Objective sleep was longitudinally associated with brain amyloid burden in mild cognitive impairment.

OBJECTIVE: Understanding the longitudinal association of objective sleep and physical activity with brain amyloid burden and cortical glucose metabolism has critical clinical and public health implications for dementia prevention in later life. METHODS: We enrolled 118 individuals aged ≥65 years with mild cognitive impairment, who were followed up on from August 2015 to September 2019. All participants continuously wore an accelerometer sensor for 7 consecutive days every 3 months and received annual 11 C-Pittsburgh compound-B and 18 F-fluorodeoxyglucose positron emission tomography (PET). Sleep and physical activity parameters were assessed using accelerometer sensor data and PET imaging was quantified using a standardized uptake-value ratio. Fifty-seven participants (48.3%) completed a lifestyle factor assessment and PET imaging over the 3-year period. A linear mixed-effects model was applied to examine the longitudinal association of sleep and physical activity parameters with PET imaging over the 3-year period, controlling for potential confounders. RESULTS: Sleep efficiency was inversely associated with amyloid uptake in the frontal lobe. Although sleep duration was positively associated with global amyloid uptake, particularly in the frontal lobe, their impact was extremely small. However, physical activity parameters were not significantly associated with the 11 C-Pittsburgh compound-B-uptake. Furthermore, sleep and physical activity parameters were not significantly associated with cortical glucose metabolism. INTERPRETATION: Lower sleep efficiency could be an early symptom of greater brain amyloid burden at the mild cognitive impairment stage. Therefore, the assessment of sleep may be useful for identifying individuals at higher risk for brain amyloid burden. Future longer term observational studies are required to confirm these findings.

Lifestyle factors that affect cognitive function-a longitudinal objective analysis.

Background: Identifying lifestyle factors associated with cognitive decline has critical clinical and public health implications for dementia prevention in later life. The longitudinal associations of sleep and physical activity with cognitive function remain unclear. This study examined whether objectively measured sleep and physical activity were longitudinally associated with cognitive function in older adults over a three-year period. Methods: This prospective cohort study enrolled 855 community-dwelling adults aged 65 and older, who were followed from 2015 to 2019. All participants were required to wear a wearable sensor for 7 consecutive days every 3 months and had annual cognitive assessments. Wearable sensor data (August 2015-September 2019) and Mini-Mental State Examination (MMSE) scores (August 2015-April 2019) were collected over 3 years of follow-up. First, principal component analysis was conducted to reduce the dimensions of the sleep and physical activity variables to two principal components for inclusion in a mixed-effects model. The sleep index consisted of sleep efficiency, time awake after sleep onset, and waking frequency. The physical activity index was composed of walking comprised steps per day and time devoted to light or moderate-to-vigorous physical activity. A higher sleep index indicated poor sleep quality, whereas a lower physical activity index indicated less physical activity. Second, a linear mixed effect model was used to examine the longitudinal association of sleep and physical activity indices with cognitive decline over time. Results: In total, 855 adults were recruited for this study at baseline. Of these, 729 adults (85.3%) completed a measurement of lifestyle factors and an annual cognitive testing, whereas 126 were excluded because of death or loss during follow-up. After adjusting for age, sex, education level, and time, the sleep index was inversely associated with MMSE scores (estimate, -0.06229; standard error, 0.02202; p = 0.0047) and the physical activity index was positively associated with MMSE scores (estimate, 0.06699; standard error, 0.03343; p = 0.0453). Conclusion: Poor sleep quality and lower physical activity were significant risk factors for subsequent cognitive decline in older adults. The present study facilitates the development of novel evidence-based interventions for physical activity and sleep quality to delay cognitive decline.

Effects of angiotensin II receptor blockers on serum potassium level and hyperkalemia risk: retrospective single-centre analysis.

