Tracking mitochondrial Cu(I) fluctuations through a ratiometric fluorescent probe in AD model cells: Towards understanding how AßOs induce mitochondrial Cu(I) dyshomeostasis.

Mitochondrial copper signaling pathway plays a role in Alzheimer's disease (AD), especially in relevant Amyloid-ß oligomers (AßOs) neurotoxicity and mitochondrial dysfunction. Clarifying the relationship between mitochondrial copper homeostasis and both of mitochondrial dysfunction and AßOs neurotoxicity is important for understanding AD pathogenesis. Herein, we designed and synthesized a ratiometric fluorescent probe CHC-NS4 for Cu(I). CHC-NS4 possesses excellent ratiometric response, high selectivity to Cu(I) and specific ability to target mitochondria. Under mitochondrial dysfunction induced by oligomycin, mitochondrial Cu(I) levels gradually increased, which may be related to inhibition of ATP7A-mediated Cu(I) exportation and/or high expression of COX. On this basis, CHC-NS4 was further utilized to visualize the fluctuations of mitochondrial Cu(I) levels during progression of AD model cells induced by AßOs. It was found that mitochondrial Cu(I) levels were gradually elevated during the AD progression, which depended on not only AßOs concentration but also incubation time. Moreover, endocytosis maybe served as a prime pathway mode for mitochondrial Cu(I) dyshomeostasis induced by AßOs during AD progression. These results have provided a novel inspiration into mitochondrial copper biology in AD pathogenesis.

Effect of weekend versus weekday admission on the mortality of acute ischemic stroke patients in China: an analysis of data from the Chinese acute ischemic stroke treatment outcome registry.

Background: Due to disparities in medical resources in rural and urban areas as well as in different geographic regions in China, the effect of weekend versus weekday admission on the outcomes of acute ischemic stroke (AIS) patients is unknown. Our aim was to investigate whether the outcomes of AIS patients differ according to the day of admission in China. Methods: The data were extracted from the Chinese Acute Ischemic Stroke Treatment Outcome Registry (CASTOR), a multicenter prospective study database of patients diagnosed with AIS. The chi-square test (χ2) and logistic regression were used to assess mortality for weekday and weekend admissions among AIS patients stratified by rural or urban status and geographic region (including the eastern, northeastern, central, and western regions). Results: In total, 9,256 patients were included in this study. Of these patients, 57.2% were classified as urban, and 42.8% were classified as rural. A total of 6,760 (73%) patients were admitted on weekdays, and 2,496 (27%) were admitted on weekends. There was no significant difference in the mortality rate among patients admitted on weekends compared with those admitted on weekdays in urban (7.5% versus 7.4%) or rural areas (8.8% versus 8.1%; p > 0.05). The mortality rate was the highest among patients admitted on weekends and weekdays (11.6% versus 10.3%) in the northeastern area, without statistical significance before and after adjusting for the patients' background characteristics (p > 0.05). In addition, regression analysis revealed that the mortality of patients admitted on weekdays was more likely to be influenced by regional subgroup, hospital level and intravenous thrombolysis than that of patients admitted on weekends. Conclusion: The weekend effect was not observed in the mortality of patients with AIS regardless of rural-urban status or geographic region in China.

Sleep Characteristics in Older Adults with Different Levels of Risk for Dementia: A Cross-sectional Study.

