The clinical use of cerebrospinal fluid biomarker testing for Alzheimer's disease diagnosis: A consensus paper from the Alzheimer's Biomarkers Standardization Initiative

BackgroundCerebrospinal fluid (CSF) biomarkers β-amyloid 1-42 (Aβ_1-42), also expressed as Aβ_1-42:Aβ_1-40 ratio, T-tau, and P-tau_181P, have proven diagnostic accuracy for mild cognitive impairment and Alzheimer's disease (AD). How to use, interpret, and disclose biomarker results drives the need for standardization.MethodsPrevious Alzheimer's Biomarkers Standardization Initiative meetings discussed preanalytical issues affecting Aβ_1-42 and tau in CSF. This second round of consensus meetings focused on issues related to clinical use of AD CSF biomarkers.ResultsConsensus was reached that lumbar puncture for AD CSF biomarker analysis be considered as a routine clinical test in patients with early-onset dementia, at the prodromal stage or with atypical AD. Moreover, consensus was reached on which biomarkers to use, how results should be interpreted, and potential confounding factors.ConclusionsChanges in Aβ_1-42, T-tau, and P-tau_181P allow diagnosis of AD in its prodromal stage. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up.     

Alzheimer’s disease CSF biomarkers: clinical indications and rational use

This review focusses on the validation and standardization of Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers, as well as on the current clinical indications and rational use of CSF biomarkers in daily clinical practice. The validated AD CSF biomarkers, Aβ_1-42, T-tau, and P-tau₁₈₁, have an added value in the (differential) diagnosis of AD and related disorders, including mixed pathologies, atypical presentations, and in case of ambiguous clinical dementia diagnosis. CSF biomarkers should not be routinely used in the diagnostic work-up of dementia and cannot be used to diagnose non-AD dementias. In cognitively healthy subjects, CSF biomarkers can only be applied for research purposes, e.g., to identify pre-clinical AD in the context of clinical trials with potentially disease-modifying drugs. Therefore, biomarker-based early diagnosis of AD offers great opportunities for preventive treatment development in the near future.     

Biomarkers of neuronal injury and amyloid metabolism in the cerebrospinal fluid of patients infected with HIV-1 subtypes B and C

Based on prior reports that the HIV-1 Tat protein modulates amyloid-beta (Aβ) metabolism, this study aimed to compare CSF neural injury biomarkers between 27 patients with HIV subtype B, 26 patients with HIV subtype C, 18 healthy HIV-negative controls, and 24 patients with Alzheimer’s disease (AD). Immunoassays were used to measure soluble amyloid precursor protein α and β (sAPPα, sAPPβ), Aβ oligomers 38, 40, 42, and Aβ-total; phosphorylated tau (P-tau₁₈₁), and total tau (T-tau). Comparisons between HIV(+) and HIV(?) (including AD) were adjusted by linear regression for gender and age; HIV subtype comparisons were adjusted for nadir CD4 and plasma viral load suppression. The p values were corrected for multiple testing with the Benjamini-Hochberg procedure. CSF Aβ-42 and Hulstaert (P-tau₁₈₁) index were lower in HIV1-C than B (p = 0.03, and 0.049 respectively); subtypes did not differ on other CSF biomarkers or ratios. Compared to AD, HIV(+) had lower CSF levels of T-tau, P-tau₁₈₁ (p < 0.001), and sAPPα (p = 0.041); HIV(+) had higher CSF Aβ-42 (p = 0.002) and higher CSF indexes: [Aß-42/(240 + 1.18 T-tau)], P-tau₁₈₁/Aβ-42, T-tau/Aβ-42, P-tau₁₈₁/T-tau, sAPPα/β (all p ≤ 0.01) than AD. Compared to HIV(?), HIV(+) had lower CSF Aβ-42, and T-tau (all p ≤ 0.004). As conclusion, amyloid metabolism was influenced by HIV infection in a subtype-dependent manner. Aß-42 levels were lower in HIV1-C than B, suggesting that there may be greater deposition of Aß-42 in HIV1-C. These findings are supported by CSF Hulstaert (P-tau₁₈₁) index. Differences between HIV and AD in the patterns of Aß and Tau biomarkers suggest that CNS HIV infection and AD may not share some of same mechanisms of neuronal injury.     

