0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

RF07.39.1 – Genetic risk factors and peripheral biological markers of conversion from Mild…
– which has been recently found to hamper Ab deposition [Mi et al. (2007) Nat
Genetics 39:1440-1442] and mediators of neuroinflammation – an early event
in AD pathogenesis – are of particular interest.
With regard to AD genetics, the major known risk factor (i.e. ApoE4 aplotype)
does not possess predictive value for the conversion of MCI to AD. In
this respect, more promising markers include the H1c haplotype of the tau
locus [Meyers et al. (2005) Hum Mol Gen 14:2399-404] and allelic variants of
genes associated with Ab processing such as SORL1 (Lee et al. (2007) Neurology
online], of the Cystatin C gene [Finckh et al. (2000) Arch Neurol 57:1579-
1583] and genes involved in neuroin-flammation.
What the project adds to the information already available
This project will allow to:
1. Establish Standard Operating Procedures (SOPs) and Quality Control
(QC) for determination of Ab, total tau and phospho-tau concentrations in
CSF, and define the essential protocol having the greatest sensitivity, specificity
and reproducibility for AD diagnosis to be transferred to the Alzheimer
Centers of the Italian NHS. The recognition of the factors that account for the
wide inter- and intra-laboratory variability of the above determinations will
allow to apply controlled procedures, granting consistent results within the
NHS.
2. Identify new peripheral markers and determine which genetic and biochemical
(CSF and plasma) markers among those identified recently effectively
increase the diagnostic specificity and sensitivity of the basic protocol.
This will enable to design an integrated, multivariate molecular protocol for
the diagnosis of incipient AD and the prediction of conversion of MCI into
AD.
OBJECTIVE(S)
The project involves a series of Alzheimer Centers with long experience in
biochemical and molecular diagnosis of AD, that have collected hundreds of
biological samples (DNA, plasma, CSF) from patients affected by AD
(NINCDS-ADRDA criteria), from MCI patients (Petersen’s criteria) with follow-up
of their cognitive status, from patients with other forms of dementia
and from non-demented controls. This set-up will allow to generate and foster
collaboration between the different centers and to gather an adequate number
of cases for appropriate statistical analysis of the results. The project is articulated
in four work-packages having the following aims.
WP1. The main objective is to define and harmonize the Standard Operating
Procedures (SOP) and Quality Control (QC) for the analysis of cerebrospinal
fluid (CSF) markers currently used for the diagnosis of AD.
The SOP defined in 4 laboratories (Units 1,3,6,8) during the first 6
months will be immediately available to all Alzheimer Centers. This protocol
will be implemented during the project in relation to the results obtained.
This will help to define the essential protocol with the greatest sensitivity,
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