78 results on '"Yan, Lin"'
Search Results
2. Association between Life’s Simple 7 and cerebrospinal fluid biomarkers of Alzheimer’s disease pathology in cognitively intact adults: the CABLE study
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Yong-Li Zhao, Ya-Nan Ou, Ya-Hui Ma, Yu-Yuan Huang, Yan-Lin Bi, Lan Tan, and Jin-Tai Yu
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Life’s Simple 7 ,Cerebrospinal fluid ,Biomarkers ,Alzheimer’s disease ,Pathogenesis ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Introduction This study sought to explore the association between Life’s Simple 7 (LS7) and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) pathological biomarkers in the cognitively normal northern Chinese population. Methods From the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study, 1106 cognitively normal participants were enrolled. The mean age was 62.34 years, and 39.6% were female. LS7 scores were summed with each metric assigned 0, 1, or 2 scores. The multiple linear regression models were used to investigate the association between LS7 scores and CSF AD biomarkers. Results We found that LS7 scores were significantly associated with CSF AD pathologies, including Aβ42/40 (β = 0.034, P = .041), p-tau181 (β = − 0.043, P = .006), and t-tau (β = − 0.044, P = .003). In subscales, the biological metrics (blood pressure, cholesterol, glucose) were significantly related to CSF tau-related biomarkers. These associations were observed in the APOE ε4 allele non-carriers, yet not in carriers. The relationship of behavior metrics was found in the middle age and males. Conclusion Improving LS7 scores might do a favor to alleviate the pathology of AD in the preclinical stage, especially among the APOE ε4 allele non-carriers.
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- 2022
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3. Association between Life’s Simple 7 and cerebrospinal fluid biomarkers of Alzheimer’s disease pathology in cognitively intact adults: the CABLE study
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Zhao, Yong-Li, Ou, Ya-Nan, Ma, Ya-Hui, Huang, Yu-Yuan, Bi, Yan-Lin, Tan, Lan, and Yu, Jin-Tai
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- 2022
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4. Anaemia and cerebrospinal fluid biomarkers of Alzheimer’s pathology in cognitively normal elders: the CABLE study
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Xin-Yu Yang, Xiao-He Hou, Yan-Lin Bi, Hao Hu, Xi-Peng Cao, Lan Tan, Jiu-Long Yang, and Jin-Tai Yu
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Anaemia ,Severity ,Alzheimer’s disease ,Cerebrospinal fluid ,Biomarkers ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Anaemia has been reported to be associated with cognitive decline and Alzheimer’s disease (AD), but the associations between anaemia and cerebrospinal fluid (CSF) AD biomarkers are still unknown. This study aimed to investigate the associations between anaemia and CSF AD biomarkers. Methods Participants were included from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study. The associations of anaemia and its severity with CSF AD biomarkers including β-amyloid 1–42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau) were analysed by multiple linear regression models. Adjusted for age, gender, educational levels, APOE ε4 alleles, comorbidities (history of coronary heart disease, history of stroke, hypertension, diabetes mellitus, dyslipidaemia) and glomerular filtration rate. Results A total of 646 cognitively normal older adults, consisting of 117 anaemia patients and 529 non-anaemia individuals, were included in this study. Anaemia patients had lower levels of CSF Aβ42 than individuals without anaemia (p = 0.035). Besides, participants with more severe anaemia had lower CSF Aβ42 levels (p = 0.045). No significant association of anaemia with CSF t-tau and p-tau levels was found. Conclusion Cross-sectionally, anaemia was associated with lower CSF Aβ42 levels. These findings consolidated the causal close relationship between anaemia and AD.
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- 2021
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5. Echocardiographic measures of the left heart and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: The CABLE study.
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Hu, He‐Ying, Hu, Hao, Jiang, Jing, Bi, Yan‐Lin, Sun, Yan, Ou, Ya‐Nan, Tan, Lan, and Yu, Jin‐Tai
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INTRODUCTION: This study delineated the interrelationships between subclinical alterations in the left heart, cerebrospinal fluid (CSF), Alzheimer's disease (AD) biomarkers, and cognition. METHODS: Multiple linear regressions were conducted in 1244 cognitively normal participants (mean age = 65.5; 43% female) who underwent echocardiography (left atrial [LA] and left ventricular [LV] morphologic or functional parameters) and CSF AD biomarkers measurements. Mediating effects of AD pathologies were examined. Differences in cardiac parameters across ATN categories were tested using analysis of variance (ANOVA) and logistic regressions. RESULTS: LA or LV enlargement (characterized by increased diameters and volumes) and LV hypertrophy (increased interventricular septal or posterior wall thickness and ventricular mass) were associated with higher CSF phosphorylated (p)‐tau and total (t)‐tau levels, and poorer cognition. Tau pathologies mediated the heart‐cognition relationships. Cardiac parameters were higher in stage 2 and suspected non‐Alzheimer's pathology groups than controls. DISCUSSION: These findings suggested close associations of subclinical cardiac changes with tau pathologies and cognition. Highlights: Various subclinical alterations in the left heart related to poorer cognition.Subclinical cardiac changes related to tau pathologies in cognitively normal adults.Tau pathologies mediated the heart‐cognition relationships.Subclinical cardiac changes related to the AD continuum, especially to stage 2.The accumulation of cardiac alterations magnified their damage to the brain. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Sleep Characteristics and Cerebrospinal Fluid Progranulin in Older Adults: The CABLE Study
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Wang, Meng, Sun, Fu-Rong, Bi, Yan-Lin, Ma, Ya-Hui, Yin, Jian-Jun, Shen, Xue-Ning, Wang, Xiao-Tong, Tan, Lan, and Yu, Jin-Tai
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- 2021
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7. Associations of healthy lifestyles with cerebrospinal fluid biomarkers of Alzheimer’s disease pathology in cognitively intact older adults: the CABLE study
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Xiao-He Hou, Wei Xu, Yan-Lin Bi, Xue-Ning Shen, Ya-Hui Ma, Qiang Dong, Lan Tan, and Jin-Tai Yu
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Alzheimer’s disease ,Lifestyle ,Social isolation ,Physical activity ,Cerebrospinal fluid ,Biomarker ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective We aimed to investigate the associations between healthy lifestyles and Alzheimer’s disease (AD) biomarkers in cerebrospinal fluid (CSF). Methods A total of 1108 cognitively intact individuals from Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study were examined to evaluate the associations of AD biomarkers with healthy lifestyle factors, including no current smoking, no harmful drinking, absence of social isolation, and regular physical activity. The participants were categorized into groups of favorable, intermediate, and unfavorable lifestyles according to the lifestyle factors. The associations between overall lifestyle and CSF biomarkers were also analyzed. Results Among cognitively intact older adults, those having more social engagement had lower CSF tau (p = 0.009) and p-tau (p
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- 2021
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8. Associations of healthy lifestyles with cerebrospinal fluid biomarkers of Alzheimer’s disease pathology in cognitively intact older adults: the CABLE study
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Hou, Xiao-He, Xu, Wei, Bi, Yan-Lin, Shen, Xue-Ning, Ma, Ya-Hui, Dong, Qiang, Tan, Lan, and Yu, Jin-Tai
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- 2021
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9. Anaemia and cerebrospinal fluid biomarkers of Alzheimer’s pathology in cognitively normal elders: the CABLE study
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Yang, Xin-Yu, Hou, Xiao-He, Bi, Yan-Lin, Hu, Hao, Cao, Xi-Peng, Tan, Lan, Yang, Jiu-Long, and Yu, Jin-Tai
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- 2021
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10. Increased neuronal activity in motor cortex reveals prominent calcium dyshomeostasis in tauopathy mice
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Qian Wu, Yang Bai, Wei Li, Erin E. Congdon, Wenke Liu, Yan Lin, Changyi Ji, Wen-Biao Gan, and Einar M. Sigurdsson
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Alzheimer's disease ,Frontotemporal dementia ,Tau ,Antibody ,Ca2+ ,Two-photon imaging ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Perturbed neuronal Ca2+ homeostasis is implicated in Alzheimer's disease, which has primarily been demonstrated in mice with amyloid-β deposits but to a lesser and more variable extent in tauopathy models.In this study, we injected AAV to express Ca2+ indicator in layer II/III motor cortex neurons and measured neuronal Ca2+ activity by two photon imaging in awake transgenic JNPL3 tauopathy and wild-type mice. Various biochemical measurements were conducted in postmortem mouse brains for mechanistic insight and a group of animals received two intravenous injections of a tau monoclonal antibody spaced by four days to test whether the Ca2+ dyshomeostasis was related to pathological tau protein.Under running conditions, we found abnormal neuronal Ca2+ activity in tauopathy mice compared to age-matched wild-type mice with higher frequency of Ca2+ transients, lower amplitude of peak Ca2+ transients and lower total Ca2+ activity in layer II/III motor cortex neurons. While at resting conditions, only Ca2+ frequency was increased. Brain levels of soluble pathological tau correlated better than insoluble tau levels with the degree of Ca2+ dysfunction in tauopathy mice. Furthermore, tau monoclonal antibody 4E6 partially rescued Ca2+ activity abnormalities in tauopathy mice after two intravenous injections and decreased soluble pathological tau protein within the brain. This correlation and antibody effects strongly suggest that the neuronal Ca2+ dyshomeostasis is causally linked to pathological tau protein.These findings also reveal more pronounced neuronal Ca2+ dysregulation in tauopathy mice than previously reported by two-photon imaging that can be partially corrected with an acute tau antibody treatment.
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- 2021
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11. Dynamic changes of CSF sTREM2 in preclinical Alzheimer’s disease: the CABLE study
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Ma, Ling-Zhi, Tan, Lan, Bi, Yan-Lin, Shen, Xue-Ning, Xu, Wei, Ma, Ya-Hui, Li, Hong-Qi, Dong, Qiang, and Yu, Jin-Tai
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- 2020
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12. Curcumin pretreatment and post-treatment both improve the antioxidative ability of neurons with oxygen-glucose deprivation
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Jing-xian Wu, Lu-yu Zhang, Yan-lin Chen, Shan-shan Yu, Yong Zhao, and Jing Zhao
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tamoxifen ,Src kinase ,PP2 ,trauma ,regeneration ,neuroprotection ,auranofin ,dextromethorphan ,rosiglitazone ,Alzheimer′s disease ,neuroinflammation ,neurodegeneration ,microglia ,astrocytes ,nerve regeneration ,spinal cord ,electroacupuncture therapy ,neural stem cells ,notch signaling pathway ,inflammation ,survival curve ,proliferation ,differentiation ,real-time quantitative PCR ,western blot assay ,neural regeneration ,superparamagnetic iron oxide ,magnetic guidance ,bone marrow mesenchymal stem cells ,spinal cord injury ,cell transplantation ,magnetic resonance image ,lumbar puncture ,spinal cord transection ,average combined score ,magnetic resonance imaging ,diffusion tensor imaging ,fractional anisotropy ,apparent diffusion coefficient ,fiber tractography ,peripheral nerve injury ,sciatic nerve ,hypothermia ,blood-nerve barrier ,Evans blue tracer ,neural degeneration ,polyethyleneimine-polyethylene glycol ,spiral ganglion cells ,X-linked inhibitor of apoptosis protein ,gene therapy ,nanocarrier ,cisplatin ,ototoxicity ,cochlea ,ocular hypertension ,JNK3 ,retinal ganglion cell ,glaucoma ,laser photocoagulation ,intraocular pressure ,brain injury ,apoptosis ,cerebral ischemia ,SMAD3 ,transforming growth factor β1 ,NSFC grant ,Chinese herbal formula ,Tneurotrophic factor ,ongluo Jiunao injection ,nerve growth factor receptor ,Xuesai Tong ,hippocampus ,dentate gyrus ,lipid peroxidation ,type 1 diabetes ,malondialdehyde ,neurons ,acupuncture ,cerebral hemorrhage ,immunohistochemistry ,Notch1 ,Hes1 ,rats ,DAPT ,transcranial direct current stimulation ,visuomotor coordination ,task difficulty ,primary motor area ,motor learning ,paraquat ,poisoning ,endoplasmic reticulum stress ,ulinastatin ,CHOP ,GRP78 ,caspase-3 ,reactive oxygen species ,cognitive neuroscience ,event-related potential ,P300 ,electrophysiology ,nutritional state ,minimally conscious state ,consciousness ,disorders of consciousness ,unconsciousness ,evaluation ,prognosis ,NSFC grants ,curcumin ,ischemia/reperfusion injury ,oxidative stress ,primary cell culture ,cortical neurons ,oxygen-glucose deprivation ,pretreatment ,post-treatment ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Recent studies have shown that induced expression of endogenous antioxidative enzymes thr-ough activation of the antioxidant response element/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway may be a neuroprotective strategy. In this study, rat cerebral cortical neurons cultured in vitro were pretreated with 10 μM curcumin or post-treated with 5 μM curcumin, respectively before or after being subjected to oxygen-glucose deprivation and reoxygenation for 24 hours. Both pretreatment and post-treatment resulted in a significant decrease of cell injury as indicated by propidium iodide/Hoechst 33258 staining, a prominent increase of Nrf2 protein expression as indicated by western blot analysis, and a remarkable increase of protein expression and enzyme activity in whole cell lysates of thioredoxin before ischemia, after ischemia, and after reoxygenation. In addition, post-treatment with curcumin inhibited early DNA/RNA oxidation as indicated by immunocytochemistry and increased nuclear Nrf2 protein by inducing nuclear accumulation of Nrf2. These findings suggest that curcumin activates the expression of thioredoxin, an antioxidant protein in the Nrf2 pathway, and protects neurons from death caused by oxygen-glucose deprivation in an in vitro model of ischemia/reperfusion. We speculate that pharmacologic stimulation of antioxidant gene expression may be a promising approach to neuroprotection after cerebral ischemia.
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- 2015
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13. Preclinical systematic review of ginsenoside Rg1 for cognitive impairment in Alzheimer’s disease
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Xi-Le Zhang, Guo-Qing Zheng, Hai-Yong Liang, Yan-Ran Huang, Yan Lin, Yan-Yan Zheng, and Pei-Pei Zhang
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Genetically modified mouse ,Aging ,Ginsenosides ,Disease ,potential mechanisms ,Bioinformatics ,Synapse ,Ginseng ,Alzheimer Disease ,Memory impairment ,Medicine ,preclinical evidence ,Animals ,Humans ,Chronic stress ,Cognitive Dysfunction ,Nootropic Agents ,business.industry ,Cognition ,Cell Biology ,Alzheimer's disease ,Ginsenoside Rg1 ,ginsenoside Rg1 ,learning and memory ,business ,Research Paper - Abstract
Ginseng has been used for the treatment of aging and memory impairment for thousands of years. Several studies have found that ginsenoside Rg1, as one of the main active components of ginseng, could potentially improve cognitive function in several different animal models. A preclinical systematic review to evaluate the efficacy and mechanisms of ginsenoside Rg1 for ameliorating cognitive impairments in Alzheimer's disease is reported here. We searched six databases from their inceptions to January 2019. Thirty-two studies were selected, which included a total of 1,643 animals. According to various cognitive behavioral tests, the results of the meta-analyses showed that ginsenoside Rg1 significantly improved cognitive behavioral impairments in most Alzheimer's disease models (P < 0.05), but there were no significant effects in animals with neuronal degeneration induced by chronic stress or in SAMP8 transgenic mice. The potential mechanisms included antioxidant and anti-inflammatory effects, amelioration of Alzheimer's disease-related pathology, synapse protection, and up-regulation of nerve cells via multiple signaling pathways.
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- 2021
14. Anaemia and cerebrospinal fluid biomarkers of Alzheimer’s pathology in cognitively normal elders: the CABLE study
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Hao Hu, Xin-Yu Yang, Jin-Tai Yu, Xiao-He Hou, Lan Tan, Yan-Lin Bi, Jiu-Long Yang, and Xi-Peng Cao
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medicine.medical_specialty ,Neurology ,tau Proteins ,Anaemia ,Disease ,Severity ,Cerebrospinal fluid ,Alzheimer Disease ,hemic and lymphatic diseases ,Internal medicine ,Diabetes mellitus ,medicine ,Humans ,Neurochemistry ,Cognitive decline ,RC346-429 ,Stroke ,Aged ,Amyloid beta-Peptides ,business.industry ,Research ,Anemia ,General Medicine ,medicine.disease ,Peptide Fragments ,Biomarker (medicine) ,Neurology. Diseases of the nervous system ,Neurology (clinical) ,business ,Alzheimer’s disease ,Biomarkers - Abstract
Background Anaemia has been reported to be associated with cognitive decline and Alzheimer’s disease (AD), but the associations between anaemia and cerebrospinal fluid (CSF) AD biomarkers are still unknown. This study aimed to investigate the associations between anaemia and CSF AD biomarkers. Methods Participants were included from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study. The associations of anaemia and its severity with CSF AD biomarkers including β-amyloid 1–42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau) were analysed by multiple linear regression models. Adjusted for age, gender, educational levels, APOE ε4 alleles, comorbidities (history of coronary heart disease, history of stroke, hypertension, diabetes mellitus, dyslipidaemia) and glomerular filtration rate. Results A total of 646 cognitively normal older adults, consisting of 117 anaemia patients and 529 non-anaemia individuals, were included in this study. Anaemia patients had lower levels of CSF Aβ42 than individuals without anaemia (p = 0.035). Besides, participants with more severe anaemia had lower CSF Aβ42 levels (p = 0.045). No significant association of anaemia with CSF t-tau and p-tau levels was found. Conclusion Cross-sectionally, anaemia was associated with lower CSF Aβ42 levels. These findings consolidated the causal close relationship between anaemia and AD.
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- 2021
15. Plasma sex hormone-binding globulin predicts neurodegeneration and clinical progression in prodromal Alzheimer's disease
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Jie-Qiong Li, Xue-Ning Shen, Bing-Jie Su, Jin-Tai Yu, Lan Tan, Wei Xu, Chen-Chen Tan, Yan-Lin Bi, Alzheimer’s Disease Neuroimaging Initiative, Xi-Peng Cao, and Qiang Dong
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Adult ,Male ,Aging ,medicine.medical_specialty ,Prodromal Symptoms ,Neuropsychological Tests ,Hippocampus ,cerebrospinal fluid ,Sex hormone-binding globulin ,Cerebrospinal fluid ,Atrophy ,Alzheimer Disease ,Predictive Value of Tests ,Sex Hormone-Binding Globulin ,Internal medicine ,polycyclic compounds ,medicine ,Humans ,Dementia ,Hippocampus (mythology) ,Cognitive Dysfunction ,Cognitive decline ,plasma ,reproductive and urinary physiology ,Aged ,Aged, 80 and over ,Brain Chemistry ,Amyloid beta-Peptides ,biology ,business.industry ,Neurodegeneration ,Neurodegenerative Diseases ,Cell Biology ,Middle Aged ,Prognosis ,medicine.disease ,Peptide Fragments ,Cross-Sectional Studies ,Endocrinology ,Disease Progression ,biology.protein ,biomarker ,Biomarker (medicine) ,Female ,business ,Alzheimer’s disease ,Biomarkers ,hormones, hormone substitutes, and hormone antagonists ,Research Paper - Abstract
It was unclear whether sex hormone-binding globulin (SHBG) was a circulating biomarker of Alzheimer’s disease (AD). We tested the cross-sectional relationships between plasma SHBG and cerebrospinal fluid (CSF) AD biomarkers in 707 non-demented adults. Next, the influences of plasma SHBG on dynamic changes of CSF Aβ42, hippocampus volume, brain metabolism, and cognition were explored in 448 non-demented adults from the Alzheimer’s disease Neuroimaging Initiative (ADNI). Finally, the predictive and diagnostic values of plasma SHBG in AD were explored. A positive correlation was found between SHBG levels in plasma and CSF. Individuals with higher plasma SHBG levels had lower CSF Aβ42 (p < 0.005), after adjusting for age, gender, education, APOE4 allele, and cognitive scores. Though no significant difference of plasma SHBG was observed between mild AD dementia and healthy normal, plasma SHBG could contribute to accelerated rates of CSF Aβ42 decrease (p < 0.0005), decline in brain metabolism (p < 0.05), and hippocampus atrophy (p < 0.01), cognitive decline (p < 0.01), as well as higher risk of AD dementia (p < 0.05). These findings indicated plasma SHBG could be a prodromal biomarker to predict disease progression in AD.
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- 2020
16. Associations of healthy lifestyles with cerebrospinal fluid biomarkers of Alzheimer’s disease pathology in cognitively intact older adults: the CABLE study
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Lan Tan, Qiang Dong, Yan-Lin Bi, Wei Xu, Ya-Hui Ma, Jin-Tai Yu, Xue-Ning Shen, and Xiao-He Hou
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Pathology ,medicine.medical_specialty ,Neurology ,Cognitive Neuroscience ,Physical activity ,Neurosciences. Biological psychiatry. Neuropsychiatry ,tau Proteins ,Disease ,Cerebrospinal fluid ,Alzheimer Disease ,Humans ,Medicine ,Healthy Lifestyle ,Social isolation ,RC346-429 ,Life Style ,Aged ,Amyloid beta-Peptides ,business.industry ,Research ,Biomarker ,Lifestyle ,Peptide Fragments ,Csf biomarkers ,Biomarker (medicine) ,Neurology. Diseases of the nervous system ,Neurology (clinical) ,medicine.symptom ,business ,Alzheimer’s disease ,Biomarkers ,Geriatric psychiatry ,RC321-571 - Abstract
Objective We aimed to investigate the associations between healthy lifestyles and Alzheimer’s disease (AD) biomarkers in cerebrospinal fluid (CSF). Methods A total of 1108 cognitively intact individuals from Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study were examined to evaluate the associations of AD biomarkers with healthy lifestyle factors, including no current smoking, no harmful drinking, absence of social isolation, and regular physical activity. The participants were categorized into groups of favorable, intermediate, and unfavorable lifestyles according to the lifestyle factors. The associations between overall lifestyle and CSF biomarkers were also analyzed. Results Among cognitively intact older adults, those having more social engagement had lower CSF tau (p = 0.009) and p-tau (p p = 0.013) and lower levels of CSF tau (p = 0.036) and p-tau (p = 0.007). However, no significant associations were found of smoking status or alcohol intake with CSF biomarkers. When the overall lifestyle of the participants was evaluated by all the four lifestyle factors, favorable lifestyle profiles were related to lower levels of CSF tau (p p Conclusions These findings suggest that healthy lifestyles had a beneficial effect on AD pathology among cognitively intact elders.
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- 2021
17. β-Hydroxybutyrate Attenuates Painful Diabetic Neuropathy via Restoration of the Aquaporin-4 Polarity in the Spinal Glymphatic System.
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Fei-xiang Wang, Chi-liang Xu, Can Su, Jiang Li, and Jing-yan Lin
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DIABETIC neuropathies ,AQUAPORINS ,ALZHEIMER'S disease ,MAGNETIC resonance imaging ,CENTRAL nervous system - Abstract
Waste removal is essential for maintaining homeostasis and the normal function of the central nervous system (CNS). The glymphatic system based on aquaporin-4 (AQP4) water channels on the endfeet of astrocytes is recently discovered as the excretion pathway for metabolic waste products of CNS. In the CNS, a-syntrophin (SNTA1) directly or indirectly anchors AQP4 in astrocyte membranes facing blood vessels. Studies have indicated that β-hydroxybutyrate (BHB) can raise the expression of SNTA1 and thus restoring AQP4 polarity in mice models with Alzheimer's disease. The study aims to evaluate the neuroprotective mechanism of BHB in rats with painful diabetic neuropathy (PDN). PDN rats were modeled under a high-fat and high-glucose diet with a low dose of streptozotocin. Magnetic resonance imaging (MRI) was applied to observe the clearance of contrast to indicate the functional variability of the spinal glymphatic system. Mechanical allodynia was assessed by paw withdrawal threshold. The expressions of SNTA1 and AQP4 were tested, and the polarity reversal of AQP4 protein was measured. As demonstrated, PDN rats were manifested with deceased contrast clearance of the spinal glymphatic system, enhanced mechanical allodynia, lower expression of SNTA1, higher expression of AQP4, and reversed polarity of AQP4 protein. An opposite change in the above characteristics was observed in rats being treated with BHB. This is the first study that demonstrated the neuroprotective mechanism of BHB to attenuate PDN via restoration of the AQP4 polarity in the spinal glymphatic system and provides a promising therapeutic strategy for PDN. [ABSTRACT FROM AUTHOR]
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- 2022
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18. Cerebrospinal fluid α-synuclein predicts neurodegeneration and clinical progression in non-demented elders
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Lan Tan, Jie-Qiong Li, Hui-Fu Wang, Xue-Ning Shen, Jin-Tai Yu, Wei Xu, Yan-Jiang Wang, Qiang Dong, Chen-Chen Tan, and Yan-Lin Bi
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0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,China ,Neurology ,Cognitive Neuroscience ,Pathogenesis ,Cohort Studies ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Cerebrospinal fluid ,Atrophy ,Neuroimaging ,Predictive Value of Tests ,Internal medicine ,mental disorders ,medicine ,Dementia ,Humans ,Neurodegeneration ,Aged ,Aged, 80 and over ,α-Synuclein ,business.industry ,Research ,Neurodegenerative Diseases ,Biomarker ,Middle Aged ,medicine.disease ,nervous system diseases ,030104 developmental biology ,nervous system ,Disease Progression ,alpha-Synuclein ,Biomarker (medicine) ,Female ,Neurology (clinical) ,business ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Background Accumulating reports have suggested that α-synuclein is involved in the pathogenesis of Alzheimer’s disease (AD). As the cerebrospinal fluid (CSF) α-synuclein has been suggested as a potential biomarker of AD, this study was set out to test whether CSF α-synuclein is associated with other AD biomarkers and could predict neurodegeneration and clinical progression in non-demented elders. Methods The associations between CSF α-synuclein and other AD biomarkers were investigated at baseline in non-demented Chinese elders. The predictive values of CSF α-synuclein for longitudinal neuroimaging change and the conversion risk of non-demented elders were assessed using linear mixed effects models and multivariate Cox proportional hazard models, respectively, in the Alzheimer’s disease Neuroimaging Initiative (ADNI) database. Results The CSF α-synuclein levels correlated with AD-specific biomarkers, CSF total tau and phosphorylated tau levels, in 651 Chinese Han participants (training set). These positive correlations were replicated in the ADNI database (validation set). Using a longitudinal cohort from ADNI, the CSF α-synuclein concentrations were found to increase with disease severity. The CSF α-synuclein had high diagnostic accuracy for AD based on the “ATN” (amyloid, tau, neurodegeneration) system (A + T+ versus A − T − control) (area under the receiver operating characteristic curve, 0.84). Moreover, CSF α-synuclein predicted longitudinal hippocampus atrophy and conversion from MCI to AD dementia. Conclusions CSF α-synuclein is associated with CSF tau levels and could predict neurodegeneration and clinical progression in non-demented elders. This finding indicates that CSF α-synuclein is a potentially useful early biomarker for AD.
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- 2020
19. Tau Pathologies Mediate the Association of Cigarette Smoking with Cognitive Impairment in Older Adults Without Dementia: The CABLE Study.
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Hu, Hao, Fu, Jun-Ting, Bi, Yan-Lin, Ma, Ya-Hui, Huang, Yu-Yuan, Wang, Xin, Tan, Lan, and Yu, Jin-Tai
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SMOKING ,CIGARETTE smoke ,OLDER people ,COGNITION disorders ,TAU proteins ,LIFESTYLES ,ALZHEIMER'S disease ,NERVE tissue proteins ,PEPTIDES - Abstract
Background: Although cigarette smoking is an important modifiable factor of cognitive impairment, the roles of the Alzheimer's disease (AD) core pathologies in modulating this process have not been fully delineated.Objective: This study aimed to explore associations of cigarette smoking with cognition and cerebrospinal fluid (CSF) AD biomarkers.Methods: A total of 1,079 non-demented participants were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Associations of cigarette smoking with cognition and CSF AD biomarkers were explored by multiple linear regression models. The mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects.Results: Heavy cigarette smokers (pack-years > 20) had poorer global cognition as well as higher levels of CSF p-tau and t-tau compared with the non-smokers (p < 0.01). Time-dose effect analysis among smokers also suggested that both cognitive impairment and tau pathologies markedly deteriorated with greater cumulative cigarette exposure, independently of the Aβ pathology (p < 0.01). In addition, smokers with older age or APOEɛ4 showed more obvious influences on CSF tau pathologies but not on cognition. Overall, the influence of smoking on cognition was partially mediated by tau pathologies (estimated proportion: 12%), which still remained in late-life (10% ∼11%) and increased in APOEɛ4 carriers (18% ∼24%). Encouragingly, long-term smoking cessation mitigated both cognitive impairment and tau pathologies (p < 0.05).Conclusion: Cigarette smoking was associated with both cognitive impairment and tau pathologies, which were accompanied by time-dose effects. Tau pathology might be a key mediator for influences of cigarette smoking on cognitive impairments. [ABSTRACT FROM AUTHOR]- Published
- 2022
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20. Association of Subjective Cognitive Decline with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.
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Wen, Chen, Bi, Yan-Lin, Hu, Hao, Huang, Shu-Yi, Ma, Ya-Hui, Hu, He-Ying, Tan, Lan, and Yu, Jin-Tai
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PATHOLOGY , *ALZHEIMER'S disease , *COGNITION disorders , *CEREBROSPINAL fluid , *OLDER people - Abstract
Background: Subjective cognitive decline (SCD) might occur at the early stages of dementia. Individuals with SCD have an increased risk of subsequent objective cognitive decline and greater rates of progression to dementia.Objective: We aimed to explore the associations between SCD and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology in cognitively normal individuals.Methods: A total of 1,099 cognitively normal elders with available data on CSF biomarkers of AD pathology (Aβ42, P-tau, and T-tau) were included in our analysis. Linear regression was used to examine the associations of SCD status and SCD severity with CSF biomarkers. Additionally, a review was conducted to discuss the associations between SCD and CSF biomarkers of AD pathology.Results: After adjustments for covariates, SCD and SCD severity showed significant associations with CSF Aβ42 (SCD: β= -0.0003, p = 0.0263; SCD severity: β= -0.0004, p = 0.0046), CSF T-tau/Aβ42 ratio (SCD: β= 0.1080, p = 0.0064; SCD severity: β= 0.1129, p = 0.0009) and CSF P-tau/Aβ42 ratio (SCD: β= 0.0167, p = 0.0103; SCD severity: β= 0.0193, p = 0.0006) rather than T-tau and P-tau compared with cognitively normal individuals. In the review, a total of 28 studies were finally included after reviewing 174 articles. CSF Aβ42 was lower in SCD than cognitively normal (CN) individuals, but higher than those with objective cognitive decline. However, CSF tau pathology showed no difference between SCD and CN.Conclusion: The results indicated that pathophysiological changes in CSF Aβ pathology occurred in individuals with SCD, which provide new insights into early intervention of AD. [ABSTRACT FROM AUTHOR]- Published
- 2022
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21. Commentary: Chronic PD-1 Checkpoint Blockade Does Not Affect Cognition or Promote Tau Clearance in a Tauopathy Mouse Model
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Einar M. Sigurdsson, Yan Lin, Begona Gamallo-Lana, Adam C. Mar, and Leslie A. Sandusky-Beltran
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PD-L1 ,Aging ,Cognitive Neuroscience ,medicine.medical_treatment ,PD-1 blockade ,Affect (psychology) ,lcsh:RC321-571 ,antibody ,PD-1 ,Medicine ,mouse models ,tau ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,therapy ,biology ,General Commentary ,behavior ,business.industry ,tauopathy ,Neurodegeneration ,neurodegeneration ,Cognition ,Immunotherapy ,Alzheimer's disease ,immune checkpoints ,medicine.disease ,Blockade ,biology.protein ,Pd 1 blockade ,immunotherapy ,Tauopathy ,business ,Neuroscience - Published
- 2020
22. Dynamic changes of CSF sTREM2 in preclinical Alzheimer’s disease: the CABLE study
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Ling-Zhi Ma, Lan Tan, Wei Xu, Qiang Dong, Xue-Ning Shen, Yan-Lin Bi, Hong-Qi Li, Jin-Tai Yu, and Ya-Hui Ma
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Myeloid ,Neurology ,lcsh:Geriatrics ,lcsh:RC346-429 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Cerebrospinal fluid ,Alzheimer Disease ,Internal medicine ,medicine ,sTREM2 ,Humans ,Neurodegeneration ,Receptors, Immunologic ,Molecular Biology ,Pathological ,lcsh:Neurology. Diseases of the nervous system ,Aged ,Inflammation ,Aged, 80 and over ,Membrane Glycoproteins ,business.industry ,TREM2 ,Snap ,Middle Aged ,medicine.disease ,lcsh:RC952-954.6 ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Disease Progression ,Biomarker (medicine) ,Female ,Neurology (clinical) ,business ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Biomarkers ,Research Article - Abstract
Background Loss of function of triggering receptor expressed on myeloid cell 2 (TREM2), a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer’s disease (AD). Whether TREM2 levels are pathologically altered during the preclinical phase, and whether cerebrospinal fluid (CSF) soluble TREM2 protein (sTREM2) has a relationship with major pathological processes including Aβ and tau deposition are still unclear. Methods According to the NIA-AA criteria, 659 cognitively normal participants from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) cohort were divided into four groups, stage 0 (normal Aβ1–42, T-tau and P-tau), stage 1 (low Aβ1–42, normal T-tau and P-tau), stage 2 (low Aβ1–42 and high T-tau or P-tau), and suspected non-AD pathology (SNAP) (normal Aβ1–42 and high T-tau or P-tau), to examine changes of CSF sTREM2 in the preclinical AD. Biomarker cut-off was based on the assumption that one-third of adults with normal cognition have AD pathology. Results The level of CSF sTREM2 in the stage 1 decreased compared with the stage 0 (P P = 0.008). SNAP individuals also had significantly increased CSF sTREM2 (P 1–42 (β = 0.192, P P P Conclusion CSF sTREM2 levels are dynamic in preclinical AD. Aβ pathology is associated with a decrease in CSF sTREM2 in the absence of tau deposition and neurodegeneration. However, tau pathology and neurodegeneration are associated with an increase in CSF sTREM2.
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- 2020
23. Chronic PD-1 Checkpoint Blockade Does Not Affect Cognition or Promote Tau Clearance in a Tauopathy Mouse Model
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Yan Lin, Hameetha B. Rajamohamedsait, Leslie A. Sandusky-Beltran, Begona Gamallo-Lana, Adam Mar, and Einar M. Sigurdsson
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0301 basic medicine ,PD-L1 ,Aging ,Cognitive Neuroscience ,PD-1 blockade ,Affect (psychology) ,lcsh:RC321-571 ,03 medical and health sciences ,chronic treatment ,0302 clinical medicine ,Immune system ,antibody ,PD-1 ,Medicine ,mouse models ,tau ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Original Research ,therapy ,biology ,business.industry ,General Commentary ,behavior ,tauopathy ,neurodegeneration ,Cognition ,Alzheimer's disease ,immune checkpoints ,medicine.disease ,Isotype ,3. Good health ,Blockade ,Clinical trial ,030104 developmental biology ,biology.protein ,Tauopathy ,immunotherapy ,Antibody ,business ,Neuroscience ,Alzheimer’s disease ,030217 neurology & neurosurgery - Abstract
Programmed cell death protein 1 (PD-1) checkpoint blockade with an antibody has been shown to reduce amyloid-β plaques, associated pathologies and cognitive impairment in mouse models. More recently, this approach has shown effectiveness in a tauopathy mouse model to improve cognition and reduce tau lesions. Follow-up studies by other laboratories did not see similar benefits of this type of therapy in other amyloid-β plaque models. Here, we report a modest increase in locomotor activity but no effect on cognition or tau pathology, in a different more commonly used tauopathy model following a weekly treatment for 12 weeks with the same PD-1 antibody and isotype control as in the original Aβ- and tau-targeting studies. These findings indicate that further research is needed before clinical trials based on PD-1 checkpoint immune blockage are devised for tauopathies.
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- 2020
24. Publication Trends for Alzheimer's Disease Worldwide and in China: A 30-Year Bibliometric Analysis
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Hong Wang, Rui Dong, Yan-Lin Bi, Jishi Ye, and Mingshan Wang
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Gerontology ,China ,PubMed ,Bibliometric analysis ,Disease ,050105 experimental psychology ,lcsh:RC321-571 ,03 medical and health sciences ,Behavioral Neuroscience ,traditional Chinese medicine ,0302 clinical medicine ,bibliometric analysis ,Political science ,medicine ,Dementia ,0501 psychology and cognitive sciences ,Economic impact analysis ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Biological Psychiatry ,Human services ,business.industry ,05 social sciences ,Alzheimer's disease ,medicine.disease ,Psychiatry and Mental health ,Neuropsychology and Physiological Psychology ,Neurology ,Publishing ,web of science ,Systematic Review ,business ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Background: Alzheimer's disease, the most common form of dementia, has tremendous social and economic impact worldwide. This study aimed to analyze global trends in Alzheimer's disease research and to investigate China's contribution to this research. Methods: The quantity and influence of publications related to Alzheimer's disease in China and elsewhere were compared. The Web of Science (WOS) and PubMed databases were searched from 1988 to 2017 using the terms “Alzheimer's disease” or “Alzheimers disease.” Global Alzheimer's disease publications were classified and analyzed. Keywords, countries, and institutions publishing articles on Alzheimer's disease were analyzed, and citations of these articles were examined. Results: A total of 181,116 articles regarding Alzheimer's disease research were identified and analyzed. Neuroscience and neurology were the main research categories both globally and in China. Basic research dominated Alzheimer's publications, accounting for 30.93% of global publications and 95.31% of publications in China. A total of 8,935 journals published articles related to Alzheimer's disease. The journal Neurobiology of Aging published the most Alzheimer's disease-related articles, numbering 5,206 over the time period examined. The National Institutes of Health, the National Institute on Aging, and the Department of Health and Human Services jointly sponsored 11,809 articles, ranking first in the world. The National Natural Science Foundation of China funded the largest number of studies on Alzheimer's disease in China and recognized the importance of traditional Chinese medicine in Alzheimer's disease research. Conclusions: The present study provides data for global researchers to understand research perspectives and develop future research directions. In recent years, Chinese researchers have contributed significantly to global Alzheimer's research. Still, strengthening international cooperation could improve the quality and number of publications regarding Alzheimer's disease.
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- 2019
25. Tau pathologies mediate the association of blood pressure with cognitive impairment in adults without dementia: The CABLE study.
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Hao Hu, Li Meng, Yan-Lin Bi, Wei Zhang, Wei Xu, Xue-Ning Shen, Ya-Nan Ou, Ya-Hui Ma, Qiang Dong, Lan Tan, and Jin-Tai Yu
- Abstract
Introduction: This study delineated the interrelationships among blood pressure (BP), cerebrospinal fluid (CSF) core biomarkers of Alzheimer’s disease (AD), and cognition. Methods: The linear regression analyses were conducted in 1546 non-demented participants (mean age of 61.58 years, range 40 to 89 years; 40% female; average days of BP measurement, 9.10 days). Mediation analyses with 10,000 bootstrapped iterations were used to explore the mediation effects. Results: A clear age-related pattern of BP was delineated. Mid-life hypertension (especially systolic BP), late-life lower diastolic BP, as well as mid- and late-life higher pulse pressure were associated with cognitive impairment and tau-related biomarkers. BP variability was associated only with cognition but not with CSF biomarkers. Overall, the associations between BP and cognition were partially mediated (proportion: 11% to 30%) by tau pathologies, independently of amyloid pathology. Discussion: Tau pathologies might play important roles in the relationship between BP and cognition, with significant age- and BP-type dependences. [ABSTRACT FROM AUTHOR]
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- 2022
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26. Sleep Characteristics and Cognitive Function in Older Adults Without Dementia: The CABLE Study.
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Fu, Yan, Wang, Zuo-Teng, Qu, Yi, Wang, Xiao-Tong, Ma, Ya-Hui, Bi, Yan-Lin, Dong, Qiang, Tan, Lan, and Yu, Jin-Tai
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COGNITIVE ability ,CHARACTERISTIC functions ,OLDER people ,TAU proteins ,MONTREAL Cognitive Assessment ,SLEEP - Abstract
Background: The associations between sleep characteristics and cognition are complicated. Alzheimer's disease (AD) pathologies have been proven to be associated with sleep characteristics.Objective: We aimed to investigate the associations between sleep characteristics and cognitive function and examine the roles of AD pathologies in modulating the association of sleep duration with cognition.Methods: A total of 974 participants who had measurements of cerebrospinal fluid (CSF) amyloid-β (Aβ), phosphorylated tau (P-tau), total tau proteins (T-tau), cognitive function, and sleep characteristics were included from the Chinese Alzheimer's Biomarker and Lifestyle (CABLE) study. Linear regression analyses were utilized to explore the associations of sleep characteristics with cognition. Non-linear regression analyses were utilized to explore the associations of sleep habits with cognition. Causal mediation analyses were conducted to explore the mediation effects of AD pathologies on cognition.Results: The Pittsburgh Sleep Quality Index (PSQI) total score was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) score (p = 0.0176). Long latency (p = 0.0054) and low efficiency (p = 0.0273) were associated with cognitive impairment. Habitual nap behavior was associated with lower MoCA scores (p = 0.0045). U-shaped associations were observed between sleep habits (bedtime and nocturnal sleep duration) and cognition. A causal mediation analysis indicated that P-tau/Aβ42 mediated the association of sleep duration with cognition.Conclusion: These findings showed sleep characteristics were associated with cognitive functions. Sleep habits (duration, bedtime) had U-shaped associations with cognition. AD core pathologies might partially mediate the influence of sleep duration on cognitive impairments. [ABSTRACT FROM AUTHOR]- Published
- 2021
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27. Associations of Alcohol Consumption with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.
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Wang, Zuo-Teng, Li, Kun-Yan, Tan, Chen-Chen, Xu, Wei, Shen, Xue-Ning, Cao, Xi-Peng, Wang, Ping, Bi, Yan-Lin, Dong, Qiang, Tan, Lan, and Yu, Jin-Tai
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ALCOHOL drinking ,ALZHEIMER'S disease ,CEREBROSPINAL fluid ,PATHOLOGY ,OLDER people ,ALZHEIMER'S disease diagnosis ,LIFESTYLES ,RESEARCH ,NERVE tissue proteins ,SELF-evaluation ,RESEARCH methodology ,COGNITION ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,PEPTIDES - Abstract
Background: The relationship between alcohol consumption and Alzheimer's disease (AD) pathology is unclear. Amyloid-β (Aβ) and tau biomarkers in cerebrospinal fluid (CSF) have been proven valuable in establishing prognosis in pre-clinical AD.Objective: We sought to examine the associations between alcohol consumption and CSF AD biomarkers in cognitive intact subjects.Methods: A total of 806 cognitively intact participants who had measurements of CSF Aβ, pTau, and total Tau proteins and drinking characteristics were included from the Chinese Alzheimer's Biomarker and Lifestyle (CABLE) study. Linear and logistic regression analyses were utilized to explore the associations of alcohol consumption with CSF AD biomarkers. We examined the interaction effects of age, gender, and apolipoprotein epsilon (APOE) ɛ4 status on the relationships between the frequency of drinking and CSF biomarkers.Results: The multiple linear regression analyses revealed significant differences in CSF AD biomarkers between infrequent drinking (< 1 times/week) and frequent drinking groups (≥1 times/week). Participants in frequent drinking group had higher CSF p-tau/Aβ42 and tTau/Aβ42. Frequent drinking was significantly associated with greater pTau and tTau abnormalities compared to the infrequent drinking group in older (> 65 years) participants.Conclusion: The present study showed significant associations between drinking frequency and CSF AD biomarkers in cognitively intact older adults. Alcohol consumption may have an influence on AD by modulating amyloid deposition and tau phosphorylation in the preclinical stage. [ABSTRACT FROM AUTHOR]- Published
- 2021
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28. Left Ventricular Ejection Fraction and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Normal Older Adults: The CABLE Study.
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Zheng, Yi-Ming, Zhao, Yang-Yang, Zhang, Ting, Hou, Xiao-He, Bi, Yan-Lin, Ma, Ya-Hui, Xu, Wei, Shen, Xue-Ning, Dong, Qiang, Tan, Lan, and Yu, Jin-Tai
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VENTRICULAR ejection fraction ,ALZHEIMER'S disease ,PATHOLOGY ,CEREBROSPINAL fluid ,OLDER people - Abstract
Background: Heart failure has been considered as a potential modifiable risk factor for cognitive impairment and dementia. Left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, has also been associated with cognitive aging. However, the effect of LVEF on Alzheimer's disease (AD) pathology is still less known.Objective: We aimed to investigate the associations of LVEF with cerebrospinal fluid (CSF) biomarkers for AD in cognitively normal elders.Methods: A total of 423 cognitively normal individuals without heart failure were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Participants were divided into low LVEF group (50%≤LVEF < 60%) and high LVEF group (LVEF≥60%). The associations of LVEF with CSF AD biomarkers including CSF amyloid-β 42 (Aβ42), total-tau (t-tau), and phosphorylated tau (p-tau) were analyzed using multivariate linear regression models.Results: Participants with low LVEF had higher levels of CSF t-tau (β= -0.009, p = 0.006) and t-tau/Aβ42 ratios (β= -0.108, p = 0.026). Subgroup analyses showed that the associations only existed in female and middle-aged groups (< 65 years old). Besides, participants with low LVEF had higher levels of CSF p-tau (β= -0.002, p = 0.043) in middle-aged group.Conclusion: In conclusion, our findings revealed the associations between LVEF and AD pathology, which may provide new insights into AD prevention through maintaining cardiac function. [ABSTRACT FROM AUTHOR]- Published
- 2021
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29. Metabolically healthy obesity and lipids may be protective factors for pathological changes of alzheimer's disease in cognitively normal adults.
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Huang, Shu‐Juan, Ma, Ya‐Hui, Bi, Yan‐Lin, Shen, Xue‐Ning, Hou, Xiao‐He, Cao, Xi‐Peng, Ou, Ya‐Nan, Zhao, Bing, Dong, Qiang, Tan, Lan, and Yu, Jin‐Tai
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ALZHEIMER'S disease ,PATHOLOGICAL physiology ,APOLIPOPROTEIN E ,LIPIDS ,OBESITY ,TAU proteins - Abstract
The associations between obesity and Alzheimer's disease (AD) at different ages have been debated. Recent evidence implied the protective effects of metabolically healthy obesity on AD. We hypothesized that obesity and lipids could mitigate the detrimental impacts of AD pathological changes among metabolically healthy individuals in late life. In this study, a total of 604 metabolically healthy participants with normal cognition were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Multiple linear regression models were used to test the associations of body mass index (BMI) or lipids with cerebrospinal fluid (CSF) biomarkers after adjustment for age, gender, education, and Apolipoprotein E‐ɛ4 (APOE‐ɛ4). The results showed the lower CSF levels of total tau protein (t‐tau: p =.0048) and phosphorylated tau protein (p‐tau: p =.0035) in obese participants than in non‐obese participants, even after correcting for covariates. Moreover in late life, higher BMI was associated with decreased CSF t‐tau (β: −0.15, p =.0145) and p‐tau (β: −0.17, p =.0052). As for lipids, higher levels of total cholesterol (TC) and low‐density lipoprotein cholesterol (LDL‐C) were associated with decreased CSF t‐tau (TC: β: −0.16, p =.0115; LDL‐C: β: −0.16, p =.0082) and p‐tau (TC: β: −0.15, p =.0177; LDL‐C: β: −0.14, p =.0225) in obese participants. Furthermore, these associations were only significant in participants with late‐life obesity and APOE‐ɛ4 non‐carriers. Overall, in a cognitively normal population, we found metabolically healthy obesity and lipids in late life might be protective factors for neurodegenerative changes. [ABSTRACT FROM AUTHOR]
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- 2021
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30. Social Networks and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.
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Ma, Ya-Hui, Wang, Ya-Yu, Tan, Lan, Xu, Wei, Shen, Xue-Ning, Wang, Hui-Fu, Hou, Xiao-He, Cao, Xi-Peng, Bi, Yan-Lin, Dong, Qiang, Yang, Jiu-Long, and Yu, Jin-Tai
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ALZHEIMER'S disease ,SOCIAL networks ,CEREBROSPINAL fluid ,OLDER people ,PATHOLOGY - Abstract
Background: Although social networks are deemed as moderators of incident Alzheimer's disease (AD), few data are available on the mechanism relevant to AD pathology.Objective: We aimed to investigate whether social networks affect metabolism of cerebrospinal fluid (CSF) AD biomarkers during early stage and identify modification effects of genetic factor and subjective cognitive decline (SCD).Methods: We studied participants from the Chinese Alzheimer's disease Biomarker and Lifestyle (CABLE) database who received cognition assessments and CSF amyloid-β (Aβ1-42 and Aβ1-40) and tau proteins (total-tau [T-tau] and phosphorylated-tau [P-tau]) measurements. The social networks were measured using self-reported questionnaires about social ties. Linear regression models were used.Results: Data were analyzed from 886 cognitively intact individuals aged 61.91 years (SD = 10.51), including 295 preclinical AD participants and 591 healthy controls. Social networks were mostly associated with CSF indicators of AD multi-pathologies (low P-tau/Aβ1-42 and T-tau/Aβ1-42 and high Aβ1-42/Aβ1-40). Significant differences of genetic and cognitive status were observed for CSF indicators, in which associations of social network scores with CSF P-tau and indicators of multi-pathologies appeared stronger in APOE 4 carriers (versus non-carriers) and participants with SCD (versus controls), respectively. Alternatively, more pronounced associations for CSF T-tau (β= -0.005, p < 0.001), Aβ1-42/Aβ1-40 (β= 0.481, p = 0.001), and T-tau/Aβ1-42 (β= -0.047, p < 0.001) were noted in preclinical AD stage than controls.Conclusion: These findings consolidated strong links between social networks and AD risks. Social networks as a modifiable lifestyle probably affected metabolisms of multiple AD pathologies, especially among at-risk populations. [ABSTRACT FROM AUTHOR]- Published
- 2021
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31. Serum Uric Acid May Aggravate Alzheimer's Disease Risk by Affecting Amyloidosis in Cognitively Intact Older Adults: The CABLE Study.
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Li, Lin-Lin, Ma, Ya-Hui, Bi, Yan-Lin, Sun, Fu-Rong, Hu, Hao, Hou, Xiao-He, Xu, Wei, Shen, Xue-Ning, Dong, Qiang, Tan, Lan, Yang, Jiu-Long, and Yu, Jin-Tai
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ALZHEIMER'S disease ,URIC acid ,OLDER people ,TAU proteins ,AMYLOIDOSIS - Abstract
Background: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear.Objective: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD.Methods: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-β [Aβ], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models.Results: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aβ1 - 42 (p = 0.019) and Aβ1 - 42/Aβ1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aβ1 - 42 (p = 0.009) and t-Tau/Aβ1 - 42 (p = 0.043) were increased with the highest (> 75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them.Conclusion: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA. [ABSTRACT FROM AUTHOR]- Published
- 2021
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32. Preclinical Evidence and Possible Mechanisms of Extracts or Compounds from Cistanches for Alzheimer’s Disease
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Pei-Qing Rong, Meng-Bei Xu, Xiao-Li Zhou, Yan Lin, Guo-Qing Zheng, and Ting-Yu Jin
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0301 basic medicine ,Tau protein ,Morris water navigation task ,Hyperphosphorylation ,Water maze ,Review Article ,Pharmacology ,Neuroprotection ,Open field ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Dementia ,biology ,business.industry ,Cell Biology ,medicine.disease ,Clinical trial ,030104 developmental biology ,Cistanches ,biology.protein ,Neurology (clinical) ,Geriatrics and Gerontology ,business ,Alzheimer’s disease ,030217 neurology & neurosurgery ,dementia - Abstract
Currently, disease-modified strategies to prevent, halt or reverse the progress of Alzheimer's disease (AD) are still lacking. Previous studies indicated extracts or compounds from Cistanches (ECC) exert a potential neuroprotective effect against AD. Thus, we conducted a preclinical systematic review to assess preclinical evidence and possible mechanisms of ECC in experimental AD. A systematical searching strategy was carried out across seven databases from their inceptions to July 2018. Twenty studies with 1696 rats or mice were involved. Neurobehavioral function indices as primary outcome measures were established by the Morris water maze test (n = 11), step-down test (n = 10), electrical Y-maze test (n = 4), step-through test (n = 3), open field test (n = 2) and passage water maze test (n = 1). Compared with controls, the results of the meta-analysis showed ECC exerted a significant effect in decreasing the escape latency, error times and wrong reaction latency in both the training test and the retention test, and in increasing the exact time and the percentage of time in the platform-quadrant and the number of platform crossings (all P
- Published
- 2018
33. Prophylactic Active Tau Immunization Leads to Sustained Reduction in Both Tau and Amyloid-β Pathologies in 3xTg Mice
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Hameetha B. Rajamohamedsait, Suhail Rasool, Yan Lin, Wajitha J. Rajamohamedsait, and Einar M. Sigurdsson
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Male ,0301 basic medicine ,medicine.medical_treatment ,lcsh:Medicine ,Microgliosis ,Immunoglobulin G ,Amyloid beta-Protein Precursor ,Mice ,0302 clinical medicine ,Image Processing, Computer-Assisted ,lcsh:Science ,Multidisciplinary ,biology ,medicine.diagnostic_test ,Vaccination ,3. Good health ,Titer ,Female ,Immunotherapy ,Alzheimer's disease ,medicine.medical_specialty ,Mice, Transgenic ,tau Proteins ,Article ,Presenilin ,03 medical and health sciences ,Western blot ,Alzheimer Disease ,Internal medicine ,mental disorders ,Presenilin-1 ,medicine ,Animals ,Maze Learning ,CA1 Region, Hippocampal ,Amyloid beta-Peptides ,business.industry ,lcsh:R ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,biology.protein ,lcsh:Q ,business ,030217 neurology & neurosurgery - Abstract
Amyloid-β (Aβ) and tau pathologies are intertwined in Alzheimer’s disease, and various immunotherapies targeting these hallmarks are in clinical trials. To determine if tau pathology influences Aβ burden and to assess prophylactic benefits, 3xTg and wild-type mice received tau immunization from 2–6 months of age. The mice developed a high IgG titer that was maintained at 22 months of age. Pronounced tau and Aβ pathologies were primarily detected in the subiculum/CA1 region, which was therefore the focus of analysis. The therapy reduced histopathological tau aggregates by 70–74% overall (68% in males and 78–86% in females), compared to 3xTg controls. Likewise, western blot analysis revealed a 41% clearance of soluble tau (38–76% in males and 48% in females) and 42–47% clearance of insoluble tau (47–58% in males and 49% in females) in the immunized mice. Furthermore, Aβ burden was reduced by 84% overall (61% in males and 97% in females). These benefits were associated with reductions in microgliosis and microhemorrhages. In summary, prophylactic tau immunization not only prevents tau pathology but also Aβ deposition and related pathologies in a sustained manner, indicating that tau pathology can promote Aβ deposition, and that a short immunization regimen can have a long-lasting beneficial effect.
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- 2017
34. Association of serum Apolipoprotein B with cerebrospinal fluid biomarkers of Alzheimer's pathology.
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Hu, Hao, Tan, Lan, Bi, Yan‐Lin, Xu, Wei, Tan, Lin, Shen, Xue‐Ning, Hou, Xiao‐He, Ma, Ya‐Hui, Dong, Qiang, and Yu, Jin‐Tai
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APOLIPOPROTEIN B ,CEREBROSPINAL fluid ,BIOMARKERS ,ALZHEIMER'S disease ,MILD cognitive impairment ,SERUM - Abstract
Objective: To examine whether apolipoprotein B (ApoB), apolipoprotein A‐1 (ApoA1), or their ratio (ApoB/A1) were associated with early changes in cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology in elderly adults with subjective cognitive decline (SCD). Methods: This study included 507 objective cognitive normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database including 288 cognitive normal participants (CN) and 219 SCD. Multiple linear regression models were used to examine the associations of apolipoproteins with CSF AD biomarkers. Results: Compared with control group, SCD participants with significant AD biological characteristics had lower ApoB levels (P = 0.0461). In total participants, lower level of serum ApoB was associated with decreases in CSF Aβ42 (P = 0.0015) and Aβ42/40 (P = 0.0081) as well as increases in CSF p‐tau/Aβ42 (P < 0.0001) and t‐tau/Aβ42 (P = 0.0013), independent of APOEɛ4 status. In further subgroup analysis, these associations were more significant in SCD participants (ApoB × Diagnose: P < 0.05). In addition, lower levels of ApoB were also found associated with increases in p‐tau in the SCD subgroup (P = 0.0263). Furthermore, these protective associations were more significant in the overweight participants (ApoB × weight: P < 0.05). Results showed no association between ApoA1 and CSF biomarkers. Interpretation: This study is the first to find protective associations of serum ApoB with CSF AD core biomarkers, especially in SCD individuals. It indicated that ApoB may be a potential biomarker for preclinical AD and may play different roles in different stages of AD. [ABSTRACT FROM AUTHOR]
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- 2020
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35. Associations of Green Tea Consumption and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.
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Ma, Ya-Hui, Wu, Jia-Huan, Xu, Wei, Shen, Xue-Ning, Wang, Hui-Fu, Hou, Xiao-He, Cao, Xi-Peng, Bi, Yan-Lin, Dong, Qiang, Feng, Lei, Tan, Lan, Yu, Jin-Tai, and Zhu, Ling-Qiang
- Subjects
GREEN tea ,ALZHEIMER'S disease ,CEREBROSPINAL fluid ,PATHOLOGY ,OLDER people ,RESEARCH ,NERVE tissue proteins ,RESEARCH methodology ,COGNITION ,BEHAVIOR ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,TEA ,PEPTIDES ,LONGITUDINAL method - Abstract
Background: Green tea has been widely recognized in ameliorating cognitive impairment and Alzheimer's disease (AD), especially the progression of cognitive dysfunction. But the underlying mechanism is still unclear.Objective: This study was designed to determine the role of green tea consumption in the association with cerebrospinal fluid (CSF) biomarkers of AD pathology and to ascertain whether specific population backgrounds showed the differences toward these relationships.Methods: Multivariate linear models analyzed the available data on CSF biomarkers and frequency of green tea consumption of 722 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database, and we additionally detected the interaction effects of tea consumption with APOEɛ4 status and gender using a two-way analysis of covariance.Results: Frequent green tea consumption was associated with a decreased level of CSF total-tau protein (t-tau) (p = 0.041) but not with the levels of CSF amyloid-β 42 (Aβ42) and CSF phosphorylated tau. The more pronounced associations of green tea consumption with CSF t-tau (p = 0.007) and CSF t-tau/Aβ42 (p = 0.039) were observed in individuals aged 65 years or younger. Additionally, males with frequent green tea consumption had a significantly low level of CSF t-tau/Aβ42 and a modest trend toward decreased CSF t-tau. There were no interaction effects of green tea consumption with APOEɛ4 and gender.Conclusion: Collectively, our findings consolidated the favorable effects of green tea on the mitigation of AD risk. The constituents of green tea may improve abnormal tau metabolism and are promising targets in interventions and drug therapies. [ABSTRACT FROM AUTHOR]- Published
- 2020
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36. Sleep characteristics and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: The CABLE study.
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Xu, Wei, Tan, Lan, Su, Bing‐Jie, Yu, Huan, Bi, Yan‐Lin, Yue, Xiao‐Fang, Dong, Qiang, and Yu, Jin‐Tai
- Abstract
Introduction: This study tested the self‐reported sleep characteristics associated with cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in cognitively intact older adults. Methods: The linear and non‐linear regression analyses were conducted in 736 cognitively normal participants (mean [standard deviation; SD] age, 62.3 [10.5] years, range 40 to 88 years, 59% female) who had measurements of cerebrospinal fluid (CSF) amyloid beta (Aβ) and tTau proteins and sleep characteristics, after adjusting for age, gender, education, apolipoprotein E gene (APOE) ε4 status, and general cognition. Results: Greater daytime sleepiness was associated with higher CSF indicators of amyloid deposition in female patients. No significant associations were revealed for CSF tTau proteins after Bonferroni correction. A U‐shaped relationship was revealed for nocturnal sleep habits, such that those with insufficient or excessive nocturnal sleep duration had greater CSF biomarkers of amyloid deposition (the reflection range: bedtime: around 10:00 p.m. and sleep duration: 6.0 to 6.5 hours). Discussion: These findings consolidated the close relationship between sleep and AD. [ABSTRACT FROM AUTHOR]
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- 2020
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37. An Overview of Systematic Reviews of Ginkgo biloba Extracts for Mild Cognitive Impairment and Dementia
- Author
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Li-bo Huang, Yan Lin, Hong-feng Zhang, Guo-Qing Zheng, Yan-Biao Zhong, Hui-Lin Wang, and Qi-Hui Zhou
- Subjects
Ginkgo biloba extracts ,Aging ,medicine.medical_specialty ,Cognitive Neuroscience ,Placebo ,lcsh:RC321-571 ,03 medical and health sciences ,mild cognitive impairment ,0302 clinical medicine ,Internal medicine ,mental disorders ,medicine ,Dementia ,030212 general & internal medicine ,Cognitive decline ,Psychiatry ,Vascular dementia ,Adverse effect ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Ginkgo biloba ,vascular dementia ,Cognition ,Alzheimer's disease ,medicine.disease ,Systematic review ,medicine.symptom ,Psychology ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Tinnitus ,Neuroscience ,dementia - Abstract
Ginkgo biloba extracts (GBEs) have been recommended to improve cognitive function and to prevent cognitive decline, but earlier evidence was inconclusive. Here, we evaluated all systematic reviews of GBEs for prevention of cognitive decline, and intervention of mild cognitive impairment (MCI) and dementia. Six databases from their inception to September 2015 were searched. Ten systematic reviews were identified, including reviews about Alzheimer's disease (n = 3), about vascular dementia (n = 1), about both Alzheimer's disease and vascular dementia (n = 2), about Alzheimer's disease, vascular dementia and mixed dementia (n = 3), and a review about MCI (n = 1). Based on the overview quality assessment questionnaire, eight studies were scored with at least 5 points, while the other two scored 4 points and 3 points, respectively. Medication with GBEs showed improvement in cognition, neuropsychiatric symptoms, and daily activities, and the effect was dose-dependent. Efficacy was convincingly demonstrated only when high daily dose (240 mg) was applied. Compared with placebo, overall adverse events and serious adverse events were at the same level as placebo, with less adverse events in favor of GBE in the subgroup of Alzheimer's disease patients, and fewer incidences in vertigo, tinnitus, angina pectoris, and headache. In conclusion, there is clear evidence to support the efficacy of GBEs for MCI and dementia, whereas the question on efficacy to prevent cognitive decline is still open. In addition, GBEs seem to be generally safe.
- Published
- 2016
38. Preclinical Evidence and Possible Mechanisms of Extracts or Compounds from Cistanches for Alzheimer's Disease.
- Author
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Xiao-Li Zhou, Meng-Bei Xu, Ting-Yu Jin, Pei-Qing Rong, Guo-Qing Zheng, and Yan Lin
- Subjects
ALZHEIMER'S disease ,NEUROPROTECTIVE agents ,MORRIS water maze tests - Abstract
Currently, disease-modified strategies to prevent, halt or reverse the progress of Alzheimer's disease (AD) are still lacking. Previous studies indicated extracts or compounds from Cistanches (ECC) exert a potential neuroprotective effect against AD. Thus, we conducted a preclinical systematic review to assess preclinical evidence and possible mechanisms of ECC in experimental AD. A systematical searching strategy was carried out across seven databases from their inceptions to July 2018. Twenty studies with 1696 rats or mice were involved. Neurobehavioral function indices as primary outcome measures were established by the Morris water maze test (n = 11), step-down test (n = 10), electrical Y-maze test (n = 4), step-through test (n = 3), open field test (n = 2) and passage water maze test (n = 1). Compared with controls, the results of the meta-analysis showed ECC exerted a significant effect in decreasing the escape latency, error times and wrong reaction latency in both the training test and the retention test, and in increasing the exact time and the percentage of time in the platformquadrant and the number of platform crossings (all P<0.01). In conclusion, ECC exert potential neuroprotective effects in experimental AD, mainly through mechanisms involving antioxidant stress and antiapoptosic effects, inhibiting Aβ deposition and tau protein hyperphosphorylation and promoting synapse protection. Thus, ECC could be a candidate for AD treatment and further clinical trials. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
39. An Overview of Systematic Reviews of
- Author
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Hong-Feng, Zhang, Li-Bo, Huang, Yan-Biao, Zhong, Qi-Hui, Zhou, Hui-Lin, Wang, Guo-Qing, Zheng, and Yan, Lin
- Subjects
Ginkgo biloba extracts ,mild cognitive impairment ,mental disorders ,vascular dementia ,Review ,Alzheimer's disease ,Neuroscience ,dementia - Abstract
Ginkgo biloba extracts (GBEs) have been recommended to improve cognitive function and to prevent cognitive decline, but earlier evidence was inconclusive. Here, we evaluated all systematic reviews of GBEs for prevention of cognitive decline, and intervention of mild cognitive impairment (MCI) and dementia. Six databases from their inception to September 2015 were searched. Ten systematic reviews were identified, including reviews about Alzheimer's disease (n = 3), about vascular dementia (n = 1), about both Alzheimer's disease and vascular dementia (n = 2), about Alzheimer's disease, vascular dementia and mixed dementia (n = 3), and a review about MCI (n = 1). Based on the overview quality assessment questionnaire, eight studies were scored with at least 5 points, while the other two scored 4 points and 3 points, respectively. Medication with GBEs showed improvement in cognition, neuropsychiatric symptoms, and daily activities, and the effect was dose-dependent. Efficacy was convincingly demonstrated only when high daily dose (240 mg) was applied. Compared with placebo, overall adverse events and serious adverse events were at the same level as placebo, with less adverse events in favor of GBE in the subgroup of Alzheimer's disease patients, and fewer incidences in vertigo, tinnitus, angina pectoris, and headache. In conclusion, there is clear evidence to support the efficacy of GBEs for MCI and dementia, whereas the question on efficacy to prevent cognitive decline is still open. In addition, GBEs seem to be generally safe.