Patients with mild cognitive impairment and a reduced CSF Aβ₁₋₄₂ protein progress rapidly to Alzheimer's disease

Introduction

Some studies have shown that CSF amyloid-beta 1-42 (Aβ_1-42), total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau_181p) proteins are useful diagnostic markers for distinguishing between clinically stable mild cognitive impairment (MCI) patients and those who will develop Alzheime?s disease (AD).Our objective was to test the ability of this technique to discriminate in our cohort of MCI patients, according to the clinical outcome, one year after the lumbar puncture.

Material and methods

A total of 36 MCI patients were included from the local hospital memory clinic. Using INNO-BIA Alzbio-3 reagents from Innogenetics, we measured CSF Aβ_1-42, T-tau and P-tau_181p proteins, and calculated the T-tau/Aβ_1-42 y P-tau_181p/Aβ_1-42 ratios. This project was approved by the local ethics committee.

Results

One year after the lumbar puncture, 14 MCI patients (38%) developed AD. These patients had lower Aβ _1-42 protein levels (285.3 vs 377 ng/ml, P < .02) and higher P-tau_181p/Aβ_1-42 ratio (0,25 vs 0,16, p < .02) than the clinically stable patients.

Conclusions

Our MCI patients with lower Aβ_1-42 protein levels and an increased P-tau_181p /Aβ_1-42 ratio progressed quickly to AD. These results may help to identify those MCI patients with a poorer prognosis.     

Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer's disease diagnosis: a consensus paper from the Alzheimer's Biomarkers Standardization Initiative

BackgroundNumerous studies show that the cerebrospinal fluid biomarkers total tau (T-tau), tau phosphorylated at threonine 181 (P-tau_181P), and amyloid-β (1-42) (Aβ_1–42) have high diagnostic accuracy for Alzheimer’s disease. Variability in concentrations for Aβ_1–42, T-tau, and P-tau_181P drives the need for standardization.MethodsKey issues were identified and discussed before the first meeting of the members of the Alzheimer’s Biomarkers Standardization Initiative (ABSI). Subsequent ABSI consensus meetings focused on preanalytical issues.ResultsConsensus was reached on preanalytical issues such as the effects of fasting, different tube types, centrifugation, time and temperature before storage, storage temperature, repeated freeze/thaw cycles, and length of storage on concentrations of Aβ_1–42, T-tau, and P-tau_181P in cerebrospinal fluid.ConclusionsThe consensus reached on preanalytical issues and the recommendations put forward during the ABSI consensus meetings are presented in this paper.     

Cerebrospinal fluid biomarkers for Alzheimer’s disease: diagnostic performance in a homogeneous mono-center population

The cerebrospinal fluid (CSF) biomarkers amyloid-β (Aβ)(1-42), T-tau, and P-tau have good diagnostic accuracy for clinically diagnosed Alzheimer’s disease (AD). However, in multi-center studies, the predictive values of the CSF biomarkers have been lower, possibly due to differences in procedures for lumbar puncture and CSF handling and storage, and to differences in patient populations, clinical evaluations, and diagnostic procedures. Here we investigate the diagnostic accuracy of CSF biomarkers in a well defined homogeneous mono-center population. We also evaluate an extended panel of amyloid related biomarkers. Sixty consecutive patients admitted for cognitive impairment to a memory clinic were recruited. The participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n = 32), patients with stable MCI (n = 13), patients with other dementias diagnosed at primary evaluation or upon follow-up (n = 15), and healthy controls(n = 20). CSF was analyzed for Aβ(1-42), T-tau, and P-tau, and PA(X-38), Aβ(X-40), Aβ(X-42), sAβPPα, and sAβPPβ. In multivariate analysis, thecore biomarkers Aβ(1-42), T-tau, and P-tau demonstrated a high ability to diagnose AD versus the combined groups of controls and stable MCI, with an area under the receiver operating characteristic curve (AUROC) of 0.97 (95% CI 0.93–1.00, p < 0.0001). The additional biomarkers only marginally increased AUROC to 0.98 (95% CI 0.95–1.00, p < 0.0001), this increase mainly mediated by Aβ(X-42). In conclusion, CSF biomarkers Aβ(1-42), T-tau, and P-tau have very high diagnostic accuracy in a well defined cohort of untreated patients, demonstrating the excellent potency of CSF biomarkers to identify pathological processes in AD when astringent analytical protocol is used.     

Concordance between the assessment of Aβ42, T-tau,and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid

IntroductionNeuronal-derived exosomal Aβ42, T-tau, and P-T181-tau have been demonstrated to be biomarkers of Alzheimer's disease (AD). However, no study has assessed the association of Aβ42, T-tau, and P-T181-tau between exosomes and CSF.MethodsThis was a multicenter study with two-stage design. The subjects included 28 AD patients, 25 aMCI patients, and 29 controls in the discovery stage; the results of which were confirmed in the validation stage (73 AD, 71 aMCI, and 72 controls).ResultsThe exosomal concentrations of Aβ42, T-tau, and P-T181-tau in AD group were higher than those in aMCI and control groups (all P < .001). The level of each exosomal biomarker was highly correlated with that in CSF.DiscussionThis study verified the agreement between CSF and blood exosomal biomarkers and confirmed that exosomal Aβ42, T-tau, and P-T181-tau have the same capacity as those in CSF for the diagnosis of AD and aMCI.     

Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI

The dynamics of cerebrospinal fluid (CSF) tau and Aβ biomarkers over time in Alzheimer’s disease (AD) patients from prodromal pre-symptomatic to severe stages of dementia have not been clearly defined and recent studies, most of which are cross-sectional, present conflicting findings. To clarify this issue, we analyzed the longitudinal CSF tau and Aβ biomarker data from 142 of the AD Neuroimaging Initiative (ADNI) study subjects [18 AD, 74 mild cognitive impairment (MCI), and 50 cognitively normal subjects (CN)]. Yearly follow-up CSF collections and studies were conducted for up to 48 months (median = 36 months) for CSF Aβ_1–42, phosphorylated tau (p-tau₁₈₁), and total tau (t-tau). An unsupervised analysis of longitudinal measurements revealed that for Aβ_1–42 and p-tau₁₈₁ biomarkers there was a group of subjects with stable longitudinal CSF biomarkers measures and a group of subjects who showed a decrease (Aβ_1–42, mean = ?9.2 pg/ml/year) or increase (p-tau₁₈₁, mean = 5.1 pg/ml/year) of these biomarker values. Low baseline Aβ_1–42 values were associated with longitudinal increases in p-tau₁₈₁. Conversely, high baseline p-tau₁₈₁ values were not associated with changes in Aβ_1–42 levels. When the subjects with normal baseline biomarkers and stable concentrations during follow-up were excluded, the expected time to reach abnormal CSF levels and the mean AD values was significantly shortened. Thus, our data demonstrate for the first time that there are distinct populations of ADNI subjects with abnormal longitudinal changes in CSF p-tau₁₈₁ and Aβ_1–42 levels, and our longitudinal results favor the hypothesis that Aβ_1–42 changes precede p-tau₁₈₁ changes.     

Novel CSF biomarkers for Alzheimer’s disease and mild cognitive impairment

Altered levels of cerebrospinal fluid (CSF) peptides related to Alzheimer’s disease (AD) are associated with pathologic AD diagnosis, although cognitively normal subjects can also have abnormal levels of these AD biomarkers. To identify novel CSF biomarkers that distinguish pathologically confirmed AD from cognitively normal subjects and patients with other neurodegenerative disorders, we collected antemortem CSF samples from 66 AD patients and 25 patients with other neurodegenerative dementias followed longitudinally to neuropathologic confirmation, plus CSF from 33 cognitively normal subjects. We measured levels of 151 novel analytes via a targeted multiplex panel enriched in cytokines, chemokines and growth factors, as well as established AD CSF biomarkers (levels of Aβ42, tau and p-tau₁₈₁). Two categories of biomarkers were identified: (1) analytes that specifically distinguished AD (especially CSF Aβ42 levels) from cognitively normal subjects and other disorders; and (2) analytes altered in multiple diseases (NrCAM, PDGF, C3, IL-1α), but not in cognitively normal subjects. A multi-prong analytical approach showed AD patients were best distinguished from non-AD cases (including cognitively normal subjects and patients with other neurodegenerative disorders) by a combination of traditional AD biomarkers and novel multiplex biomarkers. Six novel biomarkers (C3, CgA, IL-1α, I-309, NrCAM and VEGF) were correlated with the severity of cognitive impairment at CSF collection, and altered levels of IL-1α and TECK associated with subsequent cognitive decline in 38 longitudinally followed subjects with mild cognitive impairment. In summary, our targeted proteomic screen revealed novel CSF biomarkers that can improve the distinction between AD and non-AD cases by established biomarkers alone.     

