Plasma biomarkers for predicting the development of dementia in a community-dwelling older Japanese population.

AIM: To assess the association between plasma amyloid ß (Aß) 42/40, phosphorylated tau (p-τ)181, glial fibrillary acidic protein (GFAP), or neurofilament light chain (NfL) and the risk of dementia and to determine whether these plasma biomarkers could improve the ability to predict incident dementia in a general older population. METHODS: A total of 1346 Japanese community-dwelling individuals aged ≥65 years without dementia were followed prospectively for 5.0 years. Plasma biomarkers were quantified using a Simoa HD-X analyzer. A Cox proportional hazards model was used to estimate the hazard ratios of each plasma biomarker level for the risk of dementia. RESULTS: During the follow-up, 151 participants developed dementia, of whom 108 had Alzheimer disease (AD) and 43 non-Alzheimer dementia (non-AD). Lower plasma Aß42/40 levels and higher plasma p-τ181 levels were significantly associated with developing AD but not non-AD, whereas significant associations were observed between higher plasma levels of GFAP and NfL and risk of both AD and non-AD (all P for trend <0.05). In addition, adding these four plasma biomarkers into a model consisting of the total score of the dementia risk model significantly improved the predictive ability for incident dementia. CONCLUSION: Our findings suggest that plasma Aß42/40 and p-τ181 are specific markers of AD, and plasma GFAP and NfL are potential biomarkers for all-cause dementia in the general Japanese older population. In addition, the measurement of these plasma biomarkers may be a useful and relatively low-invasive procedure for identifying individuals at high risk for developing dementia in clinical practice.

Serum high-sensitivity C-reactive protein and dementia in a community-dwelling Japanese older population (JPSC-AD).

In recent years, the association between neuroinflammatory markers and dementia, especially Alzheimer's disease (AD), has attracted much attention. However, the evidence for the relationship between serum-hs-CRP and dementia including AD are inconsistent. Therefore, the relationships of serum high-sensitivity CRP (hs-CRP) with dementia including AD and with regions of interest of brain MRI were investigated. A total of 11,957 community residents aged 65 years or older were recruited in eight sites in Japan (JPSC-AD Study). After applying exclusion criteria, 10,085 participants who underwent blood tests and health-related examinations were analyzed. Then, serum hs-CRP levels were classified according to clinical cutoff values, and odds ratios for the presence of all-cause dementia and its subtypes were calculated for each serum hs-CRP level. In addition, the association between serum hs-CRP and brain volume regions of interest was also examined using analysis of covariance with data from 8614 individuals in the same cohort who underwent brain MRI. After multivariable adjustment, the odds ratios (ORs) for all-cause dementia were 1.04 (95% confidence interval [CI] 0.76-1.43), 1.68 (95%CI 1.08-2.61), and 1.51 (95%CI 1.08-2.11) for 1.0-1.9 mg/L, 2.0-2.9 mg/L, and ≥ 3.0 mg/L, respectively, compared to < 1.0 mg/L, and those for AD were 0.72 (95%CI 0.48-1.08), 1.76 (95%CI 1.08-2.89), and 1.61 (95%CI 1.11-2.35), for 1.0-1.9 mg/L, 2.0-2.9 mg/L, and ≥ 3.0 mg/L, respectively, compared to < 1.0 mg/L. Multivariable-adjusted ORs for all-cause dementia and for AD prevalence increased significantly with increasing serum hs-CRP levels (p for trend < 0.001 and p = 0.001, respectively). In addition, the multivariable-adjusted temporal cortex volume/estimated total intracranial volume ratio decreased significantly with increasing serum hs-CRP levels (< 1.0 mg/L 4.28%, 1.0-1.9 mg/L 4.27%, 2.0-2.9 mg/L 4.29%, ≥ 3.0 mg/L 4.21%; p for trend = 0.004). This study's results suggest that elevated serum hs-CRP levels are associated with greater risk of presence of dementia, especially AD, and of temporal cortex atrophy in a community-dwelling Japanese older population.

Gesture imitation performance in community-dwelling older people: assessment of a gesture imitation task in the screening and diagnosis of mild cognitive impairment and dementia.

