Multiple sclerosis as a simultaneous "2 components" disease

1. Multiple sclerosis as a
“simultaneous two components”
disease
Emilie LOMMERS
4th year of the Master in Neurology
FRS-FNRSCandidat Spécialiste Doctorant 2014.

2.  MS as a “two stages” disease : classical view of MS pathology
 MS as a “two components” disease : emerging view of MS pathology
 Conclusions and perspectives
OVERVIEW
• Inflammation and focal damages
• Focal damages and disease progression
• Limitations of this model
• Histopathological point of view
• Two distinct pathways
• Is neurodegeneration exist in early MS?

3. Peripherally activated T cells enter the CNS
Episodic relapses due to inflammation
MS AS A “TWO STAGES” DISEASE:
Inflammation and focal damages
References: 1. Markiewicz et al. Acta Neurobiol Exp 2006;66:343-358. 2. Lassmann. Curr op in Neurol 2008;21:242-247. 3. Weiner. J Neurol
2008;255(S1):3-11. 4. Van der Walt et al. Pharmacol and Therapeutics 2010;126:82-93. 5. Stys et al. Nature Rev Neurosc 2012;13:507-514.

4. References: 1. De Jager et al. Annu Rev Med. 2007;58:417-32. 2. Lassmann. Curr Opin Neurol. 2008;1:242-7. 3. Markiewicz et
al. Acta Neurobiol Exp. 2006;66:343-58. 4. Nair et al. Cell Mol Life Sci. 2008;65:2702-20. 5. Van der Walt et al. Pharmacol
Ther. 2010;126:82-93. 6. Weiner. J Neurol. 2008;255 S1:3–11. 7. Zhang et al. Mol Neurobiol. 2010;41:232-41.
Proinflammatory
Cytokines
IL-1β
IFN γ
Activated
T-cell CD4+
Activated
Astrocytes
Auto-reactive
T-cell
PERIPHERY INSIDE THE CNS
Th1
Th2 B
Demylination
Axonal injury
Macrophage/microglie
activation
Direct
toxicity
TNFα, IFN γ
RO, NO
Complement
Mediated injury
Actvated
T-cell CD8+
Antibodies
CLASSICAL VIEW OF MS
PERIPHERAL T-CELL MEDIATED PATHWAY

5.  Peripheral T-cell–mediated inflammation leads to focal lesions visible on conventional MRI
MS AS A “TWO STAGES” DISEASE:
Focal damages
Reference: Bermel & Fox. MRI in multiple sclerosis. Continuum Lifelong Learning Neurol. 2010;16(5):37-57.
T2 lesions:
 Acute and chronic
demyelination
 Overall lesion burden
Gadolinium-enhanced T1 lesions:
 Acute inflammation
 Blood-brain-barrier dysfunction
Hypo-intense T1 lesions
(black holes):
 Permanent axonal
loss

6. MS AS A “TWO STAGES” DISEASE:
Focal damages and disease progression
Reference: Compston & Coles. Multiple Sclerosis. Lancet 2002;359:1221–31.

7. MS AS A “TWO STAGES” DISEASE:
CLASSICAL VIEW DOES NOT FULLY EXPLAIN LONG TERM DISABILITY
 No or weak correlation between frequency of relapses and
accumulation of irreversible disability 2,4.
Reference: Shirani, et al. JAMA. 2012;308:247-256
Time to EDSS 6
Percentageofpatients

8.  Dissociation between therapeutic effects on relapse frequency
versus effect on disability progression 2,5.
 Once EDSS 4.0 reached, the rate of disability progression seems
to be independant of the preceding disease course and unaffected
by relapses during the progressive phase 4.
References: 1. Scalfari, et al. Brain. 2010;133:1914-1929. 2. Shirani, et al. JAMA. 2012;308:247-256.
3. Confavreux & Vukusic. Brain. 2006. 4. Kurtzke, et al. Neurology; 1983;33:1444-52. 5. Confavreux et al., Clinical neurology
and neurosurgery. 2006; 327-332
MS AS A “TWO STAGES” DISEASE:
CLASSICAL VIEW DOES NOT FULLY EXPLAIN LONG TERM DISABILITY

9. References: 1. Zivadinov et al., J Neuroimaging 2005;15:10S-21S. 2. Kirov, et al. J Neurol Neurosurg Psychiatry. 2009;80(12): 1330-1336.
 Weak correlation between number of T1 Gd-enhanced lesions and long
term disability.
 Modest correlation between T2 lesion load and disability progression
 Stronger relationship between brain atrophy and disability progression but:
– Focal lesions occupy less than 3% of the total brain volume in MS
patients
– Total brain atrophy is weakly correlated to T2 lesion load
Relapses / focal lesions are NOT sufficient predictors of long-term disability
MS AS A “TWO STAGES” DISEASE:
CLASSICAL VIEW DOES NOT FULLY EXPLAIN LONG TERM DISABILITY

10.  MS as a “two stages” disease : classical view of MS pathology
 MS as a “two components” disease : emerging view of MS pathology
 Conclusions and perspectives
OVERVIEW
• Inflammation and focal damages
• Focal damages and disease progression
• Limitations of this model
• Histopathological point of view
• Two distinct pathways
• Is neurodegeneration exist in early MS?

