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Amyloid β (Aβ) and/or ATP activate the NLRP3 inflammasome (N3I) via P2X7R in microglia, which is crucial in neuroinflammation in Alzheimer’s disease (AD). Due to polymorphisms, subtypes, and ubiquitous expression of P2X7R, inhibition of P2X7R has not been effective for AD. We first report that taurodeoxycholate (TDCA), a GPCR19 ligand, inhibited the priming phase of N3I activation, suppressed P2X7R expression and P2X7R-mediated Ca++ mobilization and N3I oligomerization, which is essential for production of IL-1β/IL-18 by microglia. Furthermore, TDCA enhanced phagocytosis of Aβ and decreased the number of Aβ plaques in the brains of 5x Familial Alzheimer’s disease (5xFAD) mice. TDCA also reduced microgliosis, prevented neuronal loss, and improved memory function in 5xFAD mice. The pleiotropic roles of GPCR19 in P2X7R-mediated N3I activation suggest that targeting GPCR19 might resolve neuroinflammation in AD patients.

Background: Despite known associations between low blood hemoglobin level and Alzheimer's disease (AD) or cognitive impairment, the underlying neuropathological links are poorly understood. We aimed to examine the relationships of blood hemoglobin levels with in vivo AD pathologies (i.e., cerebral beta-amyloid [Aβ] deposition, tau deposition, and AD-signature degeneration) and white matter hyperintensities (WMHs), which are a measure of cerebrovascular injury. We also investigated the association between hemoglobin level and cognitive performance, and then assessed whether such an association is mediated by brain pathologies.Methods: A total of 428 non-demented older adults underwent comprehensive clinical assessments, hemoglobin level measurement, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging. Episodic memory score and global cognition scores were also measured.Results: A lower hemoglobin level was significantly associated with reduced AD-signature cerebral glucose metabolism (AD-CM), but not Aβ deposition, tau deposition, or WMH volume. A lower hemoglobin level was also significantly associated with poorer episodic memory and global cognition scores, but such associations disappeared when AD-CM was controlled as a covariate, indicating that AD-CM has a moderating effect.Conclusion: The present findings suggest that low blood hemoglobin in older adults is associated with cognitive decline via reduced brain metabolism, which seems to be independent of those aspects of AD-specific protein pathologies and cerebrovascular injury that are reflected in PET and MRI measures.

Tinnitus is a conscious auditory perception in the absence of an external stimulus. Despite previous reports of a recognized association between tinnitus and cognitive deficits, the effects of tinnitus on functional and structural brain changes associated with cognitive deficits remain unknown. We aimed to investigate the changes in glucose metabolism and gray matter (GM) volume in subjects diagnosed with mild cognitive impairment (MCI) depending on tinnitus. Twenty-three subjects were subclassified into MCI with the chronic tinnitus (MCI_T) and MCI without tinnitus (MCI_NT) groups. Encouraged by the identification of neural substrates associated with tinnitus and cognitive deficits, we correlated the extent of tinnitus severity with the changes in glucose metabolism and GM volume and conducted a glucose metabolic connectivity study. Compared to the MCI_NT group, the MCI_T group showed significantly lower metabolism in the right superior temporal pole and left fusiform gyrus. Additionally, the GM volume in the right insula was markedly lower in the MCI_T group compared to the MCI_NT group. Moreover, correlation analyses in metabolism or GM volumes revealed specific brain regions associated with the cognitive decline with increasing tinnitus severity. Metabolic connectivity analysis revealed that MCI_NT had markedly strengthened intra-hemispheric connectivity in the frontal, parietal, and occipital regions than did MCI_T. Furthermore, MCI_NT showed a strong negative association between the parietal and temporal and parietal and limbic regions, but the association was not observed in MCI_T. These findings indicate that tinnitus may cause metabolic and structural changes in the brain and alters complex inter- or intra-hemispheric networks in MCI. Considering the impact of MCI on accelerating dementia, these results provide a valuable basis on which yet-to-be-identified neurodegenerative markers of tinnitus can be refined.

