Pathophysiology of multiple sclerosis

Multiple sclerosis is a disease in which the myelin (a fatty substance which covers the axons of nerve cells, important for proper nerve conduction) degenerates.

At least five characteristics are present in CNS tissues of MS patients: Inflammation beyond classical white matter lesions, Intrathecal Ig production with oligoclonal bands, An environment fostering immune cell persistence, Follicle-like aggregates in the meninges and a disruption of the blood-brain barrier also outside of active lesions [Meinl E, Krumbholz M, Derfuss T, Junker A, Hohlfeld R. Compartmentalization of inflammation in the CNS: A major mechanism driving progressive multiple sclerosis, J Neurol Sci. 2008 Aug 18, PMID 18715571] .

Appart of the usually known white matter demyelination, also the cortex and deep gray matter (GM) nuclei are affected, together with diffuse injury of the normal-appearing white matter. [Lassmann H,Bruck W,Lucchinetti CF. The immunopathology of multiple sclerosis: an overview, Centre for Brain Research, Medical University of Vienna, Vienna, Austria, PMID 17388952] . GM atrophy is independent of the MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS [Pirko I, Lucchinetti CF, Sriram S, Bakshi R. Gray matter involvement in multiple sclerosis. Neurology. 2007 Feb 27;68(9):E9–10. PMID 17325269]

Demyelination process

According to the view of most researchers, a special subset of lymphocytes, called T helper cells, specifically Th1 and Th17 [cite journal |author=Fransson ME, Liljenfeldt LS, Fagius J, Tötterman TH, Loskog AS. |title=The T-cell pool is anergized in patients with multiple sclerosis in remission |journal= |volume= |issue= |pages= |year= |pmid=18624727] , play a key role in the development of MS. Under normal circumstances, these lymphocytes can distinguish between self and non-self. However, in a person with MS, these cells recognize healthy parts of the central nervous system as foreign and attack them as if they were an invading virus, triggering inflammatory processes and stimulating other immune cells and soluble factors like cytokines and antibodies. Recently other type of immune cells, B Cells, have been also implicated in the pathogenesis of MS [B-cell depletion with rituximab in relapsing-remitting multiple sclerosis [http://www.ncbi.nlm.nih.gov/pubmed/18272891?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum] ] and in the degeneration of the axons [Cause of nerve fiber damage in multiple sclerosis identified [http://www.physorg.com/news80230112.html] ] .

Normally, there is a tight barrier between the blood and brain, called the blood-brain barrier (BBB), built up of endothelial cells lining the blood vessel walls. It should prevent the passage of antibodies through it, but in MS patients it does not work. For unknown reasons leaks appear in the blood-brain barrier. These leaks, in turn, cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other proteins such as matrix metalloproteinases which are destructive [Gray E, Thomas TL, Betmouni S, Scolding N, Love S. Elevated Matrix Metalloproteinase-9 and Degradation of Perineuronal Nets in Cerebrocortical Multiple Sclerosis Plaques. PMID 18716555] . The final result is destruction of myelin, called demyelination.

Whether BBB dysfunction is the cause or the consequence of MS [ cite journal |author=Waubant E |title=Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis |journal=Dis. Markers |volume=22 |issue=4 |pages=235–44 |year=2006 |pmid=17124345] is still disputed,because activated T-Cells can cross a healthy BBB when they express adhesion proteins [ [multiple sclerosis at emedicine.com http://www.emedicine.com/neuro/topic228.htm#target1] ]

A deficiency of uric acid has been implicated in this process. Uric acid added in physiological concentrations (i.e. achieving normal concentrations) is therapeutic in MS by preventing the breakdown of the blood brain barrier through inactivation of peroxynitrite. [cite journal |author=Kean R, Spitsin S, Mikheeva T, Scott G, Hooper D |title=The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity |journal=J. Immunol. |volume=165 |issue=11 |pages=6511–8 |year=2000 |pmid=11086092Full article [http://www.jimmunol.org/cgi/content/full/165/11/6511] ] The low level of uric acid found in MS victims is manifestedly causative rather than a consequence of tissue damage in the white matter lesions, [cite journal |author=Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, Economou M, Dimitrakopoulos A, Karouli M, Vassilopoulos D |title=Serum uric acid and multiple sclerosis |journal=Clinical neurology and neurosurgery |volume=108 |issue=6 |pages=527–31 |year=2006 |pmid=16202511 |doi=10.1016/j.clineuro.2005.08.004] but not in the grey matter lesions. [van Horssen,Brink,de Vries,van der Valk,Bo. The Blood-Brain Barrier in Cortical Multiple Sclerosis Lesions. PMID 17413323] . Besides, uric acid levels are lower during relapses [Variation of serum uric acid levels in multiple sclerosis during relapses and immunomodulatory treatment, Guerrero AL, Martín-Polo J, Laherrán E, Gutiérrez F, Iglesias F, Tejero MA, Rodríguez-Gallego M, Alcázar C. [http://www.ncbi.nlm.nih.gov/pubmed/18312403?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum] ] .