BACKGROUND: Sleep problems are very prevalent in older adults, especially in those at risk for dementia. But the relationships between sleep parameters and subjective or objective cognitive decline are still inconclusive. AIM: The study aimed to investigate the self-reported and objectively measured sleep characteristics in older adults with mild cognitive impairment (MCI) and subjective cognitive decline (SCD). METHODS: This study adopted a cross-sectional design. We included older adults with SCD or MCI. Sleep quality was measured separately by the Pittsburgh sleep quality index (PSQI) and ActiGraph. Participants with SCD were divided into low, moderate, and high levels of SCD groups. Independent samples T-tests, one-way ANOVA, or nonparametric tests were used to compare the sleep parameters across groups. Covariance analyses were also performed to control the covariates. RESULTS: Around half of the participants (45.9%) reported poor sleep quality (PSQI＜7), and 71.3% of participants slept less than 7 hours per night, as measured by ActiGraph. Participants with MCI showed shorter time in bed (TIB) (p＜0.05), a tendency of shorter total sleep time (TST) at night (p = 0.074) and for each 24-hour cycle (p = 0.069), compared to those with SCD. The high SCD group reported the highest PSQI total score and longest sleep latency than all the other three groups (p＜0.05). Both the MCI and high SCD groups had shorter TIB and TST for each 24-hour cycle than the low or moderate SCD groups. Besides, participants with multiple-domain SCD reported poorer sleep quality than those with single-domain SCD (p＜0.05). CONCLUSION: Sleep dysregulation is prevalent in older adults with a risk for dementia. Our findings revealed that objectively measured sleep duration might be an early sign of MCI. Individuals with high levels of SCD demonstrated poorerself-perceived sleep quality and deserved more attention. Improving sleep quality might be a potential target to prevent cognitive decline for people with a risk for dementia.

The characteristic of nonmotor symptoms with different phenotypes and onsets in multiple system atrophy patients.

OBJECTIVES: The characteristic of nonmotor symptoms in patients with multiple system atrophy (MSA) has varied among previous studies. The objective was to investigatethe nonmotor characteristics in MSA patients with different phenotypes, sex and different onset patterns. METHODS: We performed a retrospective review of 1492 MSA patients. All cases were evaluatedby neurologists and assessed with motormanifestations, nonmotor symptoms, auxiliary examinationand brain MRI scans. RESULTS: Multiple system atrophy-cerebellar ataxia (MSA-C) was the predominant phenotype in 998 patients. Average age of onset (56.8 ± 9.2 years) was earlier, the disease duration (2.4 ± 2.2 year) was shorter and brain MRI abnormalities (49.2 %) were more frequently in MSA-C (P < 0.001). Multiple system atrophy-parkinsonism (MSA-P) patients were more likely to have nonmotor symptoms. After adjusted significant parameters, urinary dysfunction (OR 1.441, 95 %CI = 1.067-1.946, P = 0.017), constipation (OR 1.482, 95 %CI = 1.113-1.973, P = 0.007), cognitive impairment (OR 1.509, 95 %CI = 1.074-2.121, P = 0.018) and drooling (OR 2.095, 95 %CI = 1.248-3.518, P = 0.005) were associated with the MSA-P phenotype. Males were more likely to have orthostatic hypotension, urinary dysfunction, sexual dysfunction, drooling and females in constipation and probable RBD. In different onset patterns, constipation (59.2 %) and probable RBD (28.4 %) were more frequently in autonomiconset pattern. CONCLUSIONS: MSA-C is the predominant phenotype in Chinese patients, while many nonmotor symptoms are more common in MSA-P phenotype. Patients with different sex and onset patterns have different nonmotor characteristics. The different clinical features identified could help the physician counseling of MSA patients more easily and more accurately.

Mental states in caregivers toward people with Alzheimer's disease at different stages.

