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). 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. We 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. In 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.

Exosomes or extracellular vesicles have the potential as a diagnostic marker for various diseases including cancer. In order to identify novel exosomal markers for prostate cancer (PC), we performed proteomic analysis of exosomes isolated from PC cell lines and examined the usefulness of the marker in patients. Exosomes isolated by differential centrifugation from the culture medium of androgen-dependent LNCaP prostate cancer cell line and its sublines of partially androgen-independent C4, androgen-independent C4–2 and bone metastatic C4–2B were subjected to iTRAQ-based proteomic analysis. Exosomes were also isolated by immunocapture and separated by size exclusion chromatography and density gradient centrifugation. Protein expression was determined by Western blot analysis. GGT activity was measured using a fluorescent probe, γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG). Immunohistochemical analysis of tissues was performed using anti-GGT1 antibody. Among proteins upregulated in C4–2 and C4–2B cells than in LNCaP cells, we focused on gamma-glutamyltransferase 1 (GGT1), a cell-surface enzyme that regulates the catabolism of extracellular glutathione. The levels of both GGT1 large and small subunits were elevated in exosomes isolated from C4–2 and C4–2B cells by differential centrifugation and by immunocapture with anti-CD9 or -prostate-specific membrane antigen (PSMA) antibody. In cell lysates and exosomes, GGT1 expression correlated with GGT activity. Size exclusion chromatography of human serum demonstrated the presence of GGT activity and GGT1 subunits in fractions positive for CD9. Density gradient centrifugation revealed the co-presence of GGT1 subunits with CD9 in exosomes isolated by differential centrifugation from human serum. Since GGT activity correlated with GGT1 expression in serum exosomes isolated by differential centrifugation, we measured serum exosomal GGT activity in patients. Unexpectedly, we found that serum exosomal GGT activity was significantly higher in PC patients than in benign prostatic hyperplasia (BPH) patients. In support of this finding, immunohistochemical analysis showed increased GGT1 expression in PC tissues compared with BPH tissues. Our results suggest that serum exosomal GGT activity could be a useful biomarker for PC.

Background and Objectives ¹²³I-meta-iodobenzyl-guanidine (¹²³I-MIBG) myocardial scintigraphy is used as a diagnostic imaging test to differentiate Lewy body diseases (LBDs), including Parkinson disease and dementia with Lewy bodies, from other similar diseases. However, this imaging test lacks validation of its diagnostic accuracy against the gold standard. Our aim was to validate the diagnostic accuracy of ¹²³I-MIBG myocardial scintigraphy for LBD against autopsy, the gold standard. Methods This retrospective, cross-sectional study included consecutive autopsy patients from the Brain Bank for Aging Research who had undergone ¹²³I-MIBG myocardial scintigraphy. We compared the ¹²³I-MIBG myocardial scintigraphy findings with autopsy findings. Furthermore, the proportion of residual tyrosine hydroxylase (TH)–immunoreactive sympathetic fibers in the anterior wall of the left ventricle was investigated to assess the condition of the cardiac sympathetic nerves assumed to cause reduced ¹²³I-MIBG uptake in LBDs. Results We analyzed the data of 56 patients (30 with pathologically confirmed LBDs and 26 without LBD pathology). Compared with the neuropathologic diagnosis, the early heart-to-mediastinum (H/M) ratio had a sensitivity and specificity of 70.0% (95% CI 50.6%–85.3%) and 96.2% (95% CI 80.4%–99.9%), respectively. The delayed H/M ratio had a sensitivity and specificity of 80.0% (95% CI 61.4%–92.3%) and 92.3% (95% CI 74.9%–99.1%), respectively. The washout rate had a sensitivity and specificity of 80.0% (95% CI 61.4%–92.3%) and 84.6% (95% CI 65.1%–95.6%), respectively. The proportion of residual TH-immunoreactive cardiac sympathetic fibers strongly correlated with the amount of cardiac ¹²³I-MIBG uptake when assessed with early and delayed H/M ratio values (correlation coefficient 0.75 and 0.81, respectively; p < 0.001). Discussion This clinicopathologic validation study revealed that ¹²³I-MIBG myocardial scintigraphy could robustly differentiate LBDs from similar diseases. Abnormal ¹²³I-MIBG myocardial scintigraphy findings strongly support the presence of LBD and cardiac sympathetic denervation. However, LBD pathology should not necessarily be excluded by normal myocardial scintigraphy results, especially when other biomarkers suggest the presence of comorbid Alzheimer disease pathology. Classification of Evidence This study provides Class II evidence that ¹²³I-MIBG myocardial scintigraphy accurately identifies patients with LBD.

The occurrence of malignant neoplasms increases with advancing age. Although aging and carcinogenesis are basically different processes, there are phenomena common to each such as accumulation of DNA damage and abnormal proteins. Gastric and colorectal carcinomas are representative tumors in which the prevalence and the number of patients increase significantly with age. Compared with gastric and colorectal cancers occurring in younger patients, those occurring in older patients have clinicopathological differences in tumor location, gender distribution, histological type, histological diversity, multiplicity, incidence of lymph node metastasis, and prognosis. In the elderly there are peculiar types of carcinoma such as medullary‐type poorly differentiated colorectal adenocarcinoma and solid‐type poorly differentiated gastric adenocarcinoma, both of which occur in older women. Methylation, apoptosis, and telomere dysfunction play important roles in the development of gastric and colorectal cancers in the elderly.