Clinicopathologic features of a novel star-shaped transactive response DNA-binding protein 43 (TDP-43) pathology in the oldest old

Abstract Transactive response DNA-binding protein 43 (TDP-43) pathology is categorized as type A-E in frontotemporal lobar degeneration and as type α-β in Alzheimer disease (AD) based on inclusion type. We screened amygdala slides of 131 cases with varying ages at death, clinical/neuroimaging findin...

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Veröffentlicht in:Journal of neuropathology and experimental neurology 2023-12, Vol.83 (1), p.36-52
Hauptverfasser: Carlos, Arenn F, Sekiya, Hiroaki, Koga, Shunsuke, Gatto, Rodolfo G, Casey, Monica Castanedes, Pham, Nha Trang Thu, Sintini, Irene, Machulda, Mary M, Jack, Clifford R, Lowe, Val J, Whitwell, Jennifer L, Petrucelli, Leonard, Reichard, R Ross, Petersen, Ronald C, Dickson, Dennis W, Josephs, Keith A
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Sprache:eng
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Zusammenfassung:Abstract Transactive response DNA-binding protein 43 (TDP-43) pathology is categorized as type A-E in frontotemporal lobar degeneration and as type α-β in Alzheimer disease (AD) based on inclusion type. We screened amygdala slides of 131 cases with varying ages at death, clinical/neuroimaging findings, and AD neuropathologic changes for TDP-43 pathology using anti-phospho-TDP-43 antibodies. Seven cases (5%) only showed atypical TDP-43 inclusions that could not be typed. Immunohistochemistry and immunofluorescence assessed the atypical star-shaped TDP-43 pathology including its distribution, species, cellular localization, and colocalization with tau. All 7 had died at an extremely old age (median: 100 years [IQR: 94–101]) from nonneurological causes and none had dementia (4 cognitively unimpaired, 3 with amnestic mild cognitive impairment). Neuroimaging showed mild medial temporal involvement. Pathologically, the star-shaped TDP-43-positive inclusions were found in medial (subpial) amygdala and, occasionally, in basolateral regions. Hippocampus only showed TDP-43-positive neurites in the fimbria and subiculum while the frontal lobe was free of TDP-43 inclusions. The star-shaped inclusions were better detected with antibodies against N-terminal than C-terminal TDP-43. Double-labeling studies confirmed deposition of TDP-43 within astrocytes and colocalization with tau. We have identified a novel TDP-43 pathology with star-shaped morphology associated with superaging, with a homogeneous clinicopathologic picture, possibly representing a novel, true aging-related TDP-43 pathology.
ISSN:0022-3069
1554-6578
DOI:10.1093/jnen/nlad105