Fumio Yamashita

The neuropathological diagnosis of Alzheimer’s disease (AD) relies on amyloid beta (Aβ) deposition in brain tissues. To study the relationship between Aβ deposition and brain structure, as determined using ¹¹C-Pittsburgh compound B (PiB) and magnetic resonance imaging (MRI), respectively, we developed a regression model with PiB and MRI data as the predictor and response variables, respectively, and proposed a regression method for studying the association between them based on a supervised sparse multivariate analysis with dimension reduction based on a composite paired basis function. By applying this method to imaging data of 61 patients with AD (age: 55–85), the first component showed the strongest correlation with the composite score, owing to the supervised feature. The spatial pattern included the hippocampal and parahippocampal regions for MRI. The peak value was observed in the posterior cingulate and precuneus for PiB. The differences in PiB scores among the diagnosis groups 12 months after PiB imaging were significant between the normal and AD groups (p = 0.0284), but not between the normal and mild cognitive impairment (MCI) groups or the MCI and AD groups (p = 0.3508). Our method may facilitate the development of a dementia biomarker from brain imaging data. Scoring imaging data allows for visualization and the application of traditional analysis, facilitating clinical analysis for better interpretation of results.

The relationship between fatigue perception and regional gray matter volume (rGMV) has seldom been studied in healthy adults. Therefore, this study aimed to analyze sex differences in the correlation between rGMV and fatigue perception using Chalder’s fatigue questionnaire (CFQ). The CFQ was used to analyze the sexual features of rGMV related to the degree of perceived fatigue in 2955 healthy adults (male = 1560, female = 1395) of various ages (20–89 years, median 56). A higher CFQ score denotes a higher perceived fatigue level by the participant. According to the CFQ scores in males, the volumes of the right orbital part of the inferior frontal gyrus and left precuneus were negatively correlated (i.e., smaller rGMV had a higher CFQ score), whereas the left angular gyrus was positively correlated. In females, the right inferior temporal gyrus was negative, whereas the left middle temporal gyrus and right putamen were positive (i.e., larger rGMV had a higher CFQ score). The lack of identified regions in this large-scale study between males and females might be related to sex differences in clinical or pathological fatigue morbidities. Additionally, the sex differences in the negative or positive correlations between rGMV and fatigue perception may contribute to a better understanding of the neuronal mechanism in the early stages of fatigue development.

Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4 , whose DNA methylation levels have been reported to be altered in bipolar disorder, using three independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all three cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4 . We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles.

To better understand the risk factors and optimal therapeutic strategies of cerebral white matter hyperintensity (WMH), we examined a large population of adults with and without various vascular risk factors (VRFs) or vascular risk conditions (VRCs), such as hypertension (HT), diabetes mellitus (DM), and dyslipidemia (DLP), including the comorbidities. We assessed two participant groups having no medical history of stroke or dementia that underwent brain checkup using magnetic resonance imaging (MRI): 5541 participants (2760 men, 2781 women) without VRCs and 1969 participants (1169 men, 800 women) who had received drug treatments for VRCs and the combination of comorbidities. For data analysis, we constructed WMH-brain healthcare quotient (WMH-BHQ) based on the percentile rank of WMH volume. This metric has an inverse relation to WMH. Multiple linear regression analysis of 5541 participants without VRCs revealed that age, systolic blood pressure (SBP), Brinkman index (BI), and female sex were significant factors lowering WMH-BHQ, whereas body mass index (BMI), male sex, fasting blood sugar, and triglyceride levels were increasing factors. The Kruskal–Wallis test and Dunn tests showed that WMH-BHQs significantly increased or decreased with BMI or SBP and with BI classification, respectively. Regarding the impact of impaired fasting glucose and abnormal lipid metabolism, there were almost no significant relationships. For 1969 participants who had HT, DM, and DLP, as well as their comorbidities, we found that DLP played a substantial role in increasing WMH-BHQ for some comorbidities, whereas the presence of HT and DM alone tended to decrease it. Cerebral WMH can be used as a healthcare quotient for quantitatively evaluating VRFs and VRCs and their comorbidities.

OBJECTIVE: To determine whether voxel‐based morphometry of the cerebrospinal fluid (CSF) space can accurately differentiate iNPH from other related neurological disorders.METHODS: Nineteen patients with surgically proven iNPH and 24 patients with Alzheimer's disease (AD), 18 patients with Parkinson's disease (PD), and 14 healthy elderlies were examined. Regions of interest (ROIs) in the ventricular/sylvian (VS) and high convexity/midline (HCM) areas were used in VBM, and differences in CSF volume within these ROIs among the 4 groups were examined.RESULTS: The relative CSF volume in the VS‐ROI in the iNPH group (.64) was significantly higher than that in the AD, PD, and healthy control groups (.26, .29, and .17, respectively; P < .001), whereas the relative CSF volume in the HCM‐ROI was significantly reduced in the iNPH (.10) than in the other (.17, .16, and .16, respectively) groups (P < .001). Furthermore, the ratio of the 2 areas (VS/HCM) was markedly higher in the iNPH (6.87) than in the other (1.65, 1.74, .97, respectively) groups (P < .001), with sensitivity and specificity of .89 and 1.00, respectively.CONCLUSIONS: The VBM‐based CSF space analysis can detect disproportionate changes in CSF space and differentiate iNPH patients from those with AD or PD and healthy elderlies accurately.