Abstract
IntroductionThe transactivation response element DNA-binding protein 43 kDa (TDP-43) is a major component of the ubiquitin-positive and tau-negative inclusions in frontotemporal lobar degeneration and sporadic amyotrophic lateral sclerosis (ALS). TDP-43 may accumulate in cases of Alzheimer’s disease (AD), Lewy body disease (LBD), and argyrophilic grain disease (AGD). However, few studies have focused on the incidence and extent of TDP-43 deposition in aging.ResultsWe analyzed 286 consecutive autopsy brains neuropathologically. Of these, 136 brains with pathologically minimal senile changes were designated as control elderly brains (78.5 ± 9.7 y). For comparison, we selected 29 AD, 11 LBD, and 11 AGD patients from this series of autopsy brains. Sections of the hippocampus, amygdala, medulla oblongata, and lumbar spinal cord were immunostained with anti-phosphorylated TDP-43 antibody (PSer409/410). TDP-43 immunoreactive structures were classified into four types: dystrophic neurites (DNs), neuronal or glial cytoplasmic inclusions, and intranuclear inclusions. TDP-43 immunoreactive structures were observed in 55/136 control elderly (40.0 %), 21/29 AD (72.4 %), 8/11 LBD (72.7 %), and 6/11 AGD (54.5 %) brains. TDP-43 immunoreactive structures in control elderly brains were mostly DNs. These DNs were predominantly present in the uncus of the anterior hippocampus over age 65. The frequency of cases with DNs in the amygdala of control elderly brains was less than that of AD, LBD, and AGD brains. The mean age at death was significantly higher in cases with TDP-43 immunoreactive structures than cases without them.ConclusionsIn conclusion, TDP-43 immunoreactive DNs may develop as a consequence of aging processes in the human brain. In particular, the uncus of the anterior hippocampus is an area highly susceptible to TDP-43 accumulation over age 65.
Highlights
The transactivation response element DNA-binding protein 43 kDa (TDP-43) is a major component of the ubiquitin-positive and tau-negative inclusions in frontotemporal lobar degeneration and sporadic amyotrophic lateral sclerosis (ALS)
Distribution of TDP-43 pathology in control elderly brains TDP-43 immunoreactive structures were found in 55/136 (40.0 %) cases (Table 4). Most of these structures were dystrophic neurites (DNs) (53/136 cases, 39.0 %; Table 5); they were predominantly detected at the uncus of the anterior hippocampus (29/136 cases, 21.3 %; Table 5, Fig. 3a)
Age and frequencies of DNs in four groups The mean age at death was significantly higher in cases with TDP-43 immunoreactive structures than in those without TDP-43 immunoreactive structures in control elderly and argyrophilic grain disease (AGD) (Table 4)
Summary
The transactivation response element DNA-binding protein 43 kDa (TDP-43) is a major component of the ubiquitin-positive and tau-negative inclusions in frontotemporal lobar degeneration and sporadic amyotrophic lateral sclerosis (ALS). Previous studies have indicated that TDP-43 immunoreactive inclusion bodies can be detected in other neurodegenerative disorders as well, including Alzheimer’s disease (AD) [5,6,7,8,9], Lewy body disease (LBD) [6, 8, 10], and argyrophilic grain disease (AGD) [11]. Another study indicated that the incidence of TDP-43 deposition in the amygdala and hippocampus of cognitively normal elderly individuals was 36 % [14] These previous studies suggest that TDP43 deposition may be associated with specific neurodegenerative disorders and with aging and Uchino et al Acta Neuropathologica Communications (2015) 3:35 specific anatomical areas. We analyzed TDP-43 immunoreactive deposits in individuals with AD, LBD, and AGD for comparison
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