The role of CSF biomarkers in the diagnostic work-up of mixed vascular-degenerative dementia

  • Sebastiaan Engelborghs
    Corresponding author at: Reference Centre for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, BE-2610 Antwerp, Belgium. Tel.: +32 3 265 23 94; fax: +32 3 265 26 18.
    Reference Centre for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, BE-2610 Antwerp, Belgium

    Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, BE-2020 Antwerp, Belgium
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  • Nathalie Le Bastard
    Reference Centre for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, BE-2610 Antwerp, Belgium
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Published:September 04, 2012DOI:


      Low average specificity levels of 48% for clinical diagnosis of possible Alzheimer's disease (AD) reflect the overlap of clinical profiles between AD and non-AD dementias. Should diagnostic errors occur, they most likely involve one of the other primary dementias, mixed pathologies that include a vascular component, or uncertainties that are associated with early diagnosis. Vascular dementia (VaD) is overdiagnosed when a routine brain MRI or CT scan is used in the context of standard clinical diagnostic criteria, meanwhile denying significant neurodegenerative co-pathology.
      A promising approach for increasing diagnostic accuracy is the use of biochemical markers (biomarkers) that are present in the cerebrospinal fluid (CSF). The CSF biomarkers ß-amyloid protein of 42 amino acids (Aß1–42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P) are well validated. A combined analysis of these biomarkers is of help to discriminate AD from non-AD dementias (including VaD), reaching sensitivity and specificity levels that exceed 80%. Moreover, the added value of CSF biomarkers could lie within those cases in which the clinical diagnostic work-up is not able to discriminate between AD or a non-AD dementia. In case of doubt between VaD or mixed AD–VaD pathology in dementia patients, the determination of CSF Aß1–42, T-tau and P-tau181P levels is of help to confirm or exclude the AD component in the pathophysiology of the dementia syndrome.


