Advertisement

Alzheimer's disease: Elevated pigment epithelium-derived factor in the cerebrospinal fluid is mostly of systemic origin

  • Author Footnotes
    1 These authors contributed equally to this study.
    Veronika Lang
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of Neurosurgery, Experimental Neurosurgery, Charité - Universitätsmedizin, Berlin, Germany

    Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin, Berlin, Germany
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this study.
    Marietta Zille
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of Experimental Neurology, Center for Stroke Research Berlin, Charité - Universitätsmedizin, Berlin, Germany

    Department of Neurology and Neuroscience, The Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY, USA
    Search for articles by this author
  • Carmen Infante-Duarte
    Affiliations
    Experimental Neuroimmunology Research Group, Institute for Medical Immunology, Charité - Universitätsmedizin, Berlin, Germany,
    Search for articles by this author
  • Sven Jarius
    Affiliations
    Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany
    Search for articles by this author
  • Holger Jahn
    Affiliations
    Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Search for articles by this author
  • Friedemann Paul
    Affiliations
    NeuroCure Clinical Research Center, Charité - Universitätsmedizin, Berlin, Germany

    Department of Neurology, Charité - Universitätsmedizin, Berlin, Germany

    Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité – Universitätsmedizin Berlin, Berlin, Germany
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this study.
    Klemens Ruprecht
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of Neurology, Charité - Universitätsmedizin, Berlin, Germany
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this study.
    Ana Luisa Pina
    Correspondence
    Corresponding author at: Department of Neurosurgery, Experimental Neurosurgery/BCRT, Charité Universitätsmedizin, Campus Mitte, Chariteplatz 1/Virchowweg 21, Aschheim-Zondek-Haus 03-003, 10117 Berlin, Germany.
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of Neurosurgery, Experimental Neurosurgery, Charité - Universitätsmedizin, Berlin, Germany

    Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin, Berlin, Germany
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this study.
Published:January 17, 2017DOI:https://doi.org/10.1016/j.jns.2017.01.051

      Highlights

      • PEDF is increased in CSF of patients with AD, FTD, and bacterial meningitis.
      • PEDF is also elevated in serum of patients with AD.
      • Elevated PEDF in CSF of AD patients is mostly due to elevated PEDF in serum.
      • It is important to relate protein concentrations in CSF to serum concentrations.
      • This helps to avoid erroneous interpretations of increased protein in lumbar CSF.

