Evidence mapPaperPMID 42568211Full record

ArticleBrain pathology (Zurich, Switzerland)2026

Artificial intelligence-based 3D segmentation of tangle-associated TDP-43 in neurodegeneration.

Gokhan Uruk, Hossam Youssef, Rodolfo G Gatto, Nadia Hossain, Jennifer L Whitwell, Robert R Reichard, Keith A Josephs

Abstract read
In one paragraph

Article in Brain pathology (Zurich, Switzerland), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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4 · The record

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5 · Who and what money

Authors and funding

7 authors.

Gokhan UrukDepartment of Neurology, Mayo Clinic, Rochester, Minnesota, USA.ORCID https://orcid.org/0000-0002-8706-9443
Hossam YoussefDepartment of Neurology, Mayo Clinic, Rochester, Minnesota, USA.ORCID https://orcid.org/0009-0000-8876-8038
Rodolfo G GattoDepartment of Neurology, Mayo Clinic, Rochester, Minnesota, USA.ORCID https://orcid.org/0000-0003-2170-6662
Nadia HossainDepartment of Neurology, Mayo Clinic, Rochester, Minnesota, USA.ORCID https://orcid.org/0000-0001-9202-1172
Jennifer L WhitwellDepartment of Radiology, Mayo Clinic, Rochester, Minnesota, USA.ORCID https://orcid.org/0000-0001-6914-1563
Robert R ReichardDepartment of Laboratory Medicine and Pathology (Neuropathology), Mayo Clinic, Rochester, Minnesota, USA.
Keith A JosephsDepartment of Neurology, Mayo Clinic, Rochester, Minnesota, USA.ORCID https://orcid.org/0000-0003-2930-8634

Funding

NIH HHS R01-AG37491
6 · The paper itself

Abstract

TAR DNA-binding protein 43 (TDP-43) inclusions are often associated with hyperphosphorylated tau, thus neurofibrillary tangles as the hallmark of Alzheimer's disease (AD) and primary age-related tauopathy (PART). TDP-43 in AD is associated with cognitive impairment, and while staging is known, the localization, cellular and inclusion characteristics of TDP-43 are yet to be elucidated. We investigate relationships between TDP-43 inclusions and the tangle maturation continuum in AD, PART, and co-pathologies by multiplex immunostaining combined with artificial intelligence (AI)-based segmentation via object recognition, reconstruction, and quantification. We performed anti-phosphorylated TDP-43 immunofluorescence with phosphorylated tau labeling different stages and modifications of tangles (AT8, pS396, TauC3, MN423, GT38) in three controls, three cases with PART and TDP-43 (PART-TDP), five cases with high likelihood AD and TDP-43 (AD-TDP), and four cases of high likelihood AD with TDP-43 and Lewy Body disease (AD-TDP-LBD). Confocal imaging was taken from eight regions: amygdala (amygdala-BL and amygdala-CM) and hippocampus (Cornu Ammonis (CA)-1, CA2/3, CA4, dentate gyrus (DG), subiculum (SUB)), and entorhinal cortex (ERC) and quantified with AI segmentation to identify 3D spatial relations, thus the maturity of neurofibrillary tangle associated TDP-43 (TAT) inclusions. TATs, which were either identified by pTDP-43 and AT8 or pTDP-43 and pS396 double positivity, were also investigated by Thioflavin S (ThioS) histochemistry. We found pS396 labeled mature TATs predominated in PART and AD in every region. Basolateral and centromedial amygdala displayed overall greatest number of pre-TATs and mature TATs. Mature TATs were homogenously distributed among hippocampal subfields whereas CA4 and DG had the greatest mature TAT composition. ERC revealed closer numbers of pre-TATs and mature TATs yet mature TATs predominated all groups. Unbiased AI-based object identification, reconstruction, and TAT maturation analysis pipeline in conjunction with TDP-43, tau, and ThioS multiplex immunostaining demonstrated unique aggregation and maturation patterns, highlighting region-specific dynamics in the neurodegenerative processes of PART and AD.

Indexed as

Alzheimer's disease (AD)artificial intelligence (AI)neurofibrillary tangle associated TDP‐43 (TAT)phosphorylated tauprimary age‐related tauopathy (PART)TAR DNA‐binding protein 43 (TDP‐43)

Identifiers

PMID42568211
PMCPMC13451656

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.