Abstract
Background
Reliable 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.
Methods
We 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.
Results
CSF 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.
Conclusions
Although 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.
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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.
Abbreviations
- Aβ42:
-
β-Amyloid 1–42
- AD:
-
Alzheimer’s disease
- BSA:
-
Bovine serum albumin
- bvFTD:
-
Behavioural variant frontotemporal dementia
- C9orf72 :
-
Chromosome 9 open reading frame 72 (gene)
- CSF:
-
Cerebrospinal fluid
- FTD:
-
Frontotemporal dementia
- FTLD:
-
Frontotemporal lobar degeneration
- GRN :
-
Progranulin (gene)
- lvPPA:
-
Logopenic variant primary progressive aphasia
- MAPT :
-
Microtubule-associated protein tau (gene)
- nfvPPA:
-
Non-fluent variant primary progressive aphasia
- PPA:
-
Primary progressive aphasia
- PPA-NOS:
-
Primary progressive aphasia not otherwise specified
- P-tau:
-
tau phosphorylated at position threonine-181
- sTREM2:
-
soluble triggering receptor expressed on myeloid cells 2
- svPPA:
-
Semantic variant primary progressive aphasia
- TDP-43:
-
Transactive DNA response binding protein 43
- TREM2:
-
Triggering receptor expressed on myeloid cells 2
- T-tau:
-
Total tau
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Funding
This work was funded by the Medical Research Council (MRC) UK. The authors acknowledge the support of the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit and the University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre, the MRC Dementias Platform UK and the UK Dementia Research Institute. The Dementia Research Centre is an Alzheimer’s Research UK (ARUK) coordinating centre and is supported by ARUK, the Brain Research Trust and the Wolfson Foundation. IOCW is funded by an MRC Clinical Research Training Fellowship (MR/M018288/1). KMD is supported by an Alzheimer’s Society PhD Studentship. RWP is funded by an NIHR Clinical Lectureship. AK is the recipient of a PhD Fellowship awarded by the Wolfson Foundation and a grant from the Weston Brain Institute. JDW has received funding support from the Alzheimer’s Society. JMS acknowledges the support of the Engineering and Physical Sciences Research Council (EP/J020990/1), MRC Dementias Platform UK (MR/L023784/1), ARUK (ARUK-Network 2012-6-ICE, ARUK-PG2017-1946, ARUK-PG2017-1946), Brain Research UK (UCC14191), the Weston Brain Institute (UB170045) and the European Union’s Horizon 2020 research and innovation programme (grant 666992). HZ is a Wallenberg Academy Fellow. JDR is an MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration.
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The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
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IOCW and JDR conceptualised and designed the study and drafted the initial manuscript. IOCW collected CSF samples and clinical data, performed sTREM2 immunoassays, analysed data, interpreted results, produced tables and figures, and revised the initial manuscript based on edits and comments from other authors. JMN assisted with study design; provided statistical advice; and assisted in data analysis, production of figures and interpretation of results. AH developed the sTREM2 immunoassay, provided technical advice for assays, and contributed to the initial draft of the “Methods” section. CH and MSF processed CSF samples and performed INNOTEST immunoassays for quantification of CSF T-tau, P-tau and Aβ42 levels. KMD and LLR assisted with patient recruitment and collection of clinical data. RWP and AK assisted in patient recruitment and collection of CSF samples and clinical data. HZ assisted in study conceptualisation and design. All authors edited the manuscript, but JMN, AH, NCF, JDW, JMS, HZ and JDR provided major contributions to edits. All authors reviewed and approved the final version of the manuscript.
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The study was conducted in line with ethics applications approved by the Health Research Authority and NHS Research Ethics Service Committee, London, Queen Square. All individuals gave written informed consent to participate.
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Woollacott, I.O.C., Nicholas, J.M., Heslegrave, A. et al. Cerebrospinal fluid soluble TREM2 levels in frontotemporal dementia differ by genetic and pathological subgroup. Alz Res Therapy 10, 79 (2018). https://doi.org/10.1186/s13195-018-0405-8
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DOI: https://doi.org/10.1186/s13195-018-0405-8