Introduction: Caring for people with Alzheimer's disease (AD) is burdensome, especially when family members act as caregivers. This multicenter survey first aimed to investigate caregivers' mental states as well as its influencing factors in caring for people with different severities of AD in China. Methods: People with AD and their caregivers from 30 provincial regions in mainland China were enrolled from October 2020 to December 2020 to be surveyed for caregivers' mental states and living conditions, as well as caregivers' attitudes toward treatment and caring. Logistic regression was used to explore the factors that influence the positive and negative states of caregivers who care for people with different stages of AD. Results: A total of 1,966 valid questionnaires were analyzed (mild AD: 795, moderate AD: 521, severe AD: 650). A total of 73.6% of caregivers maintained normal states (mild group: 71.9%, moderate group: 73.9%, severe group: 75.2%; X2 = 2.023, p = 0.364), and the proportions of caregivers with positive and negative states were 26.3% (mild group: 38.4%, moderate group: 24.6%, severe group: 13.1%; X2 = 119.000, p < 0.001) and 36.5% (mild group: 25.2%, moderate group: 36.9%, severe group: 50.2%; X2 = 96.417, p < 0.001), respectively. The major factors that both influenced caregivers' positive and negative states were the severity of AD, perceived efficacy of treatment, safety issues after AD dementia diagnosis and perceived social support (p < 0.005), while neuropsychiatric symptoms causing stress in caregivers (p < 0.001) only affected the negative states of caregivers. The results of further analysis according to disease severity showed that safety issues after AD dementia diagnosis (p < 0.005) only made significant differences in the mild-to-moderate group. Conclusion: To reduce negative states and promote positive states among caregivers, flexible and sensitive caregiving support could be built on caregivers' demands in caring for people with different stages of AD. The support of emotion, social functioning and nursing skills is one of the significant ways for health workers to enhance caregivers' competency.

Differences in treatment for Alzheimer's disease between urban and rural areas in China.

Introduction: In China, the increasing number of people with Alzheimer's disease (AD) poses a great challenge to families and the country. Economic and cultural differences cause a urban-rural gap in medical resources. This multicenter survey aimed to investigate the real-world practice of disease treatment among people with AD. Methods: People with AD and their caregivers from 30 provincial regions in mainland China were enrolled from October 2020 to December 2020 to be surveyed for their treatment experience. Logistic regression was used to explore the factors that influence medication adherence in all areas, urban areas, and rural areas. Results: In this survey, 1,427 participants came from urban areas, and 539 participants came from rural areas. Patients in urban areas were older (mean age 74 vs. 70, p = 0.001), less frequently had mild AD (36.0 vs. 52.1%, p < 0.001), and more often were cared for at professional institutions (8.8 vs. 3.2%, p < 0.001). In terms of pharmacotherapy, 77.8% of people accepted taking lifelong medication, whereas 61.3% of patients insisted on taking medications. Although 72.0% of rural people believed in taking lifelong medication, only 30.0% adhered to drug use. The major factors that influenced medication adherence for all patients with AD were regional distribution (p < 0.001, OR = 6.18, 95% CI: 4.93-7.74) and family earnings (p = 0.003, OR = 1.22, 95% CI: 1.07-1.38). In rural areas, family earnings (p = 0.008, OR = 1.44, 95% CI: 1.10-1.89) and severity of AD (p = 0.033, OR = 1.31, 95% CI: 1.02-1.68) were the main factors. Family earnings (p = 0.038, OR = 1.16, 95% CI: 1.01-1.34) was the only factor among urban areas. Among all non-pharmaceutical activities except for cognitive intervention, the participation rates of rural patients were significantly higher than those of urban patients (p < 0.05). Conclusion: Although national progress has been made in the public awareness of disease treatment, adequate diagnosis and medication adherence need to be prompted, especially in rural areas. Furthermore, lifelong treatment should be improved based on regional characteristics through the joint efforts of the government, health workers, and social volunteers.

Mediation of the APOE Associations With Cognition Through Cerebral Blood Flow: The CIBL Study.

Background: The ε4 allele of the apolipoprotein E (APOE) gene is a strong genetic risk factor for aging-related cognitive decline. However, the causal connection between ε4 alleles and cognition is not well understood. The objective of this study was to identify the roles of cerebral blood flow (CBF) in cognitive-related brain areas in mediating the associations of APOE with cognition. Methods: The multiple linear regression analyses were conducted on 369 subjects (mean age of 68.8 years; 62.9% of women; 29.3% of APOE ε4 allele carriers). Causal mediation analyses with 5,000 bootstrapped iterations were conducted to explore the mediation effects. Result: APOE ε4 allele was negatively associated with cognition (P < 0.05) and CBF in the amygdala, hippocampus, middle temporal gyrus, posterior cingulate, and precuneus (all P < 0.05). The effect of the APOE genotype on cognition was partly mediated by the above CBF (all P < 0.05). Conclusion: CBF partially mediates the potential links between APOE genotype and cognition. Overall, the APOE ε4 allele may lead to a dysregulation of the vascular structure and function with reduced cerebral perfusion, which in turn leads to cognitive impairment.

