This presentation by Dana Horáková, Department of Neurology and Centre of Clinical Neuroscience at the Charles University in Prague, looks at why and how we should measure brain atrophy. It was presented at the MS Trust Annual Conference in November 2014.

1. Department of Neurology and Centre of Clinical Neuroscience
Charles University in Prague
1st Medical Faculty and General University Hospital
Can brain atrophy measurement help us in monitoring MS progression in routine clinical practice?
Dana Horáková

2. MS center – Prague
New center opened
March 2007
Comprehensive care
for > 4000 patients

3. ASA - 10 yrs evolution of disability on IFN
1999-2003, 181 pts, age 31 yrs, disease duration 3.7 yrs
100 confirmed
12 M progression
73 stable
173
RR MS

4. „MS world has changed“
1993
2010
2006
2013
20XX
2015 ?
Molecules in clinical studies,
not registered yet

5. „MS world has changed“
1993
2010
2006
2013
20XX
2015 ?
Molecules in clinical studies,
not registered yet

6. Department of Neurology and Centre of Clinical Neuroscience
Charles University in Prague, 1st Medical Faculty and General University Hospital
MRI is the only window
we can use to look directly
at patological processes
in MS

7. Focal inflammatory disease of white matter
Conventional MRI
Advanced MRI
Diffuse disease
Remyelination
Regeneration and repair

8. CONVE NT I ON A L
MR
I TECHN
I
QUES
T1W
T2W
FLAIR
T1W+Gd

9. Typical lesions
Peri
Ventricular
Posterior
Fossa
Juxta
Cortical
Spinal
cord

10. „Clinico-radiological paradox“
•Lack of pathologic specificity (de-, remyelination, edema, gliosis, axonal loss)
•Location – strategic areas
•Underestimation of spinal cord lesions
•Insensitivity to pathology in NAWM and NAGM
•Plasticity of the CNS
•Interaction between brain atrophy and lesion burden
•Limitations of current scales (EDSS)
Barkhof, Curr Opin in Neurology, 2002; Zivadinov, J Neurol, 2008

11. Department of Neurology and Centre of Clinical Neuroscience
Charles University in Prague, 1st Medical Faculty and General University Hospital
Advanced technique

12. New MRI Methods for Detecting Demyelination and Axonal Loss
•Brain and spinal cord atrophy
•Magnetisation transfer imaging
•Diffusion weighted and diffusion tensor imaging
•Magnetic resonance spectroscopy
•Functional MRI
•PET
•…….

13. Why should we measure brain atrophy?
Significant brain volume loss is observed from
the earliest stage of MS and proceeds throughout
the disease course
Healthy controls 0.1-0.3 % per yr
MS 0.5-1.35 % per yr
Nicola De Stefano, CNS Drugs, 2014

14. How do we measure atrophy?
Cross-sectional
Global or regional brain volume
Brain parenchymal fraction
Longitudinal
Changes in particular volumes
% changes
•Proprietary software
•SIENAX
•FreeSurfer
•Scanview.cz
•SIENA
•Proprietary softwares
–Scanview.cz
Miller D, Brain, 2002
Anderson, Journal of Magnetic Resonance Imaging, 2006
De Stefano, CNS drugs, 2014

15. How do we measure atrophy?
Cross-sectional
Global or regional brain volume
Brain parenchymal fraction
Longitudinal
Changes in particular volumes
% changes
•Proprietary software
•SIENAX
•FreeSurfer
•Scanview.cz
•SIENA
•Proprietary softwares
–Scanview.cz
Miller D, Brain, 2002 Anderson, Journal of Magnetic Resonance Imaging, 2006 De Stefano, CNS drugs, 2014

16. How do we measure atrophy?
Cross-sectional
Global or regional brain volume
Brain parenchymal fraction
Longitudinal
Changes in particular volumes
% changes
•Proprietary software
•SIENAX
•FreeSurfer
•Scanview.cz
•SIENA
•Proprietary softwares
–Scanview.cz
Miller D, Brain, 2002 Anderson, Journal of Magnetic Resonance Imaging, 2006 De Stefano, CNS drugs, 2014

17. Department of Neurology and Centre of Clinical Neuroscience
1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic
The results are good at a group level but difficult to apply at an individual level

18. Technique independent
•‘Ageing’ –
HC 0.1–0.3%/yr MS 0.7–1.5%/yr
•Physiological variability (de/hydration)
Dunning, Neurology, 2005
•Other pathology (smoking, diet, ApoE...)
•Rx effect, pseudoatrophy
Zivadinov, Neurology, 2008
Technique dependent
•Scanner !!!
•Protocol !!!
•Software (measurement accuracy – around 0.2%
•Stability of technical parameters
•Repositioning
Confounding factors
ApoE, apolipoprotein E; HC, healthy control; MS, multiple sclerosis; Rx, prescription.

19. Technique independent
•‘Ageing’ –
HC 0.1–0.3%/yr MS 0.7–1.5%/yr
•Physiological variability (de/hydration)
Dunning, Neurology, 2005
•Other pathology (smoking, diet, ApoE...)
•Rx effect, pseudoatrophy
Zivadinov, Neurology, 2008
Technique dependent
•Scanner
•Protocol
•Software (measurement accuracy – around 0.2%
•Stability of technical parameters
•Repositioning
Confounding factors

20. Department of Neurology and Centre of Clinical Neuroscience
1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic
Are we able to overcome these problems?

