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Multiple sclerosis as a simultaneous "2 components" disease

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Multiple sclerosis as a simultaneous "2 components" disease

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Multiple sclerosis as a simultaneous "2 components" disease

  1. 1. Multiple sclerosis as a “simultaneous two components” disease Emilie LOMMERS 4th year of the Master in Neurology FRS-FNRSCandidat Spécialiste Doctorant 2014.
  2. 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. 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. 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. 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. 6. MS AS A “TWO STAGES” DISEASE: Focal damages and disease progression Reference: Compston & Coles. Multiple Sclerosis. Lancet 2002;359:1221–31.
  7. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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

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