- Published
- 2016
40. Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy
- Author
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Veronica Gonzalez, Hameetha B. Rajamohamedsait, Charles A. Hoeffer, Suhail Rasool, Yan Lin, Wajitha J. Rajamohamedsait, Dov B. Shamir, Einar M. Sigurdsson, Josien Levenga, Erin E. Congdon, Senthilkumar Krishnaswamy, and Jiaping Gu
- Subjects
0301 basic medicine ,Immunogen ,Tau protein ,Clinical Neurology ,tau Proteins ,Paired helical filaments ,Epitope ,Antibodies ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,In vivo ,Alzheimer Disease ,mental disorders ,medicine ,Animals ,Humans ,Phosphorylation ,Molecular Biology ,Neurons ,biology ,Chemistry ,Neurofibrillary Tangles ,medicine.disease ,3. Good health ,Cell biology ,030104 developmental biology ,Tauopathies ,Immunology ,biology.protein ,Neurology (clinical) ,Tauopathy ,Immunotherapy ,Alzheimer's disease ,Antibody ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Ex vivo ,Research Article - Abstract
Background A few tau immunotherapies are now in clinical trials with several more likely to be initiated in the near future. A priori, it can be anticipated that an antibody which broadly recognizes various pathological tau aggregates with high affinity would have the ideal therapeutic properties. Tau antibodies 4E6 and 6B2, raised against the same epitope region but of varying specificity and affinity, were tested for acutely improving cognition and reducing tau pathology in transgenic tauopathy mice and neuronal cultures. Results Surprisingly, we here show that one antibody, 4E6, which has low affinity for most forms of tau acutely improved cognition and reduced soluble phospho-tau, whereas another antibody, 6B2, which has high affinity for various tau species was ineffective. Concurrently, we confirmed and clarified these efficacy differences in an ex vivo model of tauopathy. Alzheimer’s paired helical filaments (PHF) were toxic to the neurons and increased tau levels in remaining neurons. Both toxicity and tau seeding were prevented by 4E6 but not by 6B2. Furthermore, 4E6 reduced PHF spreading between neurons. Interestingly, 4E6’s efficacy relates to its high affinity binding to solubilized PHF, whereas the ineffective 6B2 binds mainly to aggregated PHF. Blocking 4E6's uptake into neurons prevented its protective effects if the antibody was administered after PHF had been internalized. When 4E6 and PHF were administered at the same time, the antibody was protective extracellularly. Conclusions Overall, these findings indicate that high antibody affinity for solubilized PHF predicts efficacy, and that acute antibody-mediated improvement in cognition relates to clearance of soluble phospho-tau. Importantly, both intra- and extracellular clearance pathways are in play. Together, these results have major implications for understanding the pathogenesis of tauopathies and for development of immunotherapies. Electronic supplementary material The online version of this article (doi:10.1186/s13024-016-0126-z) contains supplementary material, which is available to authorized users.
- Published
- 2016
41. Specific amyloid β clearance by a catalytic antibody construct
- Author
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Yasuhiro Nishiyama, Einar M. Sigurdsson, Robert P. Friedland, Sari Sonoda, Yan Lin, Sudhir Paul, Brian O'Nuallain, Hiroaki Taguchi, Steven J. Kolodziej, Stephanie Planque, Mariko Hara, Hameetha B.R. Sait, Richard Massey, Veronica Gonzalez, Yukie Mitsuda, and Ken Ichiro Fukuchi
- Subjects
Amyloid ,Proteolysis ,Immunology ,Gene Expression ,Antibodies, Catalytic ,Protein Engineering ,Biochemistry ,Mice ,Alzheimer Disease ,medicine ,Animals ,Humans ,Molecular Biology ,Innate immune system ,Amyloid beta-Peptides ,medicine.diagnostic_test ,biology ,Chemistry ,Hydrolysis ,fungi ,Neurotoxicity ,P3 peptide ,food and beverages ,Brain ,Cell Biology ,medicine.disease ,Immunity, Innate ,Peptide Fragments ,Recombinant Proteins ,Transthyretin ,Disease Models, Animal ,HEK293 Cells ,biology.protein ,Antibody ,Alzheimer's disease ,Single-Chain Antibodies - Abstract
Classical immunization methods do not generate catalytic antibodies (catabodies), but recent findings suggest that the innate antibody repertoire is a rich catabody source. We describe the specificity and amyloid β (Aβ)-clearing effect of a catabody construct engineered from innate immunity principles. The catabody recognized the Aβ C terminus noncovalently and hydrolyzed Aβ rapidly, with no reactivity to the Aβ precursor protein, transthyretin amyloid aggregates, or irrelevant proteins containing the catabody-sensitive Aβ dipeptide unit. The catabody dissolved preformed Aβ aggregates and inhibited Aβ aggregation more potently than an Aβ-binding IgG. Intravenous catabody treatment reduced brain Aβ deposits in a mouse Alzheimer disease model without inducing microgliosis or microhemorrhages. Specific Aβ hydrolysis appears to be an innate immune function that could be applied for therapeutic Aβ removal.
- Published
- 2015
42. Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy.
- Author
-
Congdon, Erin E., Yan Lin, Rajamohamedsait, Hameetha B., Shamir, Dov B., Krishnaswamy, Senthilkumar, Rajamohamedsait, Wajitha J., Rasool, Suhail, Gonzalez, Veronica, Levenga, Josien, Jiaping Gu, Hoeffer, Charles, and Sigurdsson, Einar M.
- Subjects
- *
ALZHEIMER'S disease , *TAU proteins , *IMMUNOGLOBULINS , *IMMUNOTHERAPY , *NEURONS - Abstract
Background: A few tau immunotherapies are now in clinical trials with several more likely to be initiated in the near future. A priori, it can be anticipated that an antibody which broadly recognizes various pathological tau aggregates with high affinity would have the ideal therapeutic properties. Tau antibodies 4E6 and 6B2, raised against the same epitope region but of varying specificity and affinity, were tested for acutely improving cognition and reducing tau pathology in transgenic tauopathy mice and neuronal cultures. Results: Surprisingly, we here show that one antibody, 4E6, which has low affinity for most forms of tau acutely improved cognition and reduced soluble phospho-tau, whereas another antibody, 6B2, which has high affinity for various tau species was ineffective. Concurrently, we confirmed and clarified these efficacy differences in an ex vivo model of tauopathy. Alzheimer's paired helical filaments (PHF) were toxic to the neurons and increased tau levels in remaining neurons. Both toxicity and tau seeding were prevented by 4E6 but not by 6B2. Furthermore, 4E6 reduced PHF spreading between neurons. Interestingly, 4E6's efficacy relates to its high affinity binding to solubilized PHF, whereas the ineffective 6B2 binds mainly to aggregated PHF. Blocking 4E6's uptake into neurons prevented its protective effects if the antibody was administered after PHF had been internalized. When 4E6 and PHF were administered at the same time, the antibody was protective extracellularly. Conclusions: Overall, these findings indicate that high antibody affinity for solubilized PHF predicts efficacy, and that acute antibody-mediated improvement in cognition relates to clearance of soluble phospho-tau. Importantly, both intra- and extracellular clearance pathways are in play. Together, these results have major implications for understanding the pathogenesis of tauopathies and for development of immunotherapies. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
43. Association of rs6265 and rs2030324 Polymorphisms in Brain-Derived Neurotrophic Factor Gene with Alzheimer’s Disease: A Meta-Analysis
- Author
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Dongfeng Zhang, Yan Lin, Shuo Cheng, and Zhutian Xie
- Subjects
Male ,Oncology ,Epidemiology ,lcsh:Medicine ,Bioinformatics ,Gene Frequency ,Risk Factors ,Medicine and Health Sciences ,lcsh:Science ,Molecular Epidemiology ,Multidisciplinary ,Epidemiology of Aging ,Neurology ,Research Design ,Genetic Epidemiology ,Meta-analysis ,Physical Sciences ,Female ,Alzheimer's disease ,rs6265 ,Statistics (Mathematics) ,Research Article ,medicine.medical_specialty ,Clinical Research Design ,Subgroup analysis ,Research and Analysis Methods ,Polymorphism, Single Nucleotide ,White People ,Alzheimer Disease ,Internal medicine ,Mental Health and Psychiatry ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Statistical Methods ,Allele ,Genetic Association Studies ,Evolutionary Biology ,Population Biology ,Models, Genetic ,business.industry ,Brain-Derived Neurotrophic Factor ,lcsh:R ,Biology and Life Sciences ,Computational Biology ,Odds ratio ,Publication bias ,medicine.disease ,Confidence interval ,Genetic Polymorphism ,lcsh:Q ,Dementia ,business ,Publication Bias ,Mathematics ,Population Genetics ,Meta-Analysis - Abstract
Background The association between polymorphisms rs6265 and rs2030324 in brain-derived neurotrophic factor (BDNF) and Alzheimer’s disease (AD) has been widely reported, but the results remain controversial. Methods A comprehensive search of Pubmed, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Med Online and China Biology Medical literature database (CBM) was performed. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed or random-effects models. We excluded the studies with OR>3.0 or OR
- Published
- 2014
44. Hippocampal Neurochemical Changes in Senescent Mice Induced with Chronic Injection of D-Galactose and NaNO2: An In Vitro High-Resolution NMR Spectroscopy Study at 9.4T
- Author
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Yan Lin, Renhua Wu, Ke-Zeng You, Haihong Li, Zhen Cao, Yaowen Chen, Jianli Yao, Li Pang, and Haiyang Dai
- Subjects
Pathology ,medicine.medical_specialty ,Multidisciplinary ,Chemistry ,Glutamate receptor ,Hippocampus ,Morris water navigation task ,Hippocampal formation ,medicine.disease ,Glial cell proliferation ,medicine.anatomical_structure ,Neurochemical ,medicine ,Neuroglia ,Alzheimer's disease - Abstract
Proton magnetic resonance spectroscopy (1H-MRS) has been used to provide useful information about the neurochemical changes reflecting early pathological alterations in Alzheimer's disease (AD) brain. In this study, we have longitudinally measured the hippocampal neurochemical profile in vitro in senescent mice induced with chronic injection of D-Galactose and NaNO2, at different time point from day 30 to day 70 with a 10-day interval. Pathological brain alterations induced by D-Galactose and NaNO2 were monitored through hematoxylin and eosin (HE) staining, Congo red staining and bielschowsky silver staining, and the cognition deficits were assessed via Morris Water Maze (MWM) test. This D-galactose and NaNO2 treated mouse model, characterized by an early-onset memory dysfunction, a robust neuronal loss, amyloid plaques and neurofibrillary tangles in hippocampal subdivision, well mimics a prodromal Alzheimer's phenotype. Consistent with previously published in vivo 1H MRS findings in human AD patients and AD transgenic mice, our in vitro 1H MRS on the perchloric acid extractions of hippocampus in senescent mice observed significant decreases of N-acetylaspartate (NAA) and Glutamate (Glu) but an increase in Myo-inositol (mIns). Elevated mIns occurred prior to the reduction of NAA and Glu during the progression of aging. In addition, changes in mIns, NAA and Glu were found to precede pathological abnormalities. Overall, our in vitro findings in senescent mice validated the concept that hippocampal neurochemical alternations preceded the pathological changes of the brain, and could serve as potential markers of AD progression. Reductions of NAA and Glu can be interpreted in terms of neuronal degeneration and dysfunctions in glutamatergic activity that may contribute to the pathophysiological mechanisms underlying AD. Elevated mIns might be related to glial activation. Further experiments are needed to explore the potential value of mIns in the early diagnosis of AD, to verify whether glial cell proliferation occurs earlier than neuronal changes.
- Published
- 2014
45. Antibody-Derived In Vivo Imaging of Tau Pathology.
- Author
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Krishnaswamy, Senthilkumar, Yan Lin, Rajamohamedsait, Wajitha J., Rajamohamedsait, Hameetha B., Krishnamurthy, Pavan, and Sigurdsson, Einar M.
- Subjects
- *
ALZHEIMER'S disease diagnosis , *TAU proteins , *IMMUNOGLOBULINS , *AMYLOID beta-protein , *DIAGNOSTIC imaging , *LABORATORY mice , *ENDOSOMES - Abstract
Antibodies or their derivatives as imaging probes for pathological tau protein have great potential, but have not been well studied. In particular, smaller, single-chain-variable antibody fragments (scFv's) are attractive for detecting tau lesions in live subjects. Here, we generated libraries of scFv's and identified numerous phospho-tau-selective scFv's. Peripheral injection of one of these scFv's consistently resulted in a strong in vivo brain signal in transgenic tauopathy mice, but not in wild-type or amyloid-ß plaque mice. The parent tau antibody provided similar results, albeit with a weaker signal intensity. The imaging signal correlated very well with colocalization of the probe with intraneuronal tau aggregates. Both were associated with markers of endosomes, autophagosomes, and lysosomes, suggesting their interaction in these degradation pathways. Such specific antibody-derived imaging probes have great potential as diagnostic markers for Alzheimer's disease and related tauopathies. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
46. Cerebrospinal fluid α-synuclein predicts neurodegeneration and clinical progression in non-demented elders.
- Author
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Li, Jie-Qiong, Bi, Yan-Lin, Shen, Xue-Ning, Wang, Hui-Fu, Xu, Wei, Tan, Chen-Chen, Dong, Qiang, Wang, Yan-Jiang, Tan, Lan, and Yu, Jin-Tai
- Subjects
- *
OLDER people , *CEREBROSPINAL fluid , *RECEIVER operating characteristic curves , *PROPORTIONAL hazards models , *NEURODEGENERATION - Abstract
Background: Accumulating reports have suggested that α-synuclein is involved in the pathogenesis of Alzheimer's disease (AD). As the cerebrospinal fluid (CSF) α-synuclein has been suggested as a potential biomarker of AD, this study was set out to test whether CSF α-synuclein is associated with other AD biomarkers and could predict neurodegeneration and clinical progression in non-demented elders. Methods: The associations between CSF α-synuclein and other AD biomarkers were investigated at baseline in non-demented Chinese elders. The predictive values of CSF α-synuclein for longitudinal neuroimaging change and the conversion risk of non-demented elders were assessed using linear mixed effects models and multivariate Cox proportional hazard models, respectively, in the Alzheimer's disease Neuroimaging Initiative (ADNI) database. Results: The CSF α-synuclein levels correlated with AD-specific biomarkers, CSF total tau and phosphorylated tau levels, in 651 Chinese Han participants (training set). These positive correlations were replicated in the ADNI database (validation set). Using a longitudinal cohort from ADNI, the CSF α-synuclein concentrations were found to increase with disease severity. The CSF α-synuclein had high diagnostic accuracy for AD based on the "ATN" (amyloid, tau, neurodegeneration) system (A + T+ versus A − T − control) (area under the receiver operating characteristic curve, 0.84). Moreover, CSF α-synuclein predicted longitudinal hippocampus atrophy and conversion from MCI to AD dementia. Conclusions: CSF α-synuclein is associated with CSF tau levels and could predict neurodegeneration and clinical progression in non-demented elders. This finding indicates that CSF α-synuclein is a potentially useful early biomarker for AD. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
47. Genome-wide association study identifies Alzheimer's risk variant in MS4A6A influencing cerebrospinal fluid sTREM2 levels.
- Author
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Hou, Xiao-He, Bi, Yan-Lin, Tan, Meng-Shan, Xu, Wei, Li, Jie-Qiong, Shen, Xue-Ning, Dou, Kai-Xin, Tan, Chen-Chen, Tan, Lan, and Yu, Jin-Tai
- Subjects
- *
CEREBROSPINAL fluid , *ALZHEIMER'S disease , *GENETIC regulation - Abstract
The triggering receptor expressed on myeloid cells 2 (TREM2) gene has been reported to increase the risk of Alzheimer's disease (AD). The soluble TREM2 protein (sTREM2) in cerebrospinal fluid (CSF) was also associated with AD. However, the role of sTREM2 in AD and its genetic modifiers remain unclear. We carried out a genome-wide association study for CSF sTREM2 levels using participants from the Alzheimer's Disease Neuroimaging Initiative and validated the significant association in an independent cohort from Chinese Alzheimer's Biomarker and LifestylE study. rs7232 in membrane spanning 4-domains A6A (MS4A6A) gene was associated with CSF sTREM2 levels at genome-wide significance (p = 1.42 × 10−15). The locus influences CSF sTREM2 levels especially in nondemented individuals. And the association was replicable in the validation cohort from Chinese Alzheimer's Biomarker and LifestylE study (p = 0.0106). Besides, the expressions of MS4A6A and TREM2 were correlated in brain regions (p < 2 × 10−16). The findings of our study suggest that the AD risk variant in the MS4A6A gene participates in the regulation of sTREM2. • Minor allele of rs7232 in membrane spanning 4-domains A6A (MS4A6A) gene was associated with higher cerebrospinal fluid soluble TREM2 protein levels. • The locus influences cerebrospinal fluid soluble TREM2 protein levels especially in nondemented individuals. • rs7232 could regulate the expression of MS4A6A in the medulla. • The expression of MS4A6A and TREM2 was correlated in the brain. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
48. Amyloid Pathologies Modulate the Associations of Minimal Depressive Symptoms With Cognitive Impairments in Older Adults Without Dementia.
- Author
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Xu, Wei, Feng, Wei, Shen, Xue-Ning, Bi, Yan-Lin, Ma, Ya-Hui, Li, Jie-Qiong, Dong, Qiang, Tan, Lan, and Yu, Jin-Tai
- Subjects
- *
COGNITION disorders , *MENTAL depression , *OLDER people , *AMYLOID , *MIDDLE-aged persons , *ALZHEIMER'S disease , *CEREBROSPINAL fluid , *NURSING home patients - Abstract
The relationship between depression and Alzheimer's disease (AD) is complex and still not well understood. We aimed to examine the roles of the AD core pathologies in modulating the associations of minimal depressive symptoms (MDSs) with cognitive impairments. A total of 721 participants who had measures of cognition, depressive symptoms, and cerebrospinal fluid AD biomarkers were included from the CABLE (Chinese Alzheimer's Biomarker and LifestylE) study. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of AD pathologies on cognition. The ADNI (Alzheimer's Disease Neuroimaging Initiative) was used 1) to replicate the mediation effects and 2) to examine the longitudinal relationships of MDSs with amyloid pathology and incident AD risk. In CABLE, MDSs were associated with poorer global cognition (p =.006) and higher amyloid burden as indicated by cerebrospinal fluid amyloid markers (p <.0001). The influence of MDSs on cognition was partially mediated by amyloid pathology (a maximum of 85%). The mediation effects were replicated in 725 elderly persons without dementia (age, mean ± SD = 73.5 ± 6.9 years; 301 female subjects [42%]) in ADNI, such that the mediation percentage varied from 10% to 30% for general cognition, memory, and executive functions. Longitudinal analyses revealed a bidirectional relationship between MDSs and amyloid pathology (p =.01). MDSs were associated with 83% increased risk of developing AD dementia (hazard ratio = 1.83, p <.01). Overall, amyloid pathology might partially mediate and magnify the influences of MDSs on cognitive impairments and AD risk. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
49. Rational design synthesis and evaluation of a novel near-infrared fluorescent probe for selective imaging of amyloid-β aggregates in Alzheimer's disease.
- Author
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Wang, Bingxin, Shi, Junzhuo, Guo, Ning, Shao, Lulian, Zhai, Weibin, Jiang, Lei, Zhao, Fenqin, Wang, Jianhong, Wang, Junfeng, Du, Lida, Pang, Xiaobin, and Yan, Lin
- Subjects
- *
ALZHEIMER'S disease , *FLUORESCENT probes , *BLOOD-brain barrier , *AMYLOID beta-protein precursor , *AMYLOID beta-protein , *TRANSGENIC mice , *STOKES shift , *DEGENERATION (Pathology) - Abstract
Alzheimer's disease (AD) is a degenerative neurological disorder that remains incurable to date, seriously affecting the quality of life and health of those affected. One of the key neuropathological hallmarks of AD is the formation of amyloid-β (Aβ) plaques. Near-infrared (NIR) probes that possess a large Stokes shift show great potential for imaging of Aβ plaques in vivo and in vitro. Herein, we proposed a rational strategy for design and synthesis of a series of NIR fluorescent probes that incorporate a tricarbonitrile group as a strong electron-withdrawing group (EWG) to enable NIR emission and large Stokes shift for optimal imaging of Aβ plaques. The probe TCM-UM exhibited remarkable in vitro performance, including strong NIR emission (λ em = 670 nm), large Stokes shift (120–245 nm), and its affinity for Aβ 42 aggregates (K d = 43.78 ± 4.09 nM) was superior to the commercially available probe Thioflavin T (ThT, K d = 896.04 ± 33.43 nM). Further, TCM-UM was selected for imaging Aβ plaques in brain tissue slices and APP/PS1 transgenic (AD) mice, the results indicated that TCM-UM had an excellent ability to penetrate the blood-brain barrier (BBB) compared with ThT, and it could effectively distinguish wild-type (Wt) mice and APP/PS1 transgenic (AD) mice. The near-infrared fluorescent probe TCM-UM with good binding ability can be used to stain Aβ plaques in vitro and in vivo. [Display omitted] • TCM-UM regulates NIR emission by introducing tricarbonitrile and morpholine. • TCM-UM can selectively detect Aβ 42 aggregates with higher affinity than ThT. • The probe can detect Aβ plaques by i n vitro staining in brain sections of AD mice. • Excellent imaging capability enables TCM-UM to effectively distinguish AD mice. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
50. Response: Commentary: Chronic PD-1 Checkpoint Blockade Does Not Affect Cognition or Promote Tau Clearance in a Tauopathy Mouse Model
- Author
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Yan Lin, Leslie A. Sandusky-Beltran, Begona Gamallo-Lana, Adam Mar, and Einar M. Sigurdsson
- Subjects
tau ,Alzheimer's disease ,tauopathy ,PD-1 blockade ,antibody ,therapy ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2020
- Full Text
- View/download PDF
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