Background

Frontotemporal dementia (FTD) is a common cause of early-onset dementia, presenting with behavioural change (behavioural variant FTD [bvFTD]) or language impairment (primary progressive aphasia [PPA]). Around one-third of cases are familial, associated most commonly with mutations in progranulin (GRN), microtubule-associated protein tau (MAPT) or chromosome 9 open reading frame 72 (C9orf72) [1]. Pathologically, the majority of individuals have frontotemporal lobar degeneration (FTLD) with inclusions containing tau or transactive response DNA binding protein 43 (TDP-43), although some, particularly 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, particularly 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.

The protein triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed on microglia and on myeloid cells outside the brain [5, 6]. TREM2 is upregulated on activated microglia and involved in microglial phagocytosis [7,8,9,21, 23,24,25], although significantly higher levels [22] or a trend towards higher levels [26] have been observed in males. Although it remains unclear whether sex affects sTREM2, we adjusted all analyses for sex.

A limitation of our study is that some of the FTD clinical and genetic subgroups were rather small, which may have limited our power to detect significant differences between groups. However, this is inherent to a disease such as FTD, where rarer subtypes exist, and it is difficult to avoid when analysing biomarker levels across a broad clinical and pathological spectrum of disease and when employing CSF collection and biomarker analysis at one centre in order to minimise inter-centre variation. Other studies with multi-centre CSF sources have shown significant variability in sTREM2 levels between centres [25], which we were keen to avoid. Our dementia group contained individuals with a diagnosis of an FTD syndrome, including those typically associated with FTLD-TDP or FTLD-tau (bvFTD, svPPA and nfvPPA) and those associated with AD pathology (lvPPA), which in theory could have differentially affected sTREM2 levels within the group as a whole. However, we were able to dissect out any differences in sTREM2 linked to differing pathologies through stratification of all patients with dementia by their CSF biomarker profile. Although most cases of dementia were not pathologically confirmed, all met recent diagnostic criteria for bvFTD [27] or PPA [28], and our CSF ratio cut-off was intentionally stringent to minimise misclassification of cases into the wrong pathology subgroup. Our dementia group combined individuals with a wide range of disease durations, which we showed was independently associated with sTREM2 levels. However, we adjusted analyses for disease duration wherever possible to account for this. We did not include any individuals with mild cognitive impairment, because this is typically a ‘pre-AD’ rather than a ‘pre-FTD’ state, nor did we analyse longitudinal CSF samples or samples from pre-symptomatic mutation carriers at risk of familial FTD. This means we cannot definitively conclude whether CSF sTREM2 levels change over the disease course, and therefore reflect disease proximity, intensity or progression in FTD, or how sTREM2 relates to changes in other CSF biomarkers such as T-tau over time.

Conclusions

Although CSF sTREM2 does not seem useful for differentiating between individuals with FTD and healthy controls, or for delineating a particular clinical subtype of FTD, levels are higher in familial FTD associated with GRN mutations (albeit within a small preliminary cohort) and in individuals with a clinical syndrome consistent with FTD but underlying AD, rather than FTLD, pathology. Because CSF sTREM2 levels correlate with a measure of neuronal injury (T-tau), they may reflect disease intensity in FTD, but this requires further exploration.

Future studies should analyse CSF sTREM2 levels within larger cohorts of individuals with FTD, across a variety of clearly defined clinical subgroups, and ideally in pathologically confirmed cases. Inclusion of a larger number of familial FTD cases with mutations in GRN, MAPT and C9orf72 (which have known pathology) would be helpful in this regard and would enable confirmation of our preliminary observations of higher levels in symptomatic GRN mutation carriers. Assessment of CSF sTREM2 levels in pre-symptomatic individuals at risk of familial FTD could establish if and when levels change prior to expected symptom onset. This would help to elucidate whether CSF sTREM2 levels may be useful as a biomarker of disease proximity in FTD, which, if validated, may be useful for guiding timely initiation of treatments or assessing treatment response in clinical trials. This would maximise the chance of benefitting individuals before significant neurodegeneration occurs. Exploration of relationships between baseline and longitudinal measurements of CSF sTREM2 levels and other markers of disease intensity (such as serum or CSF neurofilament light levels or frontal lobe atrophy rate) would also enable determination of whether CSF sTREM2 can be used as a biomarker of disease intensity in sporadic or familial FTD.