This is my note after study this paper: http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1003956

1. 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

2. Outline
1. Introduction
2. Result
3. Discussion
4. Method(Not covered today)
Feb 11,2015

3. Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method

4. Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method

5. Prof. Kuo

6. Prof. Kuo
Amyloid plaque
Neurofibrillary tangle
Dystrophic neurite

7. Ab precursor protein
ISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITL
1 16 28 40/42
C
H
ONH2 COOH
Ab
Extracellular Intracellular

b 
b (671-672)  (711-712 or
713-714)
 (687-688)
Secretase
Prof. Kuo

8. 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

9. Age at onset (years)
Corder et al. Science 1993; 261: 921–923

10. Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method

11. 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

12. Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method

13. Observation
• MP behave infectious-like
• initial host regions -> other brain regions
• disease factor accumulate -> cellular death/cortical atrophy

14. Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method

15. Assumption
• Molecular diffusion process
• Axonal process

16. Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method

17. 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

18. Outline
1. Introduction
• Background
• Model
• Observation
• Assumption
• Difficulties
• Goals
2. Result
3. Discussion
4. Method

19. Goals
• Epidemic Spreading Model to Characterize Misfolded proteins in
Aging and Associated Neurodegenerative Disorders

20. Outline
1. Introduction
2. Result
• ESM ,Epidemic Spreading Model
3. Discussion
4. Method

21. ESM

22. 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).

24. 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)

25. cingulate cortices

26. 𝑑𝑖𝑠𝑡𝑎𝑛𝑐𝑒 , Aβ level

28. 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)

31. Outline
1. Introduction
2. Result
3. Discussion
4. Method

32. Anatomic connectivity impact on intra-brain
MP propagation
• connectivity vs. random
• Connectional degree vs. vulnerability

33. Identification of MP propagation epicenter
• Hard to determine the epicenter
1. The fact
2. Located spatially close
3. Model limitation
• Improve
• Longitudinal PET Aβ
• Animal model (discover mismatch)

34. 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

35. 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/demographic
properties and clinical states in health and disease

36. Thanks to Prof. Kuo
• Introduction of AD
• Several pages of slides
• Fully support

37. Outline
1. Introduction
2. Result
3. Discussion
4. Method

38. (1) Change rate of probability
•
𝑑𝑃 𝑖
𝑑𝑡
= 1 − 𝑃𝑖 𝑡 𝜀𝑖 𝑡 − 𝑃𝑖 𝑡 𝛿𝑖 𝑡 + ℵ
• ε : probability of receiving MP infectious-like agent
• 𝛿 : probability of being clean

39. (2) Probability of being infected
• 𝜀𝑖 𝑡 = 𝑗≠𝑖 𝑃𝑎𝑗→𝑖 𝛽𝑗
𝑒𝑥𝑡
𝑡 − 𝜏𝑖𝑗 𝑃𝑗 𝑡 − 𝜏𝑖𝑗 + 𝑃𝑎𝑖→𝑖 𝛽𝑖
𝑖𝑛𝑡
𝑡 𝑃𝑖 𝑡
• 𝑃𝑎𝑗→𝑖 : weighted anatomical connection probability
The NiConnect project – Parietal

40. (3) Infection rate
• 𝛽𝑖
𝑒𝑥𝑡
𝑡 = 𝑔 𝑡 𝛽𝑖 𝑡 ,
• 𝛽𝑖
𝑖𝑛𝑡
𝑡 = (1 − 𝑔 𝑡 )𝛽𝑖 𝑡
• 𝛽𝑖 = 𝛽𝑖
𝑒𝑥𝑡
+ 𝛽𝑖
𝑖𝑛𝑡

41. (4) Infection rate(2)
• 𝛽𝑖 𝑡 = 𝛽𝑖 𝑃𝑖, 𝛽0 = 1 − 𝑒−𝛽0 𝑃 𝑖(𝑡)
• 𝛽0 ∈ [0, +∞)

42. (5) Clearance rate
• 𝛿𝑖 𝑡 = 𝛿𝑖 𝑃𝑖, 𝛿0 = 𝑒−𝛿0 𝑃 𝑖(𝑡)
• 𝛿0 ∈ [0, +∞)

43. Probability of Aβ deposition
• 𝑃𝑖
𝐴𝛽
=
1
𝑉 𝑖
𝑟∈𝑉 𝑖
𝑃(𝑃𝐸𝑇𝐶𝐵
𝑚𝑎𝑥
≤ 𝑃𝐸𝑇𝑟)

44. Thanks to Prof. Kuo
• Introduction of AD
• Several pages of slides
• Fully support

45. 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
y0028613702420400@gmail.com