Microglia in frontotemporal lobar degeneration with progranulin or C9ORF72 mutations

Abstract

Objective To identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD‐GRN) and chromosome 9 open reading frame 72 (FTLD‐C9ORF72). Methods We performed quantitative neuropathologic comparison of 17 FTLD‐C9ORF72 and 15 FTLD‐GRN with a focus on microglia. For clinical comparisons, only cases with high quality medical documentation and concurring diagnoses by at least two neurologists were included (14 FTLD‐GRN and 13 FTLD‐C9ORF72). Neuropathological analyses were limited to TDP‐43 Type A to assure consistent assessment between the groups, acknowledging that Type A is a minority of C9ORF72 patients. Furthermore, only cases with sufficient tissue from all regions were studied (11 FTLD‐GRN and 11 FTLD‐C9ORF72). FTLD cases were also compared to age– and sex–matched normal controls. Immunohistochemistry was performed for pTDP‐43, IBA‐1, CD68, and GFAP. Morphological characterization of microglia was performed in sections of cortex blinded to clinical and genetic information. Results FTLD‐GRN patients had frequent asymmetric clinical features, including aphasia and apraxia, as well as more asymmetric cortical atrophy. Neuropathologically, FTLD‐C9ORF72 had greater hippocampal tau pathology and more TDP‐43 neuronal cytoplasmic inclusions. FTLD‐GRN had more neocortical microvacuolation, as well as more IBA‐1–positive ameboid microglia in superficial cortical layers and in subcortical white matter. FTLD‐GRN also had more microglia with nuclear condensation, possibly indicating apoptosis. Microglial morphology with CD68 immunohistochemistry in FTLD‐GRN and FTLD‐C9ORF72 differed from controls. Interpretation Our findings underscore differences in microglial response in FTLD‐C9ORF72 and FTLD‐GRN as shown by significant differences in ameboid microglia in gray and white matter. These results suggest the differential contribution of microglial dysfunction in FTLD‐GRN and FTLD‐C9ORF72 and suggest that clinical, neuroimaging and pathologic differences could in part be related to differences in microglia response.

Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration

“…Microglial dystrophy has not been compared previously between FTLD and AD, but as dystrophy was similarly severe in all regions, this suggests that there is a common mechanism of excessive microglial senescence. Few studies have examined dystrophy in FTLD, mainly in genetic cases, but these indicate that dystrophy varies regionally and according to potential disease mechanism [53,54], and our results support this. More severe dystrophy was generally observed in white matter than grey matter and this may explain the poor activation of phagocytic and antigen-presenting microglia, and low burden of Iba1-positive microglia, in white matter of most FTLD and AD cases.…”

“…This study extends the few previous studies of microglial dystrophy in genetic FTLD, which have focused on FTLD-GRN or FTLD-C9orf72 [42,53,54] and describes dystrophy in FTLD-MAPT for the first time. Dystrophy was consistently extensive, particularly in FW, in all regions in FTLD-GRN cases, where there was punctate, diffuse Iba1 staining consistent with total loss of cell integrity and generalised distribution of microglial debris [16].…”

“…However, again there was a higher burden in white matter but greater activation in grey matter, suggesting microglia are dysfunctional in white matter in genetic FTLD. Results in the FTLD-GRN group support findings in a single FTLD-GRN case, containing many phagocytic and antigen-presenting microglia in frontotemporal grey and white matter, but few Iba1-positive microglia in FW [54], although others have found many phagocytic and Iba1-positive microglia in the frontal cortex of FTLD-GRN cases [53,68]. Although many antigen-presenting microglia were present in FW, these were not well activated.…”

“…One study has compared microglia between the three main genetic subtypes, showing that FTLD-MAPT cases had more numerous and/or more activated CD68-positive microglia in temporal white matter compared with FTLD-GRN, FTLD-C9orf72 and sporadic FTLD cases [39]. A more recent study of FTLD-GRN and FTLD-C9orf72 cases and controls found that the burden and morphology of CD68-and Iba1-positive microglia varied regionally depending on the mutation [53]. Dystrophic microglia have only been identified in small studies of certain subtypes of FTLD, particularly FTLD-TDPA, and these also vary regionally [42,53,54].…”

Cellular and molecular phenotypes ofC9orf72ALS/FTD patient derived iPSC-microglia mono-cultures

“…Additional studies reported enlarged lysosomes in microglia in the motor cortex and spinal cord of C9orf72 ALS patients compared to sporadic ALS (sALS) patients (30). Examination of microglia in postmortem brain tissues from patients with frontotemporal lobar degeneration revealed that microglia dysfunction differed between patients with a C9orf72 repeat expansion and patients with a mutation in progranulin, the latter accounting for 5-25% of familial FTD (31,32). This suggests that the specificity of microglia dysfunction depends on the etiology of the patient population, and further emphasizes the need to better understand how microglia contribute to ALS and FTD.…”