      Abstract

      Pigment-epithelium derived factor (PEDF) is a neurotrophic factor with neuroprotective, anti-tumorigenic, and anti-angiogenic effects. Elevated levels of PEDF have previously been proposed as a cerebrospinal fluid (CSF) biomarker for Alzheimer's disease. However, the origin of PEDF in CSF, i.e. whether it is derived from the brain or from the systemic circulation, and the specificity of this finding hitherto remained unclear. Here, we analyzed levels of PEDF in paired CSF and serum samples by ELISA in patients with Alzheimer's disease (AD, n = 12), frontotemporal dementia (FTD, n = 6), vascular dementia (n = 4), bacterial meningitis (n = 8), multiple sclerosis (n = 32), pseudotumor cerebri (n = 36), and diverse non-inflammatory neurological diseases (n = 19). We established CSF/serum quotient diagrams to determine the fraction of intrathecally synthesized PEDF in CSF. We found that PEDF is significantly increased in CSF of patients with AD, FTD, and bacterial meningitis. Remarkably, PEDF concentrations were also significantly elevated in serum of patients with AD. CSF/serum quotient diagrams demonstrated that elevated PEDF concentrations in CSF of patients with AD are mostly due to elevated PEDF concentrations in serum. These findings underscore the importance of relating concentrations of proteins in CSF to their respective concentrations in serum to avoid erroneous interpretations of increased protein concentrations in lumbar CSF.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Alzheimer's Association
        2015 Alzheimer's disease facts and figures.
        Alzheimers Dement. 2015; 11: 332-384
        • Prince M.
        • Wimo A.
        • Guerchet M.
        • Ali G.C.
        • Wu Y.T.
        • Prina M.
        • A.s.D. International
        World Alzheimer Report 2015. The Global Impact of Dementia. An Analysis of Prevalence, Incidence, Cost and Trends.
        Alzheimer's Disease International (ADI), London, UK2015
        • Knight E.M.
        • Kim S.H.
        • Kottwitz J.C.
        • Hatami A.
        • Albay R.
        • Suzuki A.
        • Lublin A.
        • Alberini C.M.
        • Klein W.L.
        • Szabo P.
        • Relkin N.R.
        • Ehrlich M.
        • Glabe C.G.
        • Gandy S.
        • Steele J.W.
        Effective anti-Alzheimer Abeta therapy involves depletion of specific Abeta oligomer subtypes.
        Neurol Neuroimmunol Neuroinflamm. 2016; 3e237
        • Tombran-Tink J.
        The neuroprotective and angiogenesis inhibitory serpin, PEDF: new insights into phylogeny, function, and signaling.
        Front. Biosci. 2005; 10: 2131-2149
        • Tombran-Tink J.
        • Johnson L.V.
        Neuronal differentiation of retinoblastoma cells induced by medium conditioned by human RPE cells.
        Invest. Ophthalmol. Vis. Sci. 1989; 30: 1700-1707
        • van Wagenen S.
        Protein Expression and Localization of Pigment Epithelium Derived Factor in the Central Nervous System of the Rat during Postnatal Development.
        Universität Regensburg, 2008
        • Yabe T.
        • Wilson D.
        • Schwartz J.P.
        NFkappaB activation is required for the neuroprotective effects of pigment epithelium-derived factor (PEDF) on cerebellar granule neurons.
        J. Biol. Chem. 2001; 276: 43313-43319
        • Guan M.
        • Yam H.F.
        • Su B.
        • Chan K.P.
        • Pang C.P.
        • Liu W.W.
        • Zhang W.Z.
        • Lu Y.
        Loss of pigment epithelium derived factor expression in glioma progression.
        J. Clin. Pathol. 2003; 56: 277-282
        • Yamagishi S.
        • Matsui T.
        • Nakamura K.
        • Inoue H.
        Pigment epithelium-derived factor is a pericyte mitogen secreted by microvascular endothelial cells: possible participation of angiotensin II-elicited PEDF downregulation in diabetic retinopathy.
        Int. J. Tissue React. 2005; 27: 197-202
        • Falk T.
        • Zhang S.
        • Sherman S.J.
        Pigment epithelium derived factor (PEDF) is neuroprotective in two in vitro models of Parkinson's disease.
        Neurosci. Lett. 2009; 458: 49-52
        • Taniwaki T.
        • Becerra S.P.
        • Chader G.J.
        • Schwartz J.P.
        Pigment epithelium-derived factor is a survival factor for cerebellar granule cells in culture.
        J. Neurochem. 1995; 64: 2509-2517
        • Taniwaki T.
        • Hirashima N.
        • Becerra S.P.
        • Chader G.J.
        • Etcheberrigaray R.
        • Schwartz J.P.
        Pigment epithelium-derived factor protects cultured cerebellar granule cells against glutamate-induced neurotoxicity.
        J. Neurochem. 1997; 68: 26-32
        • Zhu C.
        • Zhang X.
        • Qiao H.
        • Wang L.
        • Xing Y.
        • Wang C.
        • Dong L.
        • Ji Y.
        • Cao X.
        The intrinsic PEDF is regulated by PPARgamma in permanent focal cerebral ischemia of rat.
        Neurochem. Res. 2012; 37: 2099-2107
        • Terzi M.Y.
        • Casalis P.
        • Lang V.
        • Zille M.
        • Bruendl E.
        • Stoerr E.M.
        • Brawanski A.
        • Vajkoczy P.
        • Thomale U.
        • Pina A.L.
        Effects of pigment epithelium derived factor on traumatic brain injury.
        Restor. Neurol. Neurosci. 2014;
        • Sanagi T.
        • Yabe T.
        • Yamada H.
        Gene transfer of PEDF attenuates ischemic brain damage in the rat middle cerebral artery occlusion model.
        J. Neurochem. 2008; 106: 1841-1854
        • Yamagishi S.
        • Inagaki Y.
        • Takeuchi M.
        • Sasaki N.
        Is pigment epithelium-derived factor level in cerebrospinal fluid a promising biomarker for early diagnosis of Alzheimer's disease?.
        Med. Hypotheses. 2004; 63: 115-117
        • Castano E.M.
        • Roher A.E.
        • Esh C.L.
        • Kokjohn T.A.
        • Beach T.
        Comparative proteomics of cerebrospinal fluid in neuropathologically-confirmed Alzheimer's disease and non-demented elderly subjects.
        Neurol. Res. 2006; 28: 155-163
        • Abraham J.D.
        • Calvayrac-Pawlowski S.
        • Cobo S.
        • Salvetat N.
        • Vicat G.
        • Molina L.
        • Touchon J.
        • Michel B.F.
        • Molina F.
        • Verdier J.M.
        • Fareh J.
        • Mourton-Gilles C.
        Combined measurement of PEDF, haptoglobin and tau in cerebrospinal fluid improves the diagnostic discrimination between Alzheimer's disease and other dementias.
        Biomarkers. 2011; 16: 161-171
        • Roher A.E.
        • Maarouf C.L.
        • Sue L.I.
        • Hu Y.
        • Wilson J.
        • Beach T.G.
        Proteomics-derived cerebrospinal fluid markers of autopsy-confirmed Alzheimer's disease.
        Biomarkers. 2009; 14: 493-501
        • Reiber H.
        • Peter J.B.
        Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs.
        J. Neurol. Sci. 2001; 184: 101-122
        • Teunissen C.E.
        • Petzold A.
        • Bennett J.L.
        • Berven F.S.
        • Brundin L.
        • Comabella M.
        • Franciotta D.
        • Frederiksen J.L.
        • Fleming J.O.
        • Furlan R.
        • Hintzen R.Q.
        • Hughes S.G.
        • Johnson M.H.
        • Krasulova E.
        • Kuhle J.
        • Magnone M.C.
        • Rajda C.
        • Rejdak K.
        • Schmidt H.K.
        • van Pesch V.
        • Waubant E.
        • Wolf C.
        • Giovannoni G.
        • Hemmer B.
        • Tumani H.
        • Deisenhammer F.
        A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking.
        Neurology. 2009; 73: 1914-1922
        • Olesen J.
        • Steiner T.J.
        The International Classification of Headache Disorders, 2nd edn (ICDH-II).
        J. Neurol. Neurosurg. Psychiatry. 2004; 75: 808-811
        • 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
        • Polman C.H.
        • Reingold S.C.
        • Edan G.
        • Filippi M.
        • Hartung H.P.
        • Kappos L.
        • Lublin F.D.
        • Metz L.M.
        • McFarland H.F.
        • O'Connor P.W.
        • Sandberg-Wollheim M.
        • Thompson A.J.
        • Weinshenker B.G.
        • Wolinsky J.S.
        Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”.
        Ann. Neurol. 2005; 58: 840-846
        • MacLean L.
        • Reiber H.
        • Kennedy P.G.E.
        • Sternberg J.M.
        Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response.
        PLoS Negl. Trop. Dis. 2012; 6e1857
        • Kruse T.
        • Reiber H.
        • Neuhoff V.
        Amino acid transport across the human blood-CSF barrier. An evaluation graph for amino acid concentrations in cerebrospinal fluid.
        J. Neurol. Sci. 1985; 70: 129-138
        • Lewczuk P.
        • Reiber H.
        • Tumani H.
        Intercellular adhesion molecule-1 in cerebrospinal fluid—the evaluation of blood-derived and brain-derived fractions in neurological diseases.
        J. Neuroimmunol. 1998; 87: 156-161
        • Zille M.
        • Riabinska A.
        • Terzi M.Y.
        • Balkaya M.
        • Prinz V.
        • Schmerl B.
        • Nieminen-Kelha M.
        • Endres M.
        • Vajkoczy P.
        • Pina A.L.
        Influence of pigment epithelium-derived factor on outcome after striatal cerebral ischemia in the mouse.
        PLoS One. 2014; 9e114595
        • Kuncl R.W.
        • Bilak M.M.
        • Bilak S.R.
        • Corse A.M.
        • Royal W.
        • Becerra S.P.
        Pigment epithelium-derived factor is elevated in CSF of patients with amyotrophic lateral sclerosis.
        J. Neurochem. 2002; 81: 178-184
        • Davidsson P.
        • Sjogren M.
        • Andreasen N.
        • Lindbjer M.
        • Nilsson C.L.
        • Westman-Brinkmalm A.
        • Blennow K.
        Studies of the pathophysiological mechanisms in frontotemporal dementia by proteome analysis of CSF proteins.
        Brain Res. Mol. Brain Res. 2002; 109: 128-133
        • Conti A.
        • Ricchiuto P.
        • Iannaccone S.
        • Sferrazza B.
        • Cattaneo A.
        • Bachi A.
        • Reggiani A.
        • Beltramo M.
        • Alessio M.
        Pigment epithelium-derived factor is differentially expressed in peripheral neuropathies.
        Proteomics. 2005; 5: 4558-4567
        • Reiber H.
        The discrimination between different blood-CSF barrier dysfunctions and inflammatory reactions of the CNS by a recent evaluation graph for the protein profile of cerebrospinal fluid.
        J. Neurol. 1980; 224: 89-99