Salivary 3-methoxy-4-hydroxyphenylglycol and MRI-based volume change of the precuneus in community-dwelling elderly people.

BACKGROUND: The noradrenergic systems in the brain maintain cognitive functions including attention/concentration and establishment of long-term memory. In addition, hypofunction of noradrenergic systems is supposed to be involved in the pathophysiology of Alzheimer's disease. In this study, we tried to examine the possible associations of concentrations of basal salivary 3-methoxy-4-hydroxyphenylglycol (sMHPG), a major metabolite of noradrenaline, and brain volume changes during 4 years in elderly people living in a rural community. METHODS: The survey was conducted twice in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged 65 years and older. We collected data from 226 residents. Measurements of sMHPG and brain MRIs were collected at Time 1 (2005-2007). Follow-up brain MRIs were taken at Time 2 (2009-2011). A total of 70 participants (18 men, mean age 71.9 ± 4.8 years; 52 women, mean age 72.0 ± 4.3 years) completed this survey. Concentrations of sMHPG at baseline were divided into two groups using the mean value (12.83 ng/ml). We compared the brain volumes between groups with higher and lower sMHPG concentrations over time using voxel-based morphometry implemented with statistical parametric mapping. RESULTS: In participants with higher sMHPG concentrations at baseline, brain volumes including right precuneus were significantly larger 4 years after baseline than those with lower sMHPG concentrations at baseline. No interaction between sMHPG concentration and MRI acquisition interval was found. CONCLUSION: Our results suggest that higher sMHPG concentrations in elderly people might be associated with maintenance of brain volume, especially in brain regions closely related to cognitive function.

Serum oxytocin correlated with later logical memory in older Japanese women: A 7-year follow-up study.

Objectives: This study aimed to investigate the longitudinal relationship between serum oxytocin and logical memory among older adults in rural Japan and clarify sex differences in this relationship. Measurements: The first survey was conducted from October 2009 to March 2011 (Time 1) and the second from November 2016 to September 2017 (Time 2). The final analysis for Time 1 included 385 participants (median age 75 years, interquartile range [IQR] 70-81 years) and that for Time 2 included 76 participants (median age 80 years, IQR 76-83 years). We assessed cognition, logical memory, and living conditions, and measured serum oxytocin levels. Logical memory was evaluated using the Wechsler Memory Scale-Revised Logical Memory II delayed recall part A (LM II-DR). Serum oxytocin was measured using the enzyme immunoassay method. Results: The median (IQR) oxytocin level among men (n = 20) was 34 (16-78) pg/mL at Time 1 and 53 (28-140) pg/mL at Time 2. The median (IQR) oxytocin level among women (n = 56) was 117 (35-412) pg/mL at Time 1 and 76 (32-145) pg/mL at Time 2. The median oxytocin level among women at Time 2 was significantly lower than that at Time 1 (p = 0.004). The multivariate analysis showed that for women, LM II-DR score at Time 2 was positively associated with oxytocin level at Time 1 (p = 0.042) and negatively associated with age (p = 0.02). Conclusions: Our study suggests that maintaining high oxytocin levels in older women may prevent age-related decline in logical memory.

Association between cortisol and aging-related hippocampus volume changes in community-dwelling older adults: a 7-year follow-up study.

