脑脊液生物学标志物诊断阿尔茨海默病与血管性痴呆

目的探讨脑脊液β-淀粉样蛋白（Aβ1～42）、tau蛋白和磷酸化tau蛋白诊断阿尔茨海默病与血管性痴呆的敏感性和特异性。方法采用酶联免疫吸附法检测阿尔茨海默病与血管性痴呆患者脑脊液中Aβ1～42、tau蛋白和磷酸化tau蛋白浓度的变化,根据受试者工作特征曲线观察脑脊液中这3种生物学标志物用于诊断阿尔茨海默病与血管性痴呆的敏感性和特异性;采用单因素方差分析以及受试者工作特征曲线对所获结果进行统计学分析。结果阿尔茨海默病组患者脑脊液Aβ1～42浓度低于对照组（P=0.010）,tau蛋白浓度高于对照组（P=0.001）和血管性痴呆组（P=0.030）,磷酸化tau蛋白浓度高于对照组（P=0.004）。脑脊液Aβ1～42、tau蛋白和磷酸化tau蛋白用于诊断阿尔茨海默病的敏感度为60.00%～96.70%,特异度可达70.00%～90.00%。Aβ1～42、tau蛋白和磷酸化tau蛋白联合检测可提高阿尔茨海默病与血管性痴呆鉴别诊断的敏感性和特异性,敏感度可达86.57%,特异度为90.00%。结论脑脊液Aβ1～42、tau蛋白和磷酸化tau蛋白浓度的变化,不仅对诊断阿尔茨海默病具有较高的敏感性和特异性,而且亦可作为阿尔茨海默病与血管性痴呆鉴别诊断的生物学指标。     

脑脊液中β淀粉样蛋白检测对老年期痴呆的诊断意义

目的　研究阿尔茨海默病（AD）和血管性痴呆（VD）患者脑脊液(CSF)中β淀粉样蛋白（Aβ或βA     

同时测定脑脊液中Tau蛋白和Aβ1-42含量对诊断阿尔茨海默病的意义

目的:为探讨联合分析脑脊液中Tau蛋白和Aβ1-42含量作为生化指标对诊断阿尔茨海默病的意义,以及患者年龄、痴呆严重程度对脑脊液中Tau蛋白和Aβ1-42含量的影响.方法:利用夹心酶联免疫法进行同份标本同时测定,分析了63例阿尔茨海默病(AD)患者与49例帕金森病(PD)、22例非阿尔茨海默型痴呆、10例血管性痴呆、11例正常颅压脑积水以及24例非痴呆的神经科患者脑脊液中Tau蛋白和Aβ1-42的含量.结果:AD组脑脊液中Tau值(pg/mL)明显升高(491.3±379.9),Aβ1-42值(pg/mL)明显降低(486.1±293.5).脑脊液中Tau值及Aβ1-42值与年龄或痴呆的严重程度MMSE得分值间无相关性.结论:同时测定脑脊液中Tau和Aβ1-42含量较单独测定Tau值或Aβ1-42值对于AD的诊断具有良好的特异性.这一方法对于AD的诊断以及其他类型痴呆和不伴痴呆的其他神经系统疾病的鉴别诊断具有意义.但对于区别混合型痴呆的意义尚难确定.     

同时测定脑脊液中Tau蛋白和Aβ1—42含量对诊断阿尔茨海默病的意义

目的 :为探讨联合分析脑脊液中Tau蛋白和Aβ1 4 2含量作为生化指标对诊断阿尔茨海默病的意义 ,以及患者年龄、痴呆严重程度对脑脊液中Tau蛋白和Aβ1 4 2含量的影响。方法 :利用夹心酶联免疫法进行同份标本同时测定 ,分析了 6 3例阿尔茨海默病 (AD)患者与 4 9例帕金森病 (PD)、2 2例非阿尔茨海默型痴呆、10例血管性痴呆、11例正常颅压脑积水以及 2 4例非痴呆的神经科患者脑脊液中Tau蛋白和Aβ1 4 2的含量。 结果 :AD组脑脊液中Tau值 (pg mL)明显升高 (491.3± 379.9) ,Aβ1 4 2值 (pg mL)明显降低 (486 .1± 2 93.5 )。脑脊液中Tau值及Aβ1 4 2值与年龄或痴呆的严重程度MMSE得分值间无相关性。结论 :同时测定脑脊液中Tau和Aβ1 4 2含量较单独测定Tau值或Aβ1 4 2值对于AD的诊断具有良好的特异性。这一方法对于AD的诊断以及其他类型痴呆和不伴痴呆的其他神经系统疾病的鉴别诊断具有意义。但对于区别混合型痴呆的意义尚难确定。     

Alzheimer病和血管性痴呆病人脑脊液中β淀粉样蛋白含量比较

目的研究脑脊液中β－淀粉样蛋白量的变化对Ａｌｚｈｅｉｍｅｒ病（ＡＤ）和血管性痴呆（ＭＩＤ）的临床诊断有无鉴别意义。方法用单克隆抗体、ＥＬＩＳＡ方法检测两种痴呆患者各１６例和健康对照组３１例脑脊液中β－淀粉样蛋白（ＡＰ１－４０）的含量。结果在年龄构成和痴呆程度无明显差异的ＡＤ和ＭＩＤ两组间，脑脊液中ＡＰ１－４０的含量有明显差异。ＡＤ组Ａ值为０．２１７～０．３８０，平均０．２７４；ＭＩＤ组为０．２４１～０．４９２，平均０．２９０；ＡＤ组明显低于ＭＩＤ组。对照组Ａ值为０．２２８～０．５６７，平均０．３１１，明显高于ＡＤ组（Ｐ＜０．０１）而与ＭＩＤ组间差别不明显（Ｐ＞０．０５）。结论根据本研究结果，对于临床已诊断为痴呆的病例，检测脑脊液中β－淀粉样蛋白的含量对ＡＤ和ＭＩＤ的鉴别可能有所帮助     

阿尔茨海默病患者的脑脊液tau蛋白及Aβ1-42水平

目的 探讨脑脊液(cerebrospinal fluid,CSF)中tau蛋白及β-淀粉样蛋白1-42(Aβ1-42)对诊断阿尔茨海默病(Alzheimer's disease,AD)的早期诊断价值,寻找AD理想的生物学标志.方法 采用酶联免疫吸附法检测36例AD、24例血管性痴呆患者(vascular dementia,VD)和26名正常对照者(对照组)CSF中tau蛋白及Aβ1-42浓度的变化.结果 CSF中tau蛋白平均浓度:AD组(336±126)ng/L,VD组(183±96)ng/L,对照组(98±54)ng/L,AD组CSF中tau蛋白浓度明显高于对照组,差异有统计学意义(P<0.05);CSF中Aβ1-42平均浓度:AD组(341β113)ng/L,VD组(457±132)ng/L,对照组(502±167)ng/L,AD组CSF中Aβ1-42浓度明显低于对照组.差异有显著性意义(P<0.05).结论 脑脊液Aβ1-42、tau蛋白浓度的变化,不仅对诊断阿尔茨海默病具有较高的敏感性和特异性,而且亦可作为阿尔茨海默病与血管性痴呆鉴别诊断的生物学指标.     

PET脑显像和脑脊液检测对临床痴呆诊断再评估的意义

目的对首次临床诊断的痴呆患者进行再评估,寻找更适合的诊断方法与标准。方法择2011年6月 ~2012年6月共22例轻度神经退行性非血管性痴呆患者进行脑匹兹堡复合物B（PIB）-PET、选脱氧葡萄糖（FDG）-PET、脑脊液检测和神经心理学测试,每隔 1~2年进行一次简易智力状态量表（MMSE）评分,随访至 2017年4月。结果 22例受试者中 7例的痴呆诊断发生了改变。其中有 4例阿尔茨海默病转变为路易体痴呆; 2例阿尔茨海默病和 1例行为变异型额颞叶痴呆转变为不定型痴呆。诊断有变化组和无变化组的教育程度、 Aβ42浓度、理解能力测试、情景记忆测试及顶叶脑葡萄糖代谢减低程度差异有统计学意义（P＜ 0.05）。结论 PET脑显像和脑脊液检测对临床痴呆诊断再评估具有指导意义。     

血管性认知功能损害患者血液生物学指标的研究进展

血管性认知功能损害(VCI)的早期诊断和干预对防止其进展成为严重的血管性痴呆具有重要价值。虽然脑脊液变化能反映中枢神经系统疾病的真实情况,但腰椎穿刺不是常规检查手段。本文就血液中β-淀粉样蛋白、tau蛋白、胆固醇、同型半胱氨酸和C反应蛋白等生物学指标在VCI的研究进展进行综述,我们认为血液生物学指标有望用于VCI早期诊断。     

脑脊液相关标志物检测在阿尔茨海默病痴呆诊断中的应用

目的探索阿尔茨海默病(Alzheimer disease,AD)相关脑脊液标志物(Aβ_(42)、T-tau和P-tau181蛋白)检测在阿尔茨海默病痴呆患者诊断中应用的可行性,初步建立各检测指标的界定值,计算各指标诊断AD型痴呆的敏感性和特异性。方法 2015年7月至2017年2月间就诊于北京大学第一医院符合入排标准的AD型痴呆17例,其中5例完成匹兹堡复合物PET检测,正常认知对照49例,采用innotest检测试剂盒,利用酶联免疫吸附测定(enzyme-linked immuno sorbent assay,ELISA)方法对脑脊液Aβ_(42), T-tau, and P-tau181蛋白进行检测,获得各自脑脊液浓度值,并计算得出Aβ_(42)/T-tau、Aβ_(42)/P-tau181比值,采用ROC曲线获得各指标诊断AD型痴呆的敏感性、特异性及界定值。结果各脑脊液检测指标在AD痴呆组及正常认知组的差异均有统计学意义,脑脊液Aβ_(42)、T-tau、P-tau181、Aβ_(42)/T-tau、Aβ_(42)/P-tau181的界定值分别为511 ng/mL、322 ng/mL、63 ng/mL、14.72、1.74;敏感性分别为64.7%、88.2%、58.8%、82.35%、76.47%,特异性分别为97.05%、75.5%、93.87%、95.51%、93.87%。结论 AD相关脑脊液标志物能对正常认知人群及AD痴呆人群进行鉴别,检测方法可靠,所得各检测指标的敏感性和特异性较好,各指标界定值接近国外报道数值,该方法可进行进一步推广。     

血及脑脊液β-淀粉样蛋白对老年期痴呆鉴别诊断的意义

目的:探讨血及脑脊液中β-淀粉样蛋白(β-AP)对老年期痴呆主要包括老年性痴呆(AD)、血管性痴呆(VD)及其他原因所致的痴呆(OD)的鉴别诊断意义。方法:采用平衡饱和竞争放射免疫分析法对55例不同类型的痴呆患者及30例正常对照者血清及脑脊液(CSF)中β-AP进行测定。结果:在正常对照组,随着观察者年龄的增长,血清β-AP含量缓慢增高,CSF中β-AP含量缓慢下降(r分别为0.56,0.52,均P<0.01)。不同病因痴呆患者血清β-AP含量均高于对照组,其中AD组最明显;CSF中β-AP含量在AD组最低,明显低于对照组(P<0.01),在VD组最高,接近对照组(P>0.05)。AD组中的重度痴呆患者,其β-AP含量在血清中升高最明显,同时在CSF中降低也最显著。结论:血清及CSF中β-AP含量变化的测定,可能有助于各型痴呆的鉴别诊断及AD患者病情轻重的判断,但这种变化具重叠性。     

CSF biomarker profile and diagnostic value in vascular dementia

Background and purpose:  The differential diagnosis between vascular dementia (VD) and Alzheimer's disease (AD) or mixed dementia (MD) is not always easy in clinical practice. The purpose of the present study was to evaluate the cerebrospinal fluid (CSF) biomarkers tau protein in its total (τ_T) or hyperphosphorylated at threonin-181(τ_P-181) form and beta amyloid peptide 1–42 (Aβ42) alone and their combinations to investigate their diagnostic value in the discrimination between VD and AD or MD.
Methods:  The above CSF biomarkers were determined in duplicate and blind to the clinical diagnosis by double sandwich, enzyme-linked immunosorbent assay (ELISA) commercial kits (Innogenetics, Gent, Belgium) in 92 AD patients, 23 VD patients, 17 patients with MD and 68 controls.
Results:  Alzheimer's disease and MD showed increased levels of τ_T, τ_P and reduced levels of Aβ42 as compared with the controls. The best discrimination between VD and AD or MD was achieved by the combination of all three biomarkers, correctly classifying ≥85% of patients, either in the form of a discriminant function or in the form of the τ_T × τ_P-181/Aβ42 formula.
Conclusions:  Cerebrospinal fluid biomarkers may be a useful adjunct for the discrimination between AD/ MD and VD in every day clinical practice.     

Cerebrospinal fluid phospho-tau,total tau and beta-amyloid(1-42) in the differentiation between Alzheimer's disease and vascular dementia

The two most frequently examined biomarkers in the diagnosis of dementia are cerebrospinal fluid (CSF) tau and beta-amyloid(1-42) (Abeta(1-42)). An assay for tau phosphorylated at threonine 181 (phospho-tau) has recently been developed. We studied these three markers in patients with possible Alzheimer's disease (AD; n = 23), probable AD (n = 50), AD with relevant cerebrovascular disease (AD with CVD; n = 14), possible vascular dementia (VaD; n = 39), probable VaD (n = 36), cognitively impaired (n = 13) and 27 neurologically healthy controls. Compared with the controls, tau levels were significantly increased in possible AD, probable AD, AD with CVD and probable VaD. Abeta(1-42) was decreased in all dementia groups compared with the controls. In contrast, phospho-tau levels were increased only in probable AD compared with the controls. From the results of the present study, it is concluded that neither measurement of phospho-tau, tau nor Abeta(1-42) in CSF can discriminate entirely between dementia and cognitively non-disturbed controls or between dementia of different aetiologies in the clinical diagnostic procedure.     

AD with subcortical white matter lesions and vascular dementia: CSF markers for differential diagnosis

We investigated whether the cerebrospinal fluid (CSF) biomarkers beta-amyloid 1-42 (Abeta1-42), total tau (t-tau) protein and tau protein phosphorylated at threonine 181 (p-tau181) could discriminate Alzheimer's disease (AD) from vascular dementia (VD) patients. CSF samples of Abeta1-42, t-tau, and p-tau181 were collected from probable AD (n=35), probable AD with white matter changes (WMC) indicative of concomitant cerebrovascular disorder (CVD, n=31), VD (n=20), and an age-matched subgroup of patients with other neurological disorders (OND) without cognitive impairment (n=24). AD patients showed very low Abeta1-42 levels (median=393 pg/ml). Abeta1-42, but not t-tau, differentiated AD from VD patients. However, the markers did not discriminate AD vs. AD plus WMC. In particular, both subgroups showed similar CSF biomarkers but they were significantly different from VD. ROC analysis showed that Abeta1-42 could discriminate AD from VD (AUC=0.85). The cutoff of 493 pg/ml gave sensitivity and specificity values of 77% and 80%, respectively. Similar results were obtained when Abeta1-42 was employed to discriminate AD with WMC from VD (95% specificity and 60% sensitivity, but with cutoff of 750 pg/ml). T-tau increased aspecifically in all cognitively impaired patients. P-tau181 performed better than t-tau in discriminating AD (with or without WMC) vs. VD. In conclusion, Abeta1-42 proved to be a valuable tool to discriminate AD vs. VD patients and possibly to improve diagnostic accuracy in clinical forms, improperly classified as "mixed dementia" based on radiological vascular lesions.     

Addition of MHPG to Alzheimer's disease biomarkers improves differentiation of dementia with Lewy bodies from Alzheimer's disease but not other dementias

BackgroundOverlapping clinical features make it difficult to distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) and other dementia types. In this study we aimed to determine whether the combination of cerebrospinal fluid (CSF) biomarkers, amyloid-β₄₂ (Aβ₄₂), total tau protein (t-tau), and phosphorylated tau protein (p-tau), in combination with 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), could be useful in discriminating DLB from vascular dementia (VaD) and frontotemporal dementia (FTD), as we previously demonstrated for differentiation of DLB from AD.MethodsWe retrospectively analyzed concentrations of MHPG, Aβ₄₂, t-tau, and p-tau in CSF in patients with DLB, AD, VaD, and FTD. Using previously developed multivariate logistic regression models we assessed the diagnostic value of these CSF parameters.ResultsThe currently used combination of Aβ₄₂, t-tau, and p-tau yielded a sensitivity of 61.9% and a specificity of 91.7% for the discrimination between DLB and AD, but could not discriminate between DLB and VaD or FTD. The addition of MHPG to Aβ₄₂, t-tau, and p-tau improves the discrimination of DLB from AD, yielding a sensitivity of 65.1% and specificity of 100%, but could not distinguish DLB from other forms of dementia.ConclusionsOur results confirm in a separate patient cohort that addition of MHPG to Aβ₄₂, t-tau, and p-tau improves the discrimination of DLB from AD but not the differentiation of DLB from VaD or FTD.     

Clinical indications for analysis of Alzheimer's disease CSF biomarkers

The cerebrospinal fluid (CSF) biomarkers β-amyloid_1-42 (Aβ_1-42), total tau protein (T-tau) and hyperphosphorylated tau (P-tau_181P) are well-validated and are increasingly used in clinical practice as an affirmative diagnostic tool for Alzheimer's disease (AD). These biomarkers have also been implemented in the revised diagnostic criteria of AD. The combination of the CSF biomarkers Aβ_1-42, T-tau and P-tau_181P results in high levels of sensitivity, specificity and diagnostic accuracy for discriminating AD from controls (including psychiatric disorders like depression). These biomarkers can be applied for diagnosing AD in the prodromal phase of the disease (mild cognitive impairment). In case of doubt between vascular dementia (VaD) or mixed AD-VaD pathology in dementia patients, the determination of CSF Aβ_1-42, T-tau and P-tau_181P levels is of help to confirm or exclude the AD component in the pathophysiology of the dementia syndrome. However, their discriminatory power for the differential diagnosis of dementia is suboptimal. Other CSF biomarkers like Aβ_1-40, and those that are reflective of the pathology of non-AD dementias, could improve the accuracy of differential dementia diagnosis. The added differential diagnostic value of the CSF biomarkers Aβ_1-42, T-tau and P-tau_181P could lie within those cases in which the routine clinical diagnostic work-up is not able to discriminate between AD or non-AD dementias. In summary, the CSF biomarkers Aβ_1-42, T-tau and P-tau_181P can be used in clinical practice to discriminate AD from healthy aging (including psychiatric disorders like depression), to diagnose AD in its prodromal phase or in atypical forms with prominent non-memory impairment, to identify AD in patients with mixed pathologies and in case of an ambiguous (AD versus non-AD) dementia diagnosis.     

Cerebrospinal fluid matrix metalloproteinases and tissue inhibitor of metalloproteinases in combination with subcortical and cortical biomarkers in vascular dementia and Alzheimer's disease

Alzheimer's disease (AD) and vascular dementia (VaD) are intertwined by mixed dementia (MD) harboring varying degrees of AD pathology in combination with cerebrovascular disease. The aim was to assess whether there is a difference in the cerebrospinal fluid (CSF) profile, of selected proteins, between patients with VaD and MD with subcortical vascular disease (SVD), AD, and healthy controls that could contribute in the separation of the groups. The study included 30 controls, 26 SVD patients (9 VaD and 17 MD) and 30 AD patients. The protein panel included total tau (T-tau), hyperphosphorylated tau 181 (P-tau(181)), amyloid β 1-42 (Aβ(1-42)), neurofilament light (NF-L), myelin basic protein (MBP), heart fatty acid binding protein (H-FABP), matrix metalloproteinases (MMP-1, -2, -3, -9, and -10), and tissue inhibitors of metalloproteinases (TIMP-1 and -2). Immunochemical methods were utilized for quantification of the proteins in CSF and data analysis was performed with a multivariate discriminant algorithm. The concentrations of MBP, TIMP-1, P-tau(181), NF-L, T-tau, MMP-9, Aβ(1-42), and MMP-2 contributed the most to the separation between SVD and AD, with a sensitivity of 89% and a specificity of 90% (AUC = 0.92). MBP and NF-L performed the best in discriminating SVD from controls, while T-tau and Aβ(1-42) contributed the most in segregating AD from controls. The CSF biomarkers reflecting AD pathology (T-tau, P-tau(181), and Aβ(1-42)), white matter lesions (NF-L and MBP) and matrix remodeling (MMP-9 and TIMP-1) perform well in differentiating between SVD and AD patients.     

Cerebrospinal fluid biomarkers in Alzheimer’s disease, vascular dementia and ischemic stroke patients: a critical analysis

Vascular factors are thought to contribute to the development of disease pathology in neurodegenerative dementia such as Alzheimer’s disease (AD). Another entity, called vascular dementia (VaD), comprises a less defined group of dementia patients having various vascular diseases that especially emerge in the elderly population and require valid options for examination and differential diagnosis. In the context of a retrospective study, we analyzed the cerebrospinal fluid (CSF) biomarkers t-tau, p-tau and Aß42 of a total of 131 patients with AD (n = 47), mild cognitive impairment (MCI) (n = 22), VaD (n = 44) and stroke (n = 18). We found a remarkable alteration in CSF biomarker profile in AD, VaD and in acute ischemic events. CSF profile in AD patients was altered in a very similar way as in stroke patients, without statistical differences. In stroke, increase depend largely on size and duration after the initial event. Total tau levels were useful to differ between VaD and stroke. Aß42 decreased in a similar way in AD, VaD and stroke and had a trend to lower levels in MCI but not in controls.     

阿尔茨海默病与血管性痴呆患者血浆同型半胱氨酸与超氧化物歧化酶的比较

目的探讨血浆同型半胱氨酸（Hcy）水平与超氧化物歧化酶（SOD）浓度和阿尔茨海默病（AD）与血管性痴呆（VaD）患者认知功能损害之间的关系。方法将入组病例分成AD组和VaD组，分别测定血浆Hcy、SOD水平并进行比较；采用简易智能状态量表（MMSE）评定认知功能水平。结果AD组Hcy浓度为（16．24±6．62）μmol／L，VaD组为（25．81±11．81）μmol／L，两组比较差异有统计学意义（P〈0．01）。AD组SOD浓度为（165．94±35．92）μmol／L，VaD组为（167．76±29．86）μmol／L，两组比较差异无统计学意义（P〉0．05）。AD组Hcy浓度与SOD水平呈负相关（r=-0．346，P〈0．05），VaD组SOD水平与年龄呈负相关（r=-0．358，P〈0．05），两组患者的MMSE评分与Hcy浓度呈负相关（r=-0．263，P〈0．01）。结论血浆Hcy、SOD水平可能是预测认知功能损害程度的一个重要生化指标。     

Is Alzheimer’s disease a homogeneous disease entity?

The epidemic proportions of dementia in old age are a cause of great concern for the medical profession and the society at large. It is customary to consider Alzheimer’s disease (AD) as the most common cause of dementia, and vascular dementia (VaD) as being the second. This dichotomous view of a primary neurodegenerative disease as opposed to a disorder where extrinsic factors cause brain damage led to separate lines of research in these two entities. New biomarkers, particularly the introduction of modern neuroimaging and cerebrospinal fluid changes, have, in recent years, helped to identify anatomical and chemical changes of VaD and of AD. Nevertheless, there is a substantial difference between the two entities. While it is clear that VaD is a heterogeneous entity, AD is supposed to be a single disorder. Nobody attempts to use CADASIL as a template to develops treatment for sporadic VaD. On the other hand, early-onset AD is used to develop therapy for sporadic AD. This paper will discuss the problems relating to this false concept and its consequences.     

The Pocket Smell Test: successfully discriminating probable Alzheimer's dementia from vascular dementia and major depression

The present study extended previous work on olfactory dysfunction (odor identification deficits) by using the Pocket Smell Test (PST) to discriminate between groups of patients with Alzheimer's disease (AD), vascular dementia (VaD), and major depression (MD). Sixty patients meeting the DSM-IV criteria for either AD, VaD, or MD (20 per group) underwent assessment with the PST, a three-item screening measure of odor identification, and the Mini-Mental State Examination (MMSE). Patients with AD scored significantly lower than patients with either VaD or MD on the PST, even after controlling for MMSE scores. A PST score of > or =1 (i.e., 1 or 0 correct) discriminated between patients with and without AD with a classification accuracy of 95% (sensitivity 100%, specificity 92.5%). Olfactory assessment may be of diagnostic utility in the differential diagnosis of AD versus VaD versus MD in elderly patients.