脑脊液磷酸化tau蛋白与总tau蛋白比值对散发性Creutzfeldt-Jakob病的诊断价值

目的通过对CJD病人脑脊液磷酸化tau蛋白与总tau蛋白比值的研究,探讨其对散发性CJD的诊断价值。方法采用双抗体夹心酶联免疫吸附法(ELISA)检测13例散发性CJD、11例其它痴呆及29例非痴呆脑脊液磷酸化tau蛋白。同时测定脑脊液磷酸化tau蛋白与总tau蛋白的比值。结果1.CJD组与其它两组相比,p-tau/t-tau的比值有明显差异(P<0.05)。2.在CJD组高浓度的磷酸化tau蛋白与进展快,病程短有关(P<0.01)。结论测定p-tau/t-tau的比值有助于CJD与AD等痴呆类疾病的鉴别,对判定预后有一定帮助。     

脑脊液tau蛋白预测轻度认知障碍进展为阿尔茨海默病的Meta分析

目的评价脑脊液总tau(t-tau)蛋白和磷酸化tau(p-tau)蛋白预测轻度认知障碍(MCI)患者进展为阿尔茨海默病(AD)的临床价值。方法全面检索2000至2014年Pub Med、Cochrane Library、Web of Science数据库、Ovid全文电子期刊、中国知网全文数据(CNKI)和万方数据库中有关脑脊液tau蛋白预测MCI患者进展为AD的文献,收集每项研究中tau蛋白水平数据,用Stata11.0软件对数据进行Meta分析,计算合并效应量。采用Egger法对漏斗图作对称性检验评估发表偏倚、并进行敏感性分析。结果共纳入11项研究,其中9项研究完整提供了脑脊液总t-tau蛋白和p-tau蛋白浓度数据,另外2项研究仅提供了总t-tau蛋白浓度,未提供p-tau蛋白浓度。Meta分析显示:MCI进展为AD的患者脑脊液t-tau蛋白及p-tau蛋白基线浓度均高于稳定型MCI患者[t-tau:标准均数差(SMD)=1.063,95%CI:0.902~1.223,Z=13.00,P0.001;P-tau:SMD=1.335,,Z=7.44,P0.001]。结论脑脊液tau蛋白可作为预测MCI进展为AD的一项生物学指标。     

脑脊液神经蛋白质对临床拟诊Creutzfeldt-Jakob病的早期诊断价值

目的探讨和比较数种神经蛋白质对Creutzfeldt—Jakob病（CJD）的早期诊断价值。方法对14例发病2个月内CJD取脑脊液，采用蛋白捕捉法和酶联免疫试验对总tau蛋白（t-tau）、磷酸化tau蛋白（p-tau）、t-tau蛋白与p-tau蛋白比值（t-tau／p—tau）、S-100β蛋白、14-3—3蛋白及14—3—2蛋白进行定量检测，同时设非CJD痴呆（OD，11例）和无痴呆（ND，18例）的对照组。结果（1）t-tau蛋白：CJD组、OD组和ND组分别是8295、300、161pg／ml。p-tau／t—tau值分别是0．0092、0．2258、0．2471。（2）S-100β蛋白：CJD组、OD组、ND组分别是1．576、0．639、0．239ng／ml。（3）14-3-3蛋白：CJD组、OD组、ND组分别是40．00、2．65、3．10ng／ml。（4）14-3-2蛋白：CJD组、OD组与ND组分别是48．43、14．00、20．50ng／ml。（5）t—taul〉500pg／ml为阈值点，敏感度为84．6％，特异度87．5％，p-tau无诊断意义；（6）S-100β蛋白≥1．626ng／ml为阈值点，敏感度为92．3％，特异度为83．8％；（7）14-3-3蛋白以≥9ng／ml为阈值点，敏感度为86．7％，特异度为86．4％；（8）14—3—2蛋白以≥24ng／ml为阈值点，其敏感度为78．6％，特异度为77．3％。结论脑脊液神经蛋白质检测对散发性Creutzfeldt—Jakob病的早期诊断有一定价值。     

不同GCS评分颅脑损伤患者血清及CSF中tau及Aβ42水平及其临床意义

目的 观察颅脑损伤患者血清及CSF中tau及Aβ42水平的变化及其意义。方法 对本院2014年7月～2016年4月收入的60例颅脑损伤患者进行血清及CSF中tau蛋白及Aβ42的表达水平检测,分析其与患者损伤程度及预后的关系。结果 和对照组相比,试验A组和B组颅脑损伤患者血清及CSF中tau蛋白水平和Aβ42水平显著升高。不同时间GCS A组患者血清及CSF中tau蛋白水平和Aβ42水平显著高于GCS B组(P<0.05)。与GCS A组相比,GCS B组GOS评分为1～3分的患者比例显著降低,GOS评分为4～5分的患者比例显著增加(P<0.05)。结论 tau蛋白水平、Aβ42表达水平与颅脑损伤密切相关,可作为颅脑损伤患者预后的重要评价指标,而且Aβ42在重型创伤性颅脑损伤患者伤后认知功能障碍的病理生理机制中可能发挥着重要作用。     

伴有元认知损害的主观认知下降患者的自我参照网络特征研究

目的探讨不同元认知水平主观认知下降(SCD)人群的自我参照网络(SRN)功能连接特点。方法纳入阿尔茨海默病神经影像学倡议(ADNI)数据库中71例受试者进入研究, 其中认知正常组受试者25例, SCD受试者46例。采用每日认知量表(ECog)评估SCD受试者的元认知水平并将其分为元认知正常组(25例, 元认知得分>-0.074分)和元认知损害组(21例, 元认知得分≤-0.074分)。收集并比较3组受试者老年抑郁量表(GDS)、蒙特利尔认知量表(MoCA)、简易智力状态检查量表(MMSE)、Rey听觉词语学习测试(RAVLT)、逻辑记忆量表评分结果, 病理标志物[脑脊液β-淀粉样蛋白(Aβ)、总tau蛋白(t-tau)和磷酸化tau蛋白(p-tau)]表达水平、脑内葡萄糖代谢水平, 以及功能磁共振(fMRI)图像。使用独立成分分析(ICA)方法提取SRN并分析3组受试者之间差异脑区;采用Pearson相关分析检验SRN功能连接变化与受试者认知量表、病理标志物之间的相关性。结果 3组受试者年龄、性别等人口学特征, GDS、MoCA、MMSE评分, 以及Aβ、t-tau、p-tau、...     

阿尔茨海默病与血管性痴呆患者脑脊液tau蛋白及β-淀粉样蛋白1-42浓度的对照研究

目的探讨脑脊液(CSF)中tau蛋白及β-淀粉样蛋白1-42(Aβ1-42)的浓度对阿尔茨海默病(AD)的诊断价值,寻找AD理想的生物学标志。方法用酶联免疫吸附法分别检测22例AD、20例血管性痴呆(VD)患者和21名正常对照者(对照组)CSF中tau蛋白及Aβ1-42水平。结果 (1)CSF中tau蛋白平均浓度:AD组(318±249)ng／L,VD组(219±190)ng／L,对照组(119±65)ng／L,AD组CSF中tau蛋白浓度明显高于对照组,差异有显著性意义(P<0.05);CSF中Aβ1-42越平均浓度:AD组(344±166)ng／L,VD组(467±223)ng／L,对照组(480±217)ng／L,AD组明显低于对照组,差异有显著性意义(P<0.05)。依据CSF中tau蛋白和Aβ1-42浓度对三组进行判别分析时,有44％的研究对象被正确判别。结论 CSF中tau蛋白浓度的升高和Aβ1-42浓度的降低,可能对AD的临床诊断有潜在的应用价值。     

Alzheimer病患者脑脊液Tau蛋白水平的检测及其临床意义

目的研究Alzheimer病(AD)患者脑脊液(CSF)tau蛋白水平及其临床意义.方法采用ELISA 法检测11例AD、13例血管性痴呆(VD)和13例对照者CSF tau蛋白水平.结果 AD患者CSF tau蛋白水平与VD、对照组相比明显升高(分别P＜0.01和P＜0.05).CSF tau蛋白水平随着年龄增长而升高.结论早期CSF tau蛋白水平升高可用于AD的诊断.     

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.     

GCs对VD大鼠行为学及海马脑区tau蛋白P-tau蛋白、Aβ淀粉样蛋白表达影响的实验研究

目的研究肉苁蓉总苷(glycosides of cistanche,GCs)对血管性痴呆(vascular dementia,VD)模型大鼠行为学及海马脑区tau蛋白、p-tau蛋白、Aβ淀粉样蛋白表达的影响,探讨GCs对VD的防治作用。方法双侧颈总动脉结扎(2-VO法)建立VD大鼠模型,随机分为假手术组、VD模型组、GCs低、中、高剂量治疗组和药物对照共6组,Morris水迷宫实验评价各组大鼠的空间学习记忆能力;免疫组化方法检测海马脑区tau蛋白、p-tau蛋白、Aβ淀粉样蛋白表达量的改变。结果 (1)Mories水迷宫研究发现术后1 d、2 d、3 d、4 d、5 d VD组大鼠逃避潜伏期明显延长,与假手术组相比差异明显,有统计学意义(P<0.01,P<0.05);GCs治疗后,VD大鼠定位航行试验的逃避潜伏期显著缩短,有统计学意义(P<0.01);但GCs中剂量组与药物对照组相比差异无统计学意义;(2)模型组大鼠海马脑区tau蛋白、P-tau蛋白、Aβ淀粉样蛋白表达量均显著上升;GCs治疗后,表达量显著下降,与模型组相比(P<0.05),差异有统计学意义。结论 (1)本研究发现tau蛋白、p-tau蛋白、Aβ淀粉样蛋白表达量显著升高,推测VD发病过程与其他类型痴呆如AD存在共同的病理特征;(2)GCs通过减少VD大鼠海马脑区tau蛋白、p-tau蛋白、Aβ淀粉样蛋白表达,有效改善VD模型大鼠的认知功能。     

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。     

Stage-dependent agreement between cerebrospinal fluid proteins and FDG-PET findings in Alzheimer's disease

Cerebral hypometabolism and abnormal levels of amyloid beta (Aβ), total (t-tau) and phosphorylated tau (ptau) proteins in cerebrospinal fluid (CSF) are established biomarkers of Alzheimer's disease (AD). We examined the agreement between these biomarkers in a single center study of patients with AD of severity extending over a wide range. Forty seven patients (MMSE 21.4 ± 3.6, range 13-28 points) with incipient and probable AD underwent positron emission tomography with [18F]-fluorodeoxyglucose (FDG-PET) and lumbar puncture for CSF assays of Aβ1-42, p-tau181, and t-tau. All findings were classified as either positive or negative for AD. Statistical analyses were performed for the whole sample (n=47) and for the subgroups stratified as mild (MMSE > 20 points, n=30) and moderate (MMSE < 21 points, n=17) AD. In the whole patient sample, the agreement with the FDG-PET finding was 77% (chance-corrected kappa [κ]=0.34, p=0.016) for t-tau, 68% (κ=0.10, n.s.) for p-tau181, and 68% (κ=0.04, n.s.) for Aβ1-42. No significant agreement was found in the mild AD subgroup, while there was a strong agreement for t-tau (94%, κ=0.77, p=0.001) and p-tau181 (88%, κ=0.60, p=0.014) in the moderate AD group. A significant agreement between the FDG-PET and CSF tau findings in patients with AD supports the view that both are markers of neurodegeneration. CSF tau proteins and FDG-PET might substitute each other as supportive diagnostic tools in patients with suspected moderate-to-severe Alzheimer's dementia, while this is not the case in subjects at an earlier disease stage.     

Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231

BACKGROUND: Phosphorylation of tau protein at threonine 231 (using full-length tau, 441 amino acids, for the numbering scheme) (p-tau(231)) occurs specifically in postmortem brain tissue of patients with Alzheimer disease (AD) and can be sensitively detected in cerebrospinal fluid (CSF). OBJECTIVES: To determine to what extent CSF levels of p-tau(231) distinguish patients with AD from control subjects and from patients with other dementias, and to investigate whether p-tau(231) levels are a better diagnostic marker than levels of total tau protein (t-tau) in CSF. DESIGN AND SETTING: Cross-sectional, multicenter, memory clinic-based studies. PARTICIPANTS: One hundred ninety-two patients with a clinical diagnosis of AD, frontotemporal dementia (FTD), vascular dementia, Lewy body dementia, or other neurological disorder and healthy controls. MAIN OUTCOME MEASURES: Levels of CSF tau proteins as measured with enzyme-linked immunosorbent assays. RESULTS: Mean CSF levels of p-tau(231) were significantly elevated in the AD group compared with all other groups. Levels of p-tau(231) did not correlate with dementia severity in AD, and discriminated with a sensitivity of 90.2% and a specificity of 80.0% between AD and all non-AD disorders. Moreover, p-tau(231) levels improved diagnostic accuracy compared with t-tau levels when patients with AD were compared with healthy controls (P =.03) and demented subjects (P<.001), particularly those with FTD (P<.001), but not those with vascular and Lewy body dementias. Sensitivity levels between AD and FTD were raised by p-tau(231) compared with t-tau levels from 57.7% to 90.2% at a specificity level of 92.3% for both markers. CONCLUSION: Increased levels of CSF p-tau(231) may be a useful, clinically applicable biological marker for the differential diagnosis of AD, particularly for distinguishing AD from FTD.     

PSEN1 mutation carriers present lower cerebrospinal fluid amyoid-β42 levels than sporadic early-onset Alzheimer's disease patients but no differences in neuronal injury biomarkers

Most cases of early-onset Alzheimer's disease (EOAD) are sporadic. A minority of EOAD are caused by specific genetic defects in PSEN1, PSEN2, or AβPP genes. Magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarker comparisons between sporadic and monogenic EOAD are practically inexistent. CSF and MRI data from 14 amnestic-onset sporadic EOAD (sEOAD) subjects were compared with data from 8 symptomatic PSEN1 mutation carriers (PSEN1) and 14 age-matched cognitively-preserved controls. CSF concentrations of amyloid-β (Aβ)(42), total tau (t-tau), and phosphorylated tau (p-tau) were determined. Cortical thickness (CTh) and grey matter loss were compared between groups and correlated with CSF biomarkers. PSEN1 had significantly lower CSF Aβ(42) levels compared to sEOAD (mean 244.8 pg/ml versus 381.4 pg/ml; p = 0.006), but no differences in t-tau or p-tau. Both sEOAD and PSEN1 showed widespread CTh loss in AD target areas when compared with controls. No differences were found in the direct comparison between sEOAD and PSEN1 CTh after adjusting for age and Mini-Mental Status Examination scores. Neither was a correlation found between Aβ(42) levels and CTh. CTh in the left superior parietal and caudal middle frontal areas was negatively correlated with t-tau values. In conclusion, PSEN1 had lower Aβ(42) CSF levels compared with sEOAD, suggesting a greater cerebral deposition of Aβ(42). These differences in Aβ(42) deposition were not significantly reflected in the brain structure, and CTh was only correlated with total tau. The lack of significant differences in relation to t-tau and p-tau levels and to the severity of CTh or grey matter loss suggests a similar level of neuronal injury despite higher Aβ(42) load in PSEN1.     

Non-invasive vagus nerve stimulation significantly improves quality of life in patients with persistent postural-perceptual dizziness

Amyloid positron emission tomography ([18F] florbetaben (FBB) PET) can be used to determine concomitant Alzheimer’s disease (AD) in idiopathic normal pressure hydrocephalus (iNPH) patients. FBB PET scans and the tap test were performed in 31 patients with clinically suspected iNPH, and amyloid positive (iNPH/FBB+) and negative (iNPH/FBB?) groups were compared with respect to clinical characteristics. We evaluated prognostic value of FBB PET scans by analyzing the response to the tap test using a linear mixed model. We also performed a multivariable regression analysis to investigate whether amyloid PET positivity can predict the positive tap test response independent of other AD biomarkers. The results showed that the iNPH/FBB+ group (7/31, 22.6%) had a higher percentage of APOE4 carriers, lower Aβ42, higher CSF t-tau, and p-tau/Aβ42 ratio than the iNPH/FBB? group (24/31, 77.4%), while the two groups did not differ in imaging characteristics. The iNPH/FBB? group had a higher percentage of tap responders and showed a greater improvement in gait scores after the tap test than the iNPH/FBB+ group (group-tap test effect interaction, p = 0.035). A multivariable logistic regression analysis showed that amyloid positivity on PET scans (OR 0.03, p = 0.029) and CSF p-tau (OR 0.87, p = 0.044) were independently associated with the positive tap test response. Among 21 tap responders in the iNPH/FBB? group, 14 patients received shunt surgery and 12/14 (85.7%) patients showed symptom improvement. Our findings suggest that amyloid PET scans can help determine which iNPH patients will benefit from shunt surgery by discriminating concomitant AD.     

CSF tau, Aβ42, and MHPG differentiate dementia with Lewy bodies from Alzheimer's disease

Differentiating dementia with Lewy bodies (DLB) from Alzheimer's Disease (AD) can be difficult because of the substantial overlap in clinical features. Since deficits in serotonergic and dopaminergic pathways seem more pronounced in DLB patients, we investigated whether cerebrospinal fluid (CSF) analysis of neurotransmitter metabolites, in addition to brain-specific proteins, may improve the differentiation between DLB and AD. We retrospectively compared CSF concentrations of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and the brain-specific proteins total tau (t-tau), phosphorylated tau protein (p-tau), and amyloid-β42 (Aβ42) in 45 patients with AD (mean age 71.6 years; 34 (76%) men; 44 probable AD, 1 definite) and 23 patients with DLB (mean age 71.6 years; 18 (78%) men; 6 possible DLB, 16 probable, 1 definite). The concentrations of all neurotransmitter metabolites, as well as those for t-tau and p-tau protein, were significantly lower in DLB compared to AD, irrespective of the diagnostic certainty (i.e., possible or probable). The currently used combination of Aβ42, p-tau, and t-tau yielded a sensitivity of 92.9% and a specificity of 90%. The addition of MHPG resulted in an increased sensitivity of 97.6% and a specificity of 95% for the discrimination between DLB and AD. In conclusion, the combination of MHPG and the brain specific proteins t-tau, p-tau, and Aβ42 in CSF were associated with the clinical diagnosis of DLB and discriminated between AD and DLB with high diagnostic accuracy, suggesting this combination as a potential biomarker for DLB.     

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.     

Cerebrospinal fluid biomarkers and memory present distinct associations along the continuum from healthy subjects to AD patients

The objective was to study the association between cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)(1-42), t-tau, and p-tau and cognitive performance along the Alzheimer's disease (AD) continuum from healthy subjects to AD patients and, specifically, among patients in the pre-dementia stage of the disease. A total of 101 subjects were studied: 19 healthy controls (CTR), 17 subjects with subjective memory complaints (SMC), 47 with mild cognitive impairment (MCI), and 18 AD patients. Only memory performance significantly correlated with CSF levels of Aβ(1-42), t-tau, and p-tau along the AD continuum. Subgroup analyses revealed that in SMC patients Aβ(1-42) levels positively correlated with the total recall score of the Free and Cued Selective Reminding Test (FCRST) (r = 0.666; p < 0.005), Digit Span (r = 0.752; p < 0.005), and CERAD world list learning (r = 0.697; p < 0.005). In MCI patients, a significant inverse correlation was found between the word list recall score from the CERAD and t-tau (r = -0.483; p < 0.005) and p-tau levels (r = -0.495; p < 0.005), as well as between the total recall subtest score from the FCRST and both t-tau (r = -0.420; p < 0.005) and p-tau levels (r = -0.422; p < 0.005). No significant correlations were found between other aspects of cognition and CSF levels in CTR or AD patients. These results indicate that memory performance is related to Aβ(1-42) levels in SMC, while it is associated with tau in the prodromal stage of the disease. This suggests that in the continuum from healthy aging to AD, memory performance is first related with Aβ(1-42) levels and then with t-tau or p-tau, before becoming independent of biomarker levels in the dementia stage.     

The measurement of phosphorylated tau in human cerebrospinal fluid as a diagnostic marker for Alzheimer's disease]

We examined total 570 cerebrospinal fluid (CSF) samples from a variety of diseases, including Alzheimer's disease (AD; n = 236), non-AD-demented and nondemented diseases (n = 239), and normal controls (n = 95) to quantitate levels of tau protein phosphorylated at serine 199 (CSF/p-tau199) by a recently established sandwich ELISA. The CSF/p-tau199 levels in the AD group were significantly elevated compared to those in all the other non-AD groups. Receiver operating characteristics curves showed that the diagnostic sensitivity and specificity for the AD group vs all the other non-AD group using the CSF/p-tau199 were 85. 2% and 85.0%, respectively. Although there was a significant positive correlation between CSF/p-tau199 and CSF total tau (CSF/t-tau) levels in the AD group, CSF/p-tau199 classifies patients with AD and other disorders more accurately than the CSF/t-tau. Our study suggests that CSF/p-tau199 testing will help in supporting antemortem diagnosis of AD and in conducting emerging therapies that should be based on an accurate detection of AD while patients are alive.     

Longitudinal cerebrospinal fluid biomarker trajectories along the Alzheimer's disease continuum in the BIOMARKAPD study

IntroductionWithin-person trajectories of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) are not well defined.MethodsWe included 467 subjects from the BIOMARKAPD study with at least two serial CSF samples. Diagnoses were subjective cognitive decline (n = 75), mild cognitive impairment (n = 128), and AD dementia (n = 110), and a group of cognitively unimpaired subjects (n = 154) were also included. We measured baseline and follow-up CSF levels of total tau (t-tau), phosphorylated tau (p-tau), YKL-40, and neurofilament light (NfL). Median CSF sampling interval was 2.1 years.ResultsCSF levels of t-tau, p-tau, NfL, and YKL-40 were 2% higher per each year of baseline age in controls (P <.001). In AD, t-tau levels were 1% lower (P <.001) and p-tau levels did not change per each year of baseline age. Longitudinally, only NfL (P <.001) and YKL-40 (P <.02) increased during the study period.DiscussionAll four CSF biomarkers increase with age, but this effect deviates in AD for t-tau and p-tau.     

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.