BACKGROUND: Identifying peripheral biomarkers related to modifiable risk factors to prevent dementia at an early stage will be extremely beneficial. We have been studying how older adults can maintain their mental health and continue to live in a familiar community. The aim of this study is to investigate the association between serum cortisol levels and brain volume among older adults in rural Japan. METHODS: This was a longitudinal study conducted in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged 65 years and above, as reported previously. We conducted a survey twice. The first survey was conducted from October 2009 to March 2011 (Timepoint 1) and the second was conducted from November 2016 to September 2017 (Timepoint 2). Blood samples for serum cortisol levels analysis were collected from participants at Timepoint 1. Serum cortisol levels were measured using the enzyme-linked immunosorbent assay. The participants underwent brain MRI examinations, and Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) for cognitive function assessment at Timepoint 1 and Timepoint 2. We obtained 70 participants (16 men, mean age 72.69 ± 3.18 years; 54 women, mean age 72.69 ± 4.60 years, at Timepoint 1) for analysis. Correlation analysis was performed between serum cortisol levels at baseline (Timepoint 1) and brain volume (Timepoint 1, Timepoint 2, and Timepoint 1-Timepoint 2 difference) using voxel-based morphometry method. RESULTS: There was no significant difference in serum cortisol levels between men (72.32 ± 17.30 ng/ml) and women (76.60 ± 21.12 ng/ml) at baseline. Additionally, no effect of blood collection time on cortisol levels was observed in these participants. Small volume correction analysis at the cluster level by applying multiple comparison corrections (family-wise error; P < 0.05) showed a negative correlation between serum cortisol levels (Timepoint 1) and brain volume (Timepoint 2) within the region containing the left hippocampus. CONCLUSIONS: Serum cortisol levels may serve as a peripheral biomarker of age-related volume changes involving the hippocampus in older adults aged 65 years and above.

Association Between sTREM2, an Immune Biomarker of Microglial Activation, and Aging-Related Brain Volume Changes in Community-Dwelling Older Adults: A 7-Year Follow-Up Study.

BACKGROUND: This study aimed to investigate the association between serum levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a soluble form of an innate immune receptor expressed on the microglia, and brain volume in older adults. METHODS: The survey was conducted twice in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged 65 years and older. We collected data from 596 residents. Serum sTREM2 level measurements, brain MRI, Mini-Mental State Examination (MMSE), and clinical dementia rating (CDR) were performed at Time 1 (2009-2011). Follow-up brain MRI, MMSE, and CDR were performed at Time 2 (2016-2017). The interval between Time 1 and Time 2 was approximately 7 years. Sixty-nine participants (16 men, mean age 72.69 ± 3.18 years; 53 women, mean age 72.68 ± 4.64 years) completed this study. We analyzed the correlation between serum sTREM2 levels (Time 1) and brain volume (Time 1, Time 2, and Time 1-Time 2 difference) using voxel-based morphometry implemented with Statistical Parametric Mapping. RESULTS: Participants in this study had lower MMSE and higher CDR scores 7 years after the baseline evaluation. However, analyses at the cluster level by applying multiple comparison corrections (family wise error; P < 0.05) showed no correlation between serum sTREM2 levels and volume of different brain regions, either cross-sectional or longitudinal. CONCLUSION: Serum sTREM2 level could not serve as an immune biomarker of aging-related volume changes in brain regions closely related to cognitive function in older adults aged 65 years and above.

No association of both serum pro-brain-derived neurotrophic factor (proBDNF) and BDNF concentrations with depressive state in community-dwelling elderly people.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is involved in emotional and cognitive function. Low-BDNF levels occur in patients with depression, while proBDNF, a precursor of BDNF with the opposite physiological function, increases in major depression. However, it is unclear whether BDNF and proBDNF are associated with depression in the elderly. The present study aimed to investigate whether serum proBDNF and BDNF are associated with depressive state in community-dwelling elderly people. METHODS: This was a cross-sectional study conducted in Kurogawa-cho Imari, Saga Prefecture, Japan, in people aged ≥65 years. Depressive state was assessed using the Geriatric Depression Scale-Short Form (Japanese version) (GDS). Of the 274 patients who undertook the GDS, those with a medical history affecting cognitive function were excluded, as were those with Mini-Mental State Examination score ≥ 24 or a Clinical Dementia Rating < 0.5. Further, we used delayed recall of 'logical memory A' from the Wechsler Memory Scale-Revised (LMII-DR) for memory assessment. RESULTS: The final sample consisted of 155 individuals (mean age 75.4 ± 6.8 years; 55 men, mean age 74.8 ± 5.9 years; 100 women, mean age 76.3 ± 7.1 years). In the GDS, 139 participants showed a normal score (0-4) and 16 showed depressive tendencies or depression (score: ≥ 5). After examining confounders of the GDS, logistic regression using categorical covariates showed a negative significant difference between depressive state and serum BDNF in the low-BDNF group only, with a positive correlation in the trend test. None of the analyses showed any association between GDS and proBDNF levels. CONCLUSION: ProBDNF and BDNF levels seemed not to be associated with depressive state in community-dwelling elderly people.