Red blood cell distribution width in different time-points of peripheral thrombolysis period in acute ischemic stroke is associated with prognosis.

The relationship between red blood cell distribution width (RDW) in peripheral thrombolysis period and prognosis is not fully clarified in those who underwent intravenous thrombolysis (IVT) for acute ischemic stroke (AIS). Our study aimed to clarify this issue. A retrospective analysis of about 510 consecutive thrombolysis cases for AIS from January 2015 to March 2019 in a single-center database was done and followed-up for 3 months. We used univariate and multivariable models to evaluate the relationship between RDW levels at various time-points after IVT and the occurrence risk of hemorrhagic transformation (HT) and recurrent stroke, and used COX regression to assess the hazard ratios of outcomes with RDW levels. Elevated risk of HT was found in higher tertiles of RDW (OR = 10.282, 95% confidence interval (CI) 2.841-39.209, P < 0.001 in Tp tertile G3; OR = 5.650, 95% CI 1.992-16.025, P = 0.001 in T24 tertile G3; OR = 4.308, 95% CI 1.480-12.542, P = 0.007 in T48 tertile G3 and OR = 6.384, 95% CI 2.201-18.515, P = 0.001 in T72 tertile G3, respectively). Occurrence of recurrent stroke was highest in the RDW tertile G3 (HR = 4.580, 95% CI 2.123-9.883, P < 0.001 in Tp tertile G3; HR = 5.731, 95% CI 2.498-13.151, P = 0.001 in T24 tertile G3; HR = 3.019, 95% CI 1.969-4.059, P = 0.031 in T48 tertile G3; HR = 3.318, 95% CI 1.598-6.890, P = 0.001 in T72 tertile G3, respectively). Mean RDW levels ≥13.60 among AIS patients undergoing thrombolysis was associated with higher risk of HT and recurrent stroke.

Cerebrospinal Fluid sTREM2 Has Paradoxical Association with Brain Structural Damage Rate in Early- and Late-Stage Alzheimer's Disease.

BACKGROUND: Recently it has been proposed that microglial response has a stage-dependent effect on the progression of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) sTREM2 has emerged as a promising microglial activation marker. OBJECTIVE: To test the stage-dependent role of microglia by studying the association between baseline sTREM2 and dynamic brain structural changes in AD and mild cognitive impairment (MCI) patients. METHODS: 22 amyloid-ß-positive (A+) and tau-positive (T+) AD and 24 A+T+MCI patients were identified from the Alzheimer's Disease Neuroimaging Initiative. The patients had baseline CSF amyloid-ß, phosphorylated-tau, and sTREM2, and were followed up for at least one year by T1-weighted and diffusion tensor imaging scans. Gray matter volumes and white matter microstructural integrity were evaluated. Linear mixed models were applied to analyze how baseline sTREM2 may influence the rate of brain structural changes while adjusting for the effects of age, APOE4 status, and the CSF core markers. RESULTS: In A+T+AD patients, baseline CSF sTREM2 was associated with faster mean diffusivity increase in the bilateral posterior corona radiata and right superior longitudinal fasciculus. In A+T+MCI patients, baseline CSF sTREM2 was associated slower gray matter volumetric loss in parahippocampal gyrus, left fusiform cortex, left middle temporal gyrus, and left lateral occipital cortex. Baseline CSF sTREM2 also had a protective effect against mean diffusivity increase in right inferior fronto-occipital fasciculus, left superior longitudinal fasciculus, left forceps minor, and left uncinate fasciculus. CONCLUSION: Microglial activation at early stage might have a protective effect against neurodegeneration, while at late stage it might facilitate AD. Future efforts on modulating microglial activation could be promising, given a carefully selected time window for intervention.