BackgroundMultiparity – grand multiparity (i.e., five or more childbirths) in particular – has been reported to have an association with increased risk of Alzheimer’s disease (AD) dementia or related cognitive decline in women. However, the pathological links underlying this relationship are still unknown. This study was conducted to examine the relationships of multiparity with cerebral amyloid-beta (Aβ) deposition, brain atrophy, and white matter hyperintensities (WMHs).MethodsIn this study, total of 237 older women with 148 cognitively normal and 89 mild cognitive impairment from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. Participants underwent clinical and neuropsychological assessments in addition to 11C-labeled Pittsburgh Compound B positron emission tomography, and magnetic resonance imaging. The associations of parity with Aβ deposition, hippocampal volume, cortical volume, WMH volume and mini-mental status examination (MMSE) score were examined.ResultsParticipants with grand multiparity showed significantly reduced adjusted hippocampal volume, spatial pattern of atrophy for recognition of AD volume and spatial pattern of atrophy for recognition of brain aging volume even after controlling for potential confounders. Furthermore, MMSE score was also significantly lower in this group. In contrast, grand multiparity did not show any association with global Aβ retention, Aβ positivity rate, or WMH volume, regardless of covariates.ConclusionOur findings suggest that grand multiparity contributes to cognitive decline or increased dementia risk in older women by aggravating amyloid-independent hippocampal or cortical atrophy.

BackgroundDespite known associations of lower serum uric acid (UA) with Alzheimer’s disease (AD) dementia or AD-related cognitive impairment, little is known regarding the underlying patho-mechanisms. We aimed to examine the relationships of serum UA with in vivo AD pathologies including cerebral beta-amyloid (Aβ) and tau deposition, AD-signature region cerebral glucose metabolism (AD-CM), and white matter hyperintensities (WMH). We also investigated the association between serum UA and cognitive performance, and then assessed whether such an association is mediated by the brain pathologies.MethodsA total of 430 non-demented older adults underwent comprehensive clinical assessments, measurement of serum UA level, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging scans. Mini-Mental State Examination (MMSE) and word list recall (WLR) test scores were used to measure cognitive performance.ResultsSerum UA level was significantly associated with AD-CM, but not with Aβ deposition, tau deposition, or WMH volume. Serum UA levels also had significant association with WLR and marginal association with MMSE; such associations disappeared when AD-CM was controlled as a covariate, indicating that AD-CM has a mediating effect.ConclusionThe findings of the present study indicate that there is an association of low serum UA with AD-related cerebral hypometabolism, and whether this represents a causal relationship remains to be determined.

Adult reading tests (ART) have been widely used in both research and clinical settings as a measure of premorbid cognitive abilities or cognitive reserve. However, the neural substrates underlying ART performance are largely unknown. Furthermore, it has not yet been examined whether the neural substrates of ART performance reflect the cortical regions associated with premorbid intelligence or cognitive reserve. The aim of the study is to identify the functional neural correlates of ART performance using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging in the cognitively normal (CN) middle- and old-aged adults. Voxel-wise analyses revealed positive correlations between glucose metabolism and ART performance in the frontal and primary somatosensory regions, more specifically the lateral frontal cortex, anterior cingulate cortex and postcentral gyrus (PCG). When conducted again only for amyloid-β (Aβ)-negative individuals, the voxel-wise analysis showed significant correlations in broader areas of the frontal and primary somatosensory regions. This is the first neuroimaging study to directly demonstrate the cerebral resting-state glucose utilization associated with ART performance. Our findings provide important evidence at the neural level that ART predicts premorbid general intelligence and cognitive reserve, as brain areas that showed significant correlations with ART performance correspond to regions that have been associated with general intelligence and cognitive reserve.