Serum Oxytocin Levels and Logical Memory in Older People in Rural Japan.

OBJECTIVE: The present study aimed to investigate the relationship between serum oxytocin (OT) and logical memory among older people in rural Japan. METHODS: This was a cross-sectional study using a survey conducted from October 2009 through March 2011. Most of the study was conducted as part of a national prevalence survey of dementia in Japan. The final sample comprised 385 community-dwelling people aged 65 years or older living in rural Japan. The mean age and standard deviation were 75.7 ± 6.76 years (144 men, mean age 75.0 ± 6.48 years; 241 women, mean age 76.2 ± 6.91 years). The participants underwent screening examinations for a prevalence survey of dementia. The screening examinations were the Mini-Mental State Examination, Clinical Dementia Rating, and "logical memory A" from the Wechsler Memory Scale-Revised (WMSR). We used the WMSR Logical Memory II delayed recall score (LM II-DR) to assess logical memory. Levels of serum OT were obtained using the enzyme immunoassay method. RESULTS: Serum OT levels were significantly higher among women than men. The present study revealed that serum OT levels were positively associated with LM II-DR in older women living in rural Japan in multiple linear regression analyses. CONCLUSIONS: The present results suggested a positive correlation between OT and logical memory in older women living in rural Japan.

Oxytocin and elderly MRI-based hippocampus and amygdala volume: a 7-year follow-up study.

Oxytocin is deeply involved in human relations. In recent years, it is becoming clear that oxytocin is also involved in social cognition and social behaviour. Oxytocin receptors are also thought to be present in the hippocampus and amygdala, and the relationship between oxytocin and the structure and function of the hippocampus and amygdala has been reported. However, a few studies have investigated oxytocin and its relationship to hippocampus and amygdala volume in elderly people. The aim of this study is to investigate the association between serum oxytocin levels and hippocampus and amygdala volume in elderly people. The survey was conducted twice in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged 65 years and older. We collected data from 596 residents. Serum oxytocin level measurements, brain MRI, Mini-Mental State Examination and Clinical Dementia Rating were performed in Time 1 (2009-11). Follow-up brain MRI, Mini-Mental State Examination and Clinical Dementia Rating were performed in Time 2 (2016-17). The interval between Time 1 and Time 2 was about 7 years. Fifty-eight participants (14 men, mean age 72.36 ± 3.41 years, oxytocin 0.042 ± 0.052 ng/ml; 44 women, mean age 73.07 ± 4.38 years, oxytocin 0.123 ± 0.130 ng/ml) completed this study. We analysed the correlation between serum oxytocin levels (Time 1) and brain volume (Time 1, Time 2 and Times 1-2 difference) using voxel-based morphometry implemented with Statistical Parametric Mapping. Analysis at the cluster level (family-wise error; P < 0.05) showed a positive correlation between serum oxytocin levels (Time 1) and brain volume of the region containing the left hippocampus and amygdala (Time 2). This result suggests that oxytocin in people aged 65 years and older may be associated with aging-related changes in hippocampus and amygdala volume.

An association between belief in life after death and serum oxytocin in older people in rural Japan.

