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/