Decreased sAβPPβ, Aβ38, and Aβ40 cerebrospinal fluid levels in frontotemporal dementia

To improve the etiological diagnosis of neurodegenerative dementias like Alzheimer's disease (AD) or frontotemporal dementia (FTD), we evaluated the value of individual and combined measurements of the following relevant cerebrospinal fluid (CSF) biomarkers: Tau, 181p-Tau, Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. This study conducted in two centers included patients with FTD (n = 34), AD (n = 52), as well as a control group of persons without dementia (CTRL, n = 42). Identical clinical criteria and pre-analytical conditions were used while CSF biomarkers were measured using commercial single and multiplex quantitative immunoassays. Thorough statistical analyses, including ROC curves, logistic regressions, and decision trees, were performed. We validated in AD the specific increase of p-Tau levels and the decrease of Aβ42 levels, two biological hallmarks of this disease. Tau concentrations were highest in AD and intermediate in FTD when compared to CTRL. The most interesting results were obtained by focusing on amyloid biomarkers as we found out in FTD a significant decrease of sAβPPβ, Aβ38, and Aβ40 levels. Aβ38 in particular was the most useful biomarker to differentiate FTD subjects from the CTRL population. Combining p-Tau and Aβ38 led us to correctly classifying FTD patients with sensitivity at 85% and specificity at 82%. Significant changes in amyloid biomarkers, particularly for Aβ38, are therefore seen in FTD. This could be quite useful for diagnosis purposes and it might provide additional evidence on the interrelationship between Tau and AβPP biology which understanding is essential to progress towards optimal therapeutic and diagnostic approaches of dementia.     

Performance of aβ1-40, aβ1-42, total tau, and phosphorylated tau as predictors of dementia in a cohort of patients with mild cognitive impairment

Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimer's disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid-β 1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Aβ1-40, Aβ1-42, t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without dementia (OND) followed up for four years. Aβ1-42 levels were significantly lower in AD and MCI-AD than in MCI-MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Aβ1-42/Aβ1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aβ1-42/t-tau and Aβ1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aβ1-42/p-tau ratio was the best parameter for discriminating MCI-AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination annual change rate score (MMSE-ACR, rS = -0.71, p < 0.0001). Survival analysis showed that 81% of MCI with a low Aβ1-42/p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Aβ1-42 and p-tau (sensitivity 75%, 95%CI: 70-80%; specificity 96%, 95%CI: 94-98%). We can conclude that Aβ1-42 and p-tau reliably predict conversion to AD in MCI patients.     

Association study of IL10, IL1β, and IL1RN and schizophrenia using tag SNPs from a comprehensive database: Suggestive association with rs16944 at IL1β

Genetic association studies of several candidate cytokine genes have been motivated by evidence of immune dysfunction among patients with schizophrenia. Intriguing but inconsistent associations have been reported with polymorphisms of three positional candidate genes, namely IL1β, IL1RN, and IL10. We used comprehensive sequencing data from the Seattle SNPs database to select tag SNPs that represent all common polymorphisms in the Caucasian population at these loci. Associations with 28 tag SNPs were evaluated in 478 cases and 501 unscreened control individuals, while accounting for population sub-structure using the genomic control method. The samples were also stratified by gender, diagnostic category, and exposure to infectious agents. Significant association was not detected after correcting for multiple comparisons. However, meta-analysis of our data combined with previously published association studies of rs16944 (IL1β − 511) suggests that the C allele confers modest risk for schizophrenia among individuals reporting Caucasian ancestry, but not Asians (Caucasians, n = 819 cases, 1292 controls; p = 0.0013, OR = 1.24, 95% CI 1.09, 1.41).     

βCCT,an antagonist selective for α1GABAA receptors,reverses diazepam withdrawal-induced anxiety in rats

The abrupt discontinuation of prolonged benzodiazepine treatment elicits a withdrawal syndrome with increased anxiety as a major symptom. The neural mechanisms underlying benzodiazepine physical dependence are still insufficiently understood. Flumazenil, the non-selective antagonist of the benzodiazepine binding site of GABA_A receptors was capable of preventing and reversing the increased anxiety during benzodiazepine withdrawal in animals and humans in some, but not all studies. On the other hand, a number of data suggest that GABA_A receptors containing α₁ subunits are critically involved in processes developing during prolonged use of benzodiazepines, such are tolerance to sedative effects, liability to physical dependence and addiction. Hence, we investigated in the elevated plus maze the level of anxiety 24 h following 21 days of diazepam treatment and the influence of flumazenil or a preferential α₁-subunit selective antagonist βCCt on diazepam withdrawal syndrome in rats. Abrupt cessation of protracted once-daily intraperitoneal administration of 2 mg/kg diazepam induced a withdrawal syndrome, measured by increased anxiety-like behavior in the elevated plus maze 24 h after treatment cessation. Acute challenge with either flumazenil (10 mg/kg) or βCCt (1.25, 5 and 20 mg/kg) alleviated the diazepam withdrawal-induced anxiety. Moreover, both antagonists induced an anxiolytic-like response close, though not identical, to that seen with acute administration of diazepam. These findings imply that the mechanism by which antagonism at GABA_A receptors may reverse the withdrawal-induced anxiety involves the α₁ subunit and prompt further studies aimed at linking the changes in behavior with possible adaptive changes in subunit expression and function of GABA_A receptors.     

IL-1β、TNF-α、TGF-β1与缺血性脑损害相关性研究

目的　探索白细胞介素 -1 β(IL-1 β)、肿瘤坏死因子 -α(TNF-α)及转化生长因子 -β1 (TGF-β1 )在缺血性脑卒中发病过程中的作用及相互关系。方法　采用放射免疫分析法和 ELISA双抗体夹心法检测 46例急性期脑梗死患者、46例颈动脉粥样硬化症患者及 2 2名健康者血清上述 3种细胞因子水平。结果　急性期脑梗死组血清 3种细胞因子水平均较颈动脉粥样硬化组明显升高 ,颈动脉粥样硬化组较健康对照组升高 ;颈动脉粥样硬化组和急性期脑梗死组患者血清 TNF-α与 TGF-β1水平均呈直线正相关。结论　 IL-1β、TNF-α及 TGF-β1表达增强是急性期脑缺血性损伤反应 ,且在颈动脉粥样硬化期已异常升高 ,提示它们可能参与缺血性脑卒中的发病过程。     

The role of genetic variation across IL-1β, IL-2, IL-6, and BDNF in antipsychotic-induced weight gain

Objectives. Antipsychotics with high weight gain-inducing propensities influence the expression of immune and neurotrophin genes, which have been independently related to obesity indices. Thus, we investigated whether variants in the genes encoding interleukin (IL)-1β, IL-2, and IL-6 and brain-derived neurotrophic factor (BDNF) Val66Met are associated with antipsychotic-induced weight gain (AIWG). Methods. Nineteen polymorphisms were genotyped using Taqman^® assays in 188 schizophrenia patients on antipsychotic treatment for up to 14 weeks. Mean weight change (%) from baseline was compared across genotypic groups using analysis of covariance (ANCOVA). Epistatic effects between cytokine polymorphisms and BDNF Val66Met were tested using Model-Based Multifactor Dimensionality Reduction. Results. In European patients, IL-1β rs16944*GA (P = 0.013, P_corrected = 0.182), IL-1β rs1143634*G (P = 0.001, P_corrected = 0.014), and BDNF Val66Met (Val/Val, P = 0.004, P_corrected = 0.056) were associated with greater AIWG, as were IL-1β rs4849127*A (P = 0.049, P_corrected = 0.784), and IL-1β rs16944*GA (P = 0.012, P_corrected = 0.192) in African Americans. BDNF Val66Met interacted with both IL-1β rs13032029 (Val/Met+ TT, P_Perm = 0.029), and IL-6 rs2069837 (Val/Val+ AA, P_Perm = 0.021) in Europeans, in addition to IL-1β rs16944 (Val/Val+ GA, P_Perm = 0.006) in African Americans. Conclusions. SNPs across IL-1β and BDNF Val66Met may influence AIWG. Replication of these findings in larger, independent samples is warranted.     

The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease

Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.     

TGFβ1 Treatment Reduces Hippocampal Damage, Spontaneous Recurrent Seizures, and Learning Memory Deficits in Pilocarpine-Treated Rats

Studies have demonstrated the neuroprotective activity of transforming growth factor beta-1 (TGFβ1), protecting neurons against different kinds of insults. However, the role of exogenous TGFβ1 in the neuronal damage following status epilepticus (SE) and the related spontaneous recurrent seizures (SRS) is unknown. The present study aimed to determine the effect of intranasal TGFβ1 administration on SRS and cognitive function following lithium–pilocarpine-induced SE and associated hippocampal damage. We found that intranasal TGFβ1 significantly attenuated the hippocampal insults marked by hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling, and Fluoro-Jade B staining by 24, 48, and 72 h after SE was induced. The expression of the apoptosis-suppressing protein, Bcl-2, was elevated, whereas the expression of the apoptosis-promoting proteins, Bax and Caspase-3, was suppressed in TGFβ1-treated rats compared to rats without TGFβ1 treatment by 24, 48, and 72 h following induction of SE. The seizure number, severity, and duration of SRS over a 1-month period of monitoring starting 15 days after SE induction as well as the cognitive deficits detected 45 days after SE induction were significantly reduced in TGFβ1-treated rats compared to those without TGFβ1 treatment. Our results indicate that intranasal delivery of TGFβ1 immediately after SE induction not only protected against SRS but also improved cognitive function. The anti-epileptogenic properties of TGFβ1 may be related to its effect of neuroprotection or to its effect of apoptosis pathway changes.     

L-β-N-oxalyl-α,β-diaminopropionic acid toxicity in motor neurons

The excitatory amino acid L-β-N-oxalyl-α,β-diaminopropionic acid (L-β-ODAP) in Lathyrus sativus L. is proposed as the causative agent of the neurodegenerative disease neurolathyrism. We investigated the effect of L-β-ODAP on [Ca2+]i handling, redox homeostasis, and cell death in rat spinal motor neurons. L-β-ODAP and L-glutamate triggered [Ca2+]i transients, which were inhibited by the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor blockers; 2,3-dioxo-6-nitro-1,2,3, 4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide and 1-naphthyl acetylspermine, the latter specifically blocking Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors. In addition, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide, and to a lesser extent 1-naphthyl acetylspermine, protected the neurons against cell death induced by L-β-ODAP or L-glutamate. Methionine and cysteine were also protective against neuronal cell death. We conclude that deregulation of [Ca2+]i homeostasis and oxidative stress contribute to motor neuron cell death in neurolathyrism.     

PGN对Aβ1-42寡聚体促进BV2细胞分泌IL-1β的影响

目的探讨前炎介质肽聚糖(peptidoglycan,PGN)激活BV2细胞内吞β淀粉样蛋白(amyloid pro-teinβ,Aβ)1-42寡聚体后,对白细胞介素-1β(IL-1β)分泌的影响及其机制。方法采用细胞株传代法培养BV2细胞替代小胶质细胞,按Klein方法制备Aβ1-42寡聚体。将BV2细胞分为PGN(20μg/mL)组、Aβ1-42寡聚体(0.5μmol/L)组、PGN(20μg/mL)+Aβ1-42寡聚体(0.5μmol/L)组,比较BV2细胞分泌IL-1β水平;将BV2细胞予PGN(20μg/mL)及PGN+SB202190,比较两组IL-1β分泌水平;将不同浓度的PGN(0、5、10、20、40μg/mL)加入BV2细胞中培养,分别检测培养液中IL-1β的水平。采用ELISA方法测定BV2细胞培养液中IL-1β的水平。结果 PGN、Aβ1-42寡聚体、PGN+Aβ1-42寡聚体均可激活BV2细胞分泌IL-1β,分泌IL-1β高峰分别为孵育后24h、12h、24h;孵育后6、12、24h同时间相比,PGN+Aβ1-42寡聚体组BV2细胞分泌IL-1β水平均较PGN组和Aβ1-42寡聚体组明显增多(均P<0.05);PGN激活BV2细胞分泌IL-1β的水平与PGN浓度有剂量依赖关系(P<0.05);丝裂原活化蛋白激酶(MAPK)抑制剂SB202190使BV2细胞分泌IL-1β量明显减少(P<0.01)。结论 PGN可激活BV2细胞分泌IL-1β,且促进Aβ刺激BV2细胞分泌IL-1β增多,p38MAPK抑制剂可抑制IL-1β分泌,推测p38MAPK可能参与BV2细胞分泌IL-1β的过程。     

Isolated Amyloid-β(1-42) Protofibrils, But Not Isolated Fibrils, Are Robust Stimulators of Microglia

Senile plaques composed of amyloid-β protein (Aβ) are an unshakable feature of the Alzheimer's disease (AD) brain. Although there is significant debate on the role of the plaques in AD progression, there is little disagreement on their role in stimulating a robust inflammatory response within the context of the disease. Significant inflammatory markers such as activated microglia and cytokines are observed almost exclusively surrounding the plaques. However, recent evidence suggests that the plaque exterior may contain a measurable level of soluble Aβ aggregates. The observations that microglia activation in vivo is selectively stimulated by distinct Aβ deposits led us to examine what specific form of Aβ is the most effective proinflammatory mediator in vitro. We report here that soluble prefibrillar species of Aβ(1-42) were better than fibrils at inducing microglial tumor necrosis factor α (TNFα) production in either BV-2 and primary murine microglia. Reconstitution of Aβ(1-42) in NaOH followed by dilution into F-12 media and isolation with size exclusion chromatography (SEC) revealed classic curvilinear β-sheet protofibrils 100 nm in length. The protofibrils, but not monomers, markedly activated BV-2 microglia. Comparisons were also made between freshly isolated protofibrils and Aβ(1-42) fibrils prepared from SEC-purified monomer. Surprisingly, while isolated fibrils had a much higher level of thioflavin T fluorescence per mole, they were not effective at stimulating either primary or BV-2 murine microglia compared to protofibrils. Furthermore, SEC-isolated Aβ(1-40) protofibrils exhibited significantly less activity than concentration-matched Aβ(1-42). This report is the first to demonstrate microglial activation by SEC-purified protofibrils, and the overall findings indicate that small, soluble Aβ(1-42) protofibrils induce much greater microglial activation than mature insoluble fibrils.     

β,β′-Iminodipropionitrile toxicity in normal and congenitally neurofilament-deficient Japanese quails

Morphological effects of a neurotoxin, ,-iminodipropionitrile (IDPN) were analyzed in normal and cogenitally neurofilament (NF)-deficient Japanese quails. These quails (6 weeks old) were injected intraperitoneally with IDPN (0.2 g/kg body weight) three times every 3 days. They were necropsied at 10 to 12 days after the first injection. In normal quails, axonal swellings were observed histologically in the ventral motoneurons, ventral root, commissura grisea and spinal ganglion in the cervical and synsacral spinal cord. Electron microscopically, the changes consisted of increased NFs, with scattered mitochondria, smooth endoplasmic reticulum and microtubules. The myelin sheaths of the involved nerves were thinner than those of the normal axons. These lesions were similar to those induced by IDPN intoxication in mammalian experimental animals. In NF-deficient quails injected with IDPN, no axonal changes were detected. These findings suggested that IDPN selectively attacked the NFs.     

人脑胶质瘤免疫抑制因子TGFβ2及TGFβ1的基因表达

目的 研究人脑胶质瘤主要免疫抑制因子转化生长因子TGFβ2及TGFβ1的基因表达与其胶质瘤恶性程度的关系。方法 采用Northern杂交,免疫组化和Western杂交法检测了50例胶质瘤,。3例恶笥胶质瘤体外细胞系和8例正常脑细胞TGFβ2的达表水平,同时检测其同型异构体TGFβ1的表达水平,结果 正常脑组织几无TGFβ2和TGFβ1表达,而胶质瘤均表达2．8和或5．1kb的TGFβ2mRNA片段和约25000u及30000u的蛋白,TGF和TGFβ1表达水平随肿瘤恶性程度增高而增高,结论 TGFβ2和TGFβ1表达水平与肿瘤恶性程度呈正相关,TGFβ2和TGFβ1可作为恶性胶质瘤免疫基因治疗的侯选基因。     

阿欠茨海默病的Aβ表达与APOE,PS1基因的相关分析

目的 研究阿尔茨海默病的ＡＰＰ基因中Ａβ表达量与载脂蛋白Ｅ（ＡＰＯＥ）基因和早老素１（ＰＳ１）基因间相互关系。方法 应用竞争ＲＴ－ＰＣＲ技术,测定５２例ＡＤ患者,２８例血管性痴呆（ＶＤ）患者及６０名健康老人的外周单核血细胞中Ａβ相对半定量表达量,以及采用ＰＣＲ－ＲＦＬＰ方法检测所有研究对象的ＡＰＯＥ基因和ＰＳ１基因的多态性分布。疾病诊断按ＤＳＭⅢ－Ｒ标准。结果 ＡＰＯＥε４等位基因和ＰＳ１的各种     

脑微出血患者血清Aβ1-40 Aβ1-42的检测及意义

目的 探讨对脑微出血患者进行血清Aβ1-40、Aβ1-42检测的意义.方法 选择2015-04—2016-04我院收治的45例急性腔隙性梗死患者为观察组,并选取同期在我院接受治疗的无急性腔隙性梗死的43例患者为对照组.分别检测2组患者的血清Aβ1-40和Aβ1-42水平,并进行比较.结果 观察组患者血清Aβ1-40水平明显高于对照组,而Aβ1-42水平则明显低于对照组,差异具有统计学意义(P<0.05).结论 血清Aβ1-40、Aβ1-42的检测是诊断脑微出血的重要方法,Aβ1-40、Aβ1-42水平能够准确反映患者脑微出血情况.     

不典型胰岛β细胞瘤1例报告

现将我们经手术证实的一例不典型胰岛β细胞瘤的诊治体会报告如下,以供参考。您者李××,女,30岁,于84年在生气或劳累时常突然意识不清,呼唤及针刺仍不醒,2～3h之后能自醒,醒后无其它不适,85年以后发作减少。86年12月28日因受凉头昏,鼻塞,一天后突然尖叫,双手抱头,两眼向上凝视、痴呆、呻吟,双下肢舞动,大小便失禁一次。经补糖及针刺等处理一天后渐清醒,但反应迟钝,不能坐起与行走。之后均在早晨6～7时许尖叫,精神萎糜,昏睡,继之补糖后3～3h后好转。当地医院查脑脊液;无色透明,蛋白定性(-),细胞2/mm~3,氯化物660mg/dl,糖10mq/dl,诊断为病毒性脑炎?87年1月9日转入院。既往健康无烟酒嗜好。     

TGF-β1表达与垂体腺瘤纤维化

目的探讨垂体腺瘤纤维化与转化生长因子-β1(TGF-β1)表达的关系.方法 38例垂体腺瘤标本分为质地韧(纤维化)组6例与质地软(非纤维化)组32例,采用逆转录聚合酶链反应(RT-PCR)和免疫组织化学方法检测TGF-β1的表达并以天狼猩红染色法检测其胶原含量. 结果纤维化与非纤维化组胶原含量为(20.95±8.42)%、(7.98±5.18)%,两者差异显著(P<0.01);TGF-β1 mRNA表达量为0.79±0.15、0.42±0.20;蛋白表达量为0.64±0.20、0.32±0.40,两者差异显著(P<0.01);且TGF-β1的表达与胶原含量呈正相关(P<0.01). 结论垂体腺瘤纤维化的显著病理特征是胶原过度沉积,TGF-β1可能在垂体腺瘤纤维化中起重要作用.