Upregulated expression of a subset of genes in APP;ob/ob mice: Evidence of an interaction between diabetes-linked obesity and Alzheimer's disease.

Clinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. However, the mechanism by which obesity/diabetes and AD interact with each other and contribute to dementia remains elusive. To obtain insights into their interaction at molecular levels, we performed gene expression analysis of APP;ob/ob mice, which were generated by crossing transgenic AD model mice (APP23 mice) with ob/ob mice, which are obese and mildly diabetic. The Aß level in these mice was reduced compared with that in pure APP mice. However, we identified a cluster of genes (cluster 10) upregulated in APP;ob/ob mice but not in either APP or ob/ob mice. Interestingly, genes upregulated in the human AD brain were enriched in cluster 10. Moreover, genes in cluster 10 formed a network and shared upregulated genes with a cell model of neurodegeneration and other models of neurological disorders such as ischemia and epilepsy. In silico analyses showed that serum response factor (SRF), recently identified in a single-cell analysis of human brains as a transcription factor that can control the conversion from healthy cells to AD cells, might be a common transcriptional regulator for a subset of cluster 10 genes. These data suggest that upregulation of genes uniquely associated with APP;ob/ob mice is an evidence of the interaction between obesity/diabetes and AD.

Increased levels of Aß42 decrease the lifespan of ob/ob mice with dysregulation of microglia and astrocytes.

Clinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. Although the mechanisms underlying these associations remain elusive, the bidirectional interactions between obesity/diabetes and Alzheimer's disease (AD) may be involved in them. Both obesity/diabetes and AD significantly reduce life expectancy. We generated AppNL-F/wt knock-in; ob/ob mice by crossing AppNL-F/wt knock-in mice and ob/ob mice to investigate whether amyloid-ß (Aß) affects the lifespan of ob/ob mice. AppNL-F/wt knock-in; ob/ob mice displayed the shortest lifespan compared to wild-type mice, AppNL-F/wt knock-in mice, and ob/ob mice. Notably, the Aß42 levels were increased at minimum levels before deposition in AppNL-F/wt knock-in mice and AppNL-F/wt knock-in; ob/ob mice at 18 months of age. No differences in the levels of several neuronal markers were observed between mice at this age. However, we observed increased levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in AppNL-F/wt knock-in; ob/ob mice, while the levels of several microglial markers, including CD11b, TREM2, and DAP12, were decreased in both ob/ob mice and AppNL-F/wt knock-in; ob/ob mice. The increase in GFAP levels was not observed in young AppNL-F/wt knock-in; ob/ob mice. Thus, the increased Aß42 levels may decrease the lifespan of ob/ob mice, which is associated with the dysregulation of microglia and astrocytes in an age-dependent manner. Based on these findings, the imbalance in these neuroinflammatory cells may provide a clue to the mechanisms by which the interaction between obesity/diabetes and early AD reduces life expectancy.

Serum albumin/globulin ratio is associated with cognitive function in community-dwelling older people: The Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians study.

AIM: The objective of this study was to clarify the relationship between cognitive function and the serum albumin/globulin ratio (A/G ratio) in community-dwelling Japanese older adults. METHODS: Randomly extracted residents in both urban and rural parts of Japan were enrolled in this study. A total of 1827 participants with a mean age of 70 or 80 years were recruited. A venue survey method was carried out with comprehensive studies, including interviews, blood collection, physical examination and cognitive function tests. RESULTS: Univariate analysis showed a significant positive correlation between the total Japanese version of the Montreal Cognitive Assessment score and the serum A/G ratio at the age of 70 and 80 years, in which better cognitive function was associated with a high serum A/G ratio. Multiple regression analysis with the total Japanese version of the Montreal Cognitive Assessment score as the dependent variable showed that the serum albumin level, serum globulin level, serum A/G ratio, C-reactive protein, years of formal education and sex were related to the Japanese version of the Montreal Cognitive Assessment total score at the age of 70 years, and that the serum albumin level, serum globulin level, serum A/G ratio, C-reactive protein, years of formal education and stroke were related at the age of 80 years. The serum A/G ratio showed a better correlation than the serum globulin levels at the age of 70 and 80 years (70 years: ß = 0.131 vs -0.111, 80 years: ß = 0.108 vs -0.071). CONCLUSIONS: We found a correlation between cognitive function and the serum A/G ratio in community-dwelling older people, suggesting that nutritional status and chronic inflammation might influence cognitive function. Geriatr Gerontol Int 2019; 19: 967-971.

Comparison between L-type and N/L-type calcium channel blockers in the regulation of home blood-pressure variability in elderly hypertensive patients.