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        • McKhann G.
        • Drachman D.
        • Folstein M.
        • Katzman R.
        • Price D.
        • Stadlan E.M.
        Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.
        Neurology. 1984; 34: 939-944
        • Knopman D.S.
        • Dekosky S.T.
        • Cummings J.L.
        • Chui H.
        • Corey-Bloom J.
        • Relkin N.
        • et al.
        Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology.
        Neurology. 2001; 56: 1143-1153
        • Roman G.C.
        • Tatemichi T.K.
        • Erkinjuntti T.
        • Cummings J.L.
        • Masdeu J.C.
        • Garcia J.H.
        • et al.
        Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop.
        Neurology. 1993; 43: 250-260
        • Wiederkehr S.
        • Simard M.
        • Fortin C.
        • van R.R.
        Validity of the clinical diagnostic criteria for vascular dementia: a critical review. Part II.
        J Neuropsychiatry Clin Neurosci. 2008; 20: 162-177
        • Hogervorst E.
        • Bandelow S.
        • Combrinck M.
        • Irani S.R.
        • Smith A.D.
        The validity and reliability of 6 sets of clinical criteria to classify Alzheimer's disease and vascular dementia in cases confirmed post-mortem: added value of a decision tree approach.
        Dement Geriatr Cogn Disord. 2003; 16: 170-180
        • Engelborghs S.
        • De Vreese K.
        • Van de Casteele T.
        • Vanderstichele H.
        • Van Everbroeck B.
        • Cras P.
        • et al.
        Diagnostic performance of a CSF-biomarker panel in autopsy-confirmed dementia.
        Neurobiol Aging. 2008; 29: 1143-1159
        • Engelborghs S.
        • Sleegers K.
        • Cras P.
        • Brouwers N.
        • Serneels S.
        • De Leenheir E.
        • et al.
        No association of CSF biomarkers with APOEepsilon4, plaque and tangle burden in definite Alzheimer's disease.
        Brain. 2007; 130: 2320-2326
        • Engelborghs S.
        • Le Bastard N.
        • Feyen B.
        • Goeman J.
        • Martin J.J.
        • De Deyn P.P.
        Overdiagnosis of vascular dementia using structural brain imaging in the context of standard clinical diagnostic criteria.
        in: Alzheimer's Association International Conference. 2011 ([16-7-2011. Ref Type: Conference Proceeding])
        • The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group
        Consensus report of the Working Group on: "Molecular and Biochemical Markers of Alzheimer's Disease".
        Neurobiol Aging. 1998; 19: 109-116
        • Fagan A.M.
        • Shaw L.M.
        • Xiong C.
        • Vanderstichele H.
        • Mintun M.A.
        • Trojanowski J.Q.
        • et al.
        Comparison of Analytical Platforms for Cerebrospinal Fluid Measures of {beta}-Amyloid 1-42, Total tau, and P-tau181 for Identifying Alzheimer Disease Amyloid Plaque Pathology.
        Arch Neurol. 2011; 68: 1137-1144
        • Le Bastard N.
        • Coart E.
        • Vanderstichele H.
        • Vanmechelen E.
        • Martin J.J.
        • Engelborghs S.
        Comparison of two analytical platforms for the clinical qualification of Alzheimer's disease in pathologically confirmed dementia.
        J Alzheimers Dis. 2012; (in press: PMID: 22936010)
        • Blennow K.
        • Hampel H.
        • Weiner M.
        • Zetterberg H.
        Cerebrospinal fluid and plasma biomarkers in Alzheimer disease.
        Nat Rev Neurol. 2010; 6: 131-144
        • Le Bastard N.
        • De Deyn P.P.
        • Engelborghs S.
        Cerebrospinal Fluid Biomarkers for the Differential Diagnosis of Dementia.
        Curr Med Lit Neurol. 2009; 25: 59-68
        • Schoonenboom N.S.
        • Reesink F.E.
        • Verwey N.A.
        • Kester M.I.
        • Teunissen C.E.
        • van de Ven P.M.
        • et al.
        Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort.
        Neurology. 2012; 78: 47-54
        • Blennow K.
        • Johansson A.
        • Zetterberg H.
        Diagnostic value of 14-3-3beta immunoblot and T-tau/P-tau ratio in clinically suspected Creutzfeldt-Jakob disease.
        Int J Mol Med. 2005; 16: 1147-1149
        • de Jong D.
        • Jansen R.W.
        • Kremer B.P.
        • Verbeek M.M.
        Cerebrospinal fluid amyloid beta42/phosphorylated tau ratio discriminates between Alzheimer's disease and vascular dementia.
        J Gerontol A Biol Sci Med Sci. 2006; 61: 755-758
        • Le Bastard N.
        • Martin J.J.
        • Vanmechelen E.
        • Vanderstichele H.
        • De Deyn P.P.
        • Engelborghs S.
        Added diagnostic value of CSF biomarkers in differential dementia diagnosis.
        Neurobiol Aging. 2010; 31: 1867-1876
        • De Reuck J.
        • Deramecourt V.
        • Cordonnier C.
        • Leys D.
        • Pasquier F.
        • Maurage C.A.
        Prevalence of small cerebral bleeds in patients with a neurodegenerative dementia: a neuropathological study.
        J Neurol Sci. 2011; 300: 63-66
        • van Norden A.G.
        • van Dijk E.J.
        • de Laat K.F.
        • Scheltens P.
        • OldeRikkert M.G.
        • de Leeuw F.E.
        Dementia: Alzheimer pathology and vascular factors: From mutually exclusive to interaction.
        Biochim Biophys Acta. 2012; 1822: 340-349
        • Shaw L.M.
        • Vanderstichele H.
        • Knapik-Czajka M.
        • Clark C.M.
        • Aisen P.S.
        • Petersen R.C.
        • et al.
        Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects.
        Ann Neurol. 2009; 65: 403-413
        • McKhann G.M.
        • Knopman D.S.
        • Chertkow H.
        • Hyman B.T.
        • Jack Jr., C.R.
        • Kawas C.H.
        • et al.
        The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.
        Alzheimers Dement. 2011; 7: 263-269
        • Sleegers K.
        • Brouwers N.
        • Van Damme P.
        • Engelborghs S.
        • Gijselinck I.
        • van der Zee J.
        • et al.
        Serum biomarker for progranulin-associated frontotemporal degeneration.
        Ann Neurol. 2009; 65: 603-609
        • Van Damme P.
        • Van Hoecke A.
        • Lambrechts D.
        • Vanacker P.
        • Bogaert E.
        • van Swieten J.
        • et al.
        Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival.
        J Cell Biol. 2008; 181: 37-41
        • Johnstone D.
        • Milward E.A.
        • Berretta R.
        • Moscato P.
        • for the Alzheimer's Disease Neuroimaging Initiative
        Multivariate protein signatures of pre-clinical Alzheimer's disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) plasma proteome dataset.
        PLoS One. 2012; 7: e34341