Ex vivo MRI and histopathology detect novel iron-rich cortical inflammation in frontotemporal lobar degeneration with tau versus TDP-43 pathology

[Display omitted] •Comparative study of whole-hemisphere ex vivo T2*-weighted MRI and histopathology.•Sample of FTLD-Tau and FTLD-TDP subtypes with reference to healthy and AD brain.•Novel focal upper cortical-layer iron-rich pathology distinguishes FTLD-TDP from clinically-similar FTLD-Tau and AD.•...

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Veröffentlicht in:NeuroImage clinical Jg. 33; S. 102913
Hauptverfasser: Tisdall, M. Dylan, Ohm, Daniel T., Lobrovich, Rebecca, Das, Sandhitsu R., Mizsei, Gabor, Prabhakaran, Karthik, Ittyerah, Ranjit, Lim, Sydney, McMillan, Corey T., Wolk, David A., Gee, James, Trojanowski, John Q., Lee, Edward B., Detre, John A., Yushkevich, Paul, Grossman, Murray, Irwin, David J.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Netherlands Elsevier Inc 01.01.2022
Elsevier
Schlagworte:
Alzheimer’s disease
DNA-Binding Proteins
Ex vivo MRI
Frontotemporal Dementia - diagnostic imaging
Frontotemporal Dementia - pathology
Frontotemporal lobar degeneration
Frontotemporal Lobar Degeneration - diagnostic imaging
Frontotemporal Lobar Degeneration - pathology
Histopathology
Humans
Inflammation - diagnostic imaging
Iron
Magnetic Resonance Imaging
Radiology
Regular
tau Proteins
Frontotemporal lobar degeneration
Ex vivo MRI
Iron
Histopathology
Alzheimer’s disease
ISSN:2213-1582, 2213-1582
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Zusammenfassung:[Display omitted] •Comparative study of whole-hemisphere ex vivo T2*-weighted MRI and histopathology.•Sample of FTLD-Tau and FTLD-TDP subtypes with reference to healthy and AD brain.•Novel focal upper cortical-layer iron-rich pathology distinguishes FTLD-TDP from clinically-similar FTLD-Tau and AD.•Distinct novel iron-rich FTLD-Tau pathology in mid-to-deep cortical-layers and WM.•T2*-weighted MRI signatures offer in vivo biomarker targets for FTLD proteinopathy. Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging therapeutic trials tailored to disease-specific mechanisms. Moreover, MRI-derived measures have had limited success to date discriminating between FTLD-Tau or FTLD-TDP. T2*-weighted (T2*w) ex vivo MRI has previously been shown to be sensitive to non-heme iron in healthy intracortical lamination and myelin, and to pathological iron deposits in amyloid-beta plaques and activated microglia in Alzheimer’s disease neuropathologic change (ADNC). However, an integrated, ex vivo MRI and histopathology approach is understudied in FTLD. We apply joint, whole-hemisphere ex vivo MRI at 7 T and histopathology to the study autopsy-confirmed FTLD-Tau (n = 4) and FTLD-TDP (n = 3), relative to ADNC disease-control brains with antemortem clinical symptoms of frontotemporal dementia (n = 2), and an age-matched healthy control. We detect distinct laminar patterns of novel iron-laden glial pathology in both FTLD-Tau and FTLD-TDP brains. We find iron-positive ameboid and hypertrophic microglia and astrocytes largely in deeper GM and adjacent WM in FTLD-Tau. In contrast, FTLD-TDP presents prominent superficial cortical layer iron reactivity in astrocytic processes enveloping small blood vessels with limited involvement of adjacent WM, as well as more diffuse distribution of punctate iron-rich dystrophic microglial processes across all GM lamina. This integrated MRI/histopathology approach reveals ex vivo MRI features that are consistent with these pathological observations distinguishing FTLD-Tau and FTLD-TDP subtypes, including prominent irregular hypointense signal in deeper cortex in FTLD-Tau whereas FTLD-TDP showed upper cortical layer hypointense bands and diffuse cortical speckling. Moreover, differences in adjacent WM degeneration and iron-rich gliosis on histology between FTLD-Tau and FTLD-TDP were also readily apparent on MRI as hyperintense signal and irregular areas of hypointensity, respectively that were more prominent in FTLD-Tau compared to FTLD-TDP. These unique histopathological and radiographic features were distinct from healthy control and ADNC brains, suggesting that iron-sensitive T2*w MRI, adapted to in vivo application at sufficient resolution, may eventually offer an opportunity to improve antemortem diagnosis of FTLD proteinopathies using tissue-validated methods.
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ISSN:2213-1582
2213-1582
DOI:10.1016/j.nicl.2021.102913