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Objective:To investigate the tau deposition pattern in Alzheimer′s disease (AD) and its correlation with cognition by 18F-MK6240 PET imaging. Methods:From August 2021 to February 2022, 46 elderly people over 55 years old (16 males, 30 females; age (68.9±7.7) years) were included from outpatient and community in Shanghai. Structural brain MRI, β-amyloid (Aβ) PET imaging, tau-PET imaging and comprehensive neuropsychological tests batteries were conducted. The subjects were divided into AD group ( n=16) and normal cognition (NC) group ( n=30) according to the 2018 National Institute on aging and Alzheimer′s Association (NIA-AA) diagnostic criteria. Quantitative analysis was conducted to investigate the tau deposition pattern in AD after preprocessing 18F-MK6240 PET images with MRI images. SUV ratio (SUVR) of brain regions such as entorhinal cortex, hippocampus, parahippocampal gyrus, amygdala, insular lobe, frontal lobe, precuneus, occipital lobe, thalamus and putamen were analyzed, with cerebellum as reference region. The differences of tau deposition in brain regions between AD and NC groups were analyzed by independent-sample t test. The associations between SUVR and Mini-Mental State Examination (MMSE) score and Montreal Cognitive Assessment-Basic (MoCA-B) score were analyzed by Pearson correlation analysis. Results:AD displayed a significant tau deposition in frontal lobes, temporal lobes and parietal lobes compared with NC. SUVR of brain regions in AD group were higher than those in NC group ( t values: 3.37-9.61, all P<0.05). SUVR in brain regions were negatively correlated with MMSE score ( r values: from -0.735 to -0.350, all P<0.05) and MoCA-B score ( r values: from -0.723 to -0.367, all P<0.05). Conclusion:18F-MK6240 PET can demonstrate the tau deposition in the brain of AD patients, and the tau deposition is related to cognitive function.
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ABSTRACT Neurodegenerative dementias are characterized by the abnormal accumulation of misfolded proteins. However, its diagnostic criteria are still based on the clinical phenotype. The development of biomarkers allowed in vivo detection of pathophysiological processes. This article aims to make a non-systematic review of the use of molecular neuroimaging as a biomarker. Molecular neuroimaging is based on the use of radiotracers for image acquisition. The radiotracer most used in PET is 18F-fluorodeoxyglucose (FDG), with which it is possible to study the regional brain glucose metabolism. The pattern of regional hypometabolism provides neuroanatomical information on the neurodegenerative process, which, in turn, has a good specificity for each type of proteinopathy. FDG is very useful in the differential diagnosis of neurodegenerative dementias through the regional pattern of involvement, including dementia with Lewy bodies and the spectrum of frontotemporal dementia. More recently, radiotracers with specific ligands to some of the pathological proteins have been developed. Pittsburgh compound B (PIB) labeled with 11C and the ligands that use 18F (florbetapir, florbetaben and flutemetamol) are the most used radiotracers for the detection of insoluble β-amyloid peptide in Alzheimer's disease (AD). A first generation of ligands for tau protein has been developed, but it has some affinity for other non-tau protein aggregates. A second generation has the advantage of having a higher affinity for hyperphosphorylated tau protein, including in primary tauopathies.
RESUMO As demências neurodegenerativas caracterizam-se pelo acúmulo anormal de proteínas mal dobradas. Entretanto, os seus critérios diagnósticos ainda se baseiam no fenótipo clínico. O desenvolvimento de biomarcadores permitiu a detecção in vivo do processo fisiopatológico. O objetivo deste artigo é fazer uma revisão não-sistemática sobre o papel da neuroimagem molecular como biomarcador. A neuroimagem molecular baseia-se no uso de radiotraçadores para aquisição da imagem. O mais usado no PET é o 18F-fluorodeoxiglicose (FDG), com o qual é possível estudar o metabolismo regional de glicose cerebral. O padrão de hipometabolismo regional fornece uma informação neuroanatômica do processo neurodegenerativo que, por sua vez, tem uma boa especificidade para cada tipo de proteinopatia. O PET-FDG é muito útil no diagnóstico diferencial das demências neurodegenerativas através do padrão de acometimento regional, incluindo a demência com corpos de Lewy e o espectro das demências frontotemporais. Mais recentemente, radiotraçadores com ligantes específicos a algumas das proteínas patológicas têm sido desenvolvidos. O composto B de Pittsburgh (PIB) com 11C e os ligantes dos que usam 18F (florbetapir, florbetaben e flutemetamol) são os radiotraçadores mais usados para a detecção de peptídeo β-amiloide insolúvel na doença de Alzheimer (DA). Uma primeira geração de ligantes para proteína tau foi desenvolvida, mas apresenta alguma afinidade a outros agregados proteicos não-tau. Uma segunda geração tem a vantagem de apresentar uma maior afinidade à proteína tau hiperfosforilada, incluindo nas taupatias primárias.
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Parkinson′s disease is a degenerative disease of the central nervous system with abnormal protein deposition in the brain as the main pathological changes. The onset of Parkinson′s disease is related to abnormal deposition protein removal disorders, and the relevant mechanisms are still unclear. The glymphatic system is a metabolic waste and abnormal protein deposition removal system in the brain. In recent years, studies have shown that the changes of aquaporin 4, perivascular space and dural lymphatic vessels in Parkinson′s disease are closely related to the level of relevant pathological proteins in cerebrospinal fluid, leading to the occurrence and development of Parkinson′s disease. The researches on structure and biomarkers of the glymphatic system in Parkinson′s disease in recent years are reviewed in this article.
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Parkinson's disease(PD)is a progressive neurodegenerative disorder that tends to occur in the elderly.Its clinical manifestations mainly include motor symptoms and non-motor symptoms, with sleep disorders among common non-motor symptoms of PD.The latest lines of evidence show that sleep disorders are not only clinical manifestations of neurodegenerative diseases, but also an important risk factor for the development and progression of neurodegenerative diseases.There is a bidirectional relationship between sleep disorders and neurodegenerative diseases, including PD.The possible mechanisms include accelerated α-synuclein pathology, deposition of Tau protein, inhibition of the glymphatic system, neuroinflammation and changes in the circadian rhythm system.In this article, we review research progress on the bidirectional relationship between sleep disorders and PD, related mechanisms, and the outlook on the treatment of PD through the management of sleep disorders.
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Objective:To investigate the mechanism of dexmedetomidine preventing sevoflurane-indued neurotoxicity to neonatal mice and the relationship with Tau phosphorylation.Methods:Seventy-two SPF healthy newly born C57BL/6 wild-type mice of both sexes, aged 6 days, were divided into 4 groups ( n=18 each) using a random number table method: normal control group (C group), dexmedetomidine control group (D group), sevoflurane-induced neurotoxicity group (S group), and dexmedetomidine prevention group (SD group). Mice inhaled 2.1%-3.3% sevoflurane 2 h daily on postnatal days 6, 9 and 12, and dexmedetomidine 10 μg/kg was intraperitoneally injected at 30 min before anesthesia in group SD.Six mice were randomly selected after the end of injection, and the hippocampus tissues were removed for determination of the expression of phosphorylated Tau protein (AT8) and Tau46 protein at Tau-PS202 and Tau-PT205 sites by Western blot.The new object recognition test was performed on postnatal days 29-30 (the discrimination ratio of new objects was observed), and the Morris water maze test was performed from postnatal day 31 to 37 (the escape latency and the times of crossing the platform were observed). The hippocampi were harvested under anesthesia to detect the expression of postsynapatic density-95 by Western blot. Results:Compared with group C, the expression of AT8 was significantly up-regulated, the expression of PSD-95 was down-regulated, the number of crossing the platform and new object discrimination ratio were decreased ( P<0.05), and no significant change was found in Tau46 protein expression or escape latency in group S ( P>0.05). There was no significant difference in the indexes mentioned above between group D and group SD ( P>0.05). Compared with group S, the expression of AT8 was significantly down-regulated, the expression of postsynapatic density-95 was up-regulated, the number of crossing the platform and new object discrimination ratio were increased ( P<0.05), and no significant change was found in Tau46 protein expression and escape latency in group SD ( P>0.05). Conclusions:The mechanism of dexmedetomidine preventing sevoflurane-induced neurotoxicity to neonatal mice is related to the inhibition of Tau phosphorylation.
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Abstract Alzheimer's disease is a neurodegenerative condition that causes changes in memory and cognition, in addition to behavioral disorders, and most commonly affects the elderly. Several studies in the literature have presented therapeutic measures in an attempt to interfere with the pathogenic mechanisms of the disease and to mitigate its clinical manifestations. Some factors, such as excitotoxicity, cholinergic dysfunctions, oxidative stress, tau protein hyperphosphorylation, changes in amyloid-beta peptide metabolism, herpes viruses, apolipoprotein E, glycogen synthase kinase 3, insulin resistance, and the endocannabinoid system seem to be related to pathophysiology of Alzheimer's disease. Given this, a literature review was carried out to address the molecular mechanisms associated with the pathophysiological hypotheses previously mentioned, aiming to better understanding their underlying causes and contributing to possible pharmacological strategies about treatment of the disease.
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@#AIM: To detect the visual dysfunction, and investigate the changes of Tau and its phosphorylated Ser396/Ser404 forms in retinas and optic nerves in traumatic optic neuropathy(TON)model rats by using FVEP technique.<p>METHODS: Totally 30 SD rats were conducted FVEP electrode implantation. One week later, all rates were implemented TON operation with the optic nerve of left eye crushed and the optic nerve of right eye exposed(sham-operated). FVEP detections were performed respectively in these TON model rats at 1, 3, 7, 14, and 28d post crush, with 5 rats tested at each time point. After FVEP tests were taken, rats were sacrificed and then retinas and optic nerves of left eyes were separated for detecting the expression levels of Tau and pTau-Ser396/404 by Western Blot.<p>RESULTS: Typical FVEP waves were observed in the sham-operated eyes. Compared to the sham group, the N2 waves were significantly delayed and the amplitude of N2-P2 were greatly reduced at each time point in the operation eyes. However, the differences of N2 wave and the amplitude reduction of N2-P2 were not significant at each time point after crush. The contents of total Tau protein in retinas of TON rats sharply decreased at 1d post crush, briefly recovered at 7d post crush, and remained a slightly lower level than normal condition till 28d. The changes of pTau-Ser396/404 were consistent with the changes of total Tau in retains and the Ser396 was the main phosphorylation site. However, the total Tau contents in optic nerves of TON rats increased gradually, and peaked at the 14d post crush and remained till 28d. The changes of pTau-Ser396/404 were similar to the changes of total Tau in optic nerves, which peaked at 7d post crush. However, Ser404 was the main phosphorylation site of Tau in optic nerves.<p>CONCLUSION: The related indexes of N2 and P2 waves in FVEP can be used to detect the visual dysfunction in TON rats. After TON, the content changes of total Tau in retinas and optic nerves were much different while the changes of pTau-Ser396/404 followed the alterations of total Tau in the two locations. However, the main phosphorylation site of Tau was differnet according to the locations.
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Objective:To evaluate the relationship between phosphorylation of Tau protein and apolipoprotein E (ApoE) containing 18 kDa fragments and investigate the mechanism of neuronal damage induced by sevoflurane.Methods:Primary neurons (ApoE3 and ApoE2 genotypes, 24 dishes for each genotype) of fetal mice cultured until the 5th day were divided into 4 groups ( n=12 each) using a random number table method: ApoE3 control group (A3C group), ApoE3 sevoflurane group (A3S group), ApoE2 control group (A2C group) and ApoE2 sevoflurane group (A2S group). Neurons were treated with 21% oxygen + 5% carbon dioxide + 4.1% sevoflurane for 4 h in A3S and A2S groups, while the neurons were only treated with 21% oxygen + 5% carbon dioxide in A3C and A2C groups.The cell proteins were then extracted to detect the expression of full-length ApoE and ApoE, AT8 and PHF1 containing 18 kDa fragments (by Western blot), expression of ApoE mRNA (by real-time polymerase chain reaction), and concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the supernatant (by enzyme-linked immunosorbent assay). Results:Compared with A2C group, the expression of ApoE mRNA and full-length ApoE in neurons was up-regulated ( P<0.05), and no significant change was found in the expression of AT8 and PHF1 and concentrations of TNF-α and IL-6 in the supernatant in A2S group ( P>0.05). Compared with A3C group, the expression of ApoE mRNA, full-length ApoE, and ApoE, AT8 and PHF1 containing 18 kDa fragments was up-regulated, and the concentrations of TNF-α and IL-6 in the supernatant were increased in A3S group ( P<0.05). Conclusion:Sevoflurane may promote phosphorylation of Tau proteins and increase inflammatory responses through up-regulating the expression of ApoE containing 18 kDa fragments, thus leading to neuronal damage.
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Objective:To evaluate the effects of propofol, dexmedetomidine and ketamine on oncentrations of β-amyloid peptide (Aβ) and tau in cerebrospinal fluid (CSF) of sleep-deprived rats.Methods:Forty SPF healthy male Sprague-Dawley rats, aged 3-4 months, weighing 230-280 g, were divided into 5 groups ( n=8 each) using a random number table method: control group (group C), sleep deprivation group (SD), propofol group (group P), dexmedetomidine group (group D) and ketamine group (group K). The sleep deprivation was induced using the improved multi-platform sleep deprivation model.Propofol 100 mg/kg, dexmedetomidine 100 mg/kg and ketamine 80 mg/kg were intraperitoneally injected at 72 h of sleep deprivation to maintain anesthesia for 3 h in P, D and K groups, respectively.Group C entered the large platform for 72 h free activity.The CSF was collected at 3 h of anesthesia for measurement of concentrations of Aβ and tau protein by enzyme-linked immunosorbent assay. Results:The concentrations of Aβ and tau protein in CSF were significantly higher in SD, P, K and D groups than in group C ( P<0.05). Compared with group SD, the concentrations of Aβ and tau protein in CSF were significantly increased in P and K groups, and the concentrations of Aβ and tau protein in CSF were significantly decreased in group D ( P<0.05). Conclusion:Dexmedetomidine can decrease the the concentrations of Aβ and tau protein in CSF of sleep deprived rats, while propofol and ketamine lead to the opposite effect.
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Alzheimer's disease (AD)is most common in all dementia types in the elderly.Various researches have been done for studying its pathogenesis,but no single mechanism can explain all its pathological changes.AD is currently incurable and no effective treatment measures are available.So it is of prime importance to prevent the occurrence of AD.In the process of exploring the pathogenesis and treatment of AD,more and more attention is being paid to the role of diet and nutrition in the occurrence and development of AD.Mediterranean diet(MeDi)has been proved to have an unvarying role in the occurrence and development of Alzheimer's disease.This paper reviewed the relevant literatures and summarized the role of MeDi in AD,in order to provide the theoretical supports for dietary intervention and nutritional therapy in AD treatment.
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Alzheimer's disease (AD) is a neurodegenerative disease,which is insidious onset and progressive.The pathological features of AD include senile plaques composed of amyloid β (Aβ) and neurofibrillary tangles composed of Tau protein.Aβ and Tau protein targeted imaging agents,which make a non-invasive and high specificity diagnosis,might be useful for early diagnosis,efficacy monitoring and drug evaluation for AD.This review summarizes the progress and clinical applications of those agents in AD.
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Objective To investigate the plasma protein concentration of S100B protein,hyperphosphorylated tau protein (P-tau) and β-amyloid (Aβ1-42) of rheumatoid arthritis (RA) patients with mild cognitive impairment (MCI) and to provide a reference for clinical diagnosis and prevention of cognitive dysfunction of RA patients.Methods The subjects were consisted of three groups:RA patients with MCI,RA patients with normal cognitive function (NC) and healthy controls.The Montreal Cognitive Assessment (MoCA)was used to test patients' cognitive function,generalized anxiety disorder scale-7 (GAD-7) scale and 9-item patient health questionnaire-9 (PHQ-9) were used to exclude anxiety and depression of RA patients.The concentration of S100B protein,P-tau protein and Aβ1-42 protein in plasma was detected by enzyme-linked immunosorbent assay (ELISA),and the correlation among the concentration of S100B protein,P-tau protein and MoCA scores was analyzed by Pearson's chi-squared test.Results ① Cognitive scores showed that some RA patients had MCI.② The plasma levels of S100B (F=11.81,P＜0.05),P-tau (F=3.3,P＜0.05) protein in RA patients with MCI were higher than that in NC RA patients and the control group (P＜0.05).③ The clinical index analysis showed that the concentration of C reactive protein (CRP) in RA patients with MCI was higher than that in NC RA patients and healthy control,the difference was statistically significant (t=6.44,P＜0.05).④The levels of plasma P-tau (r=-0.539,P＜0.05),S100B (r=-0.346,P＜0.05),CRP (r=-0.358,P＜0.05) protein were negatively correlated with cognitive scores (P＜0.05).Conclusion CRP,S100B protein and P-tau protein are associated with the pathogenesis of RA patients with MCI.The consequences of plasma concentration test can be com-bined with cognitive assessment questionnaire to provide reference for clinical diagnosis of RA patients with MCI.
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Objective To explore the protective effects of dipeptidyl peptidase-4 inhibitor (DPP-4I) on AD-like neurodegenerative changes and its mechanism. Methods The human neuroblastoma cell line SH-SY5Y on the logarithmic phase was divided into six groups:control group (CON group, treated with PBS contained 1‰DMSO for 12 h), wortmannin intervention group (W group, treated with 0.03 μmol/L wortmannin for 12 h), DPP-4I intervention group (DPP-4I group, treated with 10μmol/L DPP-4I for 12 h), both DPP-4I and wortmannin intervention group (DPP-4I+W group, pre-treated with 10 μmol/L DPP-4I for 2 h, then 0.03 μmol/L wortmannin for 12 h), DPP-4I, wortmannin and Ex9-39 intervention group (DPP-4I+W+Ex9-39 group, pre-treated with 10μmol/L Ex9-39 for 2 h, then 10μmol/L DPP-4I for 2 h followed by 0.03μmol/L wortmannin for 12 h), and Ex9-39 intervention group (Ex9-39 group, treated with 10μmol/L Ex9-39 for 12 h). MTT assay was used to detect the cell vitality. Western blot assay was used to detect the level of total tau protein (tau-5) and phosphorylated tau at different sites (pSpS199/202, pT231 and pS396), the level of phosphorylated neurofilaments (NF-H, NF-M) and phosphorylation of critical enzyme in PI3K/Akt/GSK-3β signaling pathway. Results (1) The cell vitality decreased, the levels of pSpS199/202, pT231, pS396 and NF-H/M increased significantly in W group than those in CON group. However, comparing with CON group, the above mentioned parameters reversed in DPP-4I group. Comparing with W group, the cell vitality increased and phosphorylated levels of above mentioned indices were decreased in DPP-4I+W group. (2) The cell vitality showed a decline trend while the levels of phosphorylation tau at three different sites and NF-H/M were higher in Ex9-39 group than those in CON group. Comparing with DPP-4I+W group, the results of the phosphorylated levels showed the same changes in DPP-4I+W+Ex9-39 group. (3) Comparing with CON group, the expression levels of phosphorylated PI3K, Akt and GSK3β increased significantly in DPP-4I group, while those decreased in W group. Additionally, the expression levels of phosphorylated PI3K, Akt and GSK3β were significantly increased in DPP-4I+W group than those in W group. Conclusion DPP-4I can enhance the level of GLP-1 and activate PI3K/Akt/GSK-3βinsulin signaling pathway to improve the hyperphosphorylated tau and NFs induced by wortmannin, and to protect AD-like neurodegeneration.
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Objective To evaluate the effect of dexmedetomidine on the mammalian target of rapamycin(mTOR)/tau protein signaling pathway in the hippocampus of aged rats after splenectomy.Methods One hundred and fifty pathogen-free healthy male Sprague-Dawley rats,aged 18 months,weighing 400-540 g,were divided into 5 groups(n=30 each)using a random number table:control group(group C),sham operation group(group S),operation group(group O),normal saline group(group NS)and dexmedetomidine group(group D).Group C received no treatment.Ten percent chloral hydrate 0.3 ml/100 g was injected intraperitoneally in group S.Group O underwent splenectomy.Dexmedetomidine 50 μg/kg was injected intraperitoneally at 5 min before splenectomy in group D.The equal volume of normal saline was injected intraperitoneally at 5 min before splenectomy in group NS.Morris water maze test was performed at day 7 after surgery.At days 1,3 and 7 after surgery,the rats were sacrificed,and the hippocampi were removed for examination of the pathological changes in the hippocampal CA3 region and for determination of the expression of mTOR protein and mRNA,tau protein mRNA and phosphor-tau protein(pS396 tau protein)(by real-time polymerase chain reaction or Western blot).Results Compared with group C,the escape latency and swimming distance were significantly prolonged,and the expression of mTOR protein and mRNA,tau protein mRNA and pS396 tau protein was up-regulated in O,D and NS groups(P0.05).Compared with group O,the escape latency and swimming distance were significantly shortened,and the expression of mTOR protein and mRNA,tau protein mRNA and pS396 tau protein was down-regulated in group D(P0.05).The pathological changes in the hippocampal CA3 region were significantly attenuated in group D as compared with group O.Conclusion The mechanism by which dexmedetomidine improves postoperative cognitive function may be associated with inhibited activation of mTOR/tau protein signaling pathway in the hippocampus of aged rats.
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Objective To study whether the human bone marrow mesenchymal stem cells (HBMSCs) can repair damaged neural cells induced by okadaic acid (OA).Methods Neuroblastoma cell line SH-SY5Y cells were used to incubate with 20nmol/L okadaic acid for 24h,establishing Alzheimer's Disease cell model;Three groups were set up:normal group,okadaic acid-damaged (OA-damaged) group,hBMSCs-treatment group.The cells were injured for 24h with 20nmol/L OA in OA-damaged group,and treated with conditioned medium obtaining hBMSCs for 24h after 24h OA injury in the treatment group.Then CCK-8 was used for detecting cell vitality,immune fluorescence dyed microtubules and micro filaments for determining the dendritic cell length and fluorescence intensity,in addition,Western blotting for analyzing the protein level of phosphorylated tau and total tau proteins.Results Okadaic acid damaged SH-SY5Y cells,contributed to shrinkage,collapse,cavitation of the SH-SY5Y cell body,dendritic shortening and fracture,and irregular arrangement of microtubule microfilaments;while BMSCs conditioned medium made SHSYSY cell body become round and longer,dendrites restored,and microtubules and microfilaments arranged regularly,fluorescence intensity enhanced.Meanwhile,it also down-regulated the level of OA-induced tau phosphorylation.Conclusion hBMSCs have repair effects on the neural cell damage induced by okadaic acid.
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Objective To evaluate the effect of sevoflurane on cognitive function of mice with Alzheimer's disease.Methods Twenty male mice carrying mnutations in amyloid precusor protein (APP) and presenilin 1 genes,weighing 30-40 g,aged 7 months,were divided into either sevoflurane group (group Sev) or control group (group C),with 20 mice in each group.Mice inhaled 3％ sevoflurane for 4 h in group Sev,and mice inhaled 30％ oxygen for 4 h in group C.At 1 month after inhaling sevoflurane or oxygen,the mice underwent continuous multiple-trail inhibitory avoidance training.The mice were then sacrificed and hippocampi were isolated for determination of the number of Aβ plaques (by immunohistochemistry) and expression of APP and Tau (S396) phosphorylation (by Western blot).Results Compared with group C,the memory lateucy was significantly shortened,the number of Aβ plaques was increased,the phosphorylation of Tau (S396) was increased,and the expression of APP was up-regulated in group Sev (P＜0.05).Conclusion Sevoflurane can decrease the cognitive function of mice with Alzheimer's disease.
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Objective To study the effects of discoidin domain receptor 1 (DDR1) mediated phosphorylation of protein Tau on hypoxic-ischemic brain damage (HIBD) in neonatal rats and its possible mechanism.Methods Sixty-four seven-day-old male specific-pathogen-free Wistar rats were randomly divided into four groups with sixteen in each: Sham, HIBD, HIBD with normal saline (HIBD+NS) and HIBD with DDR1 inhibitor (HIBD+DI) groups. A rat model of HIBD was established by subjecting the rats to left common carotid artery ligation, followed by exposing them to hypoxia for two hours. In HIBD+DI group, the inhibitor of DDR1 was immediately injected into lateral cerebroventricles of the rats following modeling. Forty-eight hours after injection, tissues of left cerebral cortex were collected from each rat to evaluate histopathological changes with HE staining. Western-blotting was used to assess the phosphorylation levels of DDR1 and protein Tau. Enzyme-linked immunosorbent assay was performed to detect the concentrations of acetylcholine. Analysis of variance ort test were used for statistical analysis.Results (1) Damages in cerebral cortex: Percentages of abnormal neurons in the rats of HIBD group were higher than those in Sham group [(80.28±4.51)% vs (10.40±2.17)%,t=39.491,P<0.01]. Pyknotic or necrotic neurons in the rats of HIBD+DI group were less than those in HIBD+NS group [(31.91±3.05)% vs (82.01±7.20)%,t=18.123,P<0.01]. (2) Phosphorylation of DDR1 and protein Tau: Levels of phosphorylated DDR1 in the cerebral cortexes of rats in HIBD group were higher than those in Sham group (0.922±0.199 vs 0.095±0.023,t=10.379,P<0.01), and those levels in HIBD+NS group were higher than those in HIBD+DI group (1.200±0.171 vs 0.255±0.111,t=11.901, P<0.01). The phosphorylation of protein Tau was similar to that of DDR1 (0.919±0.228 vs 0.194±0.224 in HIBD and Sham groups,t=7.347; 1.100±0.167 vs 0.291±0.210 in HIBD+NS and HIBD+DI groups,t=9.447;bothP<0.01). (3) Levels of acetylcholine: Levels of acetylcholine in cerebral cortexes of rats in HIBD group were lower than those in Sham group [(3.685±0.472) vs (7.429±0.861) ng/g protein,t=10.781,P<0.01], and that levels in HIBD+DI group were higher than those in HIBD+NS group [(7.058±0.915) vs (2.521±0.723) ng/g protein,t=10.989,P<0.01].Conclusions Activation of DDR1 plays a key role in enhancing the phosphorylation of protein Tau and in reducing the secretion of acetylcholine in cerebral cortexes of rats with HIBD. Inhibitor of DDR1 could protect neonatal rats from HIBD through the decreasing of protein Tau phosphorylation and increasing of acetylcholine release by inhibiting the activation of DDR1.
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ABSTRACT Introduction: Several studies have been conducted in order to validate cerebrospinal fluid biomarkers for the diagnosis of Alzheimer’s disease (AD), aiming primarily to facilitate the early diagnosis. Objective: To evaluate CSF biomarkers on patients with probable AD and the applicability of the international references values in this population. Methods: 46 individuals were recruited and classified as probable AD (n = 19), mild cognitive impairment (MCI) (n = 5) and other dementias (n = 22). The cerebrospinal fluid (CSF) biomarkers were measured using the INNOTEST kits for enzyme-linked immunosorbent assay (ELISA). Higher Tau protein values and lower Aβand Innotest Amyloid Tau Index (IATI) values were observed in AD group when compared with MCI; higher levels of Tau and phosphorylated Tau (P-Tau), and lower Aβand IATI values were observed in AD group when compared to patients with other dementias. No biomarker or IATI was able to distinguish between MCI and other dementias. The kappa index between biomarkers and the clinical diagnosis was regular to Tau and IATI, and weak to Aβand P-tau. Conclusion: The cut-off values for each biomarker that showed better combined sensibility and specificity differ from the reference values suggested by the manufacturer. The CSF biomarkers represent important resources that can help with the AD diagnosis, although the results interpretation must be made based on the analysis of the three analytes together. The cut-off values must be established to address the specificities and characteristics of each population.
RESUMO Introdução: Estudos têm sido conduzidos no sentido de validar biomarcadores no liquor para o diagnóstico da doença de Alzheimer (DA), objetivando, sobretudo, facilitar o diagnóstico precoce. Objetivo: Avaliar os biomarcadores do liquor em indivíduos com provável DA, bem como a aplicabilidade dos valores de referência internacionais nesta população. Métodos: Foram recrutados 46 indivíduos, sendo classificados como provável DA (n = 19), comprometimento cognitivo leve (CCL) (n = 5) e outras demências (n = 22). Os biomarcadores foram dosados no liquor utilizando-se os kits INNOTEST por ensaio imunossorvente ligado à enzima (ELISA). Maiores valores de proteína Tau e menores valores de Aβ e índice Innotest Amiloide Tau Index (IATI) foram observados no grupo de DA quando comparados com o de CCL; maiores níveis de Tau e Tau fosforilada (Tau-P) e menores valores de Aβ e IATI foram observados no grupo de DA quando comparados com os pacientes que apresentavam outras demências. Nenhum biomarcador ou o IATI foi capaz de discernir entre CCL e outras demências. O índice kappa entre os biomarcadores e o diagnóstico clínico foi regular para a Tau e IATI, e fraco para Aβ e Tau-P. Conclusão: Os valores de cut-off para cada biomarcador que apresentou melhor sensibilidade e especificidade conjugadas diferiram dos valores de referência sugeridos pelo fabricante. Os biomarcadores do liquor representam importantes recursos que podem auxiliar no diagnóstico da DA, mas a interpretação dos resultados deve ser feita com base na análise dos três analitos em conjunto. Os valores de cut-off devem ser estabelecidos de modo a atender as especificidades e as características de cada população.
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Objective To observe the diffusion and aggregation of the microtubule associated protein tau(MAPT)modu?lated by phosphatase and tensin homolog deleted on chromosome ten(PTEN)during the nerve cell differentiation by human bone marrow stem cells(BMSC)in vitro, and to analyse the signification. Methods Adult bone marrow stem cells were iso?lated and induced into nerve-like cells by some cytokines in vitro. The mRNA expression of MAPT was detected by semi-quantitative RT-PCR and Western blot assay. The patterns of diffusion and aggregation of the MAPT association of the actin were indicated by Phalloidin-fluoresceineisothioeyanate (FITC) and immunofluorescence (IF) cyto-chemistry, and observed by the laser-confocal microscopy. Results The MAPT mRNA levels were 0.24 ± 0.04 and 0.52 ± 0.04 at 1 week and 2 weeks after the induction,which were significantly higher compared with those of BMSC (0.04 ± 0.02) after the induction (P<0.05). The MAPT protein levels were 0.18 ± 0.03 and 0.44 ± 0.05 at 1 week and 2 weeks after the induction, which were significantly higher compared those of BMSC (0.06 ± 0.04, P<0.05). The distribution patterns of MAPT were changed from the diffusion to the aggregation in cells after treatment by BPV. The nerve-like cells appeared the characteristic of po?larization. Conclusion When the nerve cells derived from bone marrow stem cells obtain the mature differentiation, PTEN may possess the ability of modulating the diffusion and aggregation of MAPT in vitro, also may provide a kind of material ba?sis for the growth of the nerve axon.
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Objective To evaluate the accuracy of cerebrospinal fluid (CSF) amyloid beta 42 (Aβ-42) to tau level ratio (Aβ-42/tau) in predicting postoperative cognitive dysfunction (POCD) in elderly patients.Methods Eighty ASA physical status Ⅱ or Ⅲ patients of both sexes,aged 65-85 yr,undergoing elective total hip or knee replacement under combined spinal-epidural anesthesia,were enrolled in the study.Epidural catheter was placed at T3,4 interspace,and after a catheter was successfully placed into the subarachnoid space,CSF 2 ml was obtained to measure Aβ-42 and tau levels (units:pg/ml),and the ratio between them was calculated.Neuropsychological tests were performed at 1 day before surgery and 1 week after surgery.The Z score was used to identity POCD.The cut-off value for POCD and nonPOCD patients was determined by using ROC curve.Results Thirty-two patients were diagnosed with POCD,and the incidence was 40％.The Aβ-42/tau was 2.6±0.3 and 1.7±0.4 in non-POCD and POCD groups,respectively,and the ratio was significantly lower in POCD group than in non-POCD group.The sensitivity of CSF Aβ-42/tau in predicting POCD was 91.7％,the specificity was 81.2％,and Youden index was 0.7.ROC curves revealed that the cut-off value for POCD and non-POCD patients was 2.0.Conclusion CSF Aβ-42/tau can accurately predict the occurrence of POCD in elderly patients.