21. CIS, clinically isolated syndrome; IFN β, beta-interferon; MRI, magnetic resonance imaging; RRMS, relapsing–remitting MS.
April 1999
Avonex-Steroid-Azathioprine (ASA) study 181 patients with RRMS, mean disease duration 5.1 years, positive for oligoclonal bands
Dec 2003
Dec
2009
Dec
2005
Dec
2013
4,050
MRI scans
1,500 MRI scans
Jul
2009
Oct
2005
Observational study of early IFN β-1a treatment in high-risk subjects after CIS (SET study)
220 CIS patients, mean disease duration 4 months, positive for oligoclonal bands
Jul
2011
Jul
2013

22. •Since 1999
–1.5 mm FLAIR
–1 mm T1W 3D
•25 min without Gd
•Same scanner –1.5 T Philips
Proprietary sofware, developed by
Dr J Krásenský
•T2, T1 lesion volume
•BPF with % whole brain volume change
•Regional atrophy – corpus callosum, thalamus
www.scanview.cz
ScanView QMRI protocol – Prague
FLAIR, fluid-attenuated inversion recovery; Gd, gadolinium; QMRI, quantitative magnetic resonance imaging; T1W, T1-weighted.

23. ASA
181 patients
10 years of follow-up
> 4,050 MRI scans
SET
220 patients
4 years of follow-up
> 1,500 MRI scans
QMRI
> 2,700 patients
1–4 years of follow-up
> 9,000 MRI scans
> 3,000 patients with MS
> 16,500 volumetric scans using the same protocol

24. ASA - 10 yrs evolution on 1 line therapy 1999-2003, 181 pts, mean age 31 yrs, DD 3.7 yrs
0,5

25. MS patients:
0,5-1,35% per year
0,5
ASA - 10 yrs evolution on 1 line therapy 1999-2003, 181 pts, mean age 31 yrs, DD 3.7 yrs

26. Healthy controls:
0,1-0,3% per year
MS patients:
0,5-1,35% per year
0,5
≈5x higher

27. Time (years)
88
90
92
94
96
98
100
102
104
0
2
8
4
6
10
12
14
16
9-Year ASA (181 Patients and 44 Healthy Controls)
% Change in Corpus Callosum Volume
Whole Brain Volume (%)
Absolute Grey
Matter Volume (mL)
Absolute White Matter Volume (mL)
Healthy Controls (n=44) Stable Patients (n=71) Patients with1-point Increase in EDSS at 12 Months (n=110)
16
400
450
500
550
600
650
700
750
800
350
Time (years)
0
2
8
4
6
10
12
14
0
0
−10
−20
10
−30
Time (years)
2
8
4
6
10
12
14
16
16
650
700
800
400
450
500
550
600
350
750
0
2
8
4
6
10
12
14
Time (years)
ASA=Avonex-Steroid-Azathioprine study. Horáková D Unpublished results.

28. Department of Neurology and Centre of Clinical Neuroscience
Charles University in Prague, 1st Medical Faculty and General University Hospital
Data we receive in
a real clinical practice

29. Patient 1: F, 1984 , onset 2006, (22y) malignant course
CC (%), corpus callosum % change; Load, T2 lesion load; NMR, nuclear magnetic resonance.
Dept
Ć.n.
Date
Code of purpose
Research
Effects
Anatomy
Pathology
Load
BPF
Atrophy
CC (%)

30. Patient 1: last examination, 22 October 2013

31. Patient 1: co-registration of all available scans
22 Oct 2013
11 Aug 2008
30 Sep 2012
12 Jan 2012
16 Aug 2006
24 Sep 2009

32. Patient 1: colour-coding system
Red = new lesion since last scan; green = reduction in lesion since last scan; yellow = new lesions since first scan.

33. Department of Neurology and Centre of Clinical Neuroscience
Charles University in Prague, 1st Medical Faculty and General University Hospital
Patient 2: F, 1975, onset 92 (17y) Stable

34. Patient 2: Stable, F, 1975, onset 92 (17y)
-1,88:11 yrs= 0,17 %
Healthy controls 0,1-0,3 %

35. Patient 2: Stable, F, 1975, onset 92 (17y)
9/02
9/13
9/11
9/12

36. Patient 2: Stable, F, 1975, onset 92 (17y)

37. 2. M, 1972, onset 2003 (31)
1. M, 1970, onset 1998 (28)
1

38. 2. M, 1972, onset 2003 (31)
1. M, 1970, onset 1998 (28)

39. 2. M, 1972, onset 2003 (31)
1. M, 1970, onset 1998 (28)
1.55 cm3
BPF 86.7
−2.2%/13 yrs = −0.17%/yr
+1.1% CC
1.52 cm3
BPF 89.47
−5.9%/11 yrs = −0.54%/yr
−21.2% CC

40. 2. M, 1972, onset 2003 (31)
1. M, 1970, onset 1998 (28)
1

41. Patient 5: F, 1985, onset 2007, (22y) Early escalation

42. Patient 5: Early escalation
-3%:3 yrs= 1,0 %
3% of CC/yr
Healthy controls 0,1-0,3 %
-1,7%:4 yrs= 0,4 %
1,25% of CC/yr
Healthy controls 0,1-0,3 %

43. .
Disease free concept NEDA 4
Without
relapses
Without
Disability
progression
Without T2 + Gd
lesions
Atrophy
within a range
of healthy
controls
Without
clinical activity
„Disease free
Concept“
Without MRI
activity
EDSS
Gait
Cognition
Havrdová a kol., Roztroušená skleróza, Triton, 2013

44. Scanview Q-MRI System in Prague
Scanner
Protocol
Volumetric software
Clinical implementation
MS Centre
Interpretation
Database
Personalised medicine
Research
Validation

45. Acknowledgements:
To all patients who have participated in clinical research
MS Center, Dpt of Neurology
Charles University, Prague
Prof E Havrdová, MD, PhD
MRI Dpt, Dpt of Radiology
Charles University, Prague
Prof Z Seidl, Dr M Vaněčková
and RNDr J Krásenský