Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort

Departments of Neurology, VU University Medical Center, Alzheimer Center, Amsterdam, The Netherlands.
Neurology (Impact Factor: 8.29). 12/2011; 78(1):47-54. DOI: 10.1212/WNL.0b013e31823ed0f0
Source: PubMed


To determine how amyloid β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels in CSF behave in a large cohort of patients with different types of dementia.
Baseline CSF was collected from 512 patients with Alzheimer disease (AD) and 272 patients with other types of dementia (OD), 135 patients with a psychiatric disorder (PSY), and 275 patients with subjective memory complaints (SMC). Aβ42, t-tau, and p-tau (at amino acid 181) were measured in CSF by ELISA. Autopsy was obtained in a subgroup of 17 patients.
A correct classification of patients with AD (92%) and patients with OD (66%) was accomplished when CSF Aβ42 and p-tau were combined. Patients with progressive supranuclear palsy had normal CSF biomarker values in 90%. Patients with Creutzfeldt-Jakob disease demonstrated an extremely high CSF t-tau at a relatively normal CSF p-tau. CSF AD biomarker profile was seen in 47% of patients with dementia with Lewy bodies (DLB), 38% in corticobasal degeneration (CBD), and almost 30% in frontotemporal lobar degeneration (FTLD) and vascular dementia (VaD). PSY and SMC patients had normal CSF biomarkers in 91% and 88%. Older patients are more likely to have a CSF AD profile. Concordance between clinical and neuropathologic diagnosis was 85%. CSF markers reflected neuropathology in 94%.
CSF Aβ42, t-tau, and p-tau are useful in differential dementia diagnosis. However, in DLB, FTLD, VaD, and CBD, a substantial group exhibit a CSF AD biomarker profile, which requires more autopsy confirmation in the future.

