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Biological ancillary study

Biological ancillary study. David Devos MD PhD and coll. Scientific rational. Recently suggested that AD may be first characterized by hypometabolism and impaired mitochondrial bioenergetic functions (Yao et al 2009, 2011)

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Biological ancillary study

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  1. Biological ancillary study David Devos MD PhD and coll.

  2. Scientific rational • Recently suggested that AD may be first characterized by hypometabolism and impaired mitochondrial bioenergetic functions (Yao et al 2009, 2011) • Brain hypometabolism is coupled with increased mitochondrial oxidative stress (Mamelak 2012) • Compromised mitochondrial bioenergetics leads to over-production and accumulation of mitochondrial b-amyloid, coupled with oxidative stress • shift from a primarily aerobic glycolysis pathway to a ketogenic/fatty acid b-oxidation pathway • neurodegeneration? • Role of wet theragnostic biomarkers

  3. Scientific rational • Impaired neuronal calcium homeostasis in AD • Mitochondriaaccumulate Ca(2+) ions for cellular bioenergeticmetabolism and suppression of mitochondiralmotility in the cell • Mitochonfrial membrane permeabilization induction of apoptosis • Modulation of different mitochondrial Ca(2+) transport pathways may have a neuroprotectiverole and represents a potential pharmacological target for future development of AD treatments (Hung et al., 2010). Using a dog model of cardiac ischemia, it has been shown that administration of nilvadipine preserved mitochondrial function (Ito et al., 1989).

  4. Aim • To analyse whether nilvadipineimproves i) mitochondrial dysfunction by the analysis of its consequences on the excessive oxidative stress and the energy metabolism and ii) endothelial function by the analysis of the endothelial microvesicules. This ancillary study may demonstrate the pleiotropic action of nilvadipine in patients with AD and assess the theragnostic value of these wet biomarkers.

  5. Standard Biology • WholeBlood Count • Prothrombinindex • TCA • Hemoglobin • Glycosylatedhemoglobin • Hématocrite • MeanCorpuscularVolume • Iron-BindingProtein Saturation Coefficient • blood electrolytes • Urea • Creatininaemia • Liverfunction : ASAT ALAT GGT • Lipidstatus (includingLDLc, HDLc, triglycerides, Apo E2/E4)protidaemiaserumalbuminProteinelectrophoresisFastingblood glucoseSedimentation rateCRP FastingammoniemiaBlood lactate levelFasting pyruvate levelPostprandial pyruvate level

  6. SpecificBiology BLOOD • Total Antixoxydativestatus (TAS) Total Oxydative StatusmiRNA 8OHdG 4-Hydroxynonenal Vitamin A & C Malonaldialdehyde (MDA) Advanced OxidationProteinProductsAntixydogramme* NQO1 Activity HMOX activityBetaOxidation   Cytokines BBB permeability (S100B) sRAGEadiponectinlectinbiliaryacidsinsulin Tau proteinwhole /phosporylatedAmyloïd beta PROTEOMIC TRANSCRIPTOMIC METABOLOMIC

  7. * QRT-PCR Analysis of : SOD1,SOD2, SOD3, CAT, GPX, GPX1-7, GSR, TXN (TXN2), peroxyredoxine PRX (PRDX2, 4, 5,6), glutaredoxine (GLRX, GLRX2,3,5), NRF2 pathway HMOX, NQO1, GPX2 CerebrospinalFluid • Standard Biology • Cytology • ProteinElectrophoresis • CSF Protein • CSF Gluose + chemistry

  8. SpecificBiology • 8-hydroxy-2'-déoxyguanosine (8-OHdG) • MALONDIALDEHYDE (MDA) • ADVANCED OXIDATION PROTEIN PRODUCTS (AOPP) • 4hydroxynonenal • CARBONYLATED-PROTEINS • STATUT ANTIOXYDANT TOTAL (TAS) • STATUT OXYDANT TOTAL (TOS) • GLUTATHION PEROXYDASE ACTIVITY (GPX) • SUPEROXYDE DISMUTASE ACTIVITY (SOD) • MicroARN • Metabolomic • OrganicAcids • MILLIPLEX MAP multiplex assays (e.g. TNFa, IL1b, IL1ra, IL6, IFNg, TGFb, VEGF)

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