Factors Associated With Alzheimer's Disease Patients' Caregiving Status and Family Caregiving Burden in China.

Background: The increasing prevalence of Alzheimer's disease (AD) has emerged as a major challenge worldwide. China as the most populous country in the globe is amid rapid aging of its population, highlighting the need for appropriate social and medical policies to meet the challenge. The current multicenter cross-sectional observational study aims to provide understanding of the current status of caring given to AD patients in China and investigate the factors that influence the family burden as well as the choice of care given to AD patients. Methods: A total of 1,675 patients with probable AD from 30 provincial regions of mainland China were enrolled in the current study from August 2019 to December 2019. We analyzed the caregiving status and its relationship with family burden and various socio-economical and medical factors. Results: In the current study, 90.87% of the AD patients enrolled adopted family care. The choice of caregiving method was influenced by factors including age (>80 years old, OR 0.648; 95% CI, 0.427-0.983), overall family burden (high, OR 0.574; 95% CI, 0.0.373-0.884), patients' income (OR 0.511; 95% CI, 0.330-0.789) and self-care ability (OR 0.329; 95% CI, 0.183-0.588). Conclusion: Family care is the primary method of care for AD patients in China and the institutional care system for AD patients is still underprepared in China.

Erythrocyte-derived extracellular vesicles aggravate inflammation by promoting the proinflammatory macrophage phenotype through TLR4-MyD88-NF-κB-MAPK pathway.

Transfusion of stored erythrocytes is associated with the increased risk of morbidity and mortality in critical infections, but the mechanism is incompletely understood. Previous studies have suggested that RBC-derived extracellular vesicles (EVs) may be potential risk factors for the occurrence of transfusion-related immunomodulation. The purpose of our study was to evaluate the effects of RBC-derived EVs under inflammatory conditions and explore the underlying mechanisms. In vivo, the activity of EVs was evaluated in cecal ligation and puncture (CLP)-induced sepsis. Our results showed that EVs significantly aggravated the inflammatory response to sepsis in serum and lung tissue by promoting the production of the proinflammatory factors tumor necrosis factor-α (TNF-α）-interleukin-6(IL-6), and interleukin-1ß (IL-1ß) and reduced the survival rate of septic mice in vivo. Importantly, adoptive transfer of EVs-pretreated bone marrow-derived macrophages (BMDMs) obviously aggravated systemic proinflammatory factors in mice after CLP surgery. In vitro, the proinflammatory properties of EVs were shown to elevate TNF-α, IL-6, and IL-1ß levels in lipopolysaccharide (LPS)-stimulated BMDMs. Moreover, EVs promoted LPS-induced macrophage polarization into a proinflammatory phenotype. The underlying mechanism might involve EV-mediated up-regulation of TLR4-MyD88-NF-κB-MAPK activity to favor macrophage cytokine production.

Blood pressure undulation of peripheral thrombolysis period in acute ischemic stroke is associated with prognosis.