OBJECTIVE: Previous research suggests that spirituality/religiosity has benefits for both mental and physical health, measured using biological indices such as cortisol and IL-6. However, there have been few studies concerning the association of religious beliefs with oxytocin, a neuropeptide hormone secreted by the pituitary. Levels of peripheral oxytocin are thought to reflect the strength of bonding and stress regulation in social relationships. As such, the oxytocin system may underpin the biological mechanisms by which belief in life after death is associated with good mental and physical health. Here, we examine associations between oxytocin and belief in life after death. METHODS: We recruited 317 community-dwelling people, aged 65 or older, without cognitive or mental deficits, and living in rural Japan. We recorded demographics, belief in life after death, and logical memory using the Wechsler Memory Scale. Levels of serum oxytocin were obtained using an enzyme immunoassay method. RESULTS: Serum oxytocin levels were higher among women than men and were negatively associated with strength of belief in life after death. CONCLUSIONS: Our findings could be interpreted differently depending on whether the anxiogenic or anxiolytic function of the oxytocin system is considered. Greater endorsement of afterlife beliefs may reduce secure attachment. Alternatively, based on the literature suggesting that basal levels of oxytocin are lower in those with reduced relational distress or anxiety, afterlife beliefs may play a role in these reductions. Copyright © 2016 John Wiley & Sons, Ltd.

Belief in life after death, salivary 3-methoxy-4-hydroxyphenylglycol, and well-being among older people without cognitive impairment dwelling in rural Japan.

OBJECTIVES: Research has found that spirituality/religiosity has a salutary association with mental/physical health. However, the association of belief in life after death with well-being has rarely been studied, and the same is true of its association with biological indices, such as monoamine transmitters. Therefore, we examined the associations between well-being and religiosity, salivary 3-methoxy-4-hydroxyphenylglycol (sMHPG), and demographic characteristics. METHODS: The participants were 346 community-dwelling people, aged 65 years or older, without cognitive or mental deficits, in rural Japan. Measures of religiosity consisted of belief in life after death, attachment to life, and experiences related to death and religion. The measures were assessed by scales specifically suited for Japanese religious orientations. Participants' well-being was assessed by a life satisfaction scale containing two subscales. We also measured sMHPG, a major metabolite of noradrenaline that is thought to reflect certain psychological states, such as psychomotor retardation and effortful attention. RESULTS: One subscale of life satisfaction was positively associated with belief in life after death and sMHPG, and the other life satisfaction subscale was positively associated with education and death/religion-related experiences (e.g., visiting family graves or loss of a friend). Gender differences were found in afterlife beliefs and each life satisfaction subscale. CONCLUSIONS: These results suggest that religiosity, including belief in life after death and death/religion-related experiences, is salubriously associated with mental health among older people, especially women, living in rural Japan. The basal level of sMHPG was positively associated with life satisfaction, but not with belief in life after death.

Association of inflammatory biomarkers with depressive symptoms and cognitive decline in a community-dwelling healthy older sample: a 3-year follow-up study.

BACKGROUND: The relationship between the pathophysiology of dementia and neuroinflammation is well-known. The number of reports stating that depression is a risk factor for dementia has recently been increasing. These epidemiological findings suggest the possibility that both depression and dementia have common pathophysiological backgrounds of neuroinflammation. METHODS: The sample consists of 64 non-demented community-dwelling older participants aged 65 years or over. Participants were assessed at baseline (2004-2006) and 3 years later (2007-2009). Plasma concentration of markers of inflammation (interleukins (IL)-1ß, IL-2, IL-6, soluble interleukin-2 receptor (sIL-2R), soluble interleukin-6 receptor (sIL-6R), high sensitivity C-reactive protein (hsCRP) and tumor necrosis factor (TNF)-α) were measured at baseline. Depression symptoms were assessed with the Beck Depression Inventory (BDI) and cognitive decline was assessed with the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB) and Clock Drawing Test (CDT) at baseline and follow-up. All analyses were adjusted for age, gender and years of education. RESULTS: In the cross-sectional analysis, the present study found soluble IL-2 receptor (sIL-2R) to be associated only with the MMSE score at baseline in men. In the longitudinal analysis, none of our inflammatory biomarkers were associated with either depressive symptoms or cognitive decline. LIMITATIONS: The present study consists of small number of participants and body mass index (BMI) scores were not obtained. CONCLUSIONS: Our findings suggest that sIL-2R is associated with current cognitive function in men. None of our inflammatory markers predicted future depressive state or cognitive decline in our community-dwelling healthy older sample.

