Peripheral Innate Immune Activation Correlates With Disease Severity in GRN Haploinsufficiency.

Peter A Ljubenkov,Joel H Kramer,Adam Staffaroni,Laura Mitic,Rodney Pearlman,Isabel Elaine Allen,Howard J Rosen,Paige Mumford,Bruce Miller,Anna Karydas,Yann Cobigo,Michael S Mcgrath,Hilary Heuer,Adam L Boxer,Zachary Miller,Julio C Rojas,Jane Zhang

doi:10.3389/fneur.2019.01004

Abstract

Objective: To investigate associations between peripheral innate immune activation and frontotemporal lobar degeneration (FTLD) in progranulin gene (GRN) haploinsufficiency.Methods: In this cross-sectional study, ELISA was used to measure six markers of innate immunity (sCD163, CCL18, LBP, sCD14, IL-18, and CRP) in plasma from 30 GRN mutation carriers (17 asymptomatic, 13 symptomatic) and 29 controls. Voxel based morphometry was used to model associations between marker levels and brain atrophy in mutation carriers relative to controls. Linear regression was used to model relationships between plasma marker levels with mean frontal white matter integrity [fractional anisotropy (FA)] and the FTLD modified Clinical Dementia Rating Scale sum of boxes score (FTLD-CDR SB).Results: Plasma sCD163 was higher in symptomatic GRN carriers [mean 321 ng/ml (SD 125)] compared to controls [mean 248 ng/ml (SD 58); p < 0.05]. Plasma CCL18 was higher in symptomatic GRN carriers [mean 56.9 pg/ml (SD 19)] compared to controls [mean 40.5 pg/ml (SD 14); p < 0.05]. Elevation of plasma LBP was associated with white matter atrophy in the right frontal pole and left inferior frontal gyrus (p FWE corrected <0.05) in all mutation carriers relative to controls. Plasma LBP levels inversely correlated with bilateral frontal white matter FA (R2 = 0.59, p = 0.009) in mutation carriers. Elevation in plasma was positively correlated with CDR-FTLD SB (b = 2.27 CDR units/μg LBP/ml plasma, R2 = 0.76, p = 0.003) in symptomatic carriers.Conclusion: FTLD-GRN is associated with elevations in peripheral biomarkers of macrophage-mediated innate immunity, including sCD163 and CCL18. Clinical disease severity and white matter integrity are correlated with blood LBP, suggesting a role for peripheral immune activation in FTLD-GRN.

Highlights

Haploinsufficiency of the progranulin gene (GRN) is a major cause of familial frontotemporal lobar degeneration (FTLD), giving rise to a variety of fatal and untreatable frontotemporal dementia (FTD-GRN) syndromes [1]
Within the symptomatic GRN mutation carrier cohort, seven individuals met consensus criteria for bvFTD [14], one met criteria for mild cognitive impairment [13], three met consensus criteria for a PPA [15], one had an amnestic syndrome resembling Alzheimer’s disease, one presented with idiopathic parkinsonism, and one individual suffered from a multifactorial dementia syndrome with behavioral, memory, language, and visuospatial impairments
Symptomatic FTD-GRN patients differed from controls and asymptomatic carriers across the majority of clinical and radiographic measures assessed (Table 1)

Summary

Introduction

Haploinsufficiency of the progranulin gene (GRN) is a major cause of familial frontotemporal lobar degeneration (FTLD), giving rise to a variety of fatal and untreatable frontotemporal dementia (FTD-GRN) syndromes [1]. In patients with FTD-GRN, there is an increased rate of autoimmunity [4], suggesting that peripheral immune dysregulation is a feature of this disease. In Grn−/− mice, peripheral myeloid cells and microglia release excessive pro-inflammatory cytokines in response to bacterial lipopolysaccharide (LPS), and both sets of mononuclear cells exhibit heightened neurotoxicity [3]. Grn−/− mice display poor reconstitution of the blood brain barrier after injury [5]. If humans recapitulate animal models of familial FTLD, patients with GRN deficiency are likely to have hyperactive monocytes, with less restricted access to the central nervous system (CNS) and greater capacity for neuronal injury. Plasma biomarkers of innate immune activation may provide evidence for a potentially treatable monocyte-driven mechanism of pathogenesis in GRN deficiency and serve as measures of drug response in future clinical therapeutic trials targeting myeloid cells. Given the documented relationship between peripheral inflammation and white matter integrity outside of FTD cohorts [6], abnormal peripheral monocyte activation may serve to explain the unique burden of white matter disease that distinguishes FTD-GRN from other familial FTD syndromes [7]

Methods

Results

Conclusion