BACKGROUND: Gesture imitation, a simple tool for assessing visuospatial/visuoconstructive functions, is reportedly useful for screening and diagnosing dementia. However, gesture imitation performance in healthy older adults is largely unknown, as are the factors associated with lower performance. To address these unknowns, we examined the gesture imitation performance of a large number of community-dwelling older adults aged ≥65 years in Arao City, Kumamoto Prefecture (southern Japan). METHODS: The examiner presented the participants with eight gesture patterns and considered it a success if they could imitate them within 10 s. The success rate of each gesture imitation was calculated for three diagnostic groups: cognitively normal (CN) (n = 1184), mild cognitive impairment (MCI) (n = 237), and dementia (n = 47). Next, we reorganised the original gesture imitation battery by combining six selected gestures with the following scoring method: if the participants successfully imitated the gestures, immediately or within 5 s, two points were assigned. If they succeeded within 5-10 s, one point was assigned. The sensitivity and specificity of the battery were investigated to detect the dementia and MCI groups. Factors associated with gesture imitation battery scores were examined. RESULTS: Except one complex gesture, the success rate of imitation in the CN group was high, approximately 90%. The sensitivity and specificity of the gesture imitation battery for discriminating between the dementia and CN groups and between the MCI and CN groups were 70%/88%, and 45%/75%, respectively. Ageing, male sex, and a diagnosis of dementia or MCI were associated with lower scores on the gesture imitation battery. CONCLUSION: Gesture imitation tasks alone may not be sufficient to detect MCI. However, by combining gestures with set time limits, gesture imitation tasks can be a low-burden and effective method for detecting dementia, even in community medicine, such as during health check-ups.

Identification of the antidepressant effect of electroconvulsive stimulation-related genes in hippocampal astrocyte.

Major depressive disorder (MDD) remains a significant global health concern, with limited and slow efficacy of existing antidepressants. Electroconvulsive therapy (ECT) has superior and immediate efficacy for MDD, but its action mechanism remains elusive. Therefore, the elucidation of the action mechanism of ECT is expected to lead to the development of novel antidepressants with superior and immediate efficacy. Recent studies suggest a potential role of hippocampal astrocyte in MDD and ECT. Hence, we investigated antidepressant effect of electroconvulsive stimulation (ECS), an animal model of ECT, -related genes in hippocampal astrocyte with a mouse model of MDD, in which corticosterone (CORT)-induced depression-like behaviors were recovered by ECS. In this model, both of CORT-induced depression-like behaviors and the reduction of hippocampal astrocyte were recovered by ECS. Following it, astrocytes were isolated from the hippocampus of this model and RNA-seq was performed with these isolated astrocytes. Interestingly, gene expression patterns altered by CORT were reversed by ECS. Additionally, cell proliferation-related signaling pathways were inhibited by CORT and recovered by ECS. Finally, serum and glucocorticoid kinase-1 (SGK1), a multi-functional protein kinase, was identified as a candidate gene reciprocally regulated by CORT and ECS in hippocampal astrocyte. Our findings suggest a potential role of SGK1 in the antidepressant effect of ECS via the regulation of the proliferation of astrocyte and provide new insights into the involvement of hippocampal astrocyte in MDD and ECT. Targeting SGK1 may offer a novel approach to the development of new antidepressants which can replicate superior and immediate efficacy of ECT.

TCF7L2: A potential key regulator of antidepressant effects on hippocampal astrocytes in depression model mice.

Clinical and preclinical studies suggest that hippocampal astrocyte dysfunction is involved in the pathophysiology of depression; however, the underlying molecular mechanisms remain unclear. Here, we attempted to identify the hippocampal astrocytic transcripts associated with antidepressant effects in a mouse model of depression. We used a chronic corticosterone-induced mouse model of depression to assess the behavioral effects of amitriptyline, a tricyclic antidepressant. Hippocampal astrocytes were isolated using fluorescence-activated cell sorting, and RNA sequencing was performed to evaluate the transcriptional profiles associated with depressive effects and antidepressant responses. Depression model mice exhibited typical depression-like behaviors that improved after amitriptyline treatment; the depression group mice also had significantly reduced GFAP-positive astrocyte numbers in hippocampal subfields. Comprehensive transcriptome analysis of hippocampal astrocytes showed opposing responses to amitriptyline in depression group and control mice, suggesting the importance of using the depression model. Transcription factor 7 like 2 (TCF7L2) was the only upstream regulator gene altered in depression model mice and restored in amitriptyline-treated depression model mice. In fact, TCF7L2 expression was significantly decreased in the depression group. The level of TCF7L2 long non-coding RNA, which controls mRNA expression of the TCF7L2 gene, was also significantly decreased in this group and recovered after amitriptyline treatment. The Gene Ontology biological processes associated with astrocytic TCF7L2 included proliferation, differentiation, and cytokine production. We identified TCF7L2 as a gene associated with depression- and antidepressant-like behaviors in response to amitriptyline in hippocampal astrocytes. Our findings could provide valuable insights into the mechanism of astrocyte-mediated antidepressant effects.