OBJECTIVE: To examine the effect of angiotensin II receptor blocker (ARB) treatment on serum potassium level and hyperkalaemia risk in a clinical setting with inpatients and outpatients using calcium channel blockers (CCBs) as a reference standard. METHODS: The increased risk of hyperkalaemia associated with ARB treatment is known, however only a few studies have used an active comparator to examine this risk. In this retrospective study at a 320-bed general hospital in Japan, the hospital information system was used to identify patients with at least one prescription for an ARB (819 patients) or a CCB (1015 patients) who were naive to these drugs before study initiation. Serum potassium levels before and after ARB treatment were compared. Additionally, the unadjusted and adjusted hazard ratios for the risk of hyperkalaemia in the ARB and CCB users were estimated. RESULTS: The serum potassium level was higher in patients receiving ARB treatment (0.05 mEq/L, p=0.02) compared with those on CCB treatment. However, there was no significant association between ARB use and hyperkalaemia (adjusted HR 0.91, 95% CI 0.42 to 1.99, p=0.82). CONCLUSION: The increase in serum potassium level after ARB initiation makes it necessary to monitor serum potassium levels continuously during ARB treatment; however, the risk of hyperkalaemia appeared to be similar for ARB and CCB treatments.

Occlusal Trauma and Bisphosphonate-Related Osteonecrosis of the Jaw in Mice.

Osteonecrosis of the jaw (ONJ) is a serious adverse event that is associated with antiresorptive agents, and it manifests as bone exposure in the maxillofacial region. Previous clinical reports suggest that mechanical trauma would trigger ONJ in a manner that is similar to tooth extractions. To the best of our knowledge, there have been few detailed pathophysiological investigations of the mechanisms by which occlusal/mechanical trauma influences ONJ. Here, we developed a novel mouse model that exhibits ONJ following experimental hyperocclusion and nitrogen-containing bisphosphonate (N-BP) treatment. This in vivo model exhibited ONJ in alveolar bone, particularly in the mandible. Moreover, the experimental hyperocclusion induced remarkable alveolar bone resorption in both mouse mandible and maxilla, whereas N-BP treatment completely prevented alveolar bone resorption. In this study, we also modeled trauma by exposing clumps of mesenchymal stem cells (MSCs)/extracellular matrix complex to hydrostatic pressure in combination with N-BP. Hydrostatic pressure loading induced lactate dehydrogenase (LDH) release by calcified cell clumps that were differentiated from MSCs; this LDH release was enhanced by N-BP priming. These in vivo and in vitro models may contribute further insights into the effect of excessive mechanical loading on ONJ onset in patients with occlusal trauma.

Association between Benton Visual Retention Test Scores and PET Imaging in Elderly Adults.

BACKGROUND: The Benton Visual Retention Test (BVRT) is a well-validated and reliable test for assessing visual memory and visuospatial function. However, the association between the BVRT score and imaging biomarker of Alzheimer's disease (AD) remains unclear. OBJECTIVE: This study examined whether the BVRT score is associated with brain amyloid burden and cortical glucose metabolism in elderly adults without dementia. METHODS: A total of 69 elderly adults without dementia, including 45 subjects with amnestic mild cognitive impairment and 24 cognitively healthy adults, underwent the BVRT and 11C-Pittsburgh compound B (PiB) and 18F-fluorodeoxyglucose (FDG) positron emission tomography. The correct scores in the BVRT were used for analyses. A multiple linear regression analysis was conducted to investigate the relationship between BVRT scores and PiB or FDG uptake. Moreover, a voxel-wise linear regression analysis of the association between BVRT scores and PiB or FDG uptake was conducted using Statistical Parametric Mapping. RESULTS: After adjusting for age, sex, education, and ApoE4 status, the BVRT scores were inversely correlated with the mean PiB uptake (ß = -0.35, P = 0.003), whereas they were positively correlated with FDG uptake (ß = 0.266, P = 0.038). Moreover, the BVRT scores were inversely correlated with amyloid burden in the right superior temporal and superior frontal gyri and the left parietal lobe, whereas they were positively correlated with cortical glucose metabolism in the right posterior cingulate and milled temporal gyri, left temporoparietal lobe, and right superior frontal gyrus. CONCLUSION: BVRT scores are correlated with brain amyloid burden and cortical glucose metabolism, mainly in regions commonly affected in AD.

Relationship between Cerebrospinal Fluid Matrix Metalloproteinases Levels and Brain Amyloid Deposition in Mild Cognitive Impairment.