BACKGROUND: Evidence suggests that patients with higher blood pressure variability (BPV) have a higher risk for stroke but the relationship between BPV and stroke outcomes is unknown in those who underwent intravenous thrombolysis (IVT) for acute ischemic stroke (AIS). The objective of this study is to investigate the association among BPV, BP values and stroke outcomes. METHODS: A retrospective analysis of about 510 consecutive thrombolysis cases for AIS from January 2015 to March 2019 in a single-center database were done. Then, these patients were followed-up for 3 months. We used univariate and multivariable models to evaluate the relationship between mean BP values, BPV and the risk of stroke outcomes from prior IVT to 72 h after IVT. Meanwhile, we also used COX regression to assess the hazard ratios of stroke outcomes with BPV within 3 months. Furthermore, we tested the effect of BP level at various time-points (prior to IVT and at 0, 2, 4, 8, 12, 24, 48 and 72 h after IVT) on development of postthrombolytic stroke outcomes. RESULTS: Higher BPV from prior IVT to 72 h after IVT was associated with higher risk of stroke outcomes within 3 months [SBPV of recurrent stroke: odds ratios (OR) = 5.298, 95% confidence interval (CI) 1.339-10.968, P = 0.018; DBPV of recurrent stroke: OR = 6.397, 95% CI 1.576-25.958, P = 0.009, respectively]. In addition, patients with recurrent stroke had significantly higher mean SBP (OR=1.037, 95% CI 1.006-1.069, P = 0.019). Furthermore, higher BP at different time points were associated with greater risk of recurrent stroke from prior IVT to 72 h after IVT. CONCLUSION: Higher BPV and SBP from prior IVT to 72 h after IVT was associated with higher risk of stroke outcomes within 3 months.

Impact of Increased Hemoglobin on Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Studies of the impact of increased hemoglobin on spontaneous intracerebral hemorrhage (ICH) are limited. The present study aimed to explore the effect of increased hemoglobin on ICH. METHODS: A retrospective single-center study using medical records from a database processed by univariate and multivariate analyses was performed in the People's Hospital of Tibet Autonomous Region in Lhasa, Tibet, China. RESULTS: The mean hemoglobin level in 211 patients with ICH was 165.03 ± 34.12 g/l, and a median hematoma volume was 18.5 ml. Eighty-eight (41.7%) patients had large hematomas (supratentorial hematoma ≥ 30 ml; infratentorial hematoma ≥ 10 ml). No differences in ICH risk factors between the groups with different hemoglobin levels were detected. Increased hemoglobin was independently associated with large hematomas [odds ratio (OR) 1.013, P = 0.023]. Increased hemoglobin was independently associated with ICH with subarachnoid hemorrhage (OR 1.014, P = 0.016), which was more pronounced in men (OR 1.027, P = 0.002). Increased hemoglobin was independently associated with basal ganglia hemorrhage and lobar hemorrhage in men (OR 0.986, P = 0.022; OR 1.013, P = 0.044, respectively) but not in women (P > 0.1). CONCLUSIONS: Increased hemoglobin was independently associated with large hemorrhage volume. Increased hemoglobin was independently associated with lobar hemorrhage in men and ICH with subarachnoid hemorrhage, which was more pronounced in men. Additional studies are needed to confirm our findings and explore potential mechanisms.

Physical Activity and its Influencing Factors in Community-Dwelling Older Adults With Dementia: A Path Analysis.

Dementia is prevalent in worldwide, and increases the care burden and potential costs. Physical activity (PA) has been increasingly shown to be beneficial for them. This was a cross-sectional observational study aiming to investigate the status of PA among community-dwelling older adults with dementia in Beijing or Hangzhou, China, and verify the relationships between neuropsychiatric symptoms, activities of daily living (ADL), caregivers' fear of patients' falling and their PA using a path analysis approach. The level of PA among 216 included people with dementia was low. PA was related to the neuropsychiatric symptoms, with ADL and caregivers' fear of patients' falling have mediation roles. The findings indicated that person-centered strategies related to the management of these symptoms might be helpful to improve ADL, relieve caregivers' concerns about them falling and consequently foster positive participation in PA.

High-fat diet caused renal damage in ApoE-/- mice via the activation of RAGE-mediated inflammation.