Association of salivary cortisol levels and later depressive state in elderly people living in a rural community: a 3-year follow-up study.

BACKGROUND: Late-life depressive disorder is becoming an important issue in health economics in the world, as it has been reported to be one of major risk factors for incidence of dementia. Identification of predictive markers associated with depression in later life is therefore of high priority in public health. The aim of the study was to examine the association of salivary cortisol levels with a later depressive state in elderly healthy people living in a rural Japan community. METHODS: Salivary cortisol levels were measured in 68 elderly healthy people (24 men; 44 women) followed by completion of the BDI, MMSE, and FAB from 2004 to 2006. The same cohort underwent BDI again from 2007 to 2009. RESULTS: In healthy elderly women subject, a significant positive correlation was found between salivary cortisol levels at baseline and BDI scores at follow-up, but not at baseline. Salivary cortisol levels at baseline were not correlated with the score of either MMSE or FAB. When the cut-off point of BDI scores were set at 20/21, logistic regression analyses revealed that salivary cortisol levels at baseline had a significant positive relationship with a later depressive state. Age and gender were also significantly related with a later depressive state. LIMITATIONS: The present study involves small number of participants. CONCLUSIONS: Higher salivary cortisol levels were associated with a later depressive state in elderly healthy women living in rural community. Salivary cortisol might be a predictive marker for a later depressive state in elderly women.

Neuroinflammation in schizophrenia especially focused on the role of microglia.

An accumulating body of evidence point to the significance of neuroinflammation and immunogenetics also in schizophrenia. Recent genome-wide studies in schizophrenia suggest immune involvement in schizophrenia. Microglia are the resident macrophage of the brain and major players in innate immunity in the CNS. They respond rapidly to even minor pathological changes in the brain and may contribute directly to the neuronal degeneration by producing various pro-inflammatory cytokines and free radicals. In many aspects, the neuropathology of schizophrenia is closely associated with microglial activation. We and other researchers have shown the inhibitory effects of some typical or atypical antipsychotics on the release of inflammatory cytokines and free radicals from activated microglia, both of which are not only directly toxic to neurons but also cause a decrease in neurogenesis as well as white matter abnormalities in the brains of the patients with schizophrenia. The treatment through the inhibition of microglial activation may shed new light on the therapeutic strategy of schizophrenia.

Saliva levels of 3-methoxy-4-hydroxyphenylglycol and clinical efficacy of mirtazapine or selective serotonin reuptake inhibitors in patients with major depression.

OBJECTIVE: This study compared saliva levels of 3-methoxy-4-hydroxyphenylglycol (sMHPG) in patients with major depressive disorder (MDD) to levels in healthy controls and explored whether sMHPG levels in patients with MDD were a predictive marker for antidepressant efficacy. METHODS: sMHPG levels were compared in 53 patients with MDD and 275 age-matched healthy controls. Patients' depressive symptoms were assessed by the 17-item Hamilton Rating Scale for Depression at baseline and 4 weeks after treatment with selective serotonin reuptake inhibitors (SSRIs, n = 23) or mirtazapine (n = 30), followed by saliva sampling. The mirtazapine group included nine patients who had been treated with an SSRI for more than 4 weeks without any improvement. sMHPG levels were measured by gas chromatography-mass spectrometry. RESULTS: sMHPG levels in MDD patients were significantly higher than in controls. The responder rate to drug treatment at 4 weeks was 62% for mirtazapine (13/21), 57% for SSRIs (13/23), and 89% (8/9) for SSRI plus mirtazapine. sMHPG at baseline in 13 responders treated with SSRIs, but not mirtazapine, was significantly higher than that in non-responder group and showed consequent reduction 4 weeks after treatment. The area under the receiver operating characteristic (ROC) curves of sMHPG for discrimination of SSRI responders and non-responders was 0.86 ± 0.10 (95% confidence interval: 0.64-1.0, p = 0.005). In contrast, the ROC curve of sMHPG levels for discrimination of mirtazapine responders and non-responders was not significant. Adjunctive treatment with mirtazapine to SSRI non-responders was effective, regardless of baseline sMHPG levels. CONCLUSION: sMHPG in patients with MDD was higher than in healthy controls. High baseline sMHPG levels in patients with MDD maybe a predictive marker for SSRI response.