G protein-biased LPAR1 agonism of prototypic antidepressants: Implication in the identification of novel therapeutic target for depression.

Prototypic antidepressants, such as tricyclic/tetracyclic antidepressants (TCAs), have multiple pharmacological properties and have been considered to be more effective than newer antidepressants, such as selective serotonin reuptake inhibitors, in treating severe depression. However, the clinical contribution of non-monoaminergic effects of TCAs remains elusive. In this study, we discovered that amitriptyline, a typical TCA, directly binds to the lysophosphatidic acid receptor 1 (LPAR1), a G protein-coupled receptor, and activates downstream G protein signaling, while exerting a little effect on ß-arrestin recruitment. This suggests that amitriptyline acts as a G protein-biased agonist of LPAR1. This biased agonism was specific to TCAs and was not observed with other antidepressants. LPAR1 was found to be involved in the behavioral effects of amitriptyline. Notably, long-term infusion of mouse hippocampus with the potent G protein-biased LPAR agonist OMPT, but not the non-biased agonist LPA, induced antidepressant-like behavior, indicating that G protein-biased agonism might be necessary for the antidepressant-like effects. Furthermore, RNA-seq analysis revealed that LPA and OMPT have opposite patterns of gene expression changes in the hippocampus. Pathway analysis indicated that long-term treatment with OMPT activated LPAR1 downstream signaling (Rho and MAPK), whereas LPA suppressed LPAR1 signaling. Our findings provide insights into the mechanisms underlying the non-monoaminergic antidepressant effects of TCAs and identify the G protein-biased agonism of LPAR1 as a promising target for the development of novel antidepressants.

Gender and age influence the association between gait speed and mild cognitive impairment in community-dwelling Japanese older adults: from the Japan Prospective Studies Collaboration for Ageing and Dementia (JPSC-AD).

BACKGROUND: Studies have shown that decreased gait speed is associated with impaired cognitive function. However, whether this association is equivalent across ages or genders in the older population remains unclear. Thus, we examined the association between mild cognitive impairment (MCI) and gait speed emphasising the influence of age and gender. METHODS: Overall, 8233 Japanese participants aged ≥65 years were enrolled in this cross-sectional study between 2016 and 2018. After stratification by gender and age group, the participants' gait speeds were divided into quintiles, and the difference in MCI prevalence at each gait speed quintile was calculated. Logistic regression analyses were performed to assess the odds of MCI for each quintile and to assess the influence of age and gender. RESULTS: Males had a consistently higher prevalence of MCI than females. The odds of MCI were increased as gait speed decreased. Logistic regression analyses revealed that in the multivariable-adjusted model 2, the odds ratios (95% confidence interval; CI) for MCI were 2.02 (1.47-2.76) for females and 1.75 (1.29-2.38) for males in the slowest gait speed quintiles compared to the fastest quintile. In the stratified analyses, only males showed an age-dependent increase in the associations between gait speed and MCI, while females exhibited comparable associations across age groups. CONCLUSIONS: Reduced gait speed was associated with increased odds of MCI, and this association may vary according to gender and age. Therefore, gait speed could serve as a valuable screening tool for MCI, with gender- and age-dependent clinical implications.

A machine learning-based scoring system and ten factors associated with hip fracture occurrence in the elderly.

