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http://www.umcn.nl/Research/Departments/cdl/PRIME/Pages/PRIMELecture.aspx

http://www.umcn.nl/Research/Departments/cdl/PRIME/Pages/PRIMELecture.aspx

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    Prime valerio zerbi Prime valerio zerbi Presentation Transcript

    • Multi nutrient enriched diets restore cerebralperfusion and protect against neurodegeneration in amouse model for Alzheimer’s diseaseValerio Zerbi1,2, D. Jansen1, X. Fang1, M. Wiesmann1, M. Mutsaers1, P.J. Dederen1,I.Arnoldussen1, A. Veltien2, S. Van Asten2, A. Heerschap2 and A.J. Kiliaan11 Dept. Anatomy, Donders Centre for Neuroscience, Radboud University Nijmegen MedicalCentre, Nijmegen, the Netherlands2 Dept. Radiology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
    • Introduction Alzheimer’s Disease (AD)AD affects more than 24 million people world wideAge is the major risk factor for AD: 47% of people olderthan 85 years affected80 million affected in 2040Clinical phenotype: gradual episodic memory impairmentNeuropathological changes:• Presence of plaque and tangle pathology• Massive loss neuronal cells and synapses• Neurodegeneration / white matter pathology
    • IntroductionGenetics & risk factors1. Sporadic AD (late onset) Epidemiology (end of 20th century) Causes unclear Risk factors for Alzheimer’s disease Risk factors Ageing Presence of APOEε4 allele Hypertension Congestive heart failure2. Familial AD (early onset) Atrial fibrillation Mutations in amyloid precursor Atherosclerosis Smoking protein (APP), presenilin (PS)-1 High intake of saturated fat or -2 genes Diabetes mellitus contribute to increased Stroke Sedentary lifestyle Aβ production Overweight White matter lesions De la Torre JC (2002), Stroke
    • Introduction Regulation of β-amyloid production / clearance Physiological situation β-amyloid Microglial cellsγ-secretase β-secretase Energy supply Blood flow
    • Introduction Regulation of β-amyloid production / clearance • Abnormal cleavage of APP by γ- and β-secretase β-amyloid Activated •monomers • Decrease Aβ clearance by •dimers Microglial cells reduced cerebral blood flowγ-secretase •trimers •Aβ oligomers and plaques β-secretase • Vascular amyloid deposition (CAA) β-amyloid β-amyloid plaques • Chronic inflammatory oligomers response • Energy crisis Energy supply Blood flow • Neurodegeneration
    • Introduction Regulation of β-amyloid production / clearance • Abnormal cleavage of APP by γ- and β-secretase β-amyloid Activated •monomers • Decrease Aβ clearance by •dimers Microglial cells reduced cerebral blood flowγ-secretase •trimers •Aβ oligomers and plaques β-secretase • Vascular amyloid deposition (CAA) β-amyloid β-amyloid plaques • Chronic inflammatory oligomers response • Energy crisis Energy supply Blood flow • Neurodegeneration
    • Introduction Prevention strategies• Immunotherapy Targeting Aβ Still need to prove their efficacy on clinical trials• “classic” vascular risk factors Prevention vascular disease (statins, aspirin, NSAIDs) No beneficial effect on Alzheimer pathology Improving neuronal connectivity Improvement of neuronal membrane fluidity• Docosahexaenoic acid (DHA) Improves vascular status and reduces atherosclerosis Decrease Aβ levels Beneficial effect in patients with mild AD # •*AD2000 collaborative group. Lancet Neurology 2008;7:41-49 •#Freund- levi et al arch neurol 2008
    • Introduction Prevention strategies• Immunotherapy Targeting Aβ Still need to prove their efficacy on clinical trials• “classic” vascular risk factors Prevention vascular disease (statins, aspirin, NSAIDs) No beneficial effect on Alzheimer pathology Improving neuronal connectivity Improvement of neuronal membrane fluidity• Docosahexaenoic acid (DHA) Improves vascular status and reduces atherosclerosis Decrease Aβ levels Beneficial effect in patients with mild AD # •*AD2000 collaborative group. Lancet Neurology 2008;7:41-49 •#Freund- levi et al arch neurol 2008
    • Introduction Prevention strategies• Immunotherapy Targeting Aβ Still need to prove their efficacy on clinical trials• “classic” vascular risk factors Prevention vascular disease (statins, aspirin, NSAIDs) No beneficial effect on Alzheimer pathology Improving neuronal connectivity Improvement of neuronal membrane fluidity• Docosahexaenoic acid (DHA) Improves vascular status and reduces atherosclerosis Decrease Aβ levels Beneficial effect in patients with mild AD # •*AD2000 collaborative group. Lancet Neurology 2008;7:41-49 •#Freund- levi et al arch neurol 2008