11. MS AS A “TWO COMPONENTS” DISEASE:
Histopathological point of view
Reference: Kutzelnigg et al., Brain 2005, 128, 2705–2712.
Focal demyelinated plaques in WM
Demyelinated lesions in cortex and deep GM
Dark dots: diffuse inflammation in WM

12.  There are two distinct pathways contributing to neurodegeneration and subsequent
disability.
 Diffuse neurodegenerative processes are partially independent of the inflammatory
immune response originating from the periphery1
 Neurodegeneration is correlated with diffuse pathology1,3,4
 Diffuse pathology
– Occurs both in grey matter and in normal-appearing white matter (NAWM)5,6
– Predominant in PP-SPMS but begins in the early stages of MS
– Plays an important in brain atrophy and long-term disability9-11
MS AS A “TWO COMPONENTS” DISEASE:
Two distinct pathways
References: 1. Charil & Filippi. J Neurol Sci. 2007;259:7-15. 2. Bo, et al. Mult. Scler. 2003;9:323–31. 3. De Stefano, et al. Neurology. 2010;74:1868. 4.
Martola, et al. Neuroradiology. 2010;52:109-117. 5. Markiewicz & Lukomska. Acta Neurobiol Exp (Wars). 2006;66(4):343-358. 6. Cambron, et al. J Cereb
Blood Flow Metab. 2012; 32:413-424. 7. De Stefano, et al. Arch Neurol. 2002;59:1565-1571. 8. Rovaris, et al. Brain. 2003;126:2323-2332. 9. Kirov, et al. J
Neurol Neurosurg Psychiatry. 2009;80(12):1330-1336. 10. Li, et al. Neurology. 2006;66(9):1384-1389. 11. Fisher, et al. Neurology. 2002;59:1412-1420.

13.  No BBB dysfunction, no peripheral
inflammation1
 Activation of astrocytes and microglia
leading to pro-inflammatory cytokines
production2,3 .
 Astrocyte activation appears prominently in
normal appearing white matter2
MS AS A “TWO COMPONENTS” DISEASE
Diffuse pathology
References: 1. Trapp & Nave. Ann Rev Neurosci. 2008;31:247-269. 2. Filippi, et al. Lancet Neurol. 2012;11:349-360. 3. Markiewicz & Lukomska. Acta Neurobiol Exp
(Wars). 2006;66(4):343-358. 4. Cambron, et al. J Cereb Blood Flow Metab. 2012; 32:413-424. 5. Sofroniew. Trends Neurosci. 2009;32(12):638-647. 6. Bjartmar, et al.
Neurology. 2001;57:1248–1252. 7. Evangelou, et al. Ann Neurol. 2000;47:391-395. 8. Watzlawik, et al. Expert Rev Neurother. 2010;10:441–457. 9. Imitola, et al. Arch
Neurol. 2006;63:25-33. 10. Nair, et al. Cell Mol Life Sci. 2008;65:2702–2720.
 Axonal density in normal-appearing white matter is decreased by 12% to 45% , which
is partly explain by Wallerian degeneration after transection 2,6,7
 Results in demyelination1,8, axonal loss1,8, glial scarring9,10 and loss of
oligodendrocytes8, partly correlated with cortical lesions but not with T2 lesion load

14. References: 1. Lassmann. Curr Opin Neurol. 2008;1:242-7. 2. Markiewicz, et al. Acta Neurobiol Exp. 2006;66:343-58. 3. Nair, et al. Cell Mol Life Sci. 2008;65:2702-20. 4.
Van der Walt, et al. Pharmacol Ther. 2010;126:82-93. 5. Weiner. J Neurol. 2008;255 S1:3–11. 6. Zhang, et al. Mol Neurobiol. 2010;41:232-41.
THE CNS-RESIDENT-CELL PATHWAY
Proinflammatory
Cytokines
Oligodendrocyte
Oligodendrocyte
Damage/Apoptosis
Astrocyte
Activated
Astrocytes
Myelin
Residue
AXONAL
DAMAGE
TNF-α, NO, O2
INSIDE THE CNS
Degenerative
Trigger
Glial Scar
Formation
Activated
Microglia

