Phosphorylated TDP-43 Staging of Primary Age-Related Tauopathy
Xiaoling Zhang1 • Bing Sun1 • Xing Wang2 • Hui Lu1 • Fangjie Shao2 • Annemieke J. M. Rozemuller3 • Huazheng Liang4 • Chong Liu1,2 • Jiadong Chen1 • Manli Huang5 • Keqing Zhu1,2,*
1China Brain Bank and Department of Neurology in Second Affiliated Hospital, Key Laboratory of Medical Neurobiology of Zhejiang Province, Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China
2Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310058, China
3Department of Pathology, Amsterdam Neuroscience, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
4Brain Structure and Function Group, Neuroscience Research Australia, Randwick, NSW 2031, Australia
5Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
Primary age-related tauopathy (PART) is characterized by tau neurofibrillary tangles (NFTs) in the absence of amyloid plaque pathology. In the present study, we analyzed the distribution patterns of phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) in the brains of patients with PART. Immunohistochemistry and immunofluorescence double-labeling in multiple brain regions was performed on brain tissues from PART, Alzheimer’s disease (AD), and aging control cases. We examined the regional distribution patterns of pTDP-43 intraneuronal inclusions in PART with Braak NFT stages > 0 and ≤ IV, and a Thal phase of 0 (no beta-amyloid present). We found four stages which indicated potentially sequential dissemination of pTDP-43 in PART. Stage I was characterized by the presence of pTDP-43 lesions in the amygdala, stage II by such lesions in the hippocampus, stage III by spread of pTDP-43 to the neocortex, and stage IV by pTDP-43 lesions in the putamen, pallidum, and insular cortex. In general, the distribution pattern of pTDP-43 pathology in PART cases was similar to the early TDP-43 stages reported in AD, but tended to be more restricted to the limbic system. However, there were some differences in the distribution patterns of pTDP-43 between PART and AD, especially in the dentate gyrus of the hippocampus. Positive correlations were found in PART between the Braak NFT stage and the pTDP-43 stage and density.