Katsuyoshi Mizukami’s research while affiliated with University of Tsukuba and other places

Background While longitudinal studies have investigated the relationships between mild cognitive impairment (MCI) subtypes and dementia subtypes, the results have been contradictory. In addition, some research shows that depression accompanied by MCI might increase the risk of Alzheimer’s disease (AD). Objective The aim of this study is to longitudinally investigate the relationships between MCI subtypes and dementia subtypes, with special attention to the effect of comorbid depressive symptoms in a Japanese rural community. Methods Non-demented participants (n = 802) completed a baseline and follow-up study. Outcomes were conversion to dementia especially AD, MCI, or no conversion. A complementary log-log analysis was conducted to investigate the risk of dementia and AD in amnestic MCI (aMCI) compared to nonamnestic MCI (naMCI) groups. The impact of depressive symptoms on the transition from MCI to AD and from cognitively normal to MCI or AD was also analyzed. Results The risk of developing dementia, in particular AD, for the aMCI group was significantly higher than that for the naMCI group. In the aMCI group, the presence of depressive symptoms increased the risk of developing AD, but depressive symptoms in the naMCI group did not. In the cognitively normal group, the presence of depressive symptoms increased the risk of aMCI but not naMCI or AD. Conclusion MCI subtyping could be useful in finding a prodrome for dementia and in particular for AD. The differing impacts of depressive symptoms on the development of AD suggest that the relationship between depressive symptoms and cognitive impairment could differ in aMCI and naMCI patients.

Background Polygenic effects have been proposed to account for some disease phenotypes; these effects are calculated as a polygenic risk score (PRS). This score is correlated with Alzheimer’s disease (AD)-related phenotypes, such as biomarker abnormalities and brain atrophy, and is associated with conversion from mild cognitive impairment (MCI) to AD. However, the AD PRS has been examined mainly in Europeans, and owing to differences in genetic structure and lifestyle, it is unclear whether the same relationships between the PRS and AD-related phenotypes exist in non-European populations. In this study, we calculated and evaluated the AD PRS in Japanese individuals using genome-wide association study (GWAS) statistics from Europeans. Methods In this study, we calculated the AD PRS in 504 Japanese participants (145 cognitively unimpaired (CU) participants, 220 participants with late mild cognitive impairment (MCI), and 139 patients with mild AD dementia) enrolled in the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) project. In order to evaluate the clinical value of this score, we (1) determined the polygenic effects on AD in the J-ADNI and validated it using two independent cohorts (a Japanese neuropathology (NP) cohort ( n = 565) and the North American ADNI (NA-ADNI) cohort ( n = 617)), (2) examined the AD-related phenotypes associated with the PRS, and (3) tested whether the PRS helps predict the conversion of MCI to AD. Results The PRS using 131 SNPs had an effect independent of APOE . The PRS differentiated between CU participants and AD patients with an area under the curve (AUC) of 0.755 when combined with the APOE variants. Similar AUC was obtained when PRS calculated by the NP and NA-ADNI cohorts was applied. In MCI patients, the PRS was associated with cerebrospinal fluid phosphorylated-tau levels ( β estimate = 0.235, p value = 0.026). MCI with a high PRS showed a significantly increased conversion to AD in APOE ε4 noncarriers with a hazard rate of 2.22. In addition, we also developed a PRS model adjusted for LD and observed similar results. Conclusions We showed that the AD PRS is useful in the Japanese population, whose genetic structure is different from that of the European population. These findings suggest that the polygenicity of AD is partially common across ethnic differences.

Aim: There is a need for a cognitive function test that is less burdensome to perform cognitive function tests used to date and can detect mild changes in the cognitive function and mild cognitive impairment (MCI). We developed a cognitive function examination using a virtual reality device (VR-E). The purpose of this study was to verify its usability. Methods: Seventy-seven participants (29 males and 48 females, average age 75.1 years old) were classified according to their Clinical Dementia Rating (CDR). To estimate the validity of VR-E in measuring cognitive function, we used the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment-Japanese version (MoCA-J) scores as benchmarks. The MMSE was performed for all subjects, while the MoCA-J was performed for subjects with an MMSE score ≥20. Results: VR-E scores were highest in the CDR 0 group (0.77±0.15, mean±SD), decreasing for subsequent groups (CDR 0.5: 0.65±0.19, CDR 1-3: 0.22±0.21). The receiver operating characteristic analysis showed that all three methods were able to distinguish CDR groups. For CDR 0 vs. 0.5, the areas under the curve for MMSE/MoCA-J/VR-E were 0.85/0.80/0.70, respectively, and those for CDR 0.5 vs. 1-3 were 0.89/0.92/0.90, respectively. The time required to complete VR-E was approximately 5 minutes. Of the 77 subjects, 12 were difficult to assess using the VR-E due to poor understanding or eye diseases or Meniere's syndrome. Conclusions: The present findings suggested that the VR-E can be used as a cognitive function test that correlates with existing standard assessments for dementia and MCI.

