Differential Lipid Mediator Involvement in the Different Forms of Genetic Frontotemporal Dementia: Novel Insights into Neuroinflammation

INTRODUCTION

The term frontotemporal dementia (FTD) encompasses a group of neurodegenerative disorders with a wide spectrum of clinical manifestations and complex disease mechanisms [1]. FTD is a highly heri-table disorder, with the majority of genetic FTD caused by mutations in progranulin (GRN), micro-tubule-associated protein tau (MAPT), and chromosome 9 open reading frame 72 (C9orf72) [2–4]. In common with other neurodegenerative diseases, inflammation appears to play a crucial role in the development of FTD and both molecular and clinical studies over recent years have highlighted its importance (reviewed in Bright et al. [5]). Neuroinflammation is complex and involves multiple stages: once it is triggered there is activation of glial cells with upregulation of several proteins, including cytokines and chemokines, that help guide the process. However, consistent inflammatory activation destroys the healthy structures surrounding the inflammatory core and leads to cellular necrosis or apoptosis. A regulatory mechanism that ameliorates inflammation-related damage is therefore required, and this is the process called ‘resolution’, which emerges after innate and adaptative inflammation has occurred [6]. Resolution involves a number of cellular processes that promote removal of dead cells and debris, restoration of vascular integrity and perfusion, and regeneration of tissue [7]. Key to the process of resolution are the specialized proresolving lipid mediators (SPMs) that are synthesized by a variety of cells including endothelial cells, macrophages and neutrophils [8]. While studies have started to investigate the presence of measures of microglial activation, cytokines, chemokines, and complement proteins in the biofluids of people with FTD (reviewed in Swift et al. [9]), there has been little investigation of SPMs and how the resolution pathway might be altered in FTD [10]. However, recent studies have suggested that impaired resolution may be a contributing mechanism leading to chronic inflammation in dementia [11].

Although the majority of lipid mediators are involved in resolution (Fig. 1), a number of those derived from arachidonic acid (eicosanoids) are in fact proinflammatory [12–14] and while little is currently known about their role in FTD, they have previously been shown to exacerbate pathology in Alzheimer’s disease (AD) [13, 14].

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Fig. 1

Schematic representation of the role of lipid mediators in modulating neuroinflammation (adapted from Tiberi et al., 2021 [12]).

We therefore set out to measure the lipid mediators underlying the resolution pathway (SPMs), as well as the closely related proinflammatory eicosanoids, in the cerebrospinal fluid (CSF) of a group of people with genetic FTD.

METHODS

RESULTS

Concentrations were below the lower limit of detection for the DHA-derived protectins, n-3 DPA-derived protectins and n-3 DPA-derived D-series resolvins. However, differences were seen between groups in four of the other nine measures (Table 1, Fig. 2). Among the SPMs, concentrations were higher in the C9orf72 expansion carriers for the DHA-derived maresins (controls mean 0.6 (standard deviation 1.6) pg/mL, MAPT 4.6 (7.9), C9orf72 7.1 (5.9), GRN 0.0 (0.0)) and the DHA-derived resolvins (controls 1.3 (2.9) pg/mL, MAPT 0.9 (0.7), C9orf72 7.7 (4.7), GRN 0.6 (1.0)) in comparison with controls and the GRN mutation carriers (but not with the MAPT group). No differences were seen in the MAPT or GRN mutation carriers compared with controls, although concentrations of the DHA-derived maresins were positively correlated with disease duration in the MAPT group (rho = 0.89, p = 0.041). No other significant correlations were seen comparing SPMs with disease duration apart from in C9orf72 expansion carriers for n-3 DPA-derived 13-series resolvins levels (rho = –0.89, p = 0.041).

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Fig. 2

Concentrations of proresolving and proinflammatory lipid mediators. Results expressed in pg/mL in controls and genetic FTD groups (MAPT, C9orf72, and GRN). Significant differences between groups shown by bars. In the docosahexaenoic acid (DHA) metabolome: MaR, maresins; PD, protectins; RvD, resolvins. In the n-3 docosapentaenoic acid (n-3 DPA) metabolome: MaR_n - 3DPA, maresins; PD_n - 3DPA, protectins; D-series RvD_n - 3DPA and 13-series (RvT), resolvins. In the eicosapentaenoic acid (EPA) metabolome: RvE, resolvins. In the arachidonic acid (AA) metabolome: LX, lipoxins; LT, leukotrienes; cysteinyl leukotrienes; PG, prostaglandins; Tx, thromboxane.