Multicentre population-based dementia prevalence survey in Japan: a preliminary report.

Community-based surveys were performed in seven rural areas in Japan to investigate the prevalence of dementia and illnesses causing dementia. A total of 5431 elderly subjects were selected based on census data from 1 October 2009. In total, 3394 participants were examined (participation rate: 62.5%), and 768 dementia cases and 529 mild cognitive impairment cases were identified. Of the illnesses causing dementia, Alzheimer's disease was the most frequent (67.4%), followed by vascular dementia (18.9%), dementia with Lewy body disease (4.6%), mixed dementia (4.2%) and other illnesses. The prevalence of dementia according to 5-year age strata between 65 and 99 years was 5.8-77.7% among the participants. The prevalence of dementia in this study was higher than in previous reports in Japan and other countries. To verify the upward trend of dementia prevalence and its background factors, we have scheduled surveys for three other urban areas in 2011-2012.

Association of saliva 3-methoxy-4-hydroxyphenylglycol levels and a later depressive state in older subjects living in a rural community: 3-year follow-up study.

OBJECTIVE: The aim of the study was to examine the association of saliva levels of 3-methoxy-4-hydroxyphenylglycol (sMHPG) with a later depressive state in older people living in a rural community. METHODS: Baseline sMHPG levels were measured in 214 older subjects followed by completion of the Beck Depression Inventory (BDI) from 2004 to 2006 (time A). The same cohort underwent BDI again from 2007 to 2009 (time B). RESULTS: One hundred forty-four subjects (44 men, 100 women) were reassessed by the BDI. Baseline sMHPG levels in men with a BDI score of ≤9 at time A and a BDI score of ≥10 at time B were significantly higher than those in men with a BDI score of ≤9 at times A and B. In men, there was a significant correlation between baseline sMHPG levels and BDI score at time B (r = 0.40, p = 0.007) but not at time A (r = 0.29, p = 0.06). This association was not significant in women. CONCLUSION: These data indicate that high sMHPG levels at time A could be associated with a later depressive state in older men living in a community.

Baseline saliva level of 3-methoxy-4-hydroxyphenylglycole (MHPG) associates with a consequent cognitive decline in non-demented elderly subjects: three-years follow-up study.

The aim of the study was to explore the relation between saliva level of 3-methoxy-4-hydroxy-phenylglycol (MHPG) and a later cognitive decline in non-demented elderly subjects. We have reported that sMHPG in 214 elderly subjects living in the community (age 74.5±5.9years) was associated with scores on the Mini-Mental State Examination (MMSE) and the Frontal Assessment Battery (FAB) in 2004 to 2006 (Time A). The same cohort underwent these cognitive tests again from 2007 to 2009 (Time B). The cognitive function of the 147 of 214 subjects could be reassessed by the same cognitive tests. The score on the FAB, but not the MMSE, was significantly reduced at Time B (14.6±2.6) compared with that of Time A (15.2±1.9). There was a significant negative correlation between the baseline sMHPG and the changes in the FAB score subtracted from Time B to Time A or the scores on the FAB at Time B in men, but not at Time A. These correlations were not found in women. These data indicate that high sMHPG might be associated with subsequent cognitive decline assessed by the FAB in non-demented elderly men living in the community.

Effective treatment with low-dose fluvoxamine for obsessive-compulsive disorder after neurosurgery: a case report.

We report the case of a 19-year-old woman who had developed obsessive-compulsive disorder after a hemorrhagic infarct in the left caudate nucleus after neurosurgery. Four years after the operation, her obsessive-compulsive disorder symptoms showed a remarkable reduction within a week of starting low-dose fluvoxamine, without any behavioral or psychological treatment.