Yasunari Nakamoto

Oxidative stress imaging using diacetyl-bis (N⁴-methylthiosemicarbazone) (Cu-ATSM) was applied to the evaluation of patients with early Alzheimer’s disease (eAD). Ten eAD patients (72 ± 9 years) and 10 age-matched healthy controls (HCs) (73 ± 9 years) participated in this study. They underwent dynamic PET/MRI using ¹¹C-PiB and ⁶⁴Cu-ATSM with multiple MRI sequences. To evaluate cerebral oxidative stress, three parameters of ⁶⁴Cu-ATSM PET were compared: standardized uptake value (SUV), tracer influx rate (K_in), and a rate constant k₃. The input functions were estimated by the image-derived input function method. The relative differences were analyzed by statistical parametric mapping (SPM) using SUV and K_in images. All eAD patients had positive and HC subjects had negative PiB accumulation, and MMSE scores were significantly different between them. The ⁶⁴Cu-ATSM accumulation tended to be higher in eAD than in HCs for both SUV and K_in. When comparing absolute values, eAD patients had a greater K_in in the posterior cingulate cortex and a greater k₃ in the hippocampus compared with lobar cortical values of HCs. In SPM analysis, eAD had an increased left operculum and decreased bilateral hippocampus and anterior cingulate cortex compared to HCs. ⁶⁴Cu-ATSM PET/MRI and tracer kinetic analysis elucidated cerebral oxidative stress in the eAD patients, particularly in the cingulate cortex and hippocampus.

Oxidative stress based on mitochondrial dysfunction is assumed to be the principal molecular mechanism for the pathogenesis of many neurodegenerative disorders. However, the effects of oxidative stress on the neurodegeneration process in living patients remain to be elucidated. Molecular imaging with positron emission tomography (PET) can directly evaluate subtle biological changes, including the redox status. The present review focuses on recent advances in PET imaging for oxidative stress, in particular the use of the Cu-ATSM radioligand, in neurodegenerative disorders associated with mitochondrial dysfunction. Since reactive oxygen species are mostly generated by leakage of excess electrons from an over-reductive state due to mitochondrial respiratory chain impairment, PET with ⁶²Cu-ATSM, the accumulation of which depends on an over-reductive state, is able to image oxidative stress. ⁶²Cu-ATSM PET studies demonstrated enhanced oxidative stress in the disease-related brain regions of patients with mitochondrial disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, the magnitude of oxidative stress increased with disease severity, indicating that oxidative stress based on mitochondrial dysfunction contributes to promoting neurodegeneration in these diseases. Oxidative stress imaging has improved our insights into the pathological mechanisms of neurodegenerative disorders, and is a promising tool for monitoring further antioxidant therapies.

An increase in cardiovascular diseases has been reported following major disasters. Previous work has shown that ultrasonographic findings from ultrasound cardiography examination (UCG) increased until the 44th month after the tsunami caused by the Great East Japan Earthquake. The present study conducted UCG among victims in the tsunami disaster area and investigated the frequency of disaster-related cardiovascular diseases and changes over time until the 55th month after the disaster. The subjects were residents of temporary housing complexes and neighboring housing in Watari-gun, Miyagi Prefecture, Japan. There were 207 subjects in the 18th month, 125 in the 30th month, 121 in the 44th month, and 106 in the 55th month after the disaster. Data were collected through UCG and self-report questionnaire. Significant changes were observed among subjects with clinical findings from the UCG, which increased over the study period—from 42.0 to 60.8, 72.7, and 73.6% beginning in the 18th month after the disaster (p < 0.0001). It is possible that the UCG can become a useful examination to visualize the potential impact of a major disaster on the cardiac function of victims. Victims with clinical findings continued increasing not only during the acute phase after a disaster but also in the long term. We therefore need to keep this in mind, and note that it is important to establish a support system to control cardiovascular diseases from the early stage of disaster. UMIN; ID000029802. R000034050 . 2 November 2017.

Increased plasma homocysteinemia is considered a risk factor of dementia, including Alzheimer’s disease (AD) and vascular dementia. However, the reason elevated plasma homocysteinemia increases the risk of dementia remains unknown. A pathological hallmark of AD is neurofibrillary tangles (NFTs) that consist of pathologically phosphorylated tau proteins. The effect of homocysteine (Hcy) on tau aggregation was explored using human neuroblastoma M1C cells that constitutively express human wild-type tau (4R0N) under the control of a tetracycline off system, primary mouse cultured neurons, and by inducing hyperhomocysteinemia in a mouse model of tauopathy (HHCy mice). A wide range of Hcy concentrations (10–1000 µM) increased total tau and phosphorylated tau protein levels. Hcy activated glycogen synthase kinase 3, and cyclin dependent kinase 5, major tau phosphokinases, and inactivated protein phosphatase 2A, a main tau phosphatase. Hcy exhibited cytotoxic effects associated with enhanced activation of caspase. Truncation of tau in the C-terminus, the cleavage site of caspase 3 (i.e., D421, detected by the TauC3 antibody) was also increased. Total tau, phosphorylated tau, as well as C-terminal cleaved tau were increased in the sarkosyl insoluble tau fraction. Hcy also increased the level of tau oligomers, as indicated by the tau oligomer complex 1 (TOC1) antibody that specifically identifies oligomeric tau species, in the tris insoluble, sarkosyl soluble fraction. The levels of TOC1-positive oligomeric tau were increased in brain lysates from HHCy mice, and treating HHCy mice with S-adenosylmethionine, an intermediate of Hcy, reduced the levels of oligomeric tau to control levels. These observations suggest that Hcy increases the levels of phosphorylated tau as well as truncated tau species via caspase 3 activation, and enhanced tau oligomerization and aggregation.

Sorafenib and hepatic arterial infusion chemotherapy (HAIC) are both indicated for unresectable hepatocellular carcinoma (HCC). In this study, we compared the efficacy and safety of HAIC to that of sorafenib in elderly patients with HCC. Eligible patients included those aged ≥70 years, with histologically or clinically confirmed advanced HCC. A total of 12 patients received sorafenib (800 mg per day) and 8 patients received HAIC with 5-fluorouracil (300 mg/m2 on days 1–5 and 8–12) with or without cisplatin (20 mg/m2 on days 1 and 8), with interferon-α (3 times per week for 4 weeks). The response rate was significantly higher in patients treated with HAIC (37.5%) compared to that in patients treated with sorafenib (no response). The median overall survival (18.6 and 11.7 months) and progression-free survival (4.0 and 5.0 months) were similar between the sorafenib and HAIC groups, respectively. In the sorafenib group, 58.3% of the patients discontinued treatment compared to none in the HAIC group. The most frequent adverse event leading to discontinuation of sorafenib was anorexia. Similar to sorafenib, HAIC appears to be a feasible treatment and may also have the advantage of an adequate safety profile for elderly patients with advanced HCC. Further study of HAIC in a larger population of elderly patients is required to assess its potential as an alternative to sorafenib for HCC.