Cerebrospinal fluid amyloid-ß and cerebral microbleed are associated with distinct neuropsychiatric sub-syndromes in cognitively impaired patients.

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent in cognitively impaired individuals including Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). Whereas several studies have reported the associations between NPS with AD pathologic biomarkers and cerebral small vessel disease (SVD), but it remains unknown whether AD pathology and SVD contribute to different sub-syndromes independently or aggravate same symptoms synergistically. METHOD: We included 445 cognitively impaired individuals (including 316 MCI and 129 AD) with neuropsychiatric, cerebrospinal fluid (CSF) biomarkers (Aß42, p-tau, and t-tau) and multi-model MRI data. Psychiatric symptoms were accessed by using the Neuropsychiatric Inventory (NPI). Visual assessment of SVD (white matter hyperintensity, microbleed, perivascular space, lacune) on MRI images was performed by experienced radiologist. Linear regression analyses were conducted to test the association between neuropsychiatric symptoms with AD pathology and CSVD burden after adjustment for age, sex, education, apolipoprotein E (APOE) ε4 carrier status, and clinical diagnosis. RESULTS: The NPI total scores were related to microbleed (estimate 2.424; 95% CI [0.749, 4.099]; P =0.005). Considering the sub-syndromes, the hyperactivity was associated with microbleed (estimate 0.925; 95% CI [0.115, 1.735]; P =0.025), whereas the affective symptoms were correlated to CSF level of Aß42 (estimate -0.006; 95% CI [-0.011, -0.002]; P =0.005). Furthermore, we found the apathy sub-syndrome was associated with CSF t-tau/Aß42 (estimate 0.636; 95% CI [0.078, 1.194]; P =0.041) and microbleed (estimate 0.693; 95% CI [0.046, 1.340]; P =0.036). In addition, we found a significant interactive effect between CSF t-tau/Aß42 and microbleed (estimate 0.993; 95% CI [0.360, 1.626]; P =0.019) on severity of apathy sub-syndrome. CONCLUSION: Our study showed that CSF Aß42 was associated with affective symptoms, but microbleed was correlated with hyperactivity and apathy, suggesting the effect of AD pathology and SVD on different neuropsychiatric sub-syndromes.

Association Between Small Vessel Disease and Financial Capacity: A Study Based on Cognitively Normal Older Adults.

Background: Financial capacity is vital for the elderly, who possess a substantial share of global wealth but are vulnerable to financial fraud. Objective: We explored the link between small vessel disease (SVD) and financial capacity in cognitively unimpaired (CU) older adults via both cross-sectional and longitudinal analyses. Methods: 414 CU participants underwent MRI and completed the Financial Capacity Instrument-Short Form (FCI-SF). Subsequent longitudinal FCI-SF data were obtained from 104, 240, and 141 participants at one, two, and four years, respectively. SVD imaging markers, encompassing white matter hyperintensities (WMH), cerebral microbleeds (CMB), and lacune were evaluated. We used linear regression analyses to cross-sectionally explore the association between FCI-SF and SVD severity, and linear mixed models to assess how baseline SVD severity impacted longitudinal FCI-SF change. The false discovery rate method was used to adjust multiple comparisons. Results: Cross-sectional analysis revealed a significant association between baseline WMH and Bank Statement (BANK, ß=-0.194), as well as between lacune number and Financial Conceptual Knowledge (FC, ß= -0.171). These associations were stronger in APOE ɛ4 carriers, with ß= -0.282 for WMH and BANK, and ß= -0.366 for lacune number and FC. Longitudinally, higher baseline SVD total score was associated with severe FCI-SF total score decrease (ß= -0.335). Additionally, baseline WMH burden predicted future decreases in Single Checkbook/Register Task (SNG, ß= -0.137) and FC (ß= -0.052). Notably, the association between baseline WMH and SNG changes was amplified in APOE ɛ4 carriers (ß= -0.187). Conclusions: Severe SVD was associated with worse FCI-SF and could predict the decline of financial capacity in CU older adults.

Alteration of functional connectivity network in population of objectively-defined subtle cognitive decline.

The objectively-defined subtle cognitive decline individuals had higher progression rates of cognitive decline and pathological deposition than healthy elderly, indicating a higher risk of progressing to Alzheimer's disease. However, little is known about the brain functional alterations during this stage. Thus, we aimed to investigate the functional network patterns in objectively-defined subtle cognitive decline cohort. Forty-two cognitive normal, 29 objectively-defined subtle cognitive decline and 55 mild cognitive impairment subjects were included based on neuropsychological measures from the Alzheimer's disease Neuroimaging Initiative dataset. Thirty cognitive normal, 22 objectively-defined subtle cognitive declines and 48 mild cognitive impairment had longitudinal MRI data. The degree centrality and eigenvector centrality for each participant were calculated by using resting-state functional MRI. For cross-sectional data, analysis of covariance was performed to detect between-group differences in degree centrality and eigenvector centrality after controlling age, sex and education. For longitudinal data, repeated measurement analysis of covariance was used for comparing the alterations during follow-up period among three groups. In order to classify the clinical significance, we correlated degree centrality and eigenvector centrality values to Alzheimer's disease biomarkers and cognitive function. The results of analysis of covariance showed significant between-group differences in eigenvector centrality and degree centrality in left superior temporal gyrus and left precuneus, respectively. Across groups, the eigenvector centrality value of left superior temporal gyrus was positively related to recognition scores in auditory verbal learning test, whereas the degree centrality value of left precuneus was positively associated with mini-mental state examination total score. For longitudinal data, the results of repeated measurement analysis of covariance indicated objectively-defined subtle cognitive decline group had the highest declined rate of both eigenvector centrality and degree centrality values than other groups. Our study showed an increased brain functional connectivity in objectively-defined subtle cognitive decline individuals at both local and global level, which were associated with Alzheimer's disease pathology and neuropsychological assessment. Moreover, we also observed a faster declined rate of functional network matrix in objectively-defined subtle cognitive decline individuals during the follow-ups.

Interferon Regulatory Factor 5 Regulates the Phagocytosis of Microglia and Alleviate Alzheimer's Pathology.

Microglia play a critical role in the pathophysiology of Alzheimer's disease. They are involved in Aß-induced neuroinflammatory responses, regulating the production of inflammatory mediators. Interferon regulatory factor 5 (IRF5) plays a central role in inflammatory diseases in the periphery, the role of which in central nervous system remains elusive. This study aimed to investigate the role of IRF5 in Aß-induced neuroinflammation and the progression of Aß pathology. We found that Aß1-42 oligomers significantly increased the level of IRF5 in BV2 microglia. The levels of proinflammatory cytokines TNF-α, IL-1ß, and IL-6 were significantly upregulated with Aß treatment. IRF5 knockdown with siRNA in microglia significantly reduced the expression of these proinflammatory factors induced by Aß and promoted Aß phagocytosis. Besides, LC3 upregulation and p62 downregulation were observed in IRF5 knockdown microglia. This was also validated in APP/PS1 mice with IRF5 knockdown, leading to reduced Aß levels in the brain. We conclude that IRF5 mediates Aß-induced microglial inflammatory responses. IRF5 knockdown attenuated Aß-induced inflammatory responses and promoted the phagocytosis and autophagy of Aß by microglia.

Gray matter structural covariance networks patterns associated with autopsy-confirmed LATE-NC compared to Alzheimer's disease pathology.

BACKGROUND: Cases with the limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC), Alzheimer's disease (AD), and mixed AD+TDP-43 pathology (AD+LATE-NC) share similar symptoms, which makes it a challenge for accurate diagnosis. Exploring the patterns of gray matter structural covariance networks (SCNs) in these three types may help to clarify the underlying mechanism and provide a basis for clinical interventions. METHODS: We included ante-mortem MRI data of 10 LATE-NC, 39  AD, and 25  AD+LATE-NC from the ADNI autopsy sample. We used four regions of interest (left posterior cingulate cortex, right entorhinal cortex, frontoinsular and dorsolateral prefrontal cortex) to anchor the default mode network (DMN), salience network (SN), and executive control network (ECN). Finally, we assessed the SCN alternations using a multi-regression model-based linear-interaction analysis. RESULTS: Cases with autopsy-confirmed LATE-NC and AD showed increased structural associations involving DMN, ECN, and SN. Cases with AD+LATE-NC showed increased structural association within DMN while decreased structural association between DMN and ECN. The volume of peak clusters showed significant associations with cognition and AD pathology. CONCLUSIONS: This study showed different SCN patterns in the cases with LATE-NC, AD, and AD+LATE-NC, and indicated the network disconnection mechanism underlying these three neuropathological progressions. Further, SCN may serve as an effective biomarker to distinguish between different types of dementia.

Decoupling of Regional Cerebral Blood Flow and Brain Function Along the Alzheimer's Disease Continuum.

BACKGROUND: Alzheimer's disease (AD) is accompanied with impaired neurovascular coupling. However, its early alteration remains elusive along the AD continuum. OBJECTIVE: This study aimed to investigate the early disruption of neurovascular coupling in cognitively normal (CN) and mild cognitive impairment (MCI) elderly and its association with cognition and AD pathologies. METHODS: We included 43 amyloid-ß-negative CN participants and 38 amyloid-ß-positive individuals (18 CN and 20 MCI) from the Alzheimer's Disease Neuroimaging Initiative dataset. Regional homogeneity (ReHo) map was used to represent neuronal activity and cerebral blood flow (CBF) map was used to represent cerebral blood perfusion. Neurovascular coupling was assessed by CBF/ReHo ratio at the voxel level. Analyses of covariance to detect the between-group differences and to further investigate the relations between CBF/ReHo ratio and AD biomarkers or cognition. In addition, the correlation of cerebral small vessel disease (SVD) burden and neurovascular coupling was assessed as well. RESULTS: Related to amyloid-ß-negative CN group, amyloid-ß-positive groups showed decreased CBF/ReHo ratio mainly in the left medial and inferior temporal gyrus. Furthermore, lower CBF/ReHo ratio was associated with a lower Mini-Mental State Examination score as well as higher AD pathological burden. No association between CBF/ReHo ratio and SVD burden was observed. CONCLUSION: AD pathology is a major correlate of the disturbed neurovascular coupling along the AD continuum, independent of SVD pathology. The CBF/ReHo ratio may be an index for detecting neurovascular coupling abnormalities, which could be used for early diagnosis in the future.

Distinct cerebral small vessel disease impairment in early- and late-onset Alzheimer's disease.

OBJECTIVE: This study investigated cerebral small vessel disease (CSVD) damage patterns in early-onset and late-onset Alzheimer's disease (EOAD and LOAD) and their effects on cognitive function. METHODS: This study included 93 participants, 45 AD patients (14 EOAD and 31 LOAD), and 48 normal controls (13 YNC and 35 ONC) from the ADNI database. All participants had diffusion tensor imaging data; some had amyloid PET and plasma p-tau181 data. The study used peak width of skeletonized mean diffusivity (PSMD) to measure CSVD severity and compared PSMD between patients and age-matched controls. The effect of age on the relationship between PSMD and cognition was also examined. The study also repeated the analysis in amyloid-positive AD patients and amyloid-negative controls in another independent database (31 EOAD and 38 LOAD), and the merged database. RESULTS: EOAD and LOAD showed similar cognitive function and disease severity. PSMD was validated as a reliable correlate of cognitive function. In the ADNI database, PSMD was significantly higher for LOAD and showed a tendency to increase for EOAD; in the independent and merged databases, PSMD was significantly higher for both LOAD and EOAD. The impact of PSMD on cognitive function was notably greater in the younger group (YNC and EOAD) than in the older group (ONC and LOAD), as supported by the ADNI and merged databases. INTERPRETATION: EOAD has less CSVD burden than LOAD, but has a greater impact on cognition. Proactive cerebrovascular prevention strategies may have potential clinical value for younger older adults with cognitive decline.

Nutritional and Chemical Composition of Sargassum zhangii and the Physical and Chemical Characterization, Binding Bile Acid, and Cholesterol-Lowering Activity in HepG2 Cells of Its Fucoidans.

Fucoidan is a marine sulfated polysaccharide that is rich in Sargassum and has a wide range of biological activities. In this study, the chemical composition and bile acid binding ability of six crude fucoidans were compared, the nutrition and chemical composition of Sargassum zhangii were analyzed, and fucoidan from Sargassum zhangii was extracted and purified. The purified fractions (ZF1, ZF2, and ZF3) were analyzed by physicochemical characterization, and the ability of binding bile acid and cholesterol lowering in HepG2 cells were evaluated. The results showed that the contents of sulfate in crude fucoidan from Sargassum Zhangii (ZF) was as high as13.63%. Its ability of binding bile acid was better than other five crude fucoidans. Sargassum zhangii was a kind of brown seaweed with high carbohydrate, and low fat and rich in minerals. The sulfate content of ZF1, ZF2, and ZF3 was 3.29%, 19.39%, and 18.89% respectively, and the molecular weight (Mw) was 4.026 × 105, 2.893 × 105, and 3.368 × 105, respectively. Three fucoidans all contained the characteristic absorption bands of polysaccharides and sulfate groups and were rich in fucose. Three fucoidans can bind to bile acid, and ZF2 showed the best binding capability. In vitro experiments showed that ZF1, ZF2, and ZF3 could reduce intracellular total cholesterol (TC) content in HepG2 cells without affecting their viability. ZF2 showed the best ability to reduce TC.

Social and environmental risk factors for road traffic injuries among children under five in rural China.

BACKGROUND: Road traffic injuries (RTIs) have become a considerable issue for children. In China, RTIs are among the top 3 contributors to injury-related mortality and disability-adjusted life years. The present study aimed to evaluate social and environmental factors that may contribute to RTIs among children under 5 in rural areas of China. METHODS: The study was based on 1 year of data (October 1, 2015 to September 30, 2016) from the National Maternal and Child Health Surveillance System (NMCHSS) from all districts in 334 National Maternal and Child Health Surveillance Districts in 30 Chinese provinces, autonomous regions, and municipalities. Data were analyzed to identify environmental, social, and primary caregiver factors related to RTIs among children under 5. RESULTS: Based on data for the 279 children registered in the NMCHSS during the study period, incidence of RTIs increased with increasing age and was higher for boys than girls. Risk of RTIs depended on distances from the child's home to roads and playgrounds. Enrollment in kindergarten and characteristics of primary caregivers affected risky road behaviors by children. Most primary caregivers (67.4%) reported never using child car seats, and 70.6% reported never using a child helmet. Among primary caregivers without a driver's license, 24.8% reported having driven motor vehicles or motorcycles. CONCLUSIONS: The living environment and behaviors of primary caregivers can affect risk of RTIs in children younger than 5 years in rural China. Road safety awareness should be strengthened at the community and kindergarten levels.