DTI in arthritis

7/27/2019 DTI in arthritis

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Financial Disclosures

No conflicts of interest to disclose



Chronic Inflammation

Infiltration with chronic

inflammatory cells

Expression of

proinflammatory

cytokines & chemokines.

Repair involving neo-

angiogenesis and fibrosis



Diffusion anisotropy can be exploited to gain information about the tissue organization at

a microscopic level.

(Denis Le Bihan at el. J Magn Reson Imagn 2001)

Diffusion Tensor Imaging

H2O H2O

H2O H2O

RF

Pulse

DiffusionGradient

Magnetic

field

H+

OH-

H+

OH-

H+

OH-

Protons Aligned in MF

H+

OH-

H+

OH-

H+

OH-

H+

OH-

Restriction in Motiondue to cell Membrane

H+

OH-

H+

OH-

H+

OH-

H+

OH-

H+

OH-

H+

OH-

H+

OH-

H+

OH-

H+

OH-

H+

OH-

H+

OH-

H+

OH- H+

OH-

H+

OH-

DTI indices

FA =Fractional Anisotropy

MD = Mean diffusivity

CL = Linear anisotropy

CP = Planar anisotropyCS= Spherical isotropy



Perfusion MRI: Dynamic Contrast Enhanced Imaging

• Provide information to changes in contrast concentration over time

• Implementation of Pharmacokinetic models

(i) Pharmacokinetics (for k transand k ep)

(ii) Hemodynamics (for BV and BF)



The DTI indices were measured in the inflamed synovial membrane whereas

inflammatory cytokines were measured in synovial fluid, But not in synovial

membrane.

Agarwal, V. et al. Rheumatology (Oxf.) 48,(2009)



Jenny Buckland; Nature Review Rheumatology volume 5; May 2009

DTI could replace synovial histology or synovial fluid analysis for serialassessment of the synovial inflammation



Hypothesis

DTI derived metrics may reflect the aggregation of the

inflammatory cells in the inflamed synovium.

DCE imaging may provide information regarding neo-angiogenesis

in the inflamed synovium.

These together may provide information about the ongoing

inflammation, and its molecular correlates in situation in vivo.



Objectives

1. To correlate DTI & DCE metrics values with the inflammatory

parameters;

Types and numbers of various immune inflammatory cells (CD4, CD8,

B cell, Macrophage, Plasma cells) infiltrating in the synovium

Proinflammatory molecules [TNF-α and IL-1β], expressed on these

cells

Adhesion molecules ICAM-1 (cd54) expressed on these cells.

Proinflammatory cytokines in the SF

2. To establish DTI & DCE metrics values as the potential surrogate

marker of active inflammation in-vivo.



Newly diagnosed subjects with a inflammatory arthritis involving

the knee joints were enrolled in the study

Age : >18 years

Inclusion criteria:

Subjects with chronic inflammatory arthritis, mono- or oligoarthritis

Early inflammatory arthritis of more than 6 weeks duration

Patients



Study Population =65 [Mean Age= 39.6 Yrs]

Image Acquisition

Conventional MRI including DTI and DCE-MRI was performed on a 3-Tesla MR scanner using a standard 8-channel knee coil

Image Quantification

Masks of synovial regions that enhanced on post contrast T1-weighted imaging were created using an automatedsegmentation algorithm.

Created masks were used to segment the inflamed synovium to extract various DCE (BV, BF, k trans, ve) and DTI(FA, MD) metrics from the segmented regions

Arthroscopic Knee Synovial Biopsy

Synovial Tissue Synovial Fluid

Cytokine Analysis

[IL-6, TNF-α, IL-1β]

Histopathology

H & E staining

Immunohistochemistry

[CD3,CD4,CD8,CD20,CD34,CD

54,CD68,CD138,IL-1β,TNF-α]

Serum



DTI and DCE Analysis

ROI(Region of Interest)

Synovial Infiltrate Analysis



ResultsDemographical Data

No. of Patients 65

Age (Mean ±SD) 39.61±13.42(18-76)

M/F 45/20

Disease duration months

( Mean ±SD)

29.2±36.6

(6-192 months)

Diagnosis

RA 6

Chronic Monoarthritis 11

OA 3

TB 15

USPA 14

Undifferentiated

Arthritis

10

JIA 1

AS 2

Reactive Arthritis 2

Leprosy 1

Descriptive DataDTI

indices Mean ±SD

FA 0.22±0.03

MD (×10-3

mm2sec-1)1.62±0.50

CL 0.05±0.02

CP 0.14±0.05

CS 0.75±0.02

DCE indices

BF(ml/100gm/

min)109.91±42.83

BV(ml/100gm) 9.544±4.20

k ep(min-1) 2.49±1.00

PCI 1820.44±211.64

Immune cells in synovium

CD3 154.93±48.65

CD4 63.41±32.85

CD8 53.58±17.62

CD20 39.33±13.96

CD34 52.93±17.27

CD54 36.35±13.14CD68 163.20±34.61

CD138 36.06±14.49

TOTALCEL

LS489.66±106.38

IL-1β 31.09±18.15

TNF-α 24.70±11.51

Cytokines in the Synovial fluid

IL6 9788.30±4734.44IL-1β 25.46±22.56

TNF-α 88.49±57.25



0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0 50 100 150 200 250 300

F A

CD3 r= 0.80 p=<0.001

CD4 r=0.77 p= <0.001

CD8 r=0.85 p= <0.001

CD 3 CD 4CD 8 Linear (CD 3)

Linear (CD 4) Linear (CD 8)

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0 20 40 60 80

F A

CD20 r=0.27 p= 0.026

CD138 r=0.30 p= 0.013

CD 20 CD 138 Linear (CD 20) Linear (CD 138)

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0 20 40 60 80 100

F A

CD34 r=0.55 p=<0.001

CD54 r=0.51 p=<0.001

CD 34 CD 54 Linear (CD 34) Linear (CD 54)

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0 20 40 60 80 100

F A

IL-1β r= 0.60 p=<0.001

TNF-α r=0.41 p=0.001

IL-1 beta TNF-alfa Linear (IL-1 beta) Linear (TNF-alfa)

Correlation between FA and Inflammatory Immune cells

in the inflamed synovium



0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0 200 400 600 800

F A

Total cells r=0.91 p=<0.001

Total Cells Linear (Total Cells)

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0 50 100 150 200 250

F A

CD68 r=0.68 p=<0.001

CD68 Linear (CD68)

DTI-MRI

Infiltrated Immune cells in synovium

CD3 CD 4 CD 8 CD 20 CD68 CD 138 CD 54 TNF-α IL-1β Total

Inflammatory

cells

FA 0.80** 0.77** 0.85** 0.27* 0.68** 0.30* 0.51** 0.41* 0.60** 0.91**

MD -0.39** -0.39** -0.46** -0.08 -0.28* -0.08 -0.20 -0.01 0.30* -0.43**

CL 0.45** 0.32** 0.41** 0.25* 0.14 0.25* 0.17 0.23 0.51** 0.46**

CP 0.04 0.05 0.12 0.02 0.10 0.02 0.08 0.08 0.06 0.07

CS -0.30* -0.37* -0.35** 0.07 -0.35** 0.07 -0.16 -0.15 -0.34* -0.32**

PCI -0.07 0.11 0.10 0.06 -0.03 0.17 -0.16 0.15 0.107 0.069

** Correlation is significant at the 0.01 level ; * Correlation is significant at the0.05 level



0

50

100

150

200

250

0 20 40 60 80 100

B l o o d F l o w

CD 34

CD34 r=0.814 p=<0.001

Series1 Linear (Series1)

0

5

10

15

20

0 20 40 60 80 100

B l o o d V o l u m e

CD34

CD34 r=0.84 p= <0.001


0

1

2

3

4

5

0 20 40 60 80 100

K e

p

CD34

CD34 r=0.30 p= 0.01


Correlation between DCE indices and Angiogenesis

in the inflamed synovium

DCE -MRI

Indices

Angiogenesis Marker in

the synovium

CD 34

BF 0.81**

BV 0.84**

k ep 0.30*

PCI 0.15



Preditor IHC

(Estimates

β0 Β1 R2 Sig. SE

(estimates)

FA CD3 -126.66 1269.34 0.64 <0.001 29.42

CD4 -120.28 828.04 0.59 <0.001 21.02

CD8 -56.01 494.02 0.73 <0.001 9.08

CD20 11.50 125.45 0.00 0.026 13.52

CD 138 3.79 145.44 0.09 0.013 13.89

CD68 -7.32 768.64 0.46 <0.001 25.55

CD54 -12.44 219.97 0.26 <0.001 11.36

IL-1β -48.16 357.25 0.36 <0.001 14.58

TNF-α -10.08 156.83 0.17 0.001 10.54

Total Cells - 213..27 3168.58 0.83 <0.001 43.67

Linear Regression Analysis Model

DTI indices predict the no. of T cells in the synovium



Dependent

Variables

(IHC)

DCE

Metrices

(Predictors)

β0 β1 R2 Sig. SE

(estimates)

CD 34 BF 16.83 0.329 0.663 <0.001 10.10

BV 19.68 3.484 0.719 <0.001 9.22

Kep 39.69 5.307 0.095 0.013 16.56

PCI 0.01 29.71 0.024 0.214 17.20

DCE MRI indices predict the angiogenesis in the synovium



Conclusions

A high FA on DTI correlated with inflammatory cell aggregation in

the inflamed synovium.

DCE parameters (BV, BF) correlated with the markers of angiogenesis i.e. CD34.

Correlation of both DTI and DCE parameters varied with the

intensity of inflammation.

Thus, DTI and DCE metrics capture cellular and molecular events of

inflammation and correlated with the degree of inflammation.



Acknowledgement

• This study was financially supported by Indian Council of MedicalResearch (ICMR, Grant No. 5/4-5/4/Ortho/08/NCD1), New Delhi,India.

DTI in arthritis

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