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

• Published in: Brain pathology (Zurich, Switzerland) Vol. 33; no. 4; pp. e13158 - n/a
• Main Authors: Giannini, Lucia A. A., Bulk, Marjolein, Kenkhuis, Boyd, Rajicic, Ana, Melhem, Shamiram, Hegeman‐Kleinn, Ingrid, Bossoni, Lucia, Suidgeest, Ernst, Dopper, Elise G. P., Swieten, John C., Weerd, Louise, Seelaar, Harro
• Format: Journal Article
• Language: English
• Published: Switzerland John Wiley & Sons, Inc 01.07.2023; John Wiley and Sons Inc
• Subjects: Accumulation; Astrocytes; C9orf72; C9orf72 Protein - genetics; Chromosome 9; Cortex (frontal); Degeneration; DNA-Binding Proteins - metabolism; Frontotemporal Dementia; frontotemporal lobar degeneration; Frontotemporal Lobar Degeneration - genetics; Frontotemporal Lobar Degeneration - pathology; Histology; Histopathology; Humans; Inflammation; Iron; iron accumulation; Magnetic resonance imaging; MAPT; Medical imaging; Microglia; Myelin; Myelination; Neurodegeneration; Neuroimaging; neuroinflammation; Neuroinflammatory Diseases; Progranulins; Tau protein; tau Proteins - metabolism; Temporal lobe; MAPT; iron accumulation; neuroinflammation; frontotemporal lobar degeneration; C9orf72
• ISSN: 1015-6305; 1750-3639; 1750-3639
• DOI: 10.1111/bpa.13158

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.