In contrast, both the GRN and MAPT mutation carriers had significantly higher concentrations of the AA-derived leukotrienes (controls 0.0 (0.1) pg/mL, MAPT 0.4 (0.5), C9orf72 0.3 (0.3), GRN 0.4 (0.2)), and AA-derived thromboxane (controls 0.8 (1.0) pg/mL, MAPT 3.1 (1.8), C9orf72 2.4 (2.2), GRN 1.8 (0.7)) compared with controls. The AA-derived leukotrienes were also higher than controls in the C9orf72 group. For the AA-derived leukotrienes, concentrations were strongly positively correlated with disease duration in the MAPT group: rho = 0.97, p = 0.005. No other correlations were found in any of the groups comparing proinflammatory eicosanoid levels with disease duration.

DISCUSSION

In this preliminary study, we show that SPMs and the proinflammatory eicosanoids are abnormal in genetic FTD, with a differential pattern in the different forms: the SPMs are higher in concentration in C9orf72 mutation carriers but normal in GRN and MAPT mutation carriers whilst the proinflammatory eicosanoids are higher in GRN and MAPT mutation carriers with only AA-derived leukotrienes higher in C9orf72 mutation carriers.

Only one previous study has investigated SPMs in FTD: Fraga and colleagues studied the levels of the lipoxin LXA₄ and found no differences in behavioral variant FTD in either plasma or CSF compared to healthy controls or people with AD [10]. In contrast, studies of AD have shown abnormalities of SPMs both in tissue and CSF, e.g., downregulation of DHA-derived mediators such as MaR1, PD1, and RvD5 as well as LXA₄ is seen in the entorhinal cortex and hippocampus [16, 17], while concentrations of LXA₄ are lower in the CSF of people with AD [18], suggesting that the impairment of resolution may potentiate chronic inflammation in AD [11]. Intriguingly, we found the opposite pattern in C9orf72-related neurodegeneration with increased levels of SPMs. One prior study of DHA-derived resolvins does in fact show increased levels in the spinal cord tissue of people with amyotrophic lateral sclerosis [19], one of the phenotypes of C9orf72 expansions. The mechanisms of how this affects the pathophysiology of FTD or amyotrophic lateral sclerosis remains unclear, and further studies both in tissue and biofluids will be important to understand this more clearly.

The finding of abnormal proinflammatory eico-sanoids in GRN mutation carriers is consistent with previous studies showing that inflammation plays a major role in this form of FTD [5, 20]. In CSF, abnormalities have previously been shown in microglial activation markers [21–24], chemokines and cytokines [20, 25], and complement proteins [26]. Here, we add to these findings, suggesting a further biomarker that may be useful in disease modifying trials—lowering of the concentrations of the proinflammatory eicosanoids may help to show a therapeutic effect in GRN-related FTD with improvement of chronic neuroinflammation, although more validation work would need to be done in the first instance. An increase in proinflammatory eicosanoids was seen in MAPT-related FTD as well; this group has also been previously associated with abnormal neuroinflammation in prior studies [27]. Only an increase in the AA-derived leukotrienes was seen in the C9orf72 group, likely due to the complex nature of neuroinflammation and the different pathways affected.

Although there has been little work in SPMs in FTD, there is a growing literature on the involvement of lipids in the pathophysiology of the disease [28–30], including biomarker studies in CSF. One study showed an association with survival [30] (with cholesterol levels), whilst a lipidomic study found widespread abnormalities in different lipid species [29]. However, most of the studies so far have focused on clinically-defined populations with the association of abnormal lipid processing in FTD and underlying molecular pathology remaining unclear.

The limitations of the study include the small number of cases investigated here, reducing the power to detect changes. However, even with these small numbers, we found differences within the genetic groups. One further potential limitation is that as this was an exploratory study we did not correct for multiple comparisons [31]. Further studies will be needed to extend this pilot investigation, including a wider group of mutation carriers across the spectrum from the presymptomatic to symptomatic stages. Another limitation was the lack of data collected on concurrent medication including particularly anti-inflammatory drugs; such information will be an important factor to take into account in future studies.

Overall, our results suggest that there are differential alterations in SPMs and proinflammatory eicosanoids in the different forms of genetic FTD and that these changes can be detected and monitored in CSF supporting the use of such lipids as biomarkers to understand underlying disease pathophysiology in FTD, and potentially as markers of neuroinflammation in future therapeutic trials. Further studies will be needed in a larger cohort, including in very early disease, to determine when and how alterations of lipid mediators occur, and how they change over time.