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NEUROCHEMISTRY & BIOMARKERS UNIT

Neurochemistry Unit, 1st Department of Neurology,

National and Kapodistrian University of Athens,

Athens, Greece.

 

Staff

Head: Elisabeth Kapaki, Professor of Neurology and Neurochemistry

Senior Investigator: George Paraskevas, Associate Professor of Neurology

Investigator: Vasilios Constantinides, MD, PhD

Technician: Olga Petropoulou

 

PhD candidates: Anastasia Bougea, MD, Mara Bourbouli, George Liakakis, MD

 

Laboratory activity

The “Neurochemistry Unit” (formerly part of the “Research Laboratory” founded in 1986) has become an independent unit of the 1st Dept. of Neurology in 1995, under the leadership of Professor Elisabeth Kapaki. In its long course, various methods have been developed, for the study of neurodegenerative disorders, mainly Alzheimer’s and Parkinson’s diseases and related disorders, includingmethods for:

(a) Trace elements in the CSF and serum by atomic absorption spectrophotometry

(b) Free amino acids in the CSF and serum by high pressure liquid chromatography (HPLC)

(c) Substances with special interest for the nervous system,including monoamines and substances related to oxidative stress, such as ascorbic acid, vitamin E, glutathione and protein carbonyls.

However, the main focus of the Lab during recent years has been the applicationof methods for the quantitative analysis of CSF total tau (T-tau), phosphorylated tau (phospho-tau) and beta-amyloid peptide (1-42), as biomarkers of particular importance for the diagnosis of Alzheimer's disease and other dementias. Results of this activity have been published in high impact factor journals1-15,18,25 and two of thesehave been included in the recent European guidelines for the diagnosis and treatment of dementia (EFNS Task Force 2007),2,4 which was also translated and published by the Dementia Branch of the Hellenic Neurological Society (co-ordinator and editor of the Greek edition E. Kapaki).26

We have participated in various international quality control programs16,19 and, recently,we participated as partner #34 in the Joint Programming on Neurodegenerative Diseases (JPND) - Biological markers for Alzheimer's disease and Parkinson's Disease (BIOMARKAPD) (“European S & T Cooperation - Grant Act of Greek actors who are participating successfully in Joint Call for Proposals of the initiatives of the Joint planning –Joint Programming Initiatives”, 2012). This activity has led to significant contributions regarding pre-analytical and analytical recommendations of CSF sample handling, towards harmonization of standard operation procedures worldwide and reduction of in-between laboratory variation.17

In collaboration with the Laboratory of Neurodegenerative Disorders of the Academy of Athens, we have studied the levels of α-synuclein in the CSF by a new sensitive ELISA method and investigated its diagnostic value as a surrogate biomarker for “synucleinopathies” (Parkinson’s disease, Dementia with Lewy bodies, Multiple System Atrophy). Our findings are compatible with high specificity and moderate sensitivity for the differential diagnosis between Lewy body dementia and either normal ageing or Alzheimer’s disease. Part of this work has been published in PLOS-One.20 We have also participated in a systematic review of the utility of CSF α-synuclein as biomarker in neurodegenerative diseases.21

Additionally, thenewly developed surrogate biomarker for the FTD-ALS spectrum TDP-43 has been recently introduced in the panel of our biomarkers.22 Correlation of this and the classical biomarkers with the genetic subtypes of FTD-ALS is in progress in an effort to create a basis of personalized medicine.

Our latest plans include studying specific markers for diagnosis of vascular cognitive impairment.

Since part of the above staff (E.K., G.P., V.C.) are also in charge of the Cognitive and Movement disorders Clinic– 1st Department of Neurology, University of Athens, we examine and hospitalize patients with Parkinson’s disease  and other movement disorders and we maintain a “CSF bank” of well characterized samples according to recent preanalytical considerations.24

 