This study aimed to investigate whether the midlife cognitive activity and physical activity moderate the relationship between apolipoprotein Eε4 (APOE4) and in vivo Alzheimer’s disease (AD) pathologies. In total, 287 non-demented older adults (mean age 72 years) from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease cohort were included. Participants underwent a comprehensive clinical assessment including the evaluation for midlife CA and physical activity, [11C]-Pittsburgh-Compound-B-positron emission tomography (PET), [18F]-fluorodeoxyglucose PET, structural magnetic resonance imaging (MRI), and APOE genotyping. We used linear regression and regression-based mediated-moderation models for statistical analyses. Neither midlife cognitive activity nor physical activity moderated the effect of APOE4 on β-amyloid (Aβ) retention itself. Midlife cognitive activity significantly moderated the effect of APOE4 on hippocampal volume [B (SE) = − 627.580 (252.327), t = −2.488, p = 0.014]: APOE4 carriers had smaller hippocampal volume than non-carriers at relatively high cognitive activity state (p = 0.004), but not at relatively low cognitive activity condition (p = 0.937). Midlife physical activity significantly moderated the effect of Aβ retention, which was closely related to APOE4, on AD-signature region cerebral glucose metabolism [AD-CM; B (SE) = 0.004 (0.002), t = 2.030, p = 0.043]: higher Aβ accumulation was associated with lower AD-CM in relatively low physical activity condition (p < 0.001), whereas no such association was observed in relatively high physical activity state (p = 0.791). The findings suggest that high midlife cognitive activity may accelerate hippocampal atrophy induced by APOE4, whereas high midlife physical activity may delay AD-related cerebral hypometabolism by weakening the influence of APOE4-associated Aβ retention.

Background: Given the barriers prohibiting the broader utilization of amyloid imaging and high screening failure rate in clinical trials, an easily available and valid screening method for identifying cognitively impaired patients with cerebral amyloid deposition is needed. Therefore, we developed a prediction model for cerebral amyloid positivity in cognitively impaired patients using variables that are routinely obtained in memory clinics.Methods: Six hundred and fifty two cognitively impaired subjects from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer disease (KBASE) and the Alzheimer’s Disease Neuroimaging Initiative-2 (ADNI-2) cohorts were included in this study (107 amnestic mild cognitive impairment (MCI) and 69 Alzheimer’s disease (AD) dementia patients for KBASE cohort, and 332 MCI and 144 AD dementia patients for ADNI-2 cohort). Using the cross-sectional dataset from the KBASE cohort, a multivariate stepwise logistic regression analysis was conducted to develop a cerebral amyloid prediction model using variables commonly obtained in memory clinics. For each participant, the logit value derived from the final model was calculated, and the probability for being amyloid positive, which was calculated from the logit value, was named the amyloid prediction index. The final model was validated using an independent dataset from the ADNI-2 cohort.Results: The final model included age, sex, years of education, history of hypertension, apolipoprotein ε4 positivity, and score from a word list recall test. The model predicted that younger age, female sex, higher educational level, absence of hypertension history, presence of apolipoprotein ε4 allele, and lower score of word list recall test are associated with higher probability for being amyloid positive. The amyloid prediction index derived from the model was proven to be valid across the two cohorts. The area under the curve was 0.873 (95% confidence interval 0.815 to 0.918) for the KBASE cohort, and 0.808 (95% confidence interval = 0.769 to 0.842) for ADNI-2 cohort.Conclusion: The amyloid prediction index, which was based on commonly available clinical information, can be useful for screening cognitively impaired individuals with a high probability of amyloid deposition in therapeutic trials for early Alzheimer’s disease as well as in clinical practice.

Background: Although increased cognitive activity (CA), both current and past, is known to be associated with a decreased occurrence of Alzheimer’s disease (AD) dementia in older adults, the exact neural mechanisms underlying the association between CA during different stages of life and human dementia remain unclear. Therefore, we investigated whether CA during different life stages is associated with cerebral amyloid-beta (Aβ) pathology and AD-related neurodegeneration in non-demented older adults.Methods: Cross-sectional analyses of data collected between April 2014 and March 2016 from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort. In total, 321 community-dwelling, non-demented older adults were involved in this study. Cerebral Aβ deposition and Aβ positivity were measured using 11C-Pittsburgh compound B (PiB)-positron emission tomography (PET). AD-signature region cerebral glucose metabolism (AD-CMglu) and AD-signature region neurodegeneration (AD-ND) positivity were measured using 18F-fluorodeoxyglucose (FDG)-PET. In addition, CA in early, mid, and late life was systematically evaluated using a structured questionnaire.Results: Of the 321 participants, 254 were cognitively normal (CN) and 67 had mild cognitive impairment (MCI). The mean age of participants was 69.6 years old [standard deviation (SD) = 8.0]. Higher early-life CA (CAearly) was associated with significantly increased AD-CMglu (B = 0.035, SE = 0.013, P = 0.009) and a decreasing trend of AD-ND positivity (OR = 0.65, 95% CI 0.43–0.98, P = 0.04) but was not associated with Aβ deposition or positivity. We observed no association between midlife CA (CAmid) and any AD-related brain changes. Late-life CA (CAlate) showed an association with both global Aβ deposition and AD-CMglu, although it was not statistically significant. Sensitivity analyses controlling for current depression or conducted only for CN individuals revealed similar results.Conclusion: Our results suggest that CA in early life may be protective against late-life AD-related neurodegeneration, independently of cerebral Aβ pathology.

Alzheimer's disease (AD), characterized by progressive cognitive decline, is the most prevalent neurodegenerative disease in the elderly. Cerebral β-amyloid (Aβ) deposition is the major pathological hallmark of AD. Recent studies also have shown that the serum level of phosphorus correlates to the risk of incident dementia. To date, the linkage between cerebral Aβ deposition and the serum phosphorus level remains unknown. In this study, we analyzed the levels of serum phosphorus in 109 mild cognitive impairment (MCI) and 73 AD dementia (ADD) subjects. All subjects underwent Pittsburgh compound B positron emission tomography (PiB-PET) imaging to measure cerebral Aβ deposition. The results with Aβ deposition was compared with the serum levels of phosphorus. The subjects with cerebral Aβ deposition showed lower levels of serum phosphorus than those without Aβ deposition. Furthermore, multiple regression analyses showed that a low level of serum phosphorus correlated with cerebral Aβ deposition, even when age, sex, apolipoprotein E ε4 genotype, and MMSE z-score were controlled for. Serum levels of other ions, including calcium, iron, zinc, and copper, showed no such correlation. In conclusion, our results suggest that the serum level of phosphorus may be used as an easily accessible blood biomarker for cerebral Aβ deposition in a cognitively impaired population.

Previous literature suggests that Alzheimer’s disease (AD) process may contribute to late-life onset depression (LLOD). Therefore, we investigated the association of LLOD with cerebral amyloidosis and neuronal injury, the two key brain changes in AD, along with vascular risks. Twenty nine non-demented individuals who first experienced major depressive disorder (MDD) after age of 60 years were included as LLOD subjects, and 27 non-demented elderly individuals without lifetime experience of MDD were included as normal controls (NC). Comorbid mild cognitive impairment (MCI) was diagnosed in 48% of LLOD subjects and in 0% of NC. LLOD, irrespective of comorbid MCI diagnosis, was associated with prominent prefrontal cortical atrophy. Compared to NC, LLOD subjects with comorbid MCI (LLODMCI) showed increased cerebral 11C-Pittsburg compound B (PiB) retention and plasma beta-amyloid 1-40 and 1-42 peptides, as measures of cerebral amyloidosis; and, such relationship was not observed in overall LLOD or LLOD without MCI (LLODwoMCI). LLOD subjects, particularly the LLODwoMCI, had higher systolic blood pressure (SBP) than NC. When analyzed in the same multiple logistic regression model that included prefrontal gray matter (GM) density, cerebral amyloidosis and SBP as independent variables, only prefrontal GM density showed a significant independent association with LLOD regardless of MCI comorbidity status. Our findings suggest AD process might be related to LLOD via prefrontal neuronal injury in the MCI stage, whereas vascular processes—SBP elevation, in particular—are associated with LLOD via prefrontal neuronal injury even in cognitively intact or less impaired individuals.