The axons themselves can also be damaged by the attacks. [cite journal |author=Pascual AM, Martínez-Bisbal MC, Boscá I, "et al" |title=Axonal loss is progressive and partly dissociated from lesion load in early multiple sclerosis |journal=Neurology |volume=69 |issue=1 |pages=63–7 |year=2007 |pmid=17606882 |doi=10.1212/01.wnl.0000265054.08610.12] Often, the brain is able to compensate for some of this damage, due to an ability called neuroplasticity. MS symptoms develop as the cumulative result of multiple lesions in the brain and spinal cord. This is why symptoms can vary greatly between different individuals, depending on where their lesions occur.

Repair processes, called remyelination, also play an important role in MS. Remyelination is one of the reasons why, especially in early phases of the disease, symptoms tend to decrease or disappear temporarily. Nevertheless, nerve damage and irreversible loss of neurons occur early in MS.
Proton magnetic resonance spectroscopy has shown that there is widespread neuronal loss even at the onset of MS, largely unrelated to inflammation. [cite journal |author=Filippi M, Bozzali M, Rovaris M, Gonen O, Kesavadas C, Ghezzi A, Martinelli V, Grossman R, Scotti G, Comi G, Falini A |title=Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis |journal=Brain |volume=126 |issue=Pt 2 |pages=433–7 |year=2003 |pmid=12538409 |doi=10.1093/brain/awg038]

The oligodendrocytes that originally formed a myelin sheath cannot completely rebuild a destroyed myelin sheath. However, the central nervous system can recruit oligodendrocyte stem cells capable of proliferation and migration and differentiation into mature myelinating oligodendrocytes. The newly-formed myelin sheaths are thinner and often not as effective as the original ones. Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons. Under laboratory conditions, stem cells are quite capable of proliferating and differentiating into remyelinating oligodendrocytes; it is therefore suspected that inflammatory conditions or axonal damage somehow inhibit stem cell proliferation and differentiation in affected areas [Wolswijk, G. "Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells" J Neurosci, 1998;18: 601-9. PMID 9425002]

Blood-brain barrier disruption

A healthy blood-brain barrier shouldn't allow T-cells to enter the nervous system. Therefore BBB disruption has always been considered one of the early problems in the MS lesions. Recently it has been found that this happens even in non-enhancing lesions [cite journal |author=Soon D, Tozer DJ, Altmann DR, Tofts PS, Miller DH |title=Quantification of subtle blood-brain barrier disruption in non-enhancing lesions in multiple sclerosis: a study of disease and lesion subtypes |journal= |volume= |issue= |pages= |year=2007 |pmid=17468443 |doi=10.1177/1352458507076970] , and it has been found with iron oxide nanoparticles how macrophages produce the BBB disruption [cite journal |author=Petry KG, Boiziau C, Dousset V, Brochet B |title=Magnetic resonance imaging of human brain macrophage infiltration |journal=Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics |volume=4 |issue=3 |pages=434–42 |year=2007 |pmid=17599709 |doi=10.1016/j.nurt.2007.05.005] . The BBB breakdown is responsible of monocyte infiltration and inflammation in the brain [cite journal |author=Reijerkerk A, Kooij G, van der Pol SM, Leyen T, van Het Hof B, Couraud PO, Vivien D, Dijkstra CD, de Vries HE. |title=Tissue-type plasminogen activator is a regulator of monocyte diapedesis through the brain endothelial barrier |journal= |volume= |issue= |pages= |year= |pmid=18714030 |doi=] .

Normally, gadolinium enhancement is used to show BBB disruption on MRIs [Waubant E. Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis. PMID 17124345] . Abnormal tight junctions are present in both SPMS and PPMS. They appear in active white matter lesions, and gray matter in SPMS. They persist in inactive lesions, particularly in PPMS [cite journal |author=Leech S, Kirk J, Plumb J, McQuaid S |title=Persistent endothelial abnormalities and blood-brain barrier leak in primary and secondary progressive multiple sclerosis |journal=Neuropathol. Appl. Neurobiol. |volume=33 |issue=1 |pages=86–98 |year=2007 |pmid=17239011 |doi=10.1111/j.1365-2990.2006.00781.x]

A special role is played by Matrix metalloproteinases. These are a group of proteases that increase T-cells permeability of the blood-brain barrier, specially in the case of MMP-9 [Gray E, Thomas TL, Betmouni S, Scolding N, Love S. Elevated matrix metalloproteinase-9 and degradation of perineuronal nets in cerebrocortical multiple sclerosis plaques PMID 18716555] , and are supposed to be related to the mechanism of action of interferons [Boz C, Ozmenoglu M, Velioglu S, Kilinc K, Orem A, Alioglu Z, Altunayoglu V. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in patients with relapsing-remitting multiple sclerosis treated with interferon beta PMID 16412833] ,

Apart from that, activated T-Cells can cross a healthy BBB when they express adhesion proteins [ [multiple sclerosis at emedicine.com http://www.emedicine.com/neuro/topic228.htm#target1] ] . In particular, one of these adhesion proteins involved is ALCAM (Activated Leukocyte Cell Adhesion Molecule, also called CD166), and is under study as therapeutic target [Alexandre Prat, Nicole Beaulieu, Sylvain-Jacques Desjardins, New Therapeutic Target For Treatment Of Multiple Sclerosis, Jan. 2008 [http://www.medicalnewstoday.com/articles/94734.php] ] . Other protein also involved is CXCL12 [Pathological Expression of CXCL12 at the Blood-Brain Barrier Correlates with Severity of Multiple Sclerosis [http://www.ncbi.nlm.nih.gov/pubmed/18276777?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum] ] , which could be related to the behavior of CXCL13 under methylprednisolone therapy [Michałowska-Wender G, Losy J, Biernacka-Łukanty J, Wender M., Impact of methylprednisolone treatment on the expression of macrophage inflammatory protein 3alpha and B lymphocyte chemoattractant in serum of multiple sclerosis patients, PMID 18799824] .

Haemodynamics of the lesions has been measured and distortion has been found related to plaque distribution [Intracranial Venous Haemodynamics in Multiple Sclerosis, Zamboni, Paolo; Menegatti, Erica; Bartolomei, Ilaria; Galeotti, Roberto; Malagoni, Anna M.; Tacconi, Giovanna; Salvi, Fabrizio [http://www.ingentaconnect.com/content/ben/cnr/2007/00000004/00000004/art00004;jsessionid=2t4etumjan81n.alexandra] ] . It was measured through transcranial color-coded duplex sonography (TCCS). The permeability of two cytokines, IL15 and LPS, could be involved in the BBB breakdown [cite journal |author=Pan W, Hsuchou H, Yu C, Kastin AJ |title=Permeation of blood-borne IL15 across the blood-brain barrier and the effect of LPS |journal=J. Neurochem. |volume= |issue= |pages= |year=2008 |pmid=18384647 |doi=10.1111/j.1471-4159.2008.05390.x] .

The importance of vascular misbehaviour in MS pathogenesis has been confirmed by seven-tesla MRI [cite journal |author=Ge Y, Zohrabian VM, Grossman RI. |title=Seven-tesla magnetic resonance imaging: new vision of microvascular abnormalities in multiple sclerosis |journal= |volume= |issue= |pages= |year=2008 |pmid=18541803 |doi=] . A number of histopathologic studies have provided evidence of vascular occlusion in MS, suggesting that there is possible primary vascular injury in MS lesions as well as the NAWM and NAGM [cite journal |author=M. Filippi, G. Comi, and M. Rovaris, eds. New York: Springer; |title=Normal-appearing White and Grey Matter Damage in Multiple Sclerosis. Book review. |journal=AJRN |volume= |issue= |pages= |year=2004 |pmid= |doi= [http://www.ajnr.org/cgi/content/full/27/4/945] ] . Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1alpha through Lyn kinase [Malik M, Chen YY, Kienzle MF, Tomkowicz BE, Collman RG, Ptasznik A. Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1alpha through Lyn kinase. PMID 18802065]

Nevertheless, the idea of the BBB disruption as primary trigger event in lesion development has been disputed and its have been proposed that previous changes in White Matter structure are a previous trigger [D. J. Werring,*, D. Brassat,*, A. G. Droogan, C. A. Clark, M. R. Symms, G. J Barker, D. G. MacManus, A. J. Thompson and D. H. Miller, The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis [http://brain.oxfordjournals.org/cgi/content/abstract/123/8/1667] ] .

=Spinal cord da

Progressive tissue loss and injury occur in the cervical cord of MS patients. These two components of cord damage are not interrelated, suggesting that a multiparametric MRI approach is needed to get estimates of such a damage. MS cord pathology is independent of brain changes, develops at different rates according to disease phenotype, and is associated to medium-term disability accrual [Agosta F, Absinta M, Sormani MP, Ghezzi A, Bertolotto A, Montanari E, Comi G, Filippi M. In vivo assessment of cervical cord damage in MS patients: a longitudinal diffusion tensor MRI study PMID 17535835] .

=Retina and optic nerve da

Brain tissues abnormalities

Lesion distribution

Using high field MRI system, with several variants several areas show lesions, and can be spacially clasified in infratentorial, callosal, juxtacortical, periventricular, and other white matter areas [Wattjes MP, Harzheim M, Kuhl CK, Gieseke J, Schmidt S, Klotz L, Klockgether T, Schild HH, Lutterbey GG. Does high-field MR imaging have an influence on the classification of patients with clinically isolated syndromes according to current diagnostic mr imaging criteria for multiple sclerosis? PMID 16971638] . Other authors simplify this in three regions: intracortical, mixed gray-white matter, and juxtacortical [Nelson F, Poonawalla AH, Hou P, Huang F, Wolinsky JS, Narayana PA. Improved identification of intracortical lesions in multiple sclerosis with phase-sensitive inversion recovery in combination with fast double inversion recovery MR imaging. PMID 17885241] . Others classify them as hippocampal, cortical, and WM lesions [Roosendaal SD, Moraal B, Vrenken H, Castelijns JA, Pouwels PJ, Barkhof F, Geurts JJ. In vivo MR imaging of hippocampal lesions in multiple sclerosis. PMID 18302199] , and finally, others give seven areas: intracortical, mixed white matter-gray matter, juxtacortical, deep gray matter, periventricular white matter, deep white matter, and infratentorial lesions [Geurts JJ, Pouwels PJ, Uitdehaag BM, Polman CH, Barkhof F, Castelijns JA. Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging. PMID 15987979]

Post-mortem authopsy reveal that gray matter demyelination occurs in the motor cortex, cingulate gyrus, cerebellum, thalamus and spinal cord [Gilmore CP, Donaldson I, Bö L, Owens T, Lowe JS, Evangelou N. Regional variations in the extent and pattern of grey matter demyelination in Multiple Sclerosis: a comparison between the cerebral cortex, cerebellar cortex, deep grey matter nuclei and the spinal cord PMID 18829630] . Cortical lesions have been observed specially in people with SPMS but they also appear in RRMS and clinically isolated syndrome. They are more frequent in men than in women [cite journal |author=Calabrese M, De Stefano N, Atzori M, "et al" |title=Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis |journal=Arch. Neurol. |volume=64 |issue=10 |pages=1416–22 |year=2007 |pmid=17923625 |doi=10.1001/archneur.64.10.1416] and they can partly explain cognitive deficits.

It is known that two parameters of the cortical lesions, fractional anisotropy (FA) and mean diffusivity (MD), are higher in patients than in controls [cite journal |author=Poonawalla AH, Hasan KM, Gupta RK, "et al" |title=Diffusion-Tensor MR Imaging of Cortical Lesions in Multiple Sclerosis: Initial Findings |journal=Radiology |volume= |issue= |pages= |year=2008 |pmid=18195384 |doi=10.1148/radiol.2463070486] . They are larger in SPMS than in RRMS and most of them remain unchanged for short follow-up periods. They do not spread into the subcortical white matter and never show gadolinium enhancement. Over a one-year period, CLs can increase their number and size in a relevant proportion of MS patients, without spreading into the subcortical white matter or showing inflammatory features similar to those of white matter lesions. [cite journal |author=Calabrese M, Filippi M, Rovaris M, Mattisi I, Bernardi V, Atzori M, Favaretto A, Barachino L, Rinaldi L, Romualdi C, Perini P, Gallo P. |title=Morphology and evolution of cortical lesions in multiple sclerosis. A longitudinal MRI study |journal= |volume= |issue= |pages= |year=2008 |pmid=18652903 |doi=]

Normal appearing brain tissues

Brain tissues with normal aspect under normal MRI (Normal appearing white matter, NAWM and normal appearing grey matter, NAGM) show several abnormalities under diffusion tensor MRI or Magnetic Transfer MRI. This is currently an active field of research with no definitive results. These abnormalities can be studied with special MRI techniques like Magnetization transfer multi-