Plasma biomarkers of inflammation reflect disease state in autosomal dominant forms of familial frontotemporal dementia

Abstract

AbstractBackgroundImmune dysregulation may influence disease pathogenesis in familial frontotemporal dementia (fFTD), but the utility of peripheral biomarkers of inflammation remains unclear in this cohort. We sought to investigate candidate plasma biomarkers of immune function within a large cohort of fFTD kindreds from the ARTFL and LEFFTDS Consortia.MethodsWe examined plasma samples from 148 non‐carrier healthy controls and 256 asymptomatic and symptomatic individuals carrying autosomal dominant fFTD‐associated mutations (n=73 MAPT, n=120 C9ORF72, and n=63 GRN). ELISA was used to measure three plasma biomarkers of inflammation (YKL‐40, TNF‐α,IL‐6). We used Mann–Whitney U tests to compare concentrations amongst controls and subgroups of fFTD differing in disease severity, defined by the Clinical Dementia Rating Scale plus National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR® plus NACC FTLD) global score (asymptomatic=0, early symptomatic=0.5, late symptomatic ≥1). We also used linear mixed models to assess the utility of baseline inflammatory biomarkers in predicting the subsequent annual rate of decline in functional clinical severity (CDR® plus NACC FTLD sum of boxes) and psychomotor speed (Trails A).ResultsPlasma YKL‐40 concentrations were elevated in late symptomatic fFTD (59.3ng/ml [50.1]) relative to controls (32.9ng/ml [24.0]) (p=0.0003) and asymptomatic mutation carriers (30.9ng/ml [25.4], p=0.0001). Plasma TNF‐α concentrations were relatively low in asymptomatic mutation carriers (1.96pg/ml [0.56]) compared to early symptomatic fFTD (2.35pg/ml [0.83], p= 0.009). Amongst mutation carriers (including 140 with follow up clinical data), higher baseline plasma IL‐6 and YKL‐40 concentrations were associated with greater increase in functional clinical severity and declines in psychomotor speed, respectively.ConclusionPlasma biomarkers of inflammation increase with disease severity in fFTD and predict worse clinical trajectories. While the role of inflammation remains unclear in familial FTD, plasma markers of inflammation appear to reflect the processes influencing disease trajectory in patients carrying mutations associated with familial frontotemporal dementia.