Mirjana Babić, mag.biol.mol. Laboratory for Developmental Neuropathology
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Transcript of Mirjana Babić, mag.biol.mol. Laboratory for Developmental Neuropathology
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
“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
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
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)
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.
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)
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:
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.
• 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
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
• Ultimate goal of this project is to predict AD in healthy, asymptomatic subjects
Acknowledgements
Thank you for your attention!
Please visit: http://alzbiotrack.hiim.hr/