HAI Book 2025 - Flipbook - Page 619
Gatto, Rodolfo
146
Neuropathological evaluation of the off-target binding of
flortaucipir in FTLD subcortical regions: interconnecting tau aggregates
with iron deposition and neuroinflammation
Rodolfo Gatto1, Hossam Youssef1, Gokhan Uruk1, Mu-Hui Fu1, R. Ross Reichard2, Val Lowe3,
Jennifer Whitwell3, Keith Josephs1
1
Department of Neurology, Mayo Clinic, Rochester, MN, US
Department of Laboratory Medicine and Pathology, Rochester, MN, US
3
Department of Radiology, Rochester, MN, US
2
Flortaucipir (FTP) PET uptake can be observed in the basal ganglia (BG) in patients with frontotemporal lobar
degeneration (FTLD) and controls, leading to speculation that FTP uptake reflects off-target binding. Increased
iron content is observed in FTLD's subcortical brain regions, which appear to correlate with tau aggregates. Iron is
an essential component of the oxidative stress in neuroinflammation. We hypothesize that the interplay between
tau accumulation and abnormal iron deposition could enhance neuroinflammation and increase the BG's regional
(off-target) FTP signal.
Objective: To evaluate whether FTP binding in the BG may be locally exacerbated by the abnormal accumulation
of iron and neuroinflammatory processes.
Materials and Methods: We assessed five neuropathologically confirmed cases: two controls, one patient with
high-likelihood Alzheimer9s disease (H-AD), one with progressive supranuclear palsy (PSP), and one with
corticobasal degeneration (CBD). Immunohistochemical staining was performed with antibodies for
phosphorylated tau (AT8), 4-repeat tau (RD4), iron using ferritin (Ferr), and neuroinflammatory markers
(GFAP/CD68/Iba1) in BG sections. Flortaucipir binding was assessed using a fluorescent analog (T726). The BG was
also segmented into the putamen, globus pallidum externum (GPe), and globus pallidum internum (GPi).
Results: Ferritin was increased in the putamen of the H-AD case and the putamen, GPe, and GPi in the PSP and
CBD cases. Colocalization between ferritin and T726 was observed in the PSP and CBD cases. Colocalization
between GFAP and T726 and CD68 and T726 was seen in the PSP case, while colocalization between Iba1 and T726
was observed in the CBD case.
Conclusions: FTP off-target binding observed in the BG in FTLD cases could be related to iron deposition and
locally enhanced by cell-mediated neuroinflammation.
HAI2025 - 619