A prediction model to calculate probability of Alzheimer’s disease using cerebrospinal fluid biomarkers

BackgroundWe aimed to develop a prediction model based on cerebrospinal fluid (CSF) biomarkers, that would yield a single estimate representing the probability that dementia in a memory clinic patient is due to Alzheimer’s disease (AD).MethodsAll patients suspected of dementia in whom the CSF biomarkers had been analyzed were selected from a memory clinic database. Clinical diagnosis was AD (n = 272) or non-AD (n = 289). The prediction model was developed with logistic regression analysis and included CSF amyloid β₄₂, CSF phosphorylated tau₁₈₁, and sex. Validation was performed on an independent data set from another memory clinic, containing 334 AD and 157 non-AD patients.ResultsThe prediction model estimated the probability that AD is present as follows: p(AD) = 1/(1 + e ^{– [–0.3315 + score]}), where score is calculated from –1.9486 × ln(amyloid β₄₂) + 2.7915 × ln(phosphorylated tau₁₈₁) + 0.9178 × sex (male = 0, female = 1). When applied to the validation data set, the discriminative ability of the model was very good (area under the receiver operating characteristic curve: 0.85). The agreement between the probability of AD predicted by the model and the observed frequency of AD diagnoses was very good after taking into account the difference in AD prevalence between the two memory clinics.ConclusionsWe developed a prediction model that can accurately predict the probability of AD in a memory clinic population suspected of dementia based on CSF amyloid β₄₂, CSF phosphorylated tau₁₈₁, and sex.     

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.     

A single center study: Aβ42/p-Tau<Subscript>181</Subscript> CSF ratio to discriminate AD from FTD in clinical setting

Abnormal levels of beta amyloid (Aβ42) and tau protein concentrations in the cerebral spinal fluid (CSF) have been largely described in Alzheimer’s disease (AD). Thus, CSF analysis of these biomarkers has been incorporated in recent AD diagnostic criteria, and it is increasingly performed for neurodegenerative dementia diagnostic workout in clinical setting. Nevertheless, the precise biomarkers CSF features in neurodegenerative dementia, either AD or Frontotemporal dementia (FTD), are still not fully clear today. This is mainly due to lack of CSF clear cutoff values due to a well-known intersite (but even intrasite) variability of CSF procedures, ranging from collection to analysis. Applying CSF biomarker ratios, rather than their single values could represent a useful tool, especially for the differential diagnosis of different forms of dementia. We explored clinical values of six CSF ratios (by combining Aβ42 and tau) in order to better discriminate between AD and FTD; we identified Aβ42/p-Tau₁₈₁ ratio as a potential good candidate for helping differentiating AD from FTD in the clinical practice.     

Cerebrospinal fluid Alzheimer's biomarker profiles in CNS infections

The cerebrospinal fluid (CSF) biomarker profile in Alzheimer's disease (AD) is characterized by decreased beta amyloid (Aβ_1-42), increased total and hyperphosphorylated tau (t-tau and p-tau, respectively), which is a useful diagnostic tool and gives insight in the pathogenesis of AD. It is of importance to study how these biomarkers react in other CNS diseases; therefore, we decided to analyse amyloid and tau biomarkers in different CNS infections. We also included analysis of soluble amyloid precursor proteins (sAPPα and -β). CSF Aβ_1-42, sAPPα and -β, t-tau and p-tau were analysed in bacterial meningitis (n = 12), Lyme neuroborreliosis (n = 13), herpes simplex virus type 1 (HSV-1) encephalitis (n = 10), HIV-associated dementia (HAD) (n = 21), AD (n = 21) and healthy controls (n = 42). Concurrent with AD, Aβ_1-42 was decreased in all groups except neuroborreliosis compared to controls. HSV-1 encephalitis, bacterial meningitis and HAD showed lower concentrations of sAPPα and -β compared to AD. T-tau was increased in AD and HSV-1 encephalitis compared to all other groups. P-tau was higher in AD and HSV-1 encephalitis compared to bacterial meningitis, HAD and control. Decreased CSF Aβ_1-42, sAPPα and -β in various CNS infections imply an effect of neuroinflammation on amyloid metabolism which is similar in regard to AD concerning Aβ_1-42, but differs concerning sAPPα and -β. These results clearly indicate different pathologic pathways in AD and infectious CNS disease and may provide help in the differential biomarker diagnostics. Increased p-tau in HSV-1 encephalitis probably reflect acute neuronal damage and necrosis.     