Hip fractures are fragility fractures frequently seen in persons over 80-years-old. Although various factors, including decreased bone mineral density and a history of falls, are reported as hip fracture risks, few large-scale studies have confirmed their relevance to individuals older than 80, and tools to assess contributions of various risks to fracture development and the degree of risk are lacking. We recruited 1395 fresh hip fracture patients and 1075 controls without hip fractures and comprehensively evaluated various reported risk factors and their association with hip fracture development. We initially constructed a predictive model using Extreme Gradient Boosting (XGBoost), a machine learning algorithm, incorporating all 40 variables and evaluated the model's performance using the area under the receiver operating characteristic curve (AUC), yielding a value of 0.87. We also employed SHapley Additive exPlanation (SHAP) values to evaluate each feature importance and ranked the top 20. We then used a stepwise selection method to determine key factors sequentially until the AUC reached a plateau nearly equal to that of all variables and identified the top 10 sufficient to evaluate hip fracture risk. For each, we determined the cutoff value for hip fracture occurrence and calculated scores of each variable based on the respective feature importance. Individual scores were: serum 25(OH)D levels (<10 ng/ml, score 7), femoral neck T-score (<-3, score 5), Barthel index score (<100, score 3), maximal handgrip strength (<18 kg, score 3), GLFS-25 score (≥24, score 2), number of falls in previous 12 months (≥3, score 2), serum IGF-1 levels (<50 ng/ml, score 2), cups of tea/day (≥5, score -2), use of anti-osteoporosis drugs (yes, score -2), and BMI (<18.5 kg/m2, score 1). Using these scores, we performed receiver operating characteristic (ROC) analysis and the resultant optimal cutoff value was 7, with a specificity of 0.78, sensitivity of 0.75, and AUC of 0.85. These ten factors and the scoring system may represent tools useful to predict hip fracture.

Association Between Frequency of Social Contact and Brain Atrophy in Community-Dwelling Older People Without Dementia: The JPSC-AD Study.

BACKGROUND AND OBJECTIVES: Epidemiologic evidence has shown that social isolation, a low frequency of social contact with others, is associated with the risk of dementia and late-life depressive symptoms. Therefore, we hypothesized that low frequency of social contact may be involved in brain atrophy, and depressive symptoms may play some role in this relationship. We aimed to evaluate the association between low frequency of social contact and the volumes of various brain regions and to assess the extent to which depressive symptoms mediate these relationships from a large population-based multisite cohort study. METHODS: Dementia-free community-dwelling Japanese aged 65 years or older underwent brain MRI scans and a comprehensive health examination. Frequency of contact with noncohabiting relatives and friends was determined by asking a single question with 4 categories: everyday, several times a week, several times a month, and seldom. Total and regional brain volumes, intracranial volume (ICV), and white matter lesion volume were estimated using FreeSurfer software. The associations between frequency of social contact and brain volumes per ICV were examined using analyses of covariance. Mediation analyses were conducted to calculate the proportion of the associations explained by depressive symptoms. RESULTS: We included 8,896 participants. The multivariable-adjusted mean of the total brain volume in the group with the lowest frequency of social contact was significantly lower compared with that in the group with the highest frequency of social contact (67.3% vs 67.8%), with a significant increasing trend across the groups (p value for trend <0.001). The white matter lesion volume increased significantly with lower frequency of social contact (0.30% in the lowest frequency group vs 0.26% in the highest frequency group, p value for trend <0.001). Lower frequency of social contact was associated with smaller volumes in the temporal lobe, occipital lobe, cingulum, hippocampus, and amygdala (all q values of false discovery rate correction <0.05). The relationships seemed to be partly mediated by depressive symptoms, which accounted for 15%-29% of the observed associations. DISCUSSION: Lower frequency of social contact was associated with decreased total and cognitive function-related regional brain volumes. In addition, depressive symptoms partially explained the association in community-dwelling older people without dementia in Japan.

The trajectory of non-depressed suicidal ideation in community-dwelling older people in a rural area in Japan: a prospective longitudinal study with a 3-year follow-up.

