Peripheral inflammation in behavioural variant frontotemporal dementia: associations with central degeneration and clinical measures

Abstract

Background: Neuroinflammation plays a significant role in the progression of frontotemporal dementia (FTD). However, the association between peripheral inflammatory factors and brain neurodegeneration is poorly understood. We aimed to examine changes in peripheral inflammatory markers in patients with behavioural variant FTD (bvFTD) and explore the potential association between peripheral inflammation and brain structure, metabolism, and clinical parameters.

Methods: Thirty-nine bvFTD patients and 40 healthy controls were enrolled and underwent assessment of plasma inflammatory factors, positron emission tomography/magnetic resonance imaging, and neuropsychological assessments. Group differences were tested using Student's t test, Mann‒Whitney U test, or ANOVA. Partial correlation analysis and multivariable regression analysis were implemented using age and sex as covariates to explore the association between peripheral inflammatory markers, neuroimaging, and clinical measures. The false discovery rate was used to correct for the multiple correlation test.

Results: Plasma levels of six factors, including interleukin (IL)-2, IL-12p70, IL-17A, tumour necrosis superfamily member 13B (TNFSF/BAFF), TNFSF12 (TWEAK), and TNFRSF8 (sCD30), were increased in the bvFTD group. Five factors were significantly associated with central degeneration, including IL-2, IL-12p70, IL-17A, sCD30/TNFRSF8, and tumour necrosis factor (TNF)-α; the association between inflammation and brain atrophy was mainly distributed in frontal-limbic-striatal brain regions, whereas the association with brain metabolism was mainly in the frontal-temporal-limbic-striatal regions. BAFF/TNFSF13B, IL-4, IL-6, IL-17A and TNF-α were found to correlate with clinical measures.

Conclusion: Peripheral inflammation disturbance in patients with bvFTD participates in disease-specific pathophysiological mechanisms, which could be a promising target for diagnosis, treatment, and monitoring therapeutic efficacy.

Keywords: Behavioural variant fronto-temporal dementia; Inflammation; Neurodegeneration.

Fig. 1

Comparison of inflammatory cytokine levels between groups. Compared with controls, levels of IL-2 (A-2), IL-12p70 (B-2), IL-17A (B-3), BAFF/TNFSF (C-1), TWEAK/TNFSF12 (C-2), and sCD30/TNFRSF8 (C-3) were increased in bvFTD patients. No group difference was found for IL-1β (A-1), IL-4 (A-3), IL-6 (A-4), IL-10 (B-1), IFN-γ (B-4), or TNF-α (C-4). * p < 0.05, ** < 0.001

Fig. 2

Brain regions associated with peripheral inflammation markers. Graph depiction of the brain regions significantly correlated with peripheral inflammation markers, including A IL2; B IL-12p70; C IL-17A; D sCD30/TNFRSF8; and E TNF-α. The brain regions are mainly distributed in frontal–temporal–limbic areas. The significant brain regions are demonstrated on a 3D brain template using the Brain-Net viewer toolbox. Detailed information about the brain regions is shown in Table 2. L left, R right, InfFroOrb inferior frontal orbital, MidFroOrb middle frontal orbital, SupFroOrb superior frontal orbital, MedFroOrb medial frontal orbital, Rec rectus, Olf olfactory, SupMedFro superior medial frontal, InfFroOpe inferior frontal operculum, AntCin anterior cingulate, MidTemPo middle temporal pole, SupTemPo superior temporal pole, InfTem inferior temporal gyrus, SupTem superior temporal gyrus, Hip hippocampus, ParHip para-hippocampus, Ins insula, Put putamen, Amy amygdala