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.     

Relations between personality changes and cerebrospinal fluid biomarkers of Alzheimer's disease pathology

Specific changes in personality profiles may represent early non-cognitive symptoms of Alzheimer's disease (AD). Evaluating the subject's personality changes may add significant clinical information, as well as help to better understand the interaction between personality change, cognitive decline, and cerebral pathology. With this study we aimed to describe the relationship between personality changes and cerebrospinal fluid (CSF) markers of AD pathology at early clinical stages of the disease. One hundred and ten subjects, of whom 66 cognitively impaired patients (57 with mild cognitive impairment (MCI), and 9 with mild dementia) and 44 healthy controls, had neuropsychological examination as well as lumbar puncture to determine concentrations of CSF biomarkers of AD pathology (amyloid beta_1-42 (Aβ_1-42), phosphorylated tau (ptau-181), and total-tau (tau)). The Revised NEO Personality Inventory (NEO-PI-R) was administered twice, once to evaluate subjects' current personality and once to assess personality traits retrospectively 5 years before evaluation. Subjects with an AD CSF biomarker profile showed significant increase in neuroticism and decrease in conscientiousness over time as compared to non-AD CSF biomarker group. In regression analysis controlling for global cognition as measured by the MMSE score, increasing neuroticism and decreasing extraversion, openness to experience and conscientiousness were associated with lower Aβ_1-42 concentrations but not with tau and ptau-181 concentrations. Our findings suggest that early and specific changes in personality are associated with cerebral AD pathology. Concentrations of CSF biomarkers, additionally to severity of the cognitive impairment, significantly contribute in predicting specific personality changes.     

Biomarkers and diagnosis of dementia with Lewy bodies including prodromal: Practical aspects

Dementia with Lewy Bodies (DLB) is a common form of cognitive neurodegenerative disease. More than half of the patients affected are not or misdiagnosed because of the clinical similarity with Alzheimer's disease (AD), Parkinson's disease but also psychiatric diseases such as depression or psychosis. In this review, we evaluate the interest of different biomarkers in the diagnostic process: cerebrospinal fluid (CSF), brain MRI, FP-CIT SPECT, MIBG SPECT, perfusion SPECT, FDG-PET by focusing more specifically on differential diagnosis between DLB and AD. FP-CIT SPECT is of high interest to discriminate DLB and AD, but not at the prodromal stage. Brain MRI has shown differences in group study with lower grey matter concentration of the Insula in prodromal DLB, but its interest in clinical routine is not demonstrated. Among the AD biomarkers (t-Tau, phospho-Tau₁₈₁, Aβ42 and Aβ40) used routinely, t-Tau and phospho-Tau₁₈₁ have shown excellent discrimination whatever the clinical stages severity. CSF Alpha-synuclein assay in the CSF has also an interest in the discrimination between DLB and AD but not in segregation between DLB and healthy elderly subjects. CSF synuclein RT-QuIC seems to be an excellent biomarker but its application in clinical routine remains to be demonstrated, given the non-automation of the process.     