Relevant References

  1. KAPAKI E, PARASKEVAS GP, MICHALOPOULOU M, KILIDIREAS K. Increased cerebrospinal fluid tau protein in Multiple Sclerosis.European Neurology 2000; 43: 228-232.
  2. KAPAKI E, KILIDIREAS K, PARASKEVAS GP, MICHALOPOULOU M, PATSOURIS E. Highly increased CSF Tau protein and decreased β-Amyloid(1-42) in sporadic CJD. A discrimination from Alzheimer’s disease? Journal of Neurology Neurosurgery and Psychiatry 2001; 71: 401-403.       
  3. WOLLMER AM, PAPASSSOTIROPOULOS A, STREFFER JR, GRIMALDI LME, KAPAKI E, PARASKEVAS GP, MADDALENA A, DE QUERVAIN D, BIEBER C, UMBRICHT D, LEMKE U, BOSSARDT S, DEGONDA N, HENKE-WESTERHOLT K, HEGI T, JUNG HH, PASCH T, HESS K, HOCK C, NITSCH RM. Genetic polymorphisms and CSF levels of TIMP-1 in sporadic Alzheimer’s disease.  Psychiatric Genetics 2002; 12: 155-160.                     
  4. KAPAKI E, PARASKEVAS G.P, ZALONIS J, ZOURNAS C. CSF tau protein and b-Amyloid (1–42) in Alzheimer’s disease diagnosis: Discrimination from normal ageing and other dementias in the Greek population. European Journal of Neurology 2003; 10: 119-128.
  5. FINCKH U, KUSCHEL C, ANAGNOSTOULI M, PATSOURIS E, PANTES GV, GATZONIS S, KAPAKI E, DAVAKI P, LAMSZUS K, STAVROU D, GAL A. Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics 2005; 6: 85-89.
  6. PARASKEVAS GP, KAPAKI E,  LIAPPAS I, THEOTOKA I,  MAMALI I, ZOURNAS C, LYKOURAS L. The diagnostic value of cerebrospinal fluid tau protein in dementing and non-dementing neuropsychiatric disorders.Journal of  Geriatric Psychiatry and Neurology 2005; 18: 163-173.            
  7. KAPAKI E, LIAPPAS I, PARASKEVAS G.P, THEOTOKA I, RABAVILAS A. The diagnostic value of cerebrospinal fluid tau protein, β-amyloid (1-42) and their ratio for the discrimination of alcohol-related cognitive disorders from Alzheimer’s disease in the early stages.International Journal of Geriatric Psychiatry 2005; 20: 722-729.
  8. WOLLMER MA, KAPAKI E, HERSBERGER M, MUNTWYLER J, BRUNNER F, TSOLAKI M, AKATSU H, KOSAKA K, MICHIKAWA M, MOLYVA D, PARASKEVAS GP, LÜTJOHANN D, VON ECKARDSTEIN A, HOCK C,NITSCH RM, PAPASSOTIROPOULOS A. Ethnicity-dependent genetic association of ABCA2 with sporadic Alzheimer’s disease. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 534-536.                     
  9. PAPASSOTIROPOULOS A, LAMBERT JC, WAVRANT-DE VRIEZE F, WOLLMER MA, VON DER KAMMER H, STREFFER JR, MADDALENA A, HUYNH KD, WOLLEB S, LUTJOHANN D, SCHNEIDER B, THAL DR, GRIMALDI LM, TSOLAKI M, KAPAKI E, RAVID R, KONIETZKO U, HEGI T, PASCH T, JUNG H, BRAAK H, AMOUYEL P, ROGAEV EI, HARDY J, HOCK C, NITSCH RM. Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer's disease.Neurodegenerative Diseases 2006; 2: 233-41.                  
  10. PARASKEVAS G.P, KAPAKI E, KARARIZOU E, MITSONIS C, SFAGOS K, VASSILOPOULOS D. CSF tau protein is increased in neurosyphilis. A discrimination from syphilis without nervous system involvement.Sexually Transmitted Diseases 2007; 34: 220-223.         
  11. KAPAKI E, PARASKEVAS GP, TZERAKIS NG, SFAGOS K, SERETIS A, KARARIZOU E, VASSILOPOULOS D. Cerebrospinal fluid tau, phospho-tau181 and β-amyloid1-42 in idiopathic normal pressure hydrocephalus: A discrimination from Alzheimer’s disease. European Journal of Neurology 2007 ; 14: 168-173.         
  12. WOLLMER MA, SLEEGERS K, INGELSSON M, ZEKANOWSKI C, BROUWERS N, MARUSZAK A, BRUNNER F, HUYNH KD, KILANDER L, BRUNDIN RM, HEDLUND M, GIEDRAITIS V, GLASER A, ENGELBORGHS S, DE DEYN PP, KAPAKI E, TSOLAKI M, DANIILIDOU M, MOLYVA D, PARASKEVAS GP, THAL DR, BARCIKOWSKA M, KUZNICKI J, LANNFELT L, VAN BROECKHOVEN C, NITSCH RM, HOCK C, PAPASSOTIROPOULOS A. Association study of cholesterol-related genes in Alzheimer's disease. Neurogenetics 2007; 8: 179-188     
  13. SIMONSEN AH, McGUIRE J, PODUST V, HAGNELIUS NO, NILSSON T, KAPAKI E, VASSILOPOULOS D, WALDEMAR G. A novel panel of cerebrospinal fluid biomarkers for the differential diagnosis of Alzheimer’s disease versus normal aging and Frontotemporal dementia. Dementia and Geriatric Cognitice Disorders 2007; 24: 434-440.
  14. KAPAKI E, PARASKEVAS GP, PAPAGEORGIOU SG, BONAKIS A, KALFAKIS N, ZALONIS I, VASSILOPOULOS D. Diagnostic value of CSF biomarker profile in frontotemporal lobar degeneration. Alzheimer’s Disease & Associated Disorders 2008; 22: 47-53.
  15. PARASKEVAS GP, KAPAKI E, PAPAGEORGIOU SG, KALFAKIS N, ANDREADOU E, ZALONIS I, VASSILOPOULOS D. CSF biomarker profile and diagnostic value in vascular dementia. European Journal of Neurology 2009;16:205-211.             
  16. VERWEY NA, VAN DER FLIER WM, BLENNOW K, CLARK C, SOKOLOW S, DE DEYN PP, GALASKO D, HAMPEL H, HARTMANN T, KAPAKI E, LANNFELT L, MEHTA PD, PARNETTI L, PETZOLD A, PIRTTILA T, SALEH L, SKINNINGSRUD A, SWIETEN JC, VERBEEK MM, WILTFANG J, YOUNKIN S, SCHELTENS P, BLANKENSTEIN MA. A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer's disease.Annals of ClinicalBiochemistry 2009; 46: 235-40.
  17. DEL CAMPO M, MOLLENHAUER B, BERTOLOTTO A, ENGELBORGHS S, HAMPEL H, SIMONSEN AH, KAPAKI E, KRUSE N, LE BASTARD N, LEHMANN S, MOLINUEVO JL, PARNETTI L, PERRET-LIAUDET A, SÁEZ-VALERO J, SAKA E, URBANI A, VANMECHELEN E, VERBEEK M, VISSER PJ, TEUNISSEN C. Recommendations to standardize preanalytical confounding factors in Alzheimer's and Parkinson's disease cerebrospinal fluid biomarkers: an update. Biomarkers in Medicine 2012; 6(4): 419-30.
  18. VLACHOS GS, PARASKEVAS GP, NAOUMIS D, KAPAKI E. Cerebrospinal fluid β-amyloid 1-42 correlates with rate of progression in Alzheimer's disease. Journal of Neural Transmission 2012; 119(7):799-804.
  19. MATTSSON N et al on behalf of ALZHEIMER'S ASSOCIATION QC PROGRAM WORK GROUP. CSF biomarker variability in the Alzheimer's Association quality control program. AlzheimersDement. 2013 May;9(3):251-261.
  20. KAPAKI E, PARASKEVAS GP, EMMANOUILIDOU E, VEKRELLIS K.The diagnostic value of CSF α-synuclein in the differential diagnosis of dementia with Lewy bodies vs. normal subjects and patients with Alzheimer's disease. PLoS One. 2013;8:e81654.
  21. SIMONSEN AH, KUIPERIJ B, EL-AGNAF OM, ENGELBORGHS S, HERUKKA SK, PARNETTI L, REKTOROVA I, VANMECHELEN E, KAPAKI E, VERBEEK M, MOLLENHAUER B.The utility of α-synuclein as biofluid marker in neurodegenerative diseases: a systematic review of the literature. Biomark Med. 2016;10(1):19-34.
  22. BOURBOULI M, RENTZOS M, BOUGEA A, ZOUVELOU V, CONSTANTINIDES VC, ZAGANAS I, EVDOKIMIDIS I, KAPAKI E, PARASKEVAS GP.Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders. Dement GeriatrCognDisord.2017;44(3-4):144-152.
  23. KOUTSIS G, PANAS M, PARASKEVAS GP, BOUGEA AM, KLADI A, KARADIMA G, KAPAKI E.From mild ataxia to Huntington disease phenocopy: the multiple faces of spinocerebellar ataxia 17. Case Rep Neurol Med. 2014:643289.
  24. REIJS BL, TEUNISSEN CE…KAPAKI Eet al.  The Central Biobank and Virtual Biobank of BIOMARKAPD: A Resource for Studies on Neurodegenerative Diseases.Front Neurol. 2015;6:216.
  25. PARASKEVAS GP, KASELIMIS D, KOURTIDOU E, CONSTANTINIDES V, BOUGEA A, POTAGAS C, EVDOKIMIDIS I, KAPAKI E.Cerebrospinal Fluid Biomarkers as a Diagnostic Tool of the Underlying Pathology of Primary Progressive Aphasia.J Alzheimers Dis. 2017;55(4):1453-1461
  26. WALDEMAR G, DUBOIS B, EMRE M, GEORGES J, MCKEITH I, ROSSOR M, SCHELTENS P, TARISKA P, WINBLAD B. Συστάσεις για την διάγνωση της νόσου Alzheimer και άλλων διαταραχών σχετιζομένων με άνοια: Κατευθυντήριες οδηγίες της Ευρωπαϊκής Ομοσπονδίας Νευρολογικών Εταιρειών (EFNS guidelines 2007). Επιμέλεια έκδοσης για τον κλάδο άνοιας της ΕΝΕ: E. KAΠAKH, Π. ΜΠΕΡΕΔΗΜΑΣ, Β. ΚΩΣΤΑ, Γ. ΠΑΡΑΣΚΕΥΑΣ. Μετάφραση Γ. ΝΑΣΗΣ, Π. ΜΑΪΟΒΗΣ, Κ. ΨΥΧΟΓΙΟΣ. Οι οδηγίες εκδόθηκαν σε μικρό βιβλίο αλλά και σε ειδικό τεύχος του περιοδικού Νευρολογία. (Νευρολογία, 2008;17:65-98)

1ST DEPARTMENT OF NEUROLOGY: