Measuring the invisible using Quantitative Magnetic ...qmri.org/measuring.pdf · Emeritus Professor...

Measuring the invisible using

Quantitative Magnetic

Resonance Imaging

Paul Tofts

Emeritus Professor University of Sussex, Brighton, UK

Formerly Chair in Imaging Physics, Brighton and Sussex Medical School , and

Professor at UCL Institute of Neurology, Queen Square, London, UK

www.paul-tofts-phd.org.uk

U3A Oct 7th 2016 1

http://www.paul-tofts-phd.org.uk/





BSMS research Nov 2008 2

What is qMRI?

Quantification = measure

Quantity

e.g. body mass

reliable, accurate, reproducible, easy

U3A Oct 7th 2016 3

Quantification

Quantify – to measure a quantity (size, weight,

blood sugar, cholesterol …)

Medical images have been qualitative

Look; human assessment; experience needed

Imaging is becoming quantitative

Measure e.g. tumour size, water content, tissue

destruction, volume of MS lesions…

Is accuracy important?

Rotterdam Jan 2019 4

Is accuracy important?


In a single centre short study – probably not

In longer studies – yes (withstand upgrades)

In multi-centre studies – yes

(unless you can replicate the sources of inaccuracy at each

site – ‘protocol matching’)

Multi-centre studies: MAGNIMS – MS 20 years

qMRI book pp35,36 and p132 (diffusion)

Why does random error matter?


Why is repeatability important?



What causes random variation?


B1 errors


Quality of parameter estimates depends on quality of

acquisition

B1 and image noise often dominate parameter uncertainty

[poor acquisition cannot be fixed by post-processing!]

1% error in flip angle FA gives 2% error in T1 (in Variable

Flip Angle method)


Optimisation of acquisition procedure


Image data analysis

Region of interest Test a specific location (prior information and hypothesis)

Histogram Whole brain; unbiased; for diffuse disease

Voxel-Based Morphometry VBM Unbiased testing of many locations

Each location can be correlated with external score (clinical, genetic, proteomic, cognitive)

Texture ‘dirty white matter’

tissue often becomes more heterogeneous in disease

Phantoms and healthy Controls for QA



Why are physicist so interested in

scanning normals?

Repeatedly!

Understand and minimise all the sources of variation

Serial study

Cross-sectional study

Influence of instrumental variation on sample

size in power calculation

U3A Oct 7th 2016 15

normal

Asphyxia

high Pi

U3A Oct 7th 2016 16

normal

Asphyxia

high Pi

U3A Oct 7th 2016 17

6 MR windows into brain biology

volume atrophy

diffusion cellular breakdown

magnetisation transfer macromolecules

T1,T2 water content

spectroscopy metabolites

Gd leakage blood-brain barrier

U3A Oct 7th 2016 18


volume atrophy



T1,T2 water content



U3A Oct 7th 2016 19

Volume and atrophy

High-resolution structural scan

Volumes of WM and GM

Normalise with skull size

(x-sectional)

Serial scans and spatial registration

Progressive atrophy

Normal: 0.5% pa; AD: 3% pa

MS shows progression in WM and GM

U3A Oct 7th 2016 20

expanding contracting

Progressive atrophy in a patient with Alzheimer’s Disease

Nick Fox

Queen

Square

UCL

U3A Oct 7th 2016 21

Total lesion volume in Multiple

Sclerosis trials

Clinical trials are expensive and long

Clinically variable disease; needs lots of subjects

(100+) and time (1-3y)

Increasingly MRI is used as a ‘surrogate marker’

observe biological effects of disease and treatment

more directly and quickly

more specific MRI measures to indicate biology

U3A Oct 7th 2016 22


volume atrophy



T1,T2 water content



U3A Oct 7th 2016 23

Diffusion Basics

free diffusion

restricted diffusion

RM

S

dis

pla

cem

ent

diffusion time 1/2

In a test tube, diffusion of

water is largely unhindered

(free)

characterised by the diffusion

constant

In the brain diffusion is

restricted or hindered

characterised by the apparent

diffusion coefficient (ADC)

Water diffuses 60μ in 100ms; far

enough to meet restrictions

U3A Oct 7th 2016 24

ADCx

ADCy ADCz

Diffusion Basics - 2

In a test tube, diffusion is largely

isotropic (same in all directions)

characterised by a single diffusion

constant

In the brain, diffusion may be

anisotropic

barriers to diffusion (e.g. axon walls,

cellular microstructures) are oriented

characterised by different ADCs in

different directions

Think CELERY!

