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Mirjana Babić, mag.biol.mol. Laboratory for Developmental Neuropathology

COST CM1103 Training School Structure-based drug design for diagnosis and treatment of neurological diseases Istanbul, 9-13 Sept 2013. Biomarkers of Alzheimer’s disease. Mirjana Babić, mag.biol.mol. Laboratory for Developmental Neuropathology Croatian Institute for Brain Research.

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Mirjana Babić, mag.biol.mol. Laboratory for Developmental Neuropathology

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  1. COST CM1103 Training SchoolStructure-based drug design for diagnosis and treatment of neurological diseasesIstanbul, 9-13 Sept 2013 • Biomarkers of Alzheimer’s disease Mirjana Babić, mag.biol.mol. Laboratory for DevelopmentalNeuropathology Croatian Institute for BrainResearch

  2. “Detection and tracking of biological markers for early therapeutic intervention in sporadic Alzheimer's disease”Project oftheCroatian Science Foundation grant no. 09/16 from 1st Jan 2012 – 31st Dec 2014 • neurodegenerative disorder • loss of memory and cognitive decline • in2050 - approximately 80 million people will suffer from Alzheimer’s disease Alzheimer's disease

  3. Ideal markerfor diagnosis of Alzheimer's diseaseis not foundyet! Diagnosisof AD based on criteriaof: • DSM-IV-TR • NINCDS-ADRDA • ICD 10 Characteristics ofgood marker: • sensitivity and specificity above 85% • availability • non invasiveness • acceptable price • possibility for repetitive measures • Aimof this project • to determine the diagnostic accuracy of potentially highly useful biological markers for discrimination among subjects mild cognitive impairment (MCI), non-demented HC, and patients with other primary causes of dementia

  4. Neuropsychological testing • Earlydetection of non-cognitive BPSD(behavioural and psychological symptoms of dementia): • NPI (Neuropsychiatric Inventory) • ADAS-noncog(Alzheimer's disease Assessment Scale for non-cognitive symptoms) • BEHAVE-AD(behaviour rating scale) • Additionaltestingofpatientswiththeriskof AD: • Hidden-goal task (human analogue of the Morris water maze task) Laczo et al., 2009.

  5. Imaging biomarkers • Earliestchange in the • brain of AD patientsis • atrophy of • hippocampus and • entorhinalcortex. BlennowandZetterberg, 2006. • Monitoring ofdiseaseprogressionby: • MRI (Magnetic resonance imaging) • MRS (Magnetic resonance spectroscopy) • SPECT (Single photon emission computorized tomography)

  6. Genetic biomarkers • Geneexpression profiling using the RNA extracted from cells precipitated in pellets of CSF samples • FamilialADcausedbymutationsin: • APP (amyloid precursor protein) • PSEN1 (presenilin1) • PSEN2(presenilin2) • Sporadic AD • ε4 allele of the apolipoprotein E gene (APOE)

  7. Specific polymorphisms of genes coding for components of: • serotonergicsystem (5HT-2A, 5HT-1B, 5HT-2C) • dopaminergicsystem (COMT, DBH, MAO-B) • inflammation pathways (IL-1, IL-6, IL-10, IL-10, TNF) • neuronal development and differentiation (BDNF) • lipoproteins’ metabolism (ApoE)

  8. CSF biomarkers • CSF amyloid β1-42, total tau and phosphorylated tau are the main reflect two major neuropathological hallmarks of AD - neurofibrillary tangles and senile plaques. Andreasson et al., 2007. • T-tau 300% increased in AD patients • Aβ1-4250% decreased AD patients

  9. Phospho-tau reflects phosphorylation state of tau protein and formation of neurofibrillary tangles in the brain NovelCSF biomarkers P-tau199 P-tau231 P-tau181 • VILIP-1, neuronal calcium-sensor protein • VILIP-1/Aβ1-42ratio • sphingolipids

  10. Standardization of procedures in CSF analysis • Levelsof CSF biomarkersvary among different laboratories. • Thecause are variationsin: • Pre-analytical procedures • analytical procedures • differences between ELISA kits of various manufacturers

  11. Ultimate goal of this project is to predict AD in healthy, asymptomatic subjects

  12. Acknowledgements • Thankyou for yourattention! • Pleasevisit: http://alzbiotrack.hiim.hr/

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