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http://www.umcn.nl/Research/Departments/cdl/PRIME/Pages/PRIMELecture.aspx
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Multi nutrient enriched diets restore cerebral
perfusion and protect against neurodegeneration in a
mouse model for Alzheimer’s disease
Valerio 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. Kiliaan1
1 Dept. Anatomy, Donders Centre for Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands 2 Dept. Radiology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
Alzheimer’s Disease (AD)
Introduction
Clinical phenotype: gradual episodic memory impairment
Neuropathological changes: • Presence of plaque and tangle pathology • Massive loss neuronal cells and synapses • Neurodegeneration / white matter pathology
AD affects more than 24 million people world wide Age is the major risk factor for AD: 47% of people older than 85 years affected 80 million affected in 2040
Genetics & risk factors
1. Sporadic AD (late onset)
Causes unclear
Risk factors
2. Familial AD (early onset)
Mutations in amyloid precursor
protein (APP), presenilin (PS)-1
or -2 genes
contribute to increased
Aβ production
De la Torre JC (2002), Stroke
Risk factors for Alzheimer’s disease
Ageing
Presence of APOEε4 allele
Hypertension
Congestive heart failure
Atrial fibrillation
Atherosclerosis
Smoking
High intake of saturated fat
Diabetes mellitus
Stroke
Sedentary lifestyle
Overweight
White matter lesions
Epidemiology (end of 20th century)
Introduction
Regulation of β-amyloid production / clearance
Microglial cells
Blood flow
β-amyloid γ-secretase
β-secretase
Physiological situation
Energy supply
Introduction
Regulation of β-amyloid production / clearance
Activated Microglial cells
Blood flow
β-amyloid •monomers •dimers •trimers γ-secretase
β-secretase
β-amyloid oligomers
β-amyloid plaques
• Abnormal cleavage of APP by γ- and β-secretase
• Decrease Aβ clearance by reduced cerebral blood flow
•Aβ oligomers and plaques
• Vascular amyloid deposition (CAA)
• Chronic inflammatory response
• Energy crisis
• Neurodegeneration
Energy supply
Introduction
Regulation of β-amyloid production / clearance
Activated Microglial cells
Blood flow
β-amyloid •monomers •dimers •trimers γ-secretase
β-secretase
β-amyloid oligomers
β-amyloid plaques
• Abnormal cleavage of APP by γ- and β-secretase
• Decrease Aβ clearance by reduced cerebral blood flow
•Aβ oligomers and plaques
• Vascular amyloid deposition (CAA)
• Chronic inflammatory response
• Energy crisis
• Neurodegeneration
Energy supply
Introduction
Prevention strategies
• Immunotherapy
• “classic” vascular risk factors (statins, aspirin, NSAIDs)
• Docosahexaenoic acid (DHA)
•*AD2000 collaborative group. Lancet Neurology 2008;7:41-49
•#Freund- levi et al arch neurol 2008
Introduction
Improving neuronal connectivity Improvement of neuronal membrane fluidity Improves vascular status and reduces atherosclerosis Decrease Aβ levels Beneficial effect in patients with mild AD #
Prevention vascular disease No beneficial effect on Alzheimer pathology
Targeting Aβ Still need to prove their efficacy on clinical trials
Prevention strategies
• Immunotherapy
• “classic” vascular risk factors (statins, aspirin, NSAIDs)
• Docosahexaenoic acid (DHA)
•*AD2000 collaborative group. Lancet Neurology 2008;7:41-49
•#Freund- levi et al arch neurol 2008
Introduction
Improving neuronal connectivity Improvement of neuronal membrane fluidity Improves vascular status and reduces atherosclerosis Decrease Aβ levels Beneficial effect in patients with mild AD #
Prevention vascular disease No beneficial effect on Alzheimer pathology
Targeting Aβ Still need to prove their efficacy on clinical trials
Prevention strategies
• Immunotherapy