BACKGROUND: Suicidal ideation is closely related to severe suicidal behaviour and is an important predictor of suicide attempt and completion, including in older people. Older people tend to have many opportunities to be conscious of death, and may have vague suicidal ideation because of various loss experiences, even if they are not depressed. We hypothesised that suicidal ideation among older people might be a risk factor for later transition to depression. The present study aimed to clarify risk factors that predict the incidence of depression in older people 3 years post-baseline in a rural area of Japan, and to examine the subsequent course of depression among non-depressed older people with suicidal ideation. METHODS: In 2015 and 2018, survey questionnaires were mailed to residents aged 65 years and over living in a rural area in Japan. Participants were divided into a depression group and a non-depression group using 15-item Geriatric Depression Scale scores 3 years post-baseline. Logistic regression analysis was used to identify predictive factors of late-life depression 3 years post-baseline. RESULTS: We received 597 valid responses, with a 3-year follow-up rate of 78.8%. Regarding suicidal ideation, 6.7% of non-depressed older people exhibited suicidal ideation at baseline. Of these, 9.8% exhibited depression after 3 years post-baseline. Logistic regression analysis indicated that development of late-life depression is significantly associated with suicidal ideation, being female, and poor health-related quality of life (HRQOL). CONCLUSIONS: The results revealed that suicidal ideation, being female, and poor HRQOL were predictive factors of the development of late-life depression 3 years post-baseline in a rural area of Japan. These findings provide novel information regarding the transition to depression among community-dwelling older people who are not depressed but have suicidal ideation. Whereas suicidal ideation is considered to be a symptom of depression, the current results suggest that suicidal ideation may precede depression in some older people.

Serum levels of high mobility group box-1 protein (HMGB1) and soluble receptors of advanced glycation end-products (RAGE) in depressed patients treated with electroconvulsive therapy.

AIMS: High mobility group box-1 (HMGB1) is one of the damage-associated molecular patterns produced by stress and induces inflammatory responses mediated by receptors of advanced glycation end-products (RAGE) on the cell surface. Meanwhile, soluble RAGE (sRAGE) exhibits an anti-inflammatory effect by capturing HMGB1. Animal models have shown upregulation of HMGB1 and RAGE in the brain or blood, suggesting the involvement of these proteins in depression pathophysiology. However, there have been no reports using blood from depressed patients, nor ones focusing on HMGB1 and sRAGE changes associated with treatment and their relationship to depressive symptoms. METHODS: Serum HMGB1 and sRAGE concentrations were measured by enzyme-linked immunosorbent assay in a group of patients with severe major depressive disorder (MDD) (11 males and 14 females) who required treatment with electroconvulsive therapy (ECT), and also in a group of 25 age- and gender-matched healthy subjects. HMGB1 and sRAGE concentrations were also measured before and after a course of ECT. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAMD). RESULTS: There was no significant difference in HMGB1 and sRAGE concentrations in the MDD group compared to healthy subjects. Although ECT significantly improved depressive symptoms, there was no significant change in HMGB1 and sRAGE concentrations before and after treatment. There was also no significant correlation between HMGB1 and sRAGE concentrations and the HAMD total score or subitem scores. CONCLUSION: There were no changes in HMGB1 and sRAGE in the peripheral blood of severely depressed patients, and concentrations had no relationship with symptoms or ECT.

Comparison of caregiver burden between dementia with Lewy bodies and Alzheimer's disease.

BACKGROUND: Caring for patients with dementia with Lewy bodies (DLB) would be more stressful for their caregivers than those with Alzheimer's disease (AD). In this study, we compared levels of caregiver burden and the possible influential factors on the caregiver burden between DLB and AD. METHODS: Ninety-three DLB patients and 500 AD patients were selected from the Kumamoto University Dementia Registry. Caregiver burden, neuropsychiatric symptoms, basic activities of daily living (BADL) and instrumental activities of daily living (IADL) were assessed by the Japanese version of the Zarit Caregiver Burden Interview (J-ZBI), the Neuropsychiatric Inventory (NPI), the Physical Self-Maintenance Scale (PSMS), and the Lawton IADL scale, respectively. RESULTS: Despite the comparable Mini-Mental State Examination score, the J-ZBI score was significantly higher in the DLB group than the AD group (P = 0.012). A stepwise multiple regression analysis revealed that IADL score (ß = -0.23, P = 0.049), PSMS score (ß = -0.31, P = 0.010), disinhibition (ß = 0.22, P = 0.008), and anxiety (ß = 0.19, P = 0.027) were significantly associated with J-ZBI score in DLB. In AD, caregiver's relationship with patient (child) (ß = 0.104, P = 0.005), caregiver's gender (female) (ß = 0.106, P = 0.004), IADL score (ß = -0.237, P < 0.001), irritability (ß = 0.183, P < 0.001), apathy (ß = 0.132, P = 0.001), agitation (ß = 0.118, P = 0.007), and aberrant motor behaviour (ß = 0.107, P = 0.010) were associated with caregiver burden. CONCLUSIONS: Caring for DLB patients caused a higher degree of caregiver burden than AD patients in the same level of cognitive decline. The factors responsible for the caregiver's burden were different between DLB and AD. The caregiver burden for DLB patients was associated with the disability of basic ADL, IADL impairment, anxiety and disinhibition.

CKD, Brain Atrophy, and White Matter Lesion Volume: The Japan Prospective Studies Collaboration for Aging and Dementia.

Rationale & Objective: Chronic kidney disease, defined by albuminuria and/or reduced estimated glomerular filtration rate (eGFR), has been reported to be associated with brain atrophy and/or higher white matter lesion volume (WMLV), but there are few large-scale population-based studies assessing this issue. This study aimed to examine the associations between the urinary albumin-creatinine ratio (UACR) and eGFR levels and brain atrophy and WMLV in a large-scale community-dwelling older population of Japanese. Study Design: Population-based cross-sectional study. Setting & Participants: A total of 8,630 dementia-free community-dwelling Japanese aged greater than or equal to 65 years underwent brain magnetic resonance imaging scanning and screening examination of health status in 2016-2018. Exposures: UACR and eGFR levels. Outcomes: The total brain volume (TBV)-to-intracranial volume (ICV) ratio (TBV/ICV), the regional brain volume-to-TBV ratio, and the WMLV-to-ICV ratio (WMLV/ICV). Analytical Approach: The associations of UACR and eGFR levels with the TBV/ICV, the regional brain volume-to-TBV ratio, and the WMLV/ICV were assessed by using an analysis of covariance. Results: Higher UACR levels were significantly associated with lower TBV/ICV and higher geometric mean values of the WMLV/ICV (P for trend = 0.009 and <0.001, respectively). Lower eGFR levels were significantly associated with lower TBV/ICV, but not clearly associated with WMLV/ICV. In addition, higher UACR levels, but not lower eGFR, were significantly associated with lower temporal cortex volume-to-TBV ratio and lower hippocampal volume-to-TBV ratio. Limitations: Cross-sectional study, misclassification of UACR or eGFR levels, generalizability to other ethnicities and younger populations, and residual confounding factors. Conclusions: The present study demonstrated that higher UACR was associated with brain atrophy, especially in the temporal cortex and hippocampus, and with increased WMLV. These findings suggest that chronic kidney disease is involved in the progression of morphologic brain changes associated with cognitive impairment.

Impact of age on the cerebrospinal fluid spaces: high-convexity and medial subarachnoid spaces decrease with age.

BACKGROUND: Impaired cerebrospinal fluid (CSF) dynamics may contribute to the pathophysiology of neurodegenerative diseases, and play a crucial role in brain health in older people; nonetheless, such age-related changes have not been well elucidated. Disproportionately enlarged subarachnoid-space hydrocephalus (DESH) is a neuroimaging phenotype of idiopathic normal-pressure hydrocephalus, originating from impaired CSF dynamics, and closely associated with aging. This study aimed to investigate the pathophysiology of DESH and determine age-related changes in CSF dynamics. METHODS: Using magnetic resonance imaging, we investigated the pathophysiology of DESH by quantitatively evaluating the volumes of DESH-related regions (ventricles [VS], Sylvian fissure [SF], and subarachnoid spaces at high convexity and midline [SHM]) and brain parenchyma in community-dwelling individuals aged ≥ 65 years. DESH-related regions were assessed using a visual rating scale, and volumes measured using voxel-based morphometry. Brain parenchyma volumes were measured using FreeSurfer software. RESULTS: Data from 1,356 individuals were analyzed, and 25 (1.8%) individuals had DESH. Regarding the relationships between the volume of each CSF space and age, VS and SF volumes increased with age, whereas SHM volume did not increase. VS and SF volumes increased as the whole brain volume decreased, whereas SHM volume did not increase even if the whole brain volume decreased; that is, SHM did not expand even if brain atrophy progressed. Moreover, lower Mini-Mental State Examination scores were significantly associated with lower SHM volume and higher VS volume. These associations remained significant even when individuals with DESH were excluded. CONCLUSIONS: This study showed that the volume of high-convexity and medial subarachnoid spaces did not expand and tended to decrease with age; the human brain continuously progresses toward a "DESH-like" morphology with aging in community-dwelling older persons (i.e., DESH might be an "accelerated aging stage" rather than an "age-related disorder"). Our results indicated that brain atrophy may be associated with the development of "DESH-like" morphology. In addition, this morphological change, as well as brain atrophy, is an important condition associated with cognitive decline in older adults. Our findings highlight the importance of investigating the aging process of CSF dynamics in the human brain to preserve brain health in older people.

Tetraspanin heterogeneity of small extracellular vesicles in human biofluids and brain tissue.

Extracellular vesicles (EVs) are particles released from most cell types delimited by a lipid bilayer. Small EVs (sEVs) are nanosized (<200 nm) and include exosomes. Brain-derived sEVs may provide a source for new biomarkers of brain status. CD9, CD63, and CD81 are major members of the tetraspanin family frequently used as sEV markers. However, according to a recent report, tetraspanins were not equally expressed in all sEVs, but rather show heterogeneity that reflects the expression levels in their secretory cells. We therefore investigated tetraspanin heterogeneity of sEVs in biofluids commonly used for clinical laboratory tests, and those in the brain. Expression levels and distributions of CD9, CD63 and CD81 on sEVs were determined in serum, plasma, and cerebrospinal fluid (CSF) samples collected from each healthy donor, and in post-mortem brain tissue samples. We found heterogeneous mixes of sEVs with various tetraspanin combinations among sEVs, and the predominant types and heterogeneous patterns of tetraspanins were specific to sample type. Hierarchical clustering revealed that brain sEVs were similar to those in the CSF, but different from those in peripheral blood. Our findings both provide basic information and contribute to the development of biomarkers for neurological and psychiatric disorders.

An Online Survey About Electroconvulsive Therapy in Japan During the COVID-19 Pandemic: Comparison of Early and Recent Stages.

Purpose: To provide an overview of how electroconvulsive therapy (ECT) practice in Japan has changed as the coronavirus disease 2019 (COVID-19) pandemic continues. Patients and Methods: We surveyed healthcare institutions, primarily university and general hospitals, regarding changes in the number of patients undergoing ECT and infection control measures in the early (August 2020) and recent (August 2021) stages of the COVID-19 pandemic. Data for the early and recent stages were also compared between urban and non-urban areas. Results: Among 32 facilities, the number of patients undergoing ECT decreased in 11 facilities (34.4%) from April 2020 to March 2021 compared with the previous year, whereas the number increased in 12 (37.5%) from April to June 2021 compared with the previous year. As of August 2021, some facilities had ongoing restrictions. Compared with non-urban facilities, the number of patients undergoing ECT decreased more in urban facilities, which also had more ECT restrictions. Maintenance ECT was used at the same rate as before the pandemic for 23 (82.1%) of 28 institutions. Regarding infection control measures, many facilities considered polymerase chain reaction testing before ECT and required all staff to wear surgical masks and eye shields during ECT. Conclusion: The COVID-19 pandemic in Japan greatly affected the use of ECT in 2020; however, by the summer of 2021, infection control measures were relatively well established, the number of ECT cases stabilized and increased, and the decision to use ECT was again possible.

Higher-resolution quantification of white matter hypointensities by large-scale transfer learning from 2D images on the JPSC-AD cohort.

White matter lesions (WML) commonly occur in older brains and are quantifiable on MRI, often used as a biomarker in Aging research. Although algorithms are regularly proposed that identify these lesions from T2-fluid-attenuated inversion recovery (FLAIR) sequences, none so far can estimate lesions directly from T1-weighted images with acceptable accuracy. Since 3D T1 is a polyvalent and higher-resolution sequence, it could be beneficial to obtain the distribution of WML directly from it. However a serious difficulty, both for algorithms and human, can be found in the ambiguities of brain signal intensity in T1 images. This manuscript shows that a cross-domain ConvNet (Convolutional Neural Network) approach can help solve this problem. Still, this is non-trivial, as it would appear to require a large and varied dataset (for robustness) labelled at the same high resolution (for spatial accuracy). Instead, our model was taught from two-dimensional FLAIR images with a loss function designed to handle the super-resolution need. And crucially, we leveraged a very large training set for this task, the recently assembled, multi-sites Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) cohort. We describe the two-step procedure that we followed to handle such a large number of imperfectly labeled samples. A large-scale accuracy evaluation conducted against FreeSurfer 7, and a further visual expert rating revealed that WML segmentation from our ConvNet was consistently better. Finally, we made a directly usable software program based on that trained ConvNet model, available at https://github.com/bthyreau/deep-T1-WMH.

Relationship between preoperative anxiety and onset of delirium after cardiovascular surgery in elderly patients: focus on personality and coping process.

BACKGROUND: Postoperative delirium is associated with increased mortality. Therefore, it is important to manage delirium during the entire perioperative period. Preoperative anxiety is associated with poor prognosis in postoperative patients who have undergone cardiovascular surgery. This study aims to investigate the relationship between preoperative anxiety and onset of delirium after cardiovascular surgery in elderly patients (aged 65 years or older), considering the individual psychological characteristics, such as personality and stress coping skills in response to anxiety, as confounding factors. METHODS: This prospective study included patients aged >65 years in a preoperative state before undergoing cardiovascular surgery. Subjects were divided into two groups based on whether they experienced postoperative delirium, or not. We compared clinical and demographic factors, preoperative psychiatric and psychological factors, and intraoperative and perioperative physical factors between the control and delirium groups. Multiple imputations were used to account for missing data. RESULTS: Out of 168 subjects enrolled in this study, 26 (15.5%) developed postoperative delirium. Univariate analysis showed significant differences in age (P = 0.027), cognitive function (P = 0.007), agreeableness (P = 0.029), and the Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score (P = 0.023) between the delirium and control groups. Multiple logistic regression analysis did not identify a significant association between preoperative anxiety and the onset of postoperative delirium. However, age (odds ratio (OR) = 1.114, P = 0.018), agreeableness (OR = 0.555, P = 0.008), and the APACHE-II score (OR = 1.227, P = 0.008) were identified as risk factors for postoperative delirium. CONCLUSION: Agreeableness, one of the personality traits associated with preoperative anxiety, appears to be involved in the development of postoperative delirium as an independent psychological factor, regardless of age or physical factors.

Late-manifestation of attention-deficit/hyperactivity disorder in older adults: an observational study.

BACKGROUND: The age of attention-deficit/hyperactivity disorder onset is usually during the first 12 years of life; however, there have been recent reports of late-onset attention-deficit/hyperactivity disorder. These reports have been limited to that of young adults, and details in older adults remain unknown. As such, we had previously presented the first case report of "very" late-onset attention-deficit/hyperactivity disorder, wherein the symptoms presented in senile age. In this observational study, we aimed to investigate the prevalence and clinical features of such attention-deficit/hyperactivity disorders in older adults visiting our dementia clinic. METHODS: Four hundred forty-six consecutive patients visiting our specialty outpatient clinic for dementia during the 2-year period from April 1, 2015 to March 31, 2017 were included in this study. First, the patients were examined for the presence or absence of dementia in our specialty outpatient clinic for dementia. Those not diagnosed with dementia were examined for the presence or absence of attention-deficit/hyperactivity disorder in our specialty outpatient clinic for developmental disorders. Finally, these patients who were diagnosed with attention-deficit/hyperactivity disorder were investigated in detail to clarify their clinical characteristics. RESULTS: Of 446 patients (246 women and 200 men), 7 patients were finally diagnosed with attention-deficit/hyperactivity disorder. Although these 7 patients were initially suspected to have Alzheimer's disease (considering their age, 6 of these 7 patients were suspected to have early onset Alzheimer's disease), it was found that these symptoms were due to attention-deficit/hyperactivity disorder. These patients had four characteristics in common: (1) they were significantly younger than the complete study population; (2) they predominantly showed inattention-related symptoms; (3) they showed latent manifestation; and (4) they experienced a stressful life event before manifestation. CONCLUSIONS: Our previous case report suggested that very late-onset attention-deficit/hyperactivity disorder patients could be incorrectly diagnosed with dementia. In this observational study, 1.6% of patients who were initially suspected of having dementia were actually diagnosed with attention-deficit/hyperactivity disorder. This study also showed that the "late-onset" described in our previous report would be better described as "late-manifestation." A clinician should consider late-manifestation of attention-deficit/hyperactivity disorder in the differential diagnosis when encountering dementia patients, especially early onset Alzheimer's disease.