The role of neuroinflammation in genetic Frontotemporal dementia

Frontotemporal dementia (FTD) is the second most common early onset dementia with various clinical, genetic and pathological subtypes. Genetic defects in three genes (microtubule-associated protein tau (MAPT) gene, progranulin (GRN) gene and chromosome 9 open reading frame 72 (C9ORF72) gene) with an autosomal dominant inheritance pattern account for 30 percent of all FTD cases (Olszewska et al., 2016). Pathologically there are two major distinct groups: FTD with tau or transactive response DNA binding protein of ~43 kDa (TDP-43) pathology. MAPT mutations all have tau pathology, whereas GRN mutations and C9ORF72 repeat expansions lead to the accumulation of TDP-43 in the brain. The overall hypothesis is that neuroinflammation plays an important role in the variability of the clinical onset, clinical presentation, changes in neuroimaging features, and disease progression in FTD. Biomarker studies from our own and other research groups have shown increased levels of neurofilament light (NfL) protein and neuroinflammatory biomarkers (YKL-40, C1qa, C3b, CHIT1, TREM2) in cerebrospinal fluid (CSF) and/or serum from patients with MAPT, GRN or C9ORF72 mutations although the large variation in the levels of these markers still has to be explained. There is increasing clinical, genetic, molecular and cellular evidence that neuroinflammation and immune-mediated dysfunction plays an important role in FTD. The following observations support the idea that microglia play an active role in neurodegeneration: 1. Several genes associated with FTD/ALS are directly linked to inflammatory pathways, including GRN, C9ORF72, TBK1, CHMP2B and TREM2. The corresponding proteins of these genes are highly expressed in microglia 2. FTD with TDP-43 pathology is associated with an increased frequency of autoimmune disorders (28% in patients GRN mutation, 25% in patients with C9ORF72 repeat expansion) compared to controls, and there is evidence of shared genetic risk between FTD and autoimmune disease 3. The progranulin protein is required to suppress excessive microglial activation, and its deficiency is associated with age-dependent microglial activation (visualized by CD68 staining), excessive complement production, and synaptic pruning 4. Higher levels of neuroinflammatory biomarkers (YKL-40, MCP-1, C1qa, C3b) are found in the CSF of patients with FTD 5.The TMEM106B risk allele is associated with significantly lower age of onset in GRN carriers, and is also a determinant factor in the aging brain with a microglia-specific, inflammatory profile 6. C9ORF72 protein loss is associated with increased expression of inflammatory cytokines and severe autoimmunity (Burberry et al., 2016), and C9ORF72 repeat expansions are associated with RNA foci with dipeptides in peripheral CD14+ monocytes 7. Microglial pathological features, such as microgliosis, have been observed in brain tissue from patients with FTD, and proteomic analysis of postmortem tissue shows upregulation of microglial and astrocyte markers Microglia, as a specialized population of macrophage-like cells, are the key players in the association between inflammation and neurodegeneration. The novel 18-kDa translocator-protein (TSPO) 18F-DPA-714 tracer for PET scanning has given promising results for the quantification of microglial activation in Alzheimer’s disease and multiple sclerosis. The major scientific problem now is that we currently do not know whether neuroinflammation contributes to the neurodegenerative process or is solely a pathophysiological consequence or epiphenomenon. To elucidate the role neuroinflammation, our overall objective is to elucidate the role of microglia in our longitudinal study of genetic FTD cohort at different time points (presymptomatic, conversion, symptomatic, postmortem), and with different innovative tools during life and in brains after death. The first objective is to determine changes over time in the levels of neuroinflammatory biomarkers in the CSF and/or serum in relation to other fluid and neuroimaging biomarkers from presymptomatic to symptomatic stage. The second objective is to correlate levels of neuroinflammatory biomarkers in patients with clinical variables, neuroimaging and other fluid biomarkers (NfL, tau, p-tau). The third objective is to investigate microglial activation measured by PET scanning with a novel TSPO tracer (18F-DPA-714) at pre- and symptomatic stage between different genetic FTD groups over time, and to correlate quantitative PET data with clinical variables, levels of NfL and neuroinflammatory biomarkers, and neuroimaging changes. The fourth objective is to correlate microglial activation profiles, burden of pathology and neuronal loss in different cortical regions with RNA expression in the same regions, in order to obtain different measures of neuroinflammation, which may reflect underlying or consequential pathophysiological mechanisms.