• “classic” vascular risk factors (statins, aspirin, NSAIDs)
• Docosahexaenoic acid (DHA)
•*AD2000 collaborative group. Lancet Neurology 2008;7:41-49
•#Freund- levi et al arch neurol 2008
Introduction
Improving neuronal connectivity Improvement of neuronal membrane fluidity Improves vascular status and reduces atherosclerosis Decrease Aβ levels Beneficial effect in patients with mild AD #
Prevention vascular disease No beneficial effect on Alzheimer pathology
Targeting Aβ Still need to prove their efficacy on clinical trials
Aim of the study
“to investigate the effects of DHA enriched diet on the
pathophysiology of Alzheimer’s Disease”
Aim of the study
Animal 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) 5% soy oil Standard control diet
(DHA+) DHA EPA UMP
Kamphuis PJ and Scheltens P (2010), Wurtman RJ (2008)
Material and methods
(Fortasyn) DHA EPA UMP Choline Phospholipids B-vitamins Anti-oxidants
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
Material and methods
1. 1H MR Spectroscopy
1H Magnetic Resonance Spectroscopy
Metabolites of interest:
• N-Acetylaspartate (NAA):
neuronal marker,
reflects neuronal dysfunction
• Myo-inositol (mI):
glial marker,
associated with inflammation
Methods – MRS
Results 1H MRS
Results – MRS
2. Cerebral blood flow
(X + CBF) – X = CBF
Slice selective inversion: (X+CBF)
Global inversion: (X)
Global slab
Label slab
90 180
IR
S-G Kim et al, MRM 37:425-435 (1997) KK Kwong et al, MRM 34:878-887 (1995)
FAIR (Flowsensitive alternating inversion recovery)
180
Imaging slice
Methods – Cerebral blood flow
T1-fitting selective / global
T1 selective
T1 global
TI (inversion time)
≈ CBF
Methods – Cerebral blood flow
Results – Cerebral Blood Flow
Results – Cerebral blood flow
3. Diffusion Tensor Imaging
Diffusion MR imaging
• Theoretical result
• Signal attenuation
• Loss of phase coherence
Methods – Diffusion Tensor imaging
Dr 62
Dt
rrrr
DtrtrP
4
)()(exp
)4(
1)0,|,( 00
30
2
0 exp3
xyM M G D
Brownian motion
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
zzzyzx
yzyyyx
xzxyxx
DDD
DDD
DDD
D
http://www.cs.utah.edu/~gk/papers/tvcg00/img144.png http://www.ajnr.org/content/23/5/803/F6.large.jpg
• Needs 6 measurements with non co-linear directions
Methods – Diffusion Tensor imaging
• Axial diffusivity (λ1)
• Radial diffusivity (RD) [(λ2+ λ3)/2]
• Mean diffusivity (MD) • Fractional anisotropy (FA)
2
3
2
2
2
1
2
3
2
2
2
1
2
3
Methods – 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 ↓ ↑↑ ↑ ↑
Results – Diffusion Tensor imaging
Summary
MR
Technique Hypothesis
Control
diet
DHA+
diet
Fortasyn
diet
1H MRS metabolic
alterations
FAIR - ASL Cerebral perfusion
DT-MRI
White matter
degeneration and
neuronal loss
Summary
Acknowledgements
Radboud Univ Nijmegen Medical Centre, Nijmegen, the Netherlands (RUNMC) Anatomy Amanda Kiliaan Diane Jansen Carola Janssen Maartje Mutsaers Jos Dederen Ilse Arnoldussen Xiaotian Fang Maximilian Wiesmann Michiel Kleinnijenhuis
Radiology Arend Heerschap Andor Veltien Sjaak Van Asten Alan Wright
EU consortium 7th framework LipidiDiet • Univ of Saarland (USAAR), Germany Hartmann & Fassbender • Univ of Kuopio (KU), Finland Tanila & Soininen • Univ of Szeged (USZEG), Hungary
Penke • Tel Aviv University (UTA), Israel Michaelson •Göteborgs Universitet (GU), Sweden Skoog & Gustafson • Danone Research B.V., the Netherlands Broersen •Karolinska Institutet (KAU), Sweden Wahlund •Institute of Physiology (ASCR), Czech Republic Dolezal •VU University Medical Centre (VUMC), the Netherlands Scheltens •University of Bonn (UKB), Germany Lütjohann
Support: European Community’s Seventh Framework Programme (FP7/2007-2013) Under grant agreement no 202167
Acknowledgements
Questions
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