Inverse association of cortisol serum levels with T-tau,P-tau 181 and P-tau 231 peptide levels and T-tau/Aβ 1–42 ratios in CSF in patients with mild Alzheimer’s disease dementia

Hypercortisolemia and increased levels of hyperphosphorylated tau proteins in cerebrospinal fluid (CSF) are common features with pathogenic relevance in Alzheimer`s disease (AD). Experimental studies point to an influence of cortisol on Aβ and tau pathology in AD. Association of both parameters have not yet been described in a sample of AD patients. In the present study, serum levels of cortisol were determined in 26 patients with mild AD dementia and 20 age-matched healthy elderly controls by ELISA. In addition, we measured in AD patients CSF levels of cortisol, total tau (T-tau), tau phosphorylated at threonine 181 (P-tau 181), tau protein phosphorylated at threonine 231 (P-tau 231) and beta-Amyloid (Aβ) 1–42 and determined T-tau/Aβ 1–42 ratios in CSF. We found in AD patients significantly increased cortisol serum levels (551.4 ± 146.1 nmol/l; P = 0.002) as compared to healthy controls (435.3 ± 83.9 nmol/l). In AD patients, cortisol serum levels were significantly inversely correlated with T-tau (r = −0.496; P = 0.01), P-tau 181 (r = −0.558; P = 0.003) and P-tau 231 (−0.500; P = 0.009) protein levels and T-tau/Aβ 1–42 ratios (r = −0.450; P = 0.021) in CSF. In addition, cortisol serum levels showed a trend of positive correlation with Aβ 1–42 CSF levels (r = 0.386; P = 0.052). However, no significant correlations of cortisol serum with CSF levels as well as cortisol CSF levels with CSF biomarkers could be detected in AD patients. In conclusion, our results show that increased cortisol serum but not CSF levels are associated with minor signs of AD pathology in CSF, indicating a putative neuroprotective effect of moderately elevated cortisol serum levels in patients with mild AD dementia.     

CSF α-synuclein improves diagnostic and prognostic performance of CSF tau and Aβ in Alzheimer’s disease

Alzheimer’s disease (AD) and Lewy body diseases (LBD), e.g., Parkinson’s disease (PD) dementia and dementia with Lewy bodies (DLB), are common causes of geriatric cognitive impairments. In addition, AD and LBD are often found in the same patients at autopsy; therefore, biomarkers that can detect the presence of both pathologies in living subjects are needed. In this investigation, we report the assessment of α-synuclein (α-syn) in cerebrospinal fluid (CSF) and its association with CSF total tau (t-tau), phosphorylated tau₁₈₁ (p-tau₁₈₁), and amyloid beta_1-42 (Aβ_1-42) in subjects of the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 389), with longitudinal clinical assessments. A strong correlation was noted between α-syn and t-tau in controls, as well as in patients with AD and mild cognitive impairment (MCI). However, the correlation is not specific to subjects in the ADNI cohort, as it was also seen in PD patients and controls enrolled in the Parkinson’s Progression Markers Initiative (PPMI; n = 102). A bimodal distribution of CSF α-syn levels was observed in the ADNI cohort, with high levels of α-syn in the subjects with abnormally increased t-tau values. Although a correlation was also noted between α-syn and p-tau₁₈₁, there was a mismatch (α-syn–p-tau₁₈₁-Mis), i.e., higher p-tau₁₈₁ levels accompanied by lower α-syn levels in a subset of ADNI patients. We hypothesize that this α-syn–p-tau₁₈₁-Mis is a CSF signature of concomitant LBD pathology in AD patients. Hence, we suggest that inclusion of measures of CSF α-syn and calculation of α-syn–p-tau₁₈₁-Mis improves the diagnostic sensitivity/specificity of classic CSF AD biomarkers and better predicts longitudinal cognitive changes.     

Biomarkers in non-Alzheimer dementias

Biomarkers for Alzheimer's Disease (AD) and non-AD dementias could serve as aids to diagnosis and treatment. Biochemical markers have been sought in cerebrospinal fluid (CSF), blood and urine, and are best developed for AD. Ideally, a biomarker should be unique to a dementing disorder and should have high sensitivity. The most widely studied markers for AD, CSF tau and Aβ42, also can show alterations in other disorders. Some non-AD dementias, such as Lewy Body dementia and vascular dementia may be accompanied by AD pathology, making the search for unique markers of these common disorders difficult. However, markers of general pathological processes in neurodegeneration could be used to follow change over time. Prion disorders come closest to having unique biomarkers, although it is difficult to detect the pathogenic Prion proteins (PrPsc) in body fluids. Other protein signatures, such as increased CSF levels of 14-3-3 protein and markedly increased tau have sufficiently high sensitivity and specificity to be used as aids to diagnosis. The development of markers for prion disease stands as a model to drive future research in other dementias.     

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.