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Available from: Peter Van de Ven, Feb 05, 2014
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    • "Different biomarkers probably reflect different aspects of the pathological process and may therefore not be congruent especially early in the course of the disease [9] [31]. Sensitivity and specificity as measures of diagnostic accuracy probably differ between biomarkers with higher rates for amyloid targeting PET compared to CSF biomarkers in autopsy confirmed cases [34] [35] [36]. However, the design of this study does not allow addressing the question of diagnostic accuracy since no gold standard in terms of neuropathological verification was available. "
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    ABSTRACT: Background: Biomarkers of neuronal injury and amyloid pathology play a pivotal role in the diagnosis of Alzheimer's disease (AD). The degree of AD biomarker congruence is still unclear in clinical practice. Objective: Diagnosis of AD with regard to the congruence of the clinical diagnosis and different biomarkers. Methods: In this prospective cross-sectional observational study, 54 patients with mild cognitive impairment or dementia due to AD or not due to AD were investigated. Biomarkers of neuronal injury were medial temporal lobe atrophy (MTA) on magnetic resonance imaging (MRI) and tau concentration in the cerebrospinal fluid (CSF). CSF Aβ1-42 and amyloid-targeting positron emission tomography (PET) were considered as biomarkers of amyloid pathology. Results: Forty cases were diagnosed as AD and 14 cases were diagnosed as non-AD based on clinical and routine MRI assessment. AD cases had higher MTA scores, higher levels of CSF tau and lower levels of CSF Aβ1 - 42, and higher amyloid load on PET compared to the non-AD group. In the AD group, completely consistently pathological biomarkers were found in 32.5% , non-pathological in 5% . In 62.5% the findings were inconsistent. Congruence of biomarkers was 67.5% for neuronal injury and for amyloid dysfunction, respectively. In two patients, clinical diagnosis switched to non-AD due to completely consistent non-pathological biomarker findings. The criteria of the international working group were met in 75.0% . Conclusion: Surprisingly, the number of completely congruent biomarkers was relatively low. Interpretation of AD biomarkers is complicated by multiple biomarker constellations. However, the level of biomarker consistency required to reliably diagnose AD remains uncertain.
    Journal of Alzheimer's disease: JAD 09/2015; 48(2):425-432. DOI:10.3233/JAD-150229 · 4.15 Impact Factor
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    • "Although there have been several possible cut-off values proposed [5, 20–22], there is a lack of agreement on cut-off thresholds due to the variability in CSF measurements between laboratories [23] and across techniques [24]. Combining CSF biomarkers into a single score has been shown to better discriminate between patients with an AD diagnosis compared with healthy controls than an individual biomarker [16] [23] [25] [28]. Examples include the Innotest Amyloid-Tau Index (IATI) defined by the ratio A␤ 1-42 /(240+1.18 "
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    ABSTRACT: Abstract Background: Cerebrospinal fluid (CSF) biomarkers can distinguish Alzheimer’s disease (AD) patients from normal controls; however, their interpretation and potential for use in patients with mild cognitive impairment (MCI) remains unclear. Objective: To examine whether biomarker levels allow for risk stratification among MCI patients who are at increased risk to develop AD, thus allowing for improved targeting of early interventions for those whose risk are higher. Methods: We analyzed data from the Alzheimer’s Disease Neuroimaging Initiative on MCI patients (n = 195) to estimate their risk of developing AD for up to 6 years on the basis of baseline CSF biomarkers. We used time-dependent receiver operating characteristic analysis to identify the best combination of biomarkers to discriminate those who converted to AD from those who remained stable. We used these data to construct a multi-biomarker score and estimated the risk of progression to AD for each quintile of the multi-biomarker score. Results: We found that Aβ 1-42 and P-tau181p were the best combination among CSF biomarkers to predict the overall risk of developing AD among MCI patients (area under the curve = 0.77). The hazard ratio of developing AD among MCI patients with high-risk (3rd–5th quintiles) biomarker levels was about 4 times greater than MCI patients with low-risk (1st quintile) levels (95% confidence interval, 1.93–7.26). Conclusion: Our study identifies MCI patients at increased risk of developing AD by applying a multi-biomarker score using CSF biomarker results. Our findings may be of value to MCI patients and their clinicians for planning purposes and early intervention as well as for future clinical trials.
    Journal of Alzheimer's disease: JAD 01/2015; 47(3):729-740. DOI:10.3233/JAD-150066 · 4.15 Impact Factor
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    • "To assess potential mechanisms by which CLU confers risk for AD, we examined effects of the CLU rs11136000 SNP on CSF Aβ42 and Tau levels, which are reliable disease biomarkers recently used as endophenotypes in AD genetic studies [40]. For this analysis, the AD population was enriched with patients presenting a disease CSF Tau/Aβ42 profile, which has a high diagnostic accuracy for AD over other types of dementia [41], [42]. The CSF from an initial set of 80 patients diagnosed with probable AD and 50 control non-demented individuals was evaluated for Aβ42 and Tau content by specific ELISAs. "
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    ABSTRACT: Sporadic or late-onset Alzheimer's disease (AD) is expected to affect 50% of individuals reaching 85 years of age. The most significant genetic risk factor for late-onset AD is the e4 allele of APOE gene encoding apolipoprotein E, a lipid carrier shown to modulate brain amyloid burden. Recent genome-wide association studies have uncovered additional single nucleotide polymorphisms (SNPs) linked to AD susceptibility, including those in the CLU and BIN1 genes encoding for clusterin (CLU) and the bridging integrator 1 (BIN1) proteins, respectively. Because CLU has been implicated in brain amyloid-β (Aβ) clearance in mouse models of amyloid deposition, we sought to investigate whether an AD-linked SNP in the CLU gene altered Aβ42 biomarker levels in the cerebrospinal fluid (CSF). Instead, we found that the CLU rs11136000 SNP modified CSF levels of the microtubule-associated protein Tau in AD patients. We also found that an intracellular form of CLU (iCLU) was upregulated in the brain of Tau overexpressing Tg4510 mice, but not in Tg2576 amyloid mouse model. By overexpressing iCLU and Tau in cell culture systems we discovered that iCLU was a Tau-interacting protein and that iCLU associated with brain-specific isoforms of BIN1, also recently identified as a Tau-binding protein. Through expression analysis of CLU and BIN1 variants, we found that CLU and BIN1 interacted via their coiled-coil motifs. In co-immunoprecipitation studies using human brain tissue, we showed that iCLU and the major BIN1 isoform expressed in neurons were associated with modified Tau species found in AD. Finally, we showed that expression of certain coding CLU variants linked to AD risk led to increased levels of iCLU. Together, our findings suggest that iCLU and BIN1 interaction might impact Tau function in neurons and uncover potential new mechanisms underlying the etiology of Tau pathology in AD.
    PLoS ONE 07/2014; 9(7):e103187. DOI:10.1371/journal.pone.0103187 · 3.23 Impact Factor
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