{"doi":"10.1101/2021.04.14.439064","title":"Joint <i>ex vivo</i> MRI and histology detect iron-rich cortical gliosis in Tau and TDP-43 proteinopathies","abstract":"ABSTRACT 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 (AD). However, an integrated, ex vivo MRI and histopathology approach is understudied in FTLD. We apply joint, whole-hemisphere ex vivo MRI at 7T and histopathology to the study autopsy-confirmed FTLD-Tau (n=3) and FTLD-TDP (n=2), relative to an AD disease-control brain with antemortem clinical symptoms of frontotemporal dementia 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, 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 HC and AD brains, suggesting that iron-sensitive T2*w MRI, adapted to in vivo application at sufficient resolution, may offer an opportunity to improve antemortem diagnosis of FTLD proteinopathies using tissue-validated methods.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":220605,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":642220,"name":"Daniel T. Ohm","orcid":"0000-0002-7930-5434","position":1,"is_corresponding":false},{"id":283211,"name":"Rebecca Lobrovich","orcid":null,"position":2,"is_corresponding":false},{"id":265855,"name":"Sandhitsu R. Das","orcid":"0000-0003-0530-2887","position":3,"is_corresponding":false},{"id":643524,"name":"Gabor Mizsei","orcid":null,"position":4,"is_corresponding":false},{"id":349415,"name":"Karthik Prabhakaran","orcid":null,"position":5,"is_corresponding":false},{"id":300138,"name":"Ranjit Ittyerah","orcid":null,"position":6,"is_corresponding":false},{"id":430720,"name":"Sydney Lim","orcid":"0000-0002-5359-4661","position":7,"is_corresponding":false},{"id":227422,"name":"Corey T. McMillan","orcid":"0000-0002-7581-6405","position":8,"is_corresponding":false},{"id":230045,"name":"David A. Wolk","orcid":"0000-0002-3554-3481","position":9,"is_corresponding":false},{"id":259733,"name":"James C. Gee","orcid":"0000-0002-2258-0187","position":10,"is_corresponding":false},{"id":27606,"name":"John Q. Trojanowski","orcid":"0000-0002-9239-8794","position":11,"is_corresponding":false},{"id":107087,"name":"Edward B. Lee","orcid":"0000-0002-4589-1180","position":12,"is_corresponding":false},{"id":301392,"name":"John A. Detre","orcid":"0000-0002-8115-6343","position":13,"is_corresponding":false},{"id":259082,"name":"Paul A. Yushkevich","orcid":"0000-0001-8543-4016","position":14,"is_corresponding":false},{"id":58510,"name":"Murray Grossman","orcid":"0000-0002-7447-6218","position":15,"is_corresponding":false},{"id":227417,"name":"David J. Irwin","orcid":"0000-0002-5599-5098","position":16,"is_corresponding":false},{"id":356077,"name":"M. Dylan Tisdall","orcid":"0000-0002-0454-3112","position":0,"is_corresponding":true}],"reference_count":96,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:46.965811Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}