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.