    • Aim of the studyAim of the study“to investigate the effects of DHA enriched diet on the pathophysiology of Alzheimer’s Disease”
    • Material and methodsAnimal model• 12 months old male mice – Transgenic strain resembling familial AD: APP695swe/PS1∆E9 [APP/PS1] (Dr. D. Borchelt, Baltimore, MD, USA) – C57BL/6J [wild type] control mice
    • Material and methods Diets Starting from 2 months of age…(Control) (DHA+) (Fortasyn)5% soy oil DHA DHA EPA EPAStandard UMP UMPcontrol diet Choline Phospholipids B-vitamins Anti-oxidants Kamphuis PJ and Scheltens P (2010), Wurtman RJ (2008)
    • Material and methods Delatour et al., In Vivo Imaging Biomarkers in Mouse Models of Alzheimer’s Disease: Are We Lost in Translation or Breaking Through? J Alzh dis 2010
    • 1. 1H MR Spectroscopy
    • Methods – MRS1H Magnetic Resonance Spectroscopy Metabolites of interest: • N-Acetylaspartate (NAA): neuronal marker, reflects neuronal dysfunction • Myo-inositol (mI): glial marker, associated with inflammation
    • Results – MRSResults 1H MRS
    • 2. Cerebral blood flow (X + CBF) – X = CBF
    • Methods – Cerebral blood flow FAIR (Flowsensitive alternating inversion recovery)IR 180 90 180 Slice selective inversion: (X+CBF) Label slab Imaging slice Global inversion: (X) Global slab S-G Kim et al, MRM 37:425-435 (1997) KK Kwong et al, MRM 34:878-887 (1995)
    • Methods – Cerebral blood flowT1-fitting selective / global ≈ CBF T1 selective T1 global TI (inversion time)
    • Results – Cerebral blood flowResults – Cerebral Blood Flow
    • 3. Diffusion Tensor Imaging
    • Methods – Diffusion Tensor imaging Brownian motion 1  (r  r0 )  (r  r0 ) Diffusion MR imaging P(r , t | r0 ,0)  (4Dt )3 exp    4 Dt   r 2   6D • Theoretical result • Signal attenuation • Loss of phase coherence  2   M xy  M 0 exp     G      D    3 
    • Methods – Diffusion Tensor imaging Anisotropy• Directionally dependent• Restriction in diffusion direction – Because of axonal membrane• Water molecules diffuse approximately 8 µm in ~40 ms diffusion time.
    • Methods – Diffusion Tensor imaging Diffusion tensor imaging  Dxx Dxy Dxz   • Needs 6 measurements with non co-linear directions D   Dyx Dyy Dyz  D Dzy Dzz   zx • Axial diffusivity (λ1)• Radial diffusivity (RD) [(λ2+ λ3)/2]• Mean diffusivity (MD)  3 1      2 2      2 3    2• Fractional anisotropy (FA)  2 1  2  3 2 2 2  http://www.cs.utah.edu/~gk/papers/tvcg00/img144.png http://www.ajnr.org/content/23/5/803/F6.large.jpg
    • Methods – Diffusion Tensor imaging
    • Results – Diffusion Tensor imaging Fractional anisotropy (FA, p < 0.05)Change in APP compared to WT corpus callosum ventricles optic tract hippocampus FA ↓↓ ↓ ↓ -
    • Results – Diffusion Tensor imaging Radial diffusivity (RD, p < 0.05)Change in APP compared to WT corpus callosum ventricles optic tract hippocampus RD ↓ ↑↑ ↑ ↑
    • SummarySummary MR Control DHA+ Fortasyn Hypothesis Technique diet diet diet 1H metabolic MRS alterations FAIR - ASL Cerebral perfusion White matter DT-MRI degeneration and neuronal loss
    • Acknowledgements AcknowledgementsRadboud Univ Nijmegen EU consortium 7th framework LipidiDietMedical Centre, Nijmegen,the Netherlands (RUNMC) • Univ of Saarland (USAAR), Germany Hartmann & FassbenderAnatomy • Univ of Kuopio (KU), FinlandAmanda Kiliaan Tanila & SoininenDiane Jansen • Univ of Szeged (USZEG), HungaryCarola Janssen PenkeMaartje Mutsaers • Tel Aviv University (UTA), IsraelJos Dederen MichaelsonIlse Arnoldussen •Göteborgs Universitet (GU), SwedenXiaotian Fang Skoog & GustafsonMaximilian Wiesmann • Danone Research B.V., the NetherlandsMichiel Kleinnijenhuis Broersen •Karolinska Institutet (KAU), SwedenRadiology WahlundArend Heerschap •Institute of Physiology (ASCR),Andor Veltien Czech RepublicSjaak Van Asten DolezalAlan Wright •VU University Medical Centre (VUMC), the Netherlands Scheltens Support: European Community’s Seventh •University of Bonn (UKB), Germany Framework Programme (FP7/2007-2013) Lütjohann Under grant agreement no 202167
    • Questions