We examined in vivo evidence of axonal degeneration in association with neuronal pathology in Alzheimer’s disease (AD) through analysis of fornix microstructural integrity and measures of hippocampal subfield atrophy. Based on known anatomical topography, we hypothesized that the local thickness of subiculum and CA1 hippocampus fields would be associated with fornix integrity, reflecting an association between AD-related injury to hippocampal neurons and degeneration of associated axon fibers. To test this hypothesis, multi-modal imaging, combining measures of local hippocampal radii with diffusion tensor imaging (DTI), was applied to 44 individuals clinically diagnosed with AD, 44 individuals clinically diagnosed with mild cognitive impairment (MCI), and 96 cognitively normal individuals. Fornix microstructural degradation, as measured by reduced DTI-based fractional anisotropy (FA), was prominent in both MCI and AD, and was associated with reduced hippocampal volumes. Further, reduced fornix FA was associated with reduced anterior CA1 and antero-medial subiculum thickness. Finally, while both lesser fornix FA and lesser hippocampal volume were associated with lesser episodic memory, only the hippocampal measures were significant predictors of episodic memory in models including both hippocampal and fornix predictors. The region-specific association between fornix integrity and hippocampal neuronal death may provide in vivo evidence for degenerative white matter injury in AD: axonal pathology that is closely linked to neuronal injury.

The objective of this study was to characterize the trophic structure of fish assemblages on the coasts of offshore islands and the eastern mainland of the Korean Peninsula. We compared the seasonal variability in the trophic structure of fish assemblages between the coasts of two island sites (Ulleungdo and Dokdo) and one mainland site (Hupo), which are on a similar latitude. We analyzed the stable carbon and nitrogen isotope ratios (d13C and d15N) of fish assemblages during spring (April) and summer (August) 2021. No temporal differences in the isotope values of fish and basal resources (i.e., suspended particulate organic matter (SPOM)) were found over the sampling period at the Hupo site. In contrast, at the Ulleungdo and Dokdo sites, the fishes and SPOM showed seasonal differences in the d13C and d15N values between the two seasons. In particular, the fish d15N values at the island sites were relatively higher in summer compared to those in spring, suggesting the seasonal variation in the food chains and/or trophic status between consumers and their dietary sources. These regional isotopic variations also result in differences in the seasonal tendencies of the isotopic niche parameters of fish assemblages between the mainland and island coasts. Such differences in the seasonal isotopic patterns of fish assemblages suggest a relatively substantial shift in the dietary resources available to fish consumers on island coasts compared to those on the mainland coast. Overall, our results suggest that fish assemblages in offshore island coasts have distinct seasonal variability in trophic characteristics in response to changing environmental conditions, including basal resources, compared with fish food webs on the mainland coast at similar latitudes. [ABSTRACT FROM AUTHOR]

