Cortical iron accumulation in MAPT‐ and C9orf 72‐associated frontotemporal lobar degeneration

Abstract

Neuroinflammation has been implicated in frontotemporal lobar degeneration (FTLD) pathophysiology, including in genetic forms with microtubule‐associated protein tau (MAPT) mutations (FTLD‐MAPT) or chromosome 9 open reading frame 72 (C9orf72) repeat expansions (FTLD‐C9orf72). Iron accumulation as a marker of neuroinflammation has, however, been understudied in genetic FTLD to date. To investigate the occurrence of cortical iron accumulation in FTLD‐MAPT and FTLD‐C9orf72, iron histopathology was performed on the frontal and temporal cortex of 22 cases (11 FTLD‐MAPT and 11 FTLD‐C9orf72). We studied patterns of cortical iron accumulation and its colocalization with the corresponding underlying pathologies (tau and TDP‐43), brain cells (microglia and astrocytes), and myelination. Further, with ultrahigh field ex vivo MRI on a subset (four FTLD‐MAPT and two FTLD‐C9orf72), we examined the sensitivity of T2*‐weighted MRI for iron in FTLD. Histopathology showed that cortical iron accumulation occurs in both FTLD‐MAPT and FTLD‐C9orf72 in frontal and temporal cortices, characterized by a diffuse mid‐cortical iron‐rich band, and by a superficial cortical iron band in some cases. Cortical iron accumulation was associated with the severity of proteinopathy (tau or TDP‐43) and neuronal degeneration, in part with clinical severity, and with the presence of activated microglia, reactive astrocytes and myelin loss. Ultra‐high field T2*‐weighted MRI showed a good correspondence between hypointense changes on MRI and cortical iron observed on histology. We conclude that iron accumulation is a feature of both FTLD‐MAPT and FTLD‐C9orf72 and is associated with pathological severity. Therefore, in vivo iron imaging using T2*‐weighted MRI or quantitative susceptibility mapping may potentially be used as a noninvasive imaging marker to localize pathology in FTLD.

Neuroanatomical and cellular degeneration associated with a social disorder characterized by new ritualistic belief systems in a TDP-C patient vs. a Pick patient

“…While hypointense signal and iron-rich gliosis were predominantly found in the aTL of both patients, we found somewhat different laminar patterns. Similar to previous work ( 40 , 78 ), select ventral aTL showed bands of upper layer hypointensity alongside variable mid and lower layer hypointense signal in the FTLD-TDP patient, while the FTLD-tau patient had more prominent but variable mid and deep layer bands of hypointensity in the aTL. These imaging findings corresponded to iron-rich gliosis, raising interesting questions about the potential role of non-cell autonomous neurodegeneration in FTLD.…”

Beyond Macrostructure: Is There a Role for Radiomics Analysis in Neuroimaging ?

“…Giannini et al performed a similar multimodal study in genetic forms of FTLD. 80 All of these studies employed largely qualitative approaches, which highlight the need for translating these studies into more quantitative validation work that has the potential to be more sensitive, and ultimately could lead to an opportunity for improving in-vivo diagnosis.…”

“…Therefore, it is not surprising that many of the multimodal studies linking histology and MRI have looked for iron-rich signatures of pathology, including the studies mentioned earlier in this section. 78 – 80 The potential for iron-sensitive imaging in AD is reviewed by Tran et al 83 For a broader review, see Lee and Kovacs. 82 As validation studies are being pursued, custom analysis tools are becoming available that can help scale up these multiscale, multimodal studies.…”

“…91 Another approach is the use of quantitative imaging, especially with MRI techniques such as quantitative susceptibility mapping (QSM) and multiparametric mapping methods, 92 which have seen increasing interest in imaging of neurodegenerative disease, but is not covered in this article. Another area of imaging also not covered here that is commonly thought to provide information about tissue microstructure is diffusion-weighted MRI (DW-MRI), which has recently seen renewed interest in ADRD neuroimaging (See Giannini et al 80 and Chen et al 93 ). However, we note that insofar as DW-MRI or any other imaging modalities that purportedly capture properties of underlying biological processes, one could take a radiomics-like approach to them as well.…”