This study aimed to explore whether cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) were associated with brain amyloid deposition, cortical glucose metabolism, and white matter lesions (WMLs) in individuals with amnestic mild cognitive impairment (MCI). A total of 33 individuals with amnestic MCI (mean age, 75.6 years) underwent 11C-Pittsburgh compound B positron emission tomography (PiB-PET), 18F-fluorodeoxyglucose positron emission tomography, magnetic resonance imaging or computed tomography, and CSF analysis. PET uptake of the frontal and temporoparietal lobes and posterior cingulate gyrus was assessed using the cerebellar cortex as the reference region. WMLs were assessed by the Fazekas scale. CSF levels of MMPs and TIMPs were measured with bead-based multiplex assays. After adjusting for covariates, multiple linear regression analysis showed that CSF levels of MMP-2 were negatively correlated with global PiB uptake (p = 0.035), especially in the parietotemporal lobe and posterior cingulate gyrus (p = 0.016 and p = 0.041, respectively). Moreover, CSF levels of MMP-7 were positively correlated with the severity of WMLs (p = 0.033). CSF levels of MMP-2 and MMP-7 are associated with brain amyloid deposition and severity of WMLs, respectively. These findings provide valuable insights into the role of MMPs in amyloid ß catabolism and blood-brain barrier integration at the MCI stage.

Association of Modifiable Lifestyle Factors With Cortical Amyloid Burden and Cerebral Glucose Metabolism in Older Adults With Mild Cognitive Impairment.

Importance: Understanding the association of lifestyle factors with mild cognitive impairment enables the development of evidence-based interventions for delaying cognitive impairment. Objective: To explore whether objectively measured lifestyle factors, such as physical activity, conversation, and sleep, are associated with cortical amyloid burden and cerebral glucose metabolism in older adults with mild cognitive impairment. Design, Setting, and Participants: This cohort study included 855 community-dwelling adults in Usuki, Oita Prefecture, Japan, aged 65 years or older. Data were collected from August 2015 to December 2017. Participants were reviewed to examine risk and protective lifestyle factors for dementia. Data analysis was conducted in June 2019. Exposures: Wearable sensors, carbon-11 labeled Pittsburgh compound B positron emission tomography images, and fluorine-18 fluorodeoxyglucose positron emission tomography images. Main Outcomes and Measures: Wearable sensor data, such as walking steps, conversation time, and sleep, were collected from August 2015 to October 2017, and positron emission tomography images were collected from October 2015 to December 2017. A multiple regression model and change-point regression model were used to examine the association of lifestyle factors with mean amyloid or fluorodeoxyglucose uptake, assessed on the basis of a standardized uptake value ratio of the frontal lobes, temporoparietal lobes, and posterior cingulate gyrus with the cerebellar cortex as the reference region. The bootstrap method was used to obtain nonparametric 95% CIs on the associations of lifestyle factors with cognitive decline. Results: Of the 855 adults in the study, 118 (13.8%) were diagnosed with mild cognitive impairment, with a mean (SD) age of 75.7 (5.8) years and 66 (55.9%) women. Total sleep time was inversely associated with fluorodeoxyglucose uptake after adjusting for covariates (ß = -0.287; 95% CI, -0.452 to -0.121, P < .001). Change-point regression showed an inverse association between total sleep time and mean amyloid uptake when sleep duration was longer than 325 minutes (B = -0.0018; 95% CI, -0.0031 to -0.0007). Conclusions and Relevance: To our knowledge, this is the first study to demonstrate that total sleep time was associated with brain function in older adults with mild cognitive impairment. Sleep duration is a potentially modifiable risk factor for dementia at the mild cognitive impairment stage.