Recent studies suggest that L-type calcium channel blockers (CCBs) contribute to reducing blood pressure (BP) variability. We investigated whether inhibition of the N-type calcium channel has an additional effect on BP variability by comparing the effect of L-type and L/N-type CCBs on home BP variability in elderly hypertensive patients. Twenty-six hypertensive patients (≥65 years) were subjected to repeated changes with the administration of amlodipine (L-type CCB) and cilnidipine (L/N-type CCB) every 2 months. They measured the home BP in the morning and evening, and the coefficient of variation (CV) was calculated. We measured the brachial-ankle pulse wave velocity (baPWV) and urinary catecholamine excretion as an index of the arterial stiffness and sympathetic nerve activity, respectively. There was no difference in the effect of both drugs on the CV in the morning and evening, while amlodipine was associated with a modestly higher pulse rate and lower BP than cilnidipine. By comparing individual patient data for the CV with each drug, we found that higher urinary catecholamine excretion was associated with the effectiveness of cilnidipine over amlodipine in the BP variability in the morning, which was not the case in the evening. In contrast, lower baPWV was associated with the effectiveness of amlodipine over cilnidipine on BP variability in the evening. Lower baPWV was also associated with lower BP variability in the evening. Cilnidipine has a similar capacity as amlodipine in reducing home BP variability, but the underlying mechanisms in reducing BP variability may differ.

Longitudinal association of hypertension and diabetes mellitus with cognitive functioning in a general 70-year-old population: the SONIC study.

Both hypertension and diabetes in middle-aged individuals have been suggested to be predictive indicators of cognitive decline. However, the association of hypertension, diabetes and their combination with cognitive functioning is still controversial in older people. The purpose of this study was to investigate the association between cognitive decline and hypertension, diabetes, and their combination in 70-year-old people based on a 3-year longitudinal analysis. Four hundred and fifty-four people aged 70 (±1) years who participated in the Japanese longitudinal cohort study of Septuagenarians, Octogenarians and Nonagenarians Investigation with Centenarians (SONIC) were recruited randomly from a general population and were monitored for 3 years. The data, including most of the demographics, cognitive functioning measured by the Montreal Cognitive Assessment Japanese version (MoCA-J), blood pressure, blood chemistry and other medical histories, were collected at baseline and during the follow-up. The prevalence of hypertension noted in the follow-up survey was significantly higher than than noted at baseline. The mean MoCA-J score at follow-up was not significantly different from the score obtained at baseline. However, the participants with diabetes, especially combined with hypertension at baseline, had significantly lower MoCA-J scores than those without lifestyle-related diseases. The combination of hypertension and diabetes was still a significant risk factor for cognitive decline, considering the MoCA-J scores obtained during the follow-up after adjustments at baseline, relative to sex, body mass index, dyslipidemia, smoking, excessive alcohol intake, antihypertensive treatment and education level (ß=-0.14; P<0.01). Our findings indicate that diabetes and the combination of hypertension and diabetes are clear risk factors for future cognitive decline in elderly individuals who are 70 years of age.

Differences in the association between high blood pressure and cognitive functioning among the general Japanese population aged 70 and 80 years: The SONIC study.

High blood pressure in middle age (up to 64 years) has been proposed as a predictive indicator of dementia. However, the association between hypertension and the cognitive functioning is controversial in older age groups. The aim of this study was to investigate this association in 70-80-year-old participants in the Japanese study of Septuagenarians, Octogenarians and Nonagenarians Investigation with Centenarians (SONIC). Participants aged 70 (±1) and 80 (±1) years (n=1000 and 973, respectively) were randomly recruited from the general population in Japan. Cognitive functioning was measured by the Montreal Cognitive Assessment. Blood pressure and other medical and social variables were analyzed by multiple regression analyses. High systolic blood pressure (SBP) was significantly correlated with a reduced cognitive functioning only in participants aged 70 years. Additionally, this correlation became more marked in participants with uncontrolled blood pressure at age 70 years. In contrast, SBP was not significantly correlated with the cognitive functioning at age 80 years. Nutritional status indicators such as serum albumin and frequency of going outdoors were significantly associated with cognitive functioning at age 80 years. Our findings indicate that high SBP has a significant role in cognitive functioning at age 70 years; however, blood pressure is less important as a risk factor for cognitive decline at age 80 years.

Disease-associated polymorphisms in 9p21 are not associated with extreme longevity.

AIM: The 9p21 region has been pointed out by the genome-wide association studies as a hot spot for disease-associated variants. Most of the diseases linked with the locus are aging-related conditions, such us cardiovascular disease, diabetes and cancer. Centenarians are known to present a reduced risk and delayed onset for these conditions. Here, we aimed to assess if the 9p21 variants contribute to this protection by possibly altering basic aging mechanisms. METHODS: We genotyped 15 tag single-nucleotide polymorphisms (SNP) along the CDKN2A/B/ANRIL locus in 1505 individuals. The participants were divided in three groups: centenarians, septuagenarians and young controls. Centenarians were 593 participants (age range 100-116 years, mean 105.9 years), septuagenarians were 434 volunteers aged between 69 and 71 years (mean 70.1 ± 0.9 years) and the 478 young controls were under the age of 50 years (range 14-50 years, mean 41.8 years). We genotyped the SNP rs1333049 in an additional sample of 231 coronary artery disease patients to confirm the 9p21 association. RESULTS: The leading coronary artery disease-associated SNP rs1333049 was associated with coronary artery disease; however, none of the 9p21 SNP evaluated in the present study were associated with extreme longevity. CONCLUSIONS: Our findings suggest that the 9p21 disease-associated polymorphisms do not contribute to the life-long protection from cardiovascular and other age-related diseases observed in centenarians. It is likely that this protection is mediated by mechanisms different from the ones underlying the 9p21 association.