Peripheral Innate Immune Activation Correlates With Disease Severity in GRN Haploinsufficiency

Frontiers in Neurology

Isabel Elaine Allen¹  Jane Zhang²  Michael S. McGrath³  Julio C. Rojas⁴  Paige Mumford⁴  Anna Karydas⁴  Hilary Heuer⁴  Adam L. Boxer⁴  Bruce Miller⁴  Howard J. Rosen⁴  Peter A. Ljubenkov⁴  Zachary Miller⁴  Yann Cobigo⁴  Adam Staffaroni⁴  Joel H. Kramer⁴  Laura Mitic⁵  Rodney Pearlman⁵ 

[1] Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States;Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, United States;Department of Medicine, University of California, San Francisco, San Francisco, CA, United States;Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States;The Bluefield Project to Cure Frontotemporal Dementia, San Francisco, CA, United States;

关键词: progranulin (GRN);    frontotemperal lobar degeneration;    monocyte;    innate immune system;    peripheral immune activation;   

DOI  :  10.3389/fneur.2019.01004

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown