The Utility of CSF Biomarkers in Diagnosing Alzheimer’s Disease: A Thai Cohort Study

Objectives. To determine how beta-amyloid 1-42 (Aβ 1-42), total tau (tTau), and phosphorylated tau (pTau) levels in CSF behave in a cohort of Thai patients from the Memory Clinic in Bangkok, Thailand. Methods. During 2009–2011, twenty eight subjects from the memory clinic at Siriraj Hospital had CSF analysis for AD biomarkers. Aβ 1-42, tTau, and pTau (at amino acid 181) were measured in CSF by ELISA technique. Results. Mean of Thai mental state examination (TMSE) of 28 Thai cohort was 16.48 (6.63). Fourteen had AD, ten had non-AD dementia, and four non-cases were those with subjective memory complaint (SMC) without dementia. Mean CSF Aβ 1-42, tTau, ptau (181), and pTau/Aβ 1-42 in the AD group were 241.36 (60.14) pg/mL, 222.79 (212.24) pg/mL, 40.79 (27.84) pg/mL, and 0.18 (0.12) accordingly. Mean CSF Aβ 1-42, tTau, pTau (181), and pTau/Aβ 1-42 in the non-AD dementia group were 430.40 (125.18) pg/mL, 349.30 (692.16) pg/mL, 36.80 (14.90) pg/mL, and 0.09 (0.04) accordingly. Mean CSF Aβ 1-42, tTau, pTau (181), and pTau/Aβ 1-42 in the non-cases with SMC without dementia were 499.75 (93.44) pg/mL, 137.25 (62.74) pg/mL, 31.75 (17.48) pg/mL, and 0.06 (0.02). There is significant difference (P < 0.05) among the 3 groups in CSF Aβ 1-42 and pTau/Aβ 1-42. We propose mean + 1.5 SD of CSF Aβ 1-42 in AD group (331.57 pg/mL) to be the cut-off point in Thai subjects. Conclusion. There are significant different in CSF Aβ 1-42 and CSF p-tau/Aβ 1-42 among those with AD, non-AD dementia and non cases with SMC without dementia in Thai cohort. Cut-off point of CSF Aβ 1-42 of 331.57 pg/mL is suggested in Thai study.

Clinical indications for analysis of Alzheimer's disease CSF biomarkers

Chapter 5 - Alzheimer’s Disease Cerebrospinal Fluid (CSF) Biomarkers

There are limited data regarding cerebrospinal fluid (CSF) and plasma biomarkers among patients with Cerebral Amyloid Angiopathy (CAA). We sought to investigate the levels of four biomarkers [β-amyloids (Aβ42 and Aβ40), total tau (tau) and phosphorylated tau (p-tau)] in CAA patients compared to healthy controls (HC) and patients with Alzheimer Disease (AD). A systematic review and meta-analysis of published studies, including also a 5 year single-center cohort study, with available data on CSF and plasma biomarkers in symptomatic sporadic CAA versus HC and AD was conducted. Biomarkers' comparisons were investigated using random-effects models based on the ratio of mean (RoM) biomarker concentrations. RoM < 1 and RoM > 1 indicate lower and higher biomarker concentration in CAA compared to another population, respectively. We identified nine cohorts, comprising 327 CAA patients (mean age: 71 ± 5 years; women: 45%) versus 336 HC (mean age: 65 ± 5 years; women: 45%) and 384 AD patients (mean age: 68 ± 3 years; women: 53%) with available data on CSF biomarkers. CSF Aβ42 levels [RoM: 0.47; 95% CI: 0.36-0.62; p < 0.0001], Aβ40 levels [RoM: 0.70; 95% CI: 0.63-0.79; p < 0.0001] and the ratio Aβ42/Aβ40 [RoM: 0.62; 95% CI: 0.39-0.98; p = 0.0438] differentiated CAA from HC. CSF Aβ40 levels [RoM: 0.73; 95% CI: 0.64-0.83; p = 0.0003] differentiated CAA from AD. CSF tau and p-tau levels differentiated CAA from HC [RoM: 1.71; 95% CI: 1.41-2.09; p = 0.0002 and RoM: 1.44; 95% CI: 1.20-1.73; p = 0.0014, respectively] and from AD [RoM: 0.65; 95% CI: 0.58-0.72; p < 0.0001 and RoM: 0.64; 95% CI: 0.57-0.71; p < 0.0001, respectively]. Plasma Aβ42 [RoM: 1.14; 95% CI: 0.89-1.45; p = 0.2079] and Aβ40 [RoM: 1.07; 95% CI: 0.91-1.25; p = 0.3306] levels were comparable between CAA and HC. CAA is characterized by a distinct CSF biomarker pattern compared to HC and AD. CSF Aβ40 levels are lower in CAA compared to HC and AD, while tau and p-tau levels are higher in CAA compared to HC, but lower in comparison to AD patients.

The diagnostic performances of cerebrospinal fluid (CSF) biomarkers and amyloid positron emission tomography (PET) were compared by examining the association and concordance or discordance between CSF Aβ1-42 and amyloid PET, after determining our own cut-off values for CSF Alzheimer's disease (AD) biomarkers. Furthermore, we evaluated the ability of CSF biomarkers and amyloid PET to predict clinical progression. CSF Aβ1-42, t-tau, and p-tau levels were analyzed in 203 individuals [27 normal controls, 38 mild cognitive impairment (MCI), 62 AD dementia, and 76 patients with other neurodegenerative diseases] consecutively recruited from two dementia clinics. We used both visual and standardized uptake value ratio (SUVR)-based amyloid PET assessments for analyses. The association of CSF biomarkers with amyloid PET SUVR, hippocampal atrophy, and cognitive function were investigated by linear regression analysis, and the risk of conversion from MCI to AD dementia was assessed using a Cox proportional hazards model. CSF p-tau/Aβ1-42 and t-tau/Aβ1-42 exhibited the best diagnostic accuracies among the CSF AD biomarkers examined. Correlations were observed between CSF biomarkers and global SUVR, hippocampal volume, and cognitive function. Overall concordance and discordance between CSF Aβ1-42 and amyloid PET was 77% and 23%, respectively. Baseline positive CSF Aβ1-42 for MCI demonstrated a 5.6-fold greater conversion risk than negative CSF Aβ1-42. However, amyloid PET findings failed to exhibit significant prognostic value. Therefore, despite presence of a significant correlation between the CSF Aβ1-42 level and SUVR of amyloid PET, and a relevant concordance between CSF Aβ1-42 and amyloid PET, baseline CSF Aβ1-42 better predicted AD conversion.

Brain amyloid deposition is one of the main hallmarks of Alzheimer's disease (AD) and two approaches are available for assessing amyloid pathology in vivo: cerebrospinal fluid (CSF) biomarkers levels and amyloid load visualized by amyloid beta positron emission tomography imaging (Amy-PET) probes. We aimed to investigate the concordance between CSF biomarkers and Amy-PET in a memory clinic cohort. Moreover, using a proper clinical follow-up, we wanted to assess the diagnostic accuracy of CSF and PET biomarkers in predicting the progression of patients with mild cognitive impairment (MCI) to AD dementia. We included 31 MCI patients who underwent [18F]florbetaben PET and CSF sampling (Aβ1-42, t-Tau, p-Tau). A semiquantitative visual scan assessment was used to quantify amyloid deposition in 5 brain regions, rating from 1 (negative), to 2 and 3 (positive). CSF biomarkers were considered abnormal if: Aβ1-42 < 600pg/ml, p-Tau/Aβ1-42 > 0.08 and t-Tau/Aβ1-42 > 0.52. We also applied less lenient cutoffs of 550pg/ml and 450pg/ml for Aβ1-42. The concordance rate was 77% between Amy-PET and CSF Aβ1-42 levels, and 89% between Amy-PET and p-Tau/Aβ1-42 and t-Tau/Aβ1-42. According to the clinical follow-up, Amy-PET (sensitivity [SE] 93.7%, specificity [SP] 80%) exhibited the best diagnostic accuracy in discriminating AD from non-AD, followed by p-Tau/Aβ1-42 ratio and t-Tau/Aβ1-42 ratio (SE 93.7%, SP 66.6%), and Aβ1-42 levels (SE 81%, SP 60%). The regional uptake of [18F]florbetaben PET in the precuneus and the striatum showed the best SP (86.6%). In discordant cases, the clinical diagnosis was most often in agreement with PET results. In general, concordance between CSF biomarkers and Amy-PET was good, especially when the ratios between CSF amyloid and Tau biomarkers were used. However, Amy-PET proved to be superior to CSF Aβ1-42 in terms of diagnostic accuracy for AD, with the possibility to further increase its specificity by focusing the analysis in specific areas such as the precuneus/posterior cingulate cortex and the striatum.

Neuropsychological and behavioural correlates of CSF biomarkers in dementia

IntroductionThis study aims to determine whether newly introduced biomarkers Visinin‐like protein‐1 (VILIP‐1), chitinase‐3‐like protein 1 (YKL‐40), synaptosomal‐associated protein 25 (SNAP‐25), and neurogranin (NG) in cerebrospinal fluid are useful in evaluating the asymptomatic and early symptomatic stages of Alzheimer's disease (AD). It further aims to shed new insight into the differences between stable subjects and those who progress to AD by associating cerebrospinal fluid (CSF) biomarkers and specific magnetic resonance imaging (MRI) regions with disease progression, more deeply exploring how such biomarkers relate to AD pathology.MethodsWe examined baseline and longitudinal changes over a 7‐year span and the longitudinal interactions between CSF and MRI biomarkers for subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We stratified all CSF (140) and MRI (525) cohort participants into five diagnostic groups (including converters) further dichotomized by CSF amyloid beta (Aβ) status. Linear mixed models were used to compare within‐person rates of change across diagnostic groups and to evaluate the association of CSF biomarkers as predictors of magnetic resonance imaging (MRI) biomarkers. CSF biomarkers and disease‐prone MRI regions are assessed for CSF proteins levels and brain structural changes.ResultsVILIP‐1 and SNAP‐25 displayed within‐person increments in early symptomatic, amyloid‐positive groups. CSF amyloid‐positive (Aβ+) subjects showed elevated baseline levels of total tau (tTau), phospho‐tau181 (pTau), VILIP‐1, and NG. YKL‐40, SNAP‐25, and NG are positively intercorrelated. Aβ+ subjects showed negative MRI biomarker changes. YKL‐40, tTau, pTau, and VILIP‐1 are longitudinally associated with MRI biomarkers atrophy.DiscussionConverters (CNc, MCIc) highlight the evolution of biomarkers during the disease progression. Results show that underlying amyloid pathology is associated with accelerated cognitive impairment. CSF levels of Aβ42, pTau, tTau, VILIP‐1, and SNAP‐25 show utility to discriminate between mild cognitive impairment (MCI) converter and control subjects (CN). Higher levels of YKL‐40 in the Aβ+ group were longitudinally associated with declines in temporal pole and entorhinal thickness. Increased levels of tTau, pTau, and VILIP‐1 in the Aβ+ groups were longitudinally associated with declines in hippocampal volume. These CSF biomarkers should be used in assessing the characterization of the AD progression.

VALIDATING NON-AMYLOID, NON-TAU CSF BIOMARKERS FOR ALZHEIMER'S DISEASE IN THE PRE-SYMPTOMATIC, MCI, AND DEMENTIA STAGES: A MULTI-CENTER STUDY

Decreasing body mass index is associated with cerebrospinal fluid markers of Alzheimer's pathology in MCI and mild dementia

Several studies suggest that the apolipoprotein E (APOE) ε4 allele modulates cerebrospinal fluid (CSF) levels of β-amyloid 42 (Aβ42). Whether this effect is secondary to the association of the APOE ε4 allele with cortical Aβ deposition or whether APOE ε4 directly influences CSF levels of Aβ42 independently of Aβ pathology remains unknown. To evaluate whether the APOE genotype affects the diagnostic accuracy of CSF biomarkers for Alzheimer disease (AD), in particular Aβ42 levels, and whether the association of APOE ε4 with CSF biomarkers depends on cortical Aβ status. We collected data from 4 different centers in Sweden, Finland, and Germany. Cohort A consisted of 1345 individuals aged 23 to 99 years with baseline CSF samples, including 309 with AD, 287 with prodromal AD, 399 with stable mild cognitive impairment, 99 with dementias other than AD, and 251 controls. Cohort B included 105 nondemented younger individuals (aged 20-34 years) with CSF samples available. Cohort C included 118 patients aged 60 to 80 years with mild cognitive symptoms who underwent flutemetamol F 18 ([18F]flumetamol) positron emission tomography amyloid imaging and CSF tap. Standard care. Cerebrospinal fluid levels of Aβ42 and total and phosphorylated tau in relation to the APOE ε2/ε3/ε4 polymorphism in different diagnostic groups and in cases with or without cortical uptake of [18F]flutemetamol. The CSF levels of Aβ42 but not total and phosphorylated tau were lower in APOE ε4 carriers compared with noncarriers irrespective of diagnostic group (cohort A). Despite this, CSF levels of Aβ42 differed between participants with AD when compared with controls and those with stable mild cognitive impairment, even when stratifying for APOE genotype (P < .001 to P = .006). Multiple binary logistic regression revealed that CSF levels of Aβ42 and APOE ε4 genotype were independent predictors of AD diagnosis. In cohort B, APOE ε4 carrier status did not influence CSF levels of Aβ42. Moreover, when stratifying for cortical uptake of [18F]flutemetamol in cohort C, APOE ε4 genotype did not influence CSF levels of Aβ42. This result was replicated in a cohort with individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) using carbon 11-labeled Pittsburgh Compound B scanning. Cerebrospinal fluid levels of Aβ42 are strongly associated with the diagnosis of AD and cortical Aβ accumulation independent of APOE genotype. The clinical cutoff for CSF levels of Aβ42 should be the same for all APOE genotypes.

IntroductionCerebrospinal fluid (CSF) biomarkers improve the diagnostic accuracy for Alzheimer’s disease (AD), even at the predementia stage of the disease. The ε4-allele of apolipoprotein E (ApoE ε4), female sex, and older age are well-known risk factors for AD. It is unclear how these risk factors affect the CSF biomarkers in patients with AD.AimThe objective of this study was to investigate the associations of ApoE ε4, sex, and age with CSF biomarker levels in a unicenter sample of patients with AD that includes a high proportion of patients with early-onset AD (EOAD).MethodsThe CSF levels of amyloid-β 1-42 (Aβ1-42) and total-tau of 117 subjects with mild to moderate AD (55 late-onset AD and 62 EOAD) were assessed. All subjects underwent ApoE genotyping, clinical evaluation, comprehensive neuropsychological assessments, and neuroimaging. Associations between CSF biomarker levels, ApoE ε4 allele frequency, age, and sex were evaluated.ResultsIn the whole patient sample and in the late-onset AD subgroup ε4 homozygous subjects had significantly lower CSF Aβ1-42 levels compared with ε4 heterozygous subjects and ε4 noncarriers. This association was not detected in the EOAD group. Age group, sex, and severity of cognitive decline did not have a significant impact on CSF Aβ1-42 levels. No significant associations were found between ApoE ε4 allele frequency and CSF total-tau levels.ConclusionApoE ε4 allele is associated with a reduction of CSF Aβ1-42 levels. This result is consistent with the findings of several previous studies. In the subgroup of patients with EOAD this association was not replicated. Larger studies are necessary to further investigate associations between ApoE ε4 allele frequency and CSF biomarker levels in patients with EOAD.

ObjectiveTo study CSF biomarkers of Alzheimer disease (AD) analyzed by fully automated Elecsys immunoassays compared to neuropathologic gold standards and to compare their accuracy to plasma phosphorylated tau (p-tau181) measured with a novel single molecule array method.MethodsWe studied antemortem Elecsys-derived CSF biomarkers in 45 individuals who underwent standardized postmortem assessments of AD and non-AD neuropathologic changes at autopsy. In a subset of 26 participants, we also analyzed antemortem levels of plasma p-tau181 and neurofilament light (NfL). Reference biomarker values were obtained from 146 amyloid-PET–negative healthy controls (HC).ResultsAll CSF biomarkers clearly distinguished pathology-confirmed AD dementia (n = 27) from HC (area under the curve [AUC] 0.86–1.00). CSF total tau (t-tau), p-tau181, and their ratios with β-amyloid1-42 (Aβ1-42) also accurately distinguished pathology-confirmed AD from non-AD dementia (n = 8; AUC 0.94–0.97). In pathology-specific analyses, intermediate to high Thal amyloid phases were best detected by CSF Aβ1-42 (AUC [95% confidence interval] 0.91 [0.81–1]), while intermediate to high scores for Consortium to Establish a Registry for Alzheimer's Disease neuritic plaques and Braak tau stages were best detected by CSF p-tau181 (AUC 0.89 [0.79–0.99] and 0.88 [0.77–0.99], respectively). Optimal Elecsys biomarker cutoffs were derived at 1,097, 229, and 19 pg/mL for Aβ1-42, t-tau, and p-tau181. In the plasma subsample, both plasma p-tau181 (AUC 0.91 [0.86–0.96]) and NfL (AUC 0.93 [0.87–0.99]) accurately distinguished those with pathology-confirmed AD (n = 14) from HC. However, only p-tau181 distinguished AD from non-AD dementia cases (n = 4; AUC 0.96 [0.88–1.00]) and showed a similar, although weaker, pathologic specificity for neuritic plaques (AUC 0.75 [0.52–0.98]) and Braak stage (AUC 0.71 [0.44–0.98]) as CSF p-tau181.ConclusionElecsys-derived CSF biomarkers detect AD neuropathologic changes with very high discriminative accuracy in vivo. Preliminary findings support the use of plasma p-tau181 as an easily accessible and scalable biomarker of AD pathology.Classification of EvidenceThis study provides Class II evidence that fully automated CSF t-tau and p-tau181 measurements discriminate between autopsy-confirmed AD and other dementias.

ObjectivesThe purpose of this study was to carry out systematic review of the literature and meta-analysis to evaluate the diagnostic utility of cerebrospinal fluid (CSF) levels of the 42 amino acid form of amyloid-beta (Aβ1–42) as a biomarker for differentiating Alzheimer’s disease (AD) from non-AD dementia.Methods Design. Systematic literature review was used to evaluate the effectiveness of the Aβ for the diagnosis of AD. The Scottish Intercollegiate Guidelines Network (SIGN) tool was used to evaluate independently the quality of the studies. Data sources. The literature review covered from January 1, 2004, to October 22, 2013, and searched eight domestic databases including Korea Med and international databases including Ovid-MEDLINE, EMBASE, and Cochrane Library. Data Extraction and Synthesis. Primary criteria for inclusion were valid studies on (i) patients with mild cognitive impairment with confirmed or suspected AD and non-AD dementia, and (ii) assessment of Aβ1–42 levels using appropriate comparative tests.ResultsA total of 17 diagnostic evaluation studies were identified in which levels of CSF Aβ1–42 were assessed. Meta-analysis was performed on 11 robust studies that compared confirmed AD (n = 2211) with healthy individuals (n = 1030), 10 studies that compared AD with non-AD dementias (n = 627), and 5 studies that compared amnestic mild cognitive impairment (n = 1133) with non-amnestic type subjects (n = 1276). Overall, the CSF Aβ1–42 levels were reduced in AD compared to controls or non-AD dementia. The effectiveness of test was evaluated for diagnostic accuracy (pooled sensitivity, 0.80 (95% CI 0.78–0.82); pooled specificity, 0.76 (95% CI 0.74–0.78).ConclusionsReduced CSF Aβ1–42 levels are of potential utility in the differential diagnosis of AD versus non-AD dementias and controls. Diagnostic accuracy was high in AD versus healthy controls. However, differential diagnosis for MCI or non-AD might be evaluated by other biomarkers.

While cutoffs for abnormal levels of the cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ142), total tau (t-tau), phosphorylated tau (p-tau), and the ratios of t-tau/Aβ142 and p-tau/Aβ142, have been established in Alzheimer's disease (AD), biologically relevant cutoffs have not been studied extensively in Parkinson's disease (PD). Assess the suitability and diagnostic accuracy of established AD-derived CSF biomarker cutoffs in the PD population. Baseline and longitudinal data on CSF biomarkers, cognitive diagnoses, and PET amyloid imaging in 423 newly diagnosed patients with PD from the Parkinson's Progression Markers Initiative (PPMI) cohort were used to evaluate established AD biomarker cutoffs compared with optimal cutoffs derived from the PPMI cohort. Using PET amyloid imaging as the gold standard for AD pathology, the optimal cutoff of Aβ142 was higher than the AD cutoff, the optimal cutoffs of t-tau/Aβ142 and p-tau/Aβ142 were lower than the AD cutoffs, and their confidence intervals (CIs) did not overlap with the AD cutoffs. Optimal cutoffs for t-tau and p-tau to predict cognitive impairment were significantly lower than the AD cutoffs, and their CIs did not overlap with the AD cutoffs. Optimal cutoffs for the PPMI cohort for Aβ142, t-tau/Aβ142, and p-tau/Aβ142 to predict amyloid-PET positivity and for t-tau and p-tau to predict cognitive impairment differ significantly from cutoffs derived from AD populations. The presence of additional pathologies such as alpha-synuclein in PD may lead to disease-specific CSF biomarker characteristics.