029). CSF sTREM2 levels were associated with T-tau levels in control and FTD groups and also with P-tau in those with FTD and AD-like CSF. CSF sTREM2 levels were influenced by both age and disease duration in FTD.ConclusionsAlthough CSF sTREM2 levels are not raised in FTD overall or in a particular clinical subtype of FTD, levels are raised in familial FTD associated with GRN mutations and in FTD syndromes due to AD pathology. Because CSF sTREM2 levels correlate with a marker of neuronal injury (T-tau), sTREM2 should be explored as a biomarker of disease intensity in future longitudinal studies of FTD.
Highlights
Reliable biomarkers of frontotemporal dementia (FTD) are currently lacking
cerebrospinal fluid (CSF) sTREM2 levels do not differ between FTD and controls or between clinical subtypes of FTD CSF sTREM2 levels did not significantly differ between individuals with dementia consistent with FTD and controls (Fig. 1a) or between any of the clinical subgroups and controls, adjusting for age and sex, or between any of the clinical subgroups, adjusting for age, sex and disease duration (Fig. 1b, Table 3)
We found that CSF sTREM2 levels were associated with total tau (T-tau) levels in those with FTD due to likely frontotemporal lobar degeneration (FTLD), consistent with the theory that sTREM2 levels may rise in the context of neuronal injury without concurrent hyperphosphorylated tau or amyloid pathology [22, 24,25,26]
Summary
Reliable biomarkers of frontotemporal dementia (FTD) are currently lacking. FTD may be associated with chronic immune dysfunction, microglial activation and raised inflammatory markers, in progranulin (GRN) mutation carriers. The majority of individuals have frontotemporal lobar degeneration (FTLD) with inclusions containing tau or transactive response DNA binding protein 43 (TDP-43), some, those with the logopenic variant of PPA (lvPPA), have Alzheimer’s disease (AD) pathology [2]. Reliable biomarkers that differentiate the pathological changes underlying sporadic FTD in vivo or that predict disease onset, severity or progression in sporadic and familial FTD are currently lacking. There is growing evidence that neuroinflammation and microglial dysfunction play a role in FTD, in familial FTD secondary to GRN mutations [3, 4]. Inflammatory markers are variably altered in blood or cerebrospinal fluid (CSF) of patients with neurodegenerative disease, including across the clinical, genetic and pathological spectrum of FTD, and they could be useful as disease biomarkers in future clinical trials
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