Genome-wide association studies have demonstrated that polygenic risks shape Alzheimer’s disease (AD). To elucidate the polygenic architecture of AD phenotypes at a cellular level, we established induced pluripotent stem cells from 102 patients with AD, differentiated them into cortical neurons and conducted a genome-wide analysis of the neuronal production of amyloid β (Aβ). Using such a cellular dissection of polygenicity (CDiP) approach, we identified 24 significant genome-wide loci associated with alterations in Aβ production, including some loci not previously associated with AD, and confirmed the influence of some of the corresponding genes on Aβ levels by the use of small interfering RNA. CDiP genotype sets improved the predictions of amyloid positivity in the brains and cerebrospinal fluid of patients in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Secondary analyses of exome sequencing data from the Japanese ADNI and the ADNI cohorts focused on the 24 CDiP-derived loci associated with alterations in Aβ led to the identification of rare AD variants in KCNMA1. Using more than 100 independent iPSC lines derived from patients with Alzheimer’s disease, the authors discovered loci associated with the neuronal production of amyloid β and confirmed their influence using RNA interference.

In current clinical practice, when a fall occurs in a long‐term care facility, it is often treated as an accident. Falls are classified as one of the most commonly prevalent geriatric syndromes. As their causes are extremely diverse and complex, their occurrence rate depends on individual susceptibility, even if appropriate fall prevention measures are taken. Falls are common among older adults, and fractures and intracranial hemorrhage resulting from falls can lead to the deterioration of activities of daily living and death. For this reason, it is recommended that the risk of falls is assessed in the general population of older adults, and that appropriate interventions are carried out for those at high risk. In response to this situation, the Japan Geriatrics Society and the Japan Association of Geriatric Health Services Facilities have issued the following statements on falls as a geriatric syndrome based on scientific evidence, especially considering the frequent occurrence of falls in long‐term care facilities. Geriatr Gerontol Int 2022; ••: ••–••.

Although it is well documented that exercising is good for the mental health and cognitive function as well as the physical condition in elderly people, exercising is difficult in elderly individuals with a low motor function. To develop an exercise program targeting elderly individuals unsuited for whole-body exercises, we assessed the effects of facial exercises on the mental health and mood in healthy elderly people. Community-dwelling older adults (N = 75, age range = 65-87 yrs) were randomly divided into a facial exercises group and a wait-listed control group. A facial exercises program of 30 min was given twice a week for 12 weeks. This program consisted of rhythmic facial movement, muscle stretching, facial yoga, and Tanden breathing. The GHQ-12 for mental health were administered to both groups before and after the 12-week study period. In addition, facial expression and EEG were measured. Fifty-three participants completed the protocol. In the intervention group, the GHQ-12, facial expression, and α wave in frontal lobe improved post-intervention. These results suggest that facial exercises are effective in improving the mental health, facial expression, α wave in frontal lobe of elderly people, and that exercises may be useful as a therapeutic modality in this population.

Mental disorders are increasing worldwide. Previous research has reported an association between mental health and facial expressions. Face-to-face communication, specifically, is majorly affected when wearing face masks for a long time because of the COVID-19 pandemic. However, there have been no systematic reviews of facial muscles exercise intervention studies for mental health. Thus, evidence of their effect on mental health is unclear. This review aimed to evaluate the current evidence of the effectiveness of voluntary facial muscles exercise to improve some parameters of mental health. We implemented a systematic review of experimental studies (published between 2007 and 2018, 10 years before we decided to start this review). Of the 61,096 references screened, seven studies reported that facial muscles exercise may help to improve some parameters of mental health. Moreover, the study quality was assessed, and we extracted sub outcomes for mental health. Non-coherent results of seven experimental studies were included in this review. Voluntary facial muscles exercise may help improve depressive symptoms, mood, and reduce the level of chronic stress. However, due to the low quality of analyzed studies, further studies are needed to confirm the mental health benefits of a facial muscles exercise program.