Relationship Between the Japanese Version of the Montreal Cognitive Assessment and PET Imaging in Subjects with Mild Cognitive Impairment.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) test has high sensitivity and specificity for detecting mild cognitive impairment or early dementia. How the MoCA score relates to findings of positron emission tomography imaging, however, remains unclear. OBJECTIVE: This prospective study examined the relationship between the Japanese version of the MoCA (MoCA-J) test and brain amyloid deposition or cerebral glucose metabolism among subjects with mild cognitive impairment. METHODS: A total of 125 subjects with mild cognitive impairment underwent the MoCA-J test, and amyloid- and 18F-fluorodeoxyglucose- positron emission tomography. Linear correlation analysis and multiple linear regression analysis were conducted to investigate the relationship between the MoCA-J score and demographic characteristics, amyloid deposition, and cerebral glucose metabolism. Moreover, Statistical Parametric Mapping 8 was used for a voxel-wise regression analysis of the MoCA-J score and cerebral glucose metabolism. RESULTS: The MoCA-J score significantly correlated with age, years of education, and the Mini-Mental State Examination score. After adjusting for age, sex, and education, the MoCA-J score significantly correlated negatively with amyloid retention (ß= -0.174, p= 0.031) and positively with cerebral glucose metabolism (ß= 0.183, p= 0.044). Statistical Parametric Mapping showed that Japanese version of MoCA score correlated with glucose metabolism in the bilateral frontal and parietal lobes, and the left precuneus. CONCLUSION: The total MoCA-J score correlated with amyloid deposition and frontal and parietal glucose metabolism in subjects with mild cognitive impairment. Our findings support the usefulness of the MoCA-J test for screening subjects at high risk for Alzheimer's disease.

Modifiable Lifestyle Factors and Cognitive Function in Older People: A Cross-Sectional Observational Study.

Background: The development of evidence-based interventions for delaying or preventing cognitive impairment is an important challenge. Most previous studies using self-report questionnaires face problems with reliability and consistency due to recall bias or misclassification among older people. Therefore, objective measurement of lifestyle components is needed to confirm the relationships between lifestyle factors and cognitive function. Aims: The current study examined the relationship between lifestyle factors collected with wearable sensors and cognitive function among community-dwelling older people using machine learning. Methods: In total, 855 participants (mean age: 73.8 years) wore a wristband sensor for 7.8 days on average every 3 months. Various lifestyle parameters were measured, including walking steps, conversation time, total sleep time (TST), sleep efficiency, time awake after sleep onset, awakening count, napping time, and heart rate. Random forest (RF) regression analysis was used to examine the relationships between total daily sensing data and Mini-Mental State Examination (MMSE) scores. Confounding factor analysis was conducted with models that were adjusted and unadjusted for demographic and vascular risk factors, and selected variables were assessed as risk and protective factors using partial dependence plots (PDPs). Results: Lifestyle data were collected for 31.3 ± 7.1 days per year using wristband sensors. RF regression analysis adjusted for age, gender, and education levels selected four variables, including number of walking steps, conversation time, TST, and heart rate. Moreover, walking steps, conversation time, and heart rate remained after RF regression analysis adjusted for demographic and vascular risk factors. Number of walking steps, conversation time, and heart rate were categorized as protective factors, whereas TST was categorized as a risk factor for cognitive function. Although PDPs of number of walking steps and heart rate revealed continuously increased MMSE scores, those of conversation time and TST and revealed that the tendency in the graph was reversed at the boundary of a particular threshold (321.1 min for conversation time, 434.1 min for TST). Conclusions: Lifestyle factors, such as physical activity, sleep, and social activity appear to be associated with cognitive function among older people. Physical activity and appropriate durations of sleep and conversation are important for cognitive function.

Effects of indoxylsulfate on the in vitro hepatic metabolism of various compounds using human liver microsomes and hepatocytes.

BACKGROUND: Alterations of hepatic drug metabolism in patients with renal failure are poorly understood. In this study, the effects of uremic substances that can be removed by hemodialysis on in vitrohepatic drug metabolism were studied using human liver microsomes and hepatocytes. METHODS: The metabolism of various compounds that undergo oxidation and glucuronidation in the liver was studied using human liver microsomes and hepatocytes in the presence of 11 uremic substances removable by hemodialysis. RESULTS: The formation of resorufin from ethoxyresorufin was inhibited by 3-indoxylsulfate and 3-indoleacetic acid. The formation of 6beta-hydroxytestosterone from testosterone was inhibited only by 3-indoxylsulfate. These uremic substances reduced the maximum metabolic rate but not the affinity, suggesting that the inhibitory mechanism was noncompetitive. The inhibition of formation of resorufin and 6beta-hydroxytestosterone by 3-indoxylsulfate was also observed in human hepatocytes. The elimination of nicardipine in liver microsomes was decreased significantly in the presence of 3-indoxylsulfate and 3-indoleacetic acid. CONCLUSION: The hepatic metabolism of certain drugs may be inhibited directly by uremic substances such as 3-indoxylsulfate that accumulate in the plasma in patients with chronic renal failure.