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COST CM1103 Training SchoolStructure-based drug design for diagnosis and treatment
of neurological diseasesIstanbul, 9-13 Sept 2013
Mirjana Babić, mag.biol.mol.Laboratory for Developmental Neuropathology
Croatian Institute for Brain Research
Biomarkers of Alzheimer’s disease
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“Detection and tracking of biological markers for early therapeutic intervention in sporadic Alzheimer's disease”
Project of the Croatian Science Foundation grant no. 09/16 from 1st Jan 2012 – 31st Dec 2014
• neurodegenerative disorder• loss of memory and cognitive decline• in 2050 - approximately 80 million people will suffer
from Alzheimer’s disease
Alzheimer's disease
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Ideal marker for diagnosis of Alzheimer's disease is not found yet!
Diagnosis of AD based on criteria of:• DSM-IV-TR• NINCDS-ADRDA • ICD 10
Characteristics of good marker:• sensitivity and specificity above
85%• availability• non invasiveness• acceptable price • possibility for repetitive measures
Aim of 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
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Neuropsychological testing
• Early detection of non-cognitive BPSD (behavioural and psychological symptoms of dementia):
o NPI (Neuropsychiatric Inventory)o ADAS-noncog (Alzheimer's disease Assessment Scale for non-cognitive
symptoms)o BEHAVE-AD (behaviour rating scale)
Laczo et al., 2009.
• Additional testing of patients with the risk of AD:
o Hidden-goal task (human analogue of the Morris water maze task)
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Imaging biomarkers
Earliest change in thebrain of AD patients is atrophy of hippocampus and entorhinal cortex .
Monitoring of disease progression by:• MRI (Magnetic resonance imaging)• MRS (Magnetic resonance spectroscopy)• SPECT (Single photon emission computorized tomography)
Blennow and Zetterberg, 2006.
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Genetic biomarkers
• Gene expression profiling using the RNA extracted from cells precipitated in pellets of CSF samples
• Familial AD caused by mutations in:
1. APP (amyloid precursor protein)
2. PSEN1 (presenilin 1)
3. PSEN2 (presenilin 2)
• Sporadic AD1. ε4 allele of the
apolipoprotein E gene (APOE)
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1. serotonergic system (5HT-2A, 5HT-1B, 5HT-2C)
2. dopaminergic system (COMT, DBH, MAO-B)
3. inflammation pathways (IL-1, IL-6, IL-10, IL-10, TNF)
4. neuronal development and differentiation (BDNF)
5. lipoproteins’ metabolism (ApoE)
• Specific polymorphisms of genes coding for components of:
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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.
• T-tau 300% increased in AD patients• Aβ1-42 50% decreased AD
patients
Andreasson et al., 2007.
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• Phospho-tau reflects phosphorylation state of tau protein and formation of neurofibrillary tangles in the brain
P-tau199 P-tau181P-tau231
Novel CSF biomarkers
• VILIP-1, neuronal calcium-sensor protein• VILIP-1/Aβ1-42 ratio• sphingolipids
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Standardization of procedures in CSF analysis
• Levels of CSF biomarkers vary among different laboratories.• The cause are variations in:1. Pre-analytical procedures 2. analytical procedures 3. differences between ELISA kits of various manufacturers
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• Ultimate goal of this project is to predict AD in healthy, asymptomatic subjects
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Acknowledgements
Thank you for your attention!
Please visit: http://alzbiotrack.hiim.hr/