# Peripheral immune profiling in frontotemporal dementia

## TL;DR

This study finds that immune system dysfunction, including impaired regulatory T cells and increased inflammation, is present in individuals with frontotemporal dementia.

## Contribution

The study is the first to show compromised regulatory T cell function and dysregulated inflammation in peripheral immune cells in frontotemporal dementia.

## Key findings

- Regulatory T cells in FTD individuals show reduced suppressive function compared to healthy controls.
- Monocytes from FTD patients exhibit dysregulation of 153 immune-related genes linked to chemokine signaling and inflammation.
- Plasma levels of pro-inflammatory cytokines and chemokines are significantly elevated in FTD individuals.

## Abstract

Frontotemporal dementia (FTD) encompasses a heterogenous and clinically diverse group of disorders, including the behavioural variant frontotemporal dementia, the non-fluent and the semantic variants of primary progressive aphasia. While these subtypes present with distinct clinical features, emerging evidence implicates neuroinflammation as a shared pathogenic mechanism. Nevertheless, little is known regarding the status of the peripheral immune system in the pathogenesis of FTD. Blood samples were obtained from 27 individuals with a clinical diagnosis of FTD (7 behavioural variants FTD, 10 non-fluent and 10 semantic variants of primary progressive aphasia) and 25 age-matched healthy controls. The immunophenotypes of peripheral immune cell populations were assessed with multicolour flow cytometry. Regulatory T cells were isolated and co-cultured with responder T cells and proliferation was determined by 3H-thymidine incorporation. The immune-related transcriptomic profile of isolated monocytes was analysed using the NanoString Human Inflammation Panel. Plasma levels of inflammatory cytokines and chemokines were quantified using the Olink® Target 48 Cytokine panel. Our analysis demonstrated that the suppressive function of regulatory T cells on responder T cells proliferation was significantly compromised in FTD individuals compared to healthy controls (P < 0.05). Transcriptomic profiling of FTD monocytes revealed a potential dysregulation of 153 immune-related genes. Enrichment analysis showed that these genes were mainly involved in chemokine-mediated signalling pathway, monocyte and lymphocyte chemotaxis, response to interferon-gamma and positive regulation of ERK1 and ERK2 cascades. Proteomic analysis of plasma inflammatory mediators showed a significant increase in the pro-inflammatory cytokine TNFa (P < 0.05) and the chemokines CXCL10, CCL3, CCL19, CSF1 (P < 0.05) and CXCL12 (P < 0.01) in FTD individuals compared to healthy controls. These findings provide the first evidence that the immunomodulatory function of regulatory T cells is compromised in individuals with FTD. In addition, there is a dysregulation of inflammation-related gene expression in peripheral monocytes and an increase of plasma inflammatory chemokines and cytokines in FTD individuals. Further investigation is warranted to assess the therapeutic potential of restoring dysfunctional regulatory T cells and modulating the inflammatory profile in the clinical setting of FTD.

Gamez et al., report impaired Treg function in frontotemporal dementia (FTD), accompanied by dysregulated inflammatory gene expression in monocytes and elevated plasma cytokines. These findings offer new insights into the systemic immune status in FTD and suggest that targeting inflammation holds therapeutic potential, warranting further investigation into immunomodulatory strategies.

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