15. MS AS A “TWO COMPONENTS” DISEASE
Is neurodegeneration exist in early MS?
Reference: Lassman et al., Nature reviews Neurology, 2012; 8, 647-656.
Focal lesions
Peripheral T-cell mediated pathway
Diffuse pathology
CNS-resident-cells pathway

16.  Brain atrophy measures
 Uniform longitudinal decrease in
brain volume during short and long
follow-up 1,2
 Atrophy progression rate is very
similar in the different MS
subtypes1,2
MS AS A “TWO COMPONENTS” DISEASE
Is neurodegeneration exist in early MS?
References: 1. De Stefano, et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology. 2010;74:1868.
2. Martola, et al. A longitudinal observational study of brain atrophy rate reflecting four decades of multiple sclerosis: a comparison of serial 1D, 2D, and
volumetric measurements from MRI images. Neuroradiology. 2010;52:109-117.

17.  Proton magnetic resonance
spectroscopy
• N-acetylaspartate (tNAA) is a surrogate marker for
axonal integrity.
• Myo-inositol (Ins) is a potential marker for increase of
activity or number of glial and inflammatory cells, as well
as migroglia activity.
• Choline (Cho) et Creatine (Cr) may be accounted for an
increase in cell turnover or metabolism, which might be
expected to occur with inflammatory or glial reactive
features
 CIS population
• Reduce whole brain NAA in CIS with DIT criteria
• Increased Ins and Cr in NAWM
• Partly correlated to T2 lesion load
References: 1. Charil et al., J Neurol Science, 2007; 259, 7-15. 2. Filippi et al., Brain, 2004; 126: 433-7. 3. Fernando et al., Brain, 2004; 127, 1361-9.
MS AS A “TWO COMPONENTS” DISEASE
Is neurodegeneration exist in early MS?

18.  Magnetization transfer imaging
 Reduced MTR in NAWM occurs early
in MS1
 Reduced MTR in NAWM and NAGM
in CIS patients2
• 6 months after CIS
• Partly independent from T2 lesion load
• More evident for patients who are known to
have the highest risk of converting to CDM
(those with T2 lesions and those who satisfy the
McDonald criteria)
Reference: 1. De Stefano, et al. Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability. Arch
Neurol. 2002;59:1565-1571. 2. Fernando et al., Brain 2005; 128: 2911-25.
MS AS A “TWO COMPONENTS” DISEASE
Is neurodegeneration exist in early MS?
Healthy
controls
RRMS
patients
3
1
-1
-3
ZScore
P<.001
RRMS patients
with short
disease
duration
(<3 years)
P<.005 P<.05
RRMS
patients
with low
volume
(<2 cm3) of
cerebral T2
lesions
MTR

19.  Diffusion Tensor Imaging
 Widespread pattern of significant reduction in FA value in NAWM: CIS vs HS1
 Higher average NAWM MD, lower average NAWM FA: CIS vs HS2
MS AS A “TWO COMPONENTS” DISEASE
Is neurodegeneration exist in early MS?
References: 1. Raze et al., Radiology, 2010; 254:227-234. 2. Gallo et al., Arch Neuro, 2005; 62: 803-8

20.  MS as a “two stages” disease : classical view of MS pathology
 MS as a “two components” disease : emerging view of MS pathology
 Conclusions and perspectives
OVERVIEW
• Inflammation and focal damages
• Focal damages and disease progression
• Limitations of this model
• Histopathological point of view
• Two distinct pathways
• Is neurodegeneration exist in early MS?

21. Peripheral T-cell–mediated pathway
Peripherally activated T cells enter the CNS
Episodic relapses due to inflammation
Visible by conventional MRI
CONCLUSIONS: MS as a “two components” disease
References: 1. Markiewicz et al. Acta Neurobiol Exp 2006;66:343-358. 2. Lassmann. Curr op in Neurol 2008;21:242-247. 3. Weiner. J Neurol
2008;255(S1):3-11. 4. Van der Walt et al. Pharmacol and Therapeutics 2010;126:82-93. 5. Stys et al. Nature Rev Neurosc 2012;13:507-514.
CNS-resident-cell pathway
 Involving activated astrocytes and microglia,
endogenous cells in CNS
 Results in demyelination and axonal loss, glial
scar formation, loss of oligodendrocytes
 Detectable on non-conventional MRI
Focal lesions
(acute disability)
Diffuse pathology
(long-term disability)
Both contribute to neurodegeneration
ultimately leading to disability