epidemic spreading model to characterize misfolded proteins propagation in aging and associated...
TRANSCRIPT
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Epidemic Spreading Model to Characterize Misfolded proteins
in Aging and Associated Neurodegenerative Disorders
Yasser Iturria-Medina,
Roberto C. Sotero,
Paule J. Toussaint,
Alan C. Evans,
and the Alzheimer's Disease Neuroimaging Initiative
Montreal Neurological Institute
Published: November 20, 2014
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Outline
1. Introduction
2. Result
3. Discussion
4. Method(Not covered today)
Feb 11,2015
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Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method
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Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method
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Prof. Kuo
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Prof. Kuo
Amyloid plaque
Neurofibrillary tangle
Dystrophic neurite
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Ab precursor protein
ISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITL
1 16 28 40/42
C
H
ONH2 COOHAb
Extracellular Intracellular
b
b (671-672) (711-712 or 713-714)
(687-688)
Secretase
Prof. Kuo
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APOE
Gene Frequency(Allele Frequency)
APO E2 8 % 7 %
APO E3 85 % 73 %
APO E4 7 % 20 %
Normal A.D.
http://www.alzgene.org/meta.asp?geneID=83
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Age at onset (years)Corder et al. Science 1993; 261: 921–923
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Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method
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Model
• Aβ clearance deficiency
• anatomical distance• regional Aβ arrival time & Aβ deposition likelihood
• multi-factorial (APOE e4,gender,educational level)• Aβ propagation
• Aβ propagation => τ protein
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Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method
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Observation
• MP behave infectious-like• initial host regions -> other brain regions
• disease factor accumulate -> cellular death/cortical atrophy
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Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method
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Assumption
• Molecular diffusion process
• Axonal process
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Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method
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Difficulties
• developing molecular pathological approaches capable of reproducing MP propagation• a better understanding of MP spreading factors• evaluate their contribution to disease progression in
relation with other postulated pathological mechanisms
• the ability of this model to replicate real MP propagation/deposition patterns remained unexplored
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Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method
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Goals
• Epidemic Spreading Model to Characterize Misfolded proteins in Aging and Associated Neurodegenerative Disorders
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Outline
1. Introduction
2. Result
• ESM ,Epidemic Spreading Model
3. Discussion
4. Method
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ESM
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Subjects
Characteristics AD
(n = 111)
LMCI
(n = 196)
EMCI
(n = 233)
HC
(n = 193)
Women 47(42 %) 88 (44 %) 100(43 %) 94 (49 %)
Age (years) 74.30 (7.92) 71.72 (7.71) 70.77 (7.18) 73.88(5.73)
APOE e4 (1 copy) 61 (55 %) 108 (55 %) 94 (40 %) 50 (26 %)
APOE e4 (2 copies) 19 (17 %) 30 (15 %) 14 (6 %) 4 (2 %)
Education (years) 15.82 (2.63) 16.06(2.81) 16.00(2.65) 16.46(2.71)
MMSE1 22.82(2.01) 27.60(1.80) 28.39(1.52) 29.10(1.14)
CDR2 4.45(1.66) 1.68(0.99) 1.26(0.76) 0.02(0.11)
1MMSE, mini-mental state examination; 2CDR, clinical dementia rating. Data are number (%) or mean (std).
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Epicenter
Infectious seeds (reference source) Explained variance (%)
Posterior and anterior cingulate cortices (automatic selection,
this study)
35.8±1.22
Posterior cingulate cortex and temporal-parietal junction [1] 17.5±1.87
Angular gyrus [2] 14.7±0.45
Amygdala, orbitofrontal cortex and hippocampus [3] 4.33±0.37
Entorhinal cortex [4] 3.47±0.88
*Data are regional deposition explained variance ± 0.975 quantile.
(I’ll mark PCC in next slide)
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cingulate cortices
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𝑑𝑖𝑠𝑡𝑎𝑛𝑐𝑒 , Aβ level
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Multifactor, clinical diagnosis
Modulators Aß Production
rate (β)
Aß Clearance
rate
(δ)
Noise
(σ)
Onset Age
(Ageonset)
Clinical diagnosis
(HC, EMCI, LMCI,
AD)
2.15(-0.75,3.77) 8.45(4.88,11.89) 0(-3.73,0) 6.77(3.41,9.88)
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Outline
1. Introduction
2. Result
3. Discussion
4. Method
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Anatomic connectivity impact on intra-brain MP propagation• connectivity vs. random
• Connectional degree vs. vulnerability
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Identification of MP propagation epicenter
• Hard to determine the epicenter1. The fact
2. Located spatially close
3. Model limitation
• Improve• Longitudinal PET Aβ
• Animal model (discover mismatch)
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Aβ clearance deficiency and implications for medication therapies• Aβ production rate between AD and normal control
• Cellular pathway
• Increment of Aβ and τ clearance capacities• Immunological reinforcement
• Genetically induced enhancement
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Summary
• To our knowledge, the ESM is the first computational model
highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographicproperties and clinical states in health and disease
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Thanks to Prof. Kuo
• Introduction of AD
• Several pages of slides
• Fully support
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Outline
1. Introduction
2. Result
3. Discussion
4. Method
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(1) Change rate of probability
•𝑑𝑃𝑖
𝑑𝑡= 1 − 𝑃𝑖 𝑡 휀𝑖 𝑡 − 𝑃𝑖 𝑡 𝛿𝑖 𝑡 + ℵ
• ε : probability of receiving MP infectious-like agent
• 𝛿 : probability of being clean
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(2) Probability of being infected
• 휀𝑖 𝑡 = 𝑗≠𝑖 𝑃𝑎𝑗→𝑖𝛽𝑗𝑒𝑥𝑡 𝑡 − 𝜏𝑖𝑗 𝑃𝑗 𝑡 − 𝜏𝑖𝑗 + 𝑃𝑎𝑖→𝑖𝛽𝑖
𝑖𝑛𝑡 𝑡 𝑃𝑖 𝑡
• 𝑃𝑎𝑗→𝑖 : weighted anatomical connection probability
The NiConnect project – Parietal
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(3) Infection rate
• 𝛽𝑖𝑒𝑥𝑡 𝑡 = 𝑔 𝑡 𝛽𝑖 𝑡 ,
• 𝛽𝑖𝑖𝑛𝑡 𝑡 = (1 − 𝑔 𝑡 )𝛽𝑖 𝑡
• 𝛽𝑖 = 𝛽𝑖𝑒𝑥𝑡 + 𝛽𝑖
𝑖𝑛𝑡
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(4) Infection rate(2)
• 𝛽𝑖 𝑡 = 𝛽𝑖 𝑃𝑖 , 𝛽0 = 1 − 𝑒−𝛽0𝑃𝑖(𝑡)
• 𝛽0 ∈ [0,+∞)
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(5) Clearance rate
• 𝛿𝑖 𝑡 = 𝛿𝑖 𝑃𝑖 , 𝛿0 = 𝑒−𝛿0𝑃𝑖(𝑡)
• 𝛿0 ∈ [0, +∞)
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Probability of Aβ deposition
• 𝑃𝑖𝐴𝛽=
1
𝑉𝑖 𝑟∈𝑉𝑖 𝑃(𝑃𝐸𝑇𝐶𝐵
𝑚𝑎𝑥 ≤ 𝑃𝐸𝑇𝑟)
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Thanks to Prof. Kuo
• Introduction of AD
• Several pages of slides
• Fully support
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Copyright
The article is open-access, and distributed under the term of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
I follow the license beyond , and share-alike.
If this slide is infringing the right of the authors, please inform me.
Omar Yang, 2014/12/29