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: 8.3). 12/2011; 78(1):47-54. DOI: 10.1212/WNL.0b013e31823ed0f0
Source: PubMed

ABSTRACT 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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    • "Althoughthecutoffvalueoftheratiowasclosetothemean ofthecontrols,specificitywasstillquitehigh,whichmeans therewerestillrelativelyfewfalsepositives.Anexplanation forthiscouldbethatADpatientsshowedalargevariation withinabnormalvalues—mainlyaccountedforbytau values—whereascontrolsweremorecenteredaroundlower normalvalues.Forresearchpurposes,forexampleinclusion intrials,itmightbeusefultoassessamyloidmarkersseparatelyfrominjurymarkers .Ourstudyshowshoweverthat forclinicalpurposes,CSFbiomarkersshouldbecombinedto makeuseoftheircomplementaryvalue. Previously,ithasbeenarguedtousearatiowithtaufor earlydiagnosisofAD,andaratiowithp-tauwouldbe moresuitablefordistinctionfromotherdementias[9] [37]. "
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    ABSTRACT: We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-ß1-42 (Aβ42), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimer's disease (AD). We constructed eight Alzheimer profiles with previously published combinations, including regression formulas and simple ratios. We compared their diagnostic accuracy and ability to predict dementia due to AD in 1385 patients from the Amsterdam Dementia Cohort. Results were validated in an independent cohort (n = 1442). Combinations outperformed individual biomarkers. Based on the sensitivity of the best performing regression formulas, cutoffs were chosen at 0.52 for the tau/Aβ42 ratio and 0.08 for the p-tau/Aβ42 ratio. Ratios performed similar to formulas (sensitivity, 91%-93%; specificity, 81%-84%). The same combinations best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tau/Aβ42 ratio. A tau/Aβ42 ratio of >0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 04/2014; 10(6). DOI:10.1016/j.jalz.2013.12.023 · 17.47 Impact Factor
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    • "The detection and quantification of these molecular constituents are used in clinical routine for various neurological diseases, i.e. acute and chronic inflammatory processes or in diseases as Multiple Sclerosis (MS) [5] [6] [13]. The CSF biomarkers β-amyloid (1–42/1–40), total Tau protein and phosphorylated Tau protein are increasingly quantified to discriminate Alzheimer's disease (AD) patients from controls and non-AD dementia patients, and are integrated in research criteria for the definition of AD [9] [16]. There is a strong need to identify additional novel biomarkers for other neurological diseases that can serve as objective and cost-effective tools to support early clinical diagnosis , to predict prognosis, to monitor disease progression and to facilitate (neuroprotective) treatment development. "
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    Clinical biochemistry 01/2014; 47(4-5). DOI:10.1016/j.clinbiochem.2013.12.024 · 2.23 Impact Factor
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    • "tration de peptide bêta-amyloı¨de 1-42 est abaissé e au même niveau que dans la MA dans la plupart des e ´ tudes (revue dans (Mukaetova-Ladinska et al., 2010)). La proté ine tau, ré puté e normale dans la DCL (Koopman et al., 2009), est nettement moins discriminante, une sé rie ré cente de cas consé cutifs d'un centre mé moire où plus de la moitié des patients DCL ont des concentrations de proté ine tau phosphorylé e au-dessus du seuil pathologique (Schoonenboom et al., 2012). "
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