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

Outline

1. Introduction

2. Result

3. Discussion

4. Method(Not covered today)

Feb 11,2015

Outline

1. Introduction

• Background

• Model

• Observation

• Assumption

• Difficulties

• Goals

2. Result

3. Discussion

4. Method

Outline

1. Introduction

• Background

• Model

• Observation

• Assumption

• Difficulties

• Goals

2. Result

3. Discussion

4. Method

Prof. Kuo

Prof. Kuo

Amyloid plaque

Neurofibrillary tangle

Dystrophic neurite

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

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

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

Outline

1. Introduction

• Background

• Model

• Observation

• Assumption

• Difficulties

• Goals

2. Result

3. Discussion

4. Method

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

Outline

1. Introduction

• Background

• Model

• Observation

• Assumption

• Difficulties

• Goals

2. Result

3. Discussion

4. Method

Observation

• MP behave infectious-like• initial host regions -> other brain regions

• disease factor accumulate -> cellular death/cortical atrophy

Outline

1. Introduction

• Background

• Model

• Observation

• Assumption

• Difficulties

• Goals

2. Result

3. Discussion

4. Method

Assumption

• Molecular diffusion process

• Axonal process

Outline

1. Introduction

• Background

• Model

• Observation

• Assumption

• Difficulties

• Goals

2. Result

3. Discussion

4. Method

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

Outline

1. Introduction

• Background

• Model

• Observation

• Assumption

• Difficulties

• Goals

2. Result

3. Discussion

4. Method

Goals

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

Outline

1. Introduction

2. Result

• ESM ,Epidemic Spreading Model

3. Discussion

4. Method

ESM

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).

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)

cingulate cortices

𝑑𝑖𝑠𝑡𝑎𝑛𝑐𝑒 , Aβ level

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)

Outline

1. Introduction

2. Result

3. Discussion

4. Method

Anatomic connectivity impact on intra-brain MP propagation• connectivity vs. random

• Connectional degree vs. vulnerability

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)

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

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

Thanks to Prof. Kuo

• Introduction of AD

• Several pages of slides

• Fully support

Outline

1. Introduction

2. Result

3. Discussion

4. Method

(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

(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

(3) Infection rate

• 𝛽𝑖𝑒𝑥𝑡 𝑡 = 𝑔 𝑡 𝛽𝑖 𝑡 ,

• 𝛽𝑖𝑖𝑛𝑡 𝑡 = (1 − 𝑔 𝑡 )𝛽𝑖 𝑡

• 𝛽𝑖 = 𝛽𝑖𝑒𝑥𝑡 + 𝛽𝑖

𝑖𝑛𝑡

(4) Infection rate(2)

• 𝛽𝑖 𝑡 = 𝛽𝑖 𝑃𝑖 , 𝛽0 = 1 − 𝑒−𝛽0𝑃𝑖(𝑡)

• 𝛽0 ∈ [0,+∞)

(5) Clearance rate

• 𝛿𝑖 𝑡 = 𝛿𝑖 𝑃𝑖 , 𝛿0 = 𝑒−𝛿0𝑃𝑖(𝑡)

• 𝛿0 ∈ [0, +∞)

Probability of Aβ deposition

• 𝑃𝑖𝐴𝛽=

1

𝑉𝑖 𝑟∈𝑉𝑖 𝑃(𝑃𝐸𝑇𝐶𝐵

𝑚𝑎𝑥 ≤ 𝑃𝐸𝑇𝑟)

Thanks to Prof. Kuo

• Introduction of AD

• Several pages of slides

• Fully support

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