U3A Oct 7th 2016 25

Apparent Diffusion Coefficient

(ADC)

The extent of diffusion can be characterised by an

Apparent Diffusion Coefficient (ADC)

Fewer barriers to diffusion results in greater diffusion

coefficient

Low ADC High ADC

U3A Oct 7th 2016 26

Fractional Anisotropy (FA)

The direction of water diffusion is influenced by

directional order in tissue e.g. white matter tracts

FA can range from 0 (isotropy) to 1 (anisotropy)

anisotropic (high FA)

isotropic (low FA)

U3A Oct 7th 2016 27

fractional

anisotropy

T1 Gd T2

mean

diffusivity

Diffusion tensor MRI

Acute enhancing MS lesion

U3A Oct 7th 2016 28

ADC histograms in MS

In normal appearing

brain matter there is a slight increase in diffusion compared to controls

Whole brain analysis histograms shifted to higher ADC values with a reduction in peak height

Healthy volunteer

MS Patient

Cercignani, Neurology, 54,1139 (2000)

U3A Oct 7th 2016 29


volume atrophy



T1,T2 water content



U3A Oct 7th 2016 30

NH3

OH

H

O

H

H

O

H H

O

H

H

O

H

Magnetisation Transfer

Macro molecules (invisible)

(bound protons - short T2) Surface Bulk water (visible)

(free protons- long T2)

Proteins,

Lipids,

etc.

exchange diffusion

U3A Oct 7th 2016 31

MTR histograms in Multiple Sclerosis

Whole-brain histogram depends on MS subtype; sensitive to demyelination

Dehmeshki et al MRM 2001

Current clinical score can be predicted from histogram

(using principle components analysis - PCA)

U3A Oct 7th 2016 32

qMT in MS

Davies et al Mult Scler 2004; 10:607

Frontal WM fb (%) p

Control 9.8

NAWM 8.6 <0.01

Lesion 4.6 <0.01

fb = fraction of protons that are bound

≈ myelin concentration

U3A Oct 7th 2016 33

Alzheimer’s disease

Hippocampal qMT parameter (~ fb) vs clinical score Ridha, Fox, Tofts. Quantitative magnetization transfer imaging in Alzheimer disease Radiology 2007; 244:832

0.02

0.025

0.03

0.035

0.04

0.045

0.05

0 5 10 15 20 25 30

MMSE

Me

an

Hc

fb/R

A(1

-fb)

(s)

AD patients (n=14)

Normal controls (n=14)

Principle Component Analysis of MTR histograms


U3A Oct 7th 2016 35


volume atrophy



T1,T2 water content



U3A Oct 7th 2016 36

T1 decreases during

development

U3A Oct 7th 2016 37

T1 and T2 in MS

T1 and T2 raised in

Normal Appearing

White Matter

U3A Oct 7th 2016 38


volume atrophy



T1,T2 water content



U3A Oct 7th 2016 39

spectroscopy

NAA - neuronal marker

reduced in NAWM in MS

Choline - membrane turnover

Lactate – anaerobic metabolism

Myo-inositol – raised in AD

Poor reproducibility – about 15%

U3A Oct 7th 2016 40

Magnetic Resonance Spectroscopy

Measurement of concentrations of biochemicals in living subjects

Each peak corresponds to a distinct chemical

Tumour increased Cho, Lac, decreased NAA, compared to normal tissue

tumour

normal

U3A Oct 7th 2016 41


volume atrophy



T1,T2 water content



U3A Oct 7th 2016 42

FLAIR T1w pre_Gd

d c

T1w post_Gd %E

Low Grade

Glioma

‘not visibly

enhancing’

U3A Oct 7th 2016 43

0

1

2

3

4

5

6

7

8

9

10

-30 -20 -10 0 10 20 30

% enhancement

rela

tiv

e v

olu

me

Normal Appearing

tumours

Measure size of RHS tail = volume of abnormal tissue

U3A Oct 7th 2016 44

Kaplan-Meier survival plot, using uncorrected volume from baseline scan

p<0.039 at 5 years

U3A Oct 7th 2016 45

Transformers show

progressive increase in

enhancing volume

different from NT

even at baseline

Non transformers are

stable

small SD;

homogeneous group


A Perfect Machine

Perfection is possible

Normal range depends on repeatability


An invisible problem


Between-centre difference can be eliminated


U3A Oct 7th 2016 50

qMRI – a technology whose time has come

‘The pre-eminent role of imaging now requires a new level of metric - quantitative measurements’

Robert I Grossman MD, Chair of Radiology, New York University

Medical Imaging

meets

Measurement Science

British Medical Association Radiology book

prize 2004

see qmri.org

http://www.med.nyu.edu/people/grossr03.html

http://www.qmri.org/

New edition 2018 €100 hardback; €30 Kindle


U3A Oct 7th 2016 52

Why is qMR needed?

‘Quantitative measurement of disease ... needs to become

the future of radiology in particular, and medicine in

general’ Robert Grossman MD

1. Measurement concepts - sources of variation

2. Specificity - new quantities

U3A Oct 7th 2016 53

qMRI - 2

qMRI:

Scientific instrument

following long tradition of measurement

astronomy, physics, chemistry, electrical engineering…

Measure subtle ‘invisible’ changes

diffuse or small

In ‘Normal-Appearing’ brain tissue

Measurements by physicists

U3A Oct 7th 2016 54

qMR – the future

qMR is becoming a turn-key application

Happy Snappy MRI Camera transforming into

Scientific Instrument

We are witnessing

paradigm shift

technological revolution

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Measuring the invisible using Quantitative Magnetic ...qmri.org/measuring.pdf · Emeritus Professor...

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