The geomorphology of coastal lagoons has an important effect on the hydrological balance between fresh water and seawater, which exhibit a wide range of salinity from nearly fresh water to hypersaline water. The present study aimed to characterize seasonal biogeochemical properties of suspended particulate organic matter (POM) in response to environmental variability driven by hydrological dynamics in contrasting coastal lagoon systems. We selected two lagoons distinguished by their geomorphological features, a permanently open artificial lagoon (Gyeongpoho) and an intermittently open natural lagoon (Hyangho), analyzed environmental characteristics, and compared the seasonal differences in the biochemical compositions of POM. Variations in temperature and precipitation in both lagoons showed the characteristics of a typical monsoon climate but variation in salinity differed 6.5−35.0 in Gyeongpoho and 1.1−10.8 in Hyangho. A self-organizing map analysis using the environmental data revealed that the spatiotemporal variations in salinity and nutrient concentrations differed significantly between the two lagoon systems, indicating a difference in hydrologic connectivity between lagoons and marine systems. Furthermore, a canonical correlation analysis highlighted that the POM properties differed according to physicochemical factors. The differing environmental conditions may affect the spatial and temporal variations in organic matter composition, resulting in significant differences in the biochemical composition of POM between two lagoon systems. Overall, this information provides insight into the origin and transport process of POM under changing coastal lagoon environments caused by climatic and human activities.

Background: Vascular adhesion protein-1 (VAP-1) is an oxidative enzyme of primary amines that facilitates the transmigration of inflammatory cells. Its oxidative and inflammatory effects are prominently increased in pathological conditions, such as metabolic, atherosclerotic, and cardiac diseases. However, the clinical significance of circulating VAP-1 levels in hemodialysis (HD) patients is unclear.Methods: A total of 434 HD patients were enrolled in a prospective multicenter cohort study between June 2016 and April 2019. Plasma VAP-1 levels were measured at the time of data entry, and the primary endpoint was defined as a composite of cardiovascular (CV) and cardiac events.Results: Circulating VAP-1 levels were positively correlated with plasma levels of cardiac remodeling markers, including brain natriuretic peptide, galectin-3, and matrix metalloproteinase-2. Multivariable logistic regression analysis revealed that patients with higher circulating VAP-1 levels were more likely to have left ventricular diastolic dysfunction [odds ratio, 1.40; 95% confidence interval [CI], 1.04–1.88]. The cumulative event rate of the composite of CV events was significantly greater in VAP-1 tertile 3 than in VAP-1 tertiles 1 and 2 (P = 0.009). Patients in tertile 3 were also associated with an increased cumulative event rate of cardiac events (P = 0.015), with a 2.06-fold higher risk each for CV (95% CI, 1.10–3.85) and cardiac (95% CI, 1.03–4.12) events after adjusting for multiple variables.Conclusions: Plasma VAP-1 levels were positively associated with left ventricular diastolic dysfunction and the risk of incident CV and cardiac events in HD patients. Our results indicate that VAP-1 may aid clinicians in identifying HD patients at a high risk of CV events.

Background: Neprilysin inhibition has demonstrated impressive benefits in heart failure treatment, and is the current focus of interest in cardiovascular (CV) and kidney diseases. However, the role of circulating neprilysin as a biomarker for CV events is unclear in hemodialysis (HD) patients.Methods: A total of 439 HD patients from the K-cohort were enrolled from June 2016 to April 2019. The plasma neprilysin level and echocardiographic findings at baseline were examined. The patients were prospectively followed up to assess the primary endpoint (composite of CV events and cardiac events).Results: Plasma neprilysin level was positively correlated with left ventricular (LV) mass index, LV end-systolic volume, and LV end-diastolic volume. Multivariate linear regression analysis revealed that neprilysin level was negatively correlated with LV ejection fraction (β = −2.14; p = 0.013). The cumulative event rate of the composite of CV events was significantly greater in neprilysin tertile 3 (p = 0.049). Neprilysin tertile 3 was also associated with an increased cumulative event rate of cardiac events (p = 0.016). In Cox regression analysis, neprilysin tertile 3 was associated with a 2.61-fold risk for the composite of CV events [95% confidence interval (CI), 1.37–4.97] and a 2.72-fold risk for cardiac events (95% CI, 1.33–5.56) after adjustment for multiple variables.Conclusions: Higher circulating neprilysin levels independently predicted the composite of CV events and cardiac events in HD patients. The results of this study suggest the importance of future studies on the effect of neprilysin inhibition in reducing CV events.