High-fat diet (HFD) is the primary cause of metabolic syndrome associated chronic kidney disease. This study aimed to investigate the pathogenesis of HFD-induced kidney injury. ApoE-/- mice were fed with HFD and kidney damage was examined. In addition, HK-2 human renal proximal tubular epithelial cells were treated with fructose and receptor of advanced glycation end products (RAGE) siRNA. The results showed that HFD increased body weight, blood glucose and insulin resistance in ApoE-/- mice. The kidney damage was associated with increased oxidative stress and strong staining of RAGE and NF-κB in kidney tissues, as well as high serum levels of TNF-α, IL-1ß and IL-6. Western-blot analysis showed that HFD increased the levels of RAGE, p-IκBα, p-NF-κB, bax, caspase-3 and caspase-9 but decreased the levels of Bcl-2 in kidney tissues. In HK-2 cells, fructose promoted the secretion of TNF-α, IL-1ß and IL-6 and increased the levels of RAGE, p-IκBα, p-NF-κB, bax, caspase-3 and caspase-9, but decreased the levels of Bcl-2. Moreover, RAGE siRNA could attenuate increased levels of p-IκBα, p-NF-κB, bax, caspase-3 and caspase-9 while restore decreased levels of Bcl-2 in fructose-treated HK-2 cells. In conclusion, HFD causes kidney injury by promoting oxidative stress, inflammation and apoptosis possibly through the activation of RAGE/NF-κB pathway.

Predicting Brain Regions Related to Alzheimer's Disease Based on Global Feature.

Alzheimer's disease (AD) is a neurodegenerative disease that commonly affects the elderly; early diagnosis and timely treatment are very important to delay the course of the disease. In the past, most brain regions related to AD were identified based on imaging methods, and only some atrophic brain regions could be identified. In this work, the authors used mathematical models to identify the potential brain regions related to AD. In this study, 20 patients with AD and 13 healthy controls (non-AD) were recruited by the neurology outpatient department or the neurology ward of Peking University First Hospital from September 2017 to March 2019. First, diffusion tensor imaging (DTI) was used to construct the brain structural network. Next, the authors set a new local feature index 2hop-connectivity to measure the correlation between different regions. Compared with the traditional graph theory index, 2hop-connectivity exploits the higher-order information of the graph structure. And for this purpose, the authors proposed a novel algorithm called 2hopRWR to measure 2hop-connectivity. Then, a new index global feature score (GFS) based on a global feature was proposed by combing five local features, namely degree centrality, betweenness centrality, closeness centrality, the number of maximal cliques, and 2hop-connectivity, to judge which brain regions are related to AD. As a result, the top ten brain regions identified using the GFS scoring difference between the AD and the non-AD groups were associated to AD by literature verification. The results of the literature validation comparing GFS with the local features showed that GFS was superior to individual local features. Finally, the results of the canonical correlation analysis showed that the GFS was significantly correlated with the scores of the Mini-Mental State Examination (MMSE) scale and the Montreal Cognitive Assessment (MoCA) scale. Therefore, the authors believe the GFS can also be used as a new biomarker to assist in diagnosis and objective monitoring of disease progression. Besides, the method proposed in this paper can be used as a differential network analysis method for network analysis in other domains.

Optimal blood pressure levels in different phases of peripheral thrombolysis period in acute ischemic stroke.

BACKGROUND: Dramatic changes of blood pressure (BP) were observed in the peripheral thrombolysis period, however, there is no consensus about BP control targets in the different phases. METHODS: We retrospectively studied a consecutive sample of 510 patients treated with intravenous thrombolysis and followed-up for 3 months. The peripheral thrombolysis period was divided into these phases: Phase 1 (from onset to thrombolysis), Phase 2 (thrombolysis), Phase 3 (from thrombolysis to 24 h after thrombolysis), and Phase 4 (from 24 h to 7 days after thrombolysis). Patients were divided into quintiles according to mean blood pressure in these phases, respectively. Neurological improvement was evaluated using the modified Rankin Scale score at 3-month after thrombolysis. RESULTS: Lower risk of intracerebral hemorrhage within 7 days was found in lower quintiles of SBP (OR = 0.100, 95% CI 0.011-0.887, P = 0.039 in Phase 1 quintile Q1, OR = 0.110, 95% CI 0.012-0.974, P = 0.047 in Phase 2-3 quintile Q1, and OR, 0.175, 95% CI, 0.035-0.872; P = 0.033 in Phase 4 quintile Q2, respectively). Better neurological improvement was found in SBP quintiles: Q2-Q4 (127.3-155.7 mmHg) in Phase 4 (OR = 3.095, 95% CI 1.524-6.286, P = 0.002 for Q2; OR = 2.697, 95% CI 1.354-5.370, P = 0.005 for Q3; and OR = 2.491, 95% CI 1.263-4.913, P = 0.008 for Q4, respectively). Our results also showed higher average real variability of SBP was negatively associated with better neurological outcome in Phase 1 and Phase 2-3. CONCLUSIONS: Maintaining SBP levels (≤148 mmHg) from admission to the first 24 h after thrombolysis, then keeping SBP levels (127-138 mmHg) would be beneficial.

The Association between Neprilysin gene polymorphisms and Alzheimer's disease in Tibetan population.

OBJECTIVES: Alzheimer's disease (AD) is a well-known neurodegenerative disease, of which the hallmark is the disposition of ß-amyloid (Aß) in the form of plaque in the brain. Neprilysin (NEP) is the major enzyme to degrade Aß and prevent accumulation of Aß. The present study was undertaken to elucidate the correlation between the NEP gene polymorphisms and AD in Chinese Tibetan population. METHODS: Ninety-nine sporadic AD Tibetan patients and 113 healthy Tibetan controls were enrolled in this study. The genotype frequencies and allele frequencies of multiple NEP gene loci were analyzed using the case-control association analysis. RESULTS: No significant correlation was found between polymorphisms of NEP gene loci (rs9829757, rs1816558, rs6776185, rs3736187, rs701109, rs989692) and the occurrence of AD in Tibetan population. However, allele C of NEP gene locus (rs701109) and allele T of gene locus (rs3736187) were possible risk factors of male AD patients in Tibetan population. CONCLUSIONS: NEP gene loci (rs701109, rs989692, rs9829757, rs3736187, rs1816558, rs6776185) were polymorphic in Tibetan population. No difference was found between these loci but for that male gender combined with allele C of NEP gene locus (rs701109) and T of gene locus (rs3736187) might be risk factors for AD in Tibet.

Combination of Polyethylene Glycol-Conjugated Urokinase Nanogels and Urokinase for Acute Ischemic Stroke Therapeutic Implications.

Tissue reperfusion is a serious therapeutic strategy of ischemic stroke in addition to recanalization. In this work, we aimed to establish new urokinase-based therapeutics in order to dissolve large vessel thrombus together with microthrombi for stroke implications. Formulations consisted of free urokinase (UK), polyethylene glycol-crosslinked urokinase nanogel (PEG-UK), and a 1:1 mixture of UK and PEG-UK (PEG-UK+UK) were tested both in vitro and in vivo. In vitro experiments confirmed the pH-dependent release of PEG-UK in the PEG-UK+UK formulation. It was activated at pH 6.50, an environmental pH in the infarct brain tissue, owing to the dynamic crosslink property of PEG-UK. In vivo tests on a thromboembolic stroke rat model showed that the formulations containing UK, i.e., free UK and PEG-UK+UK, demonstrated better neurological scores and smaller infarction volumes within the time window, in which the PEG-UK+UK formulation relatively performed better. On the other hand, the formulations containing PEG-UK, i.e., PEG-UK and PEG-UK+UK, gained sufficient thrombolytic efficiency beyond the time window. Further investigation on the mechanism revealed that PEG-UK could reduce microthrombus in distal microcirculation, and its destructive effect was also less than that of free UK. The PEG-UK+UK formulation actually provided a "dual targeting" delivery of UK to both the large vessels and the microcirculation, which was beneficial to the treatment of cerebral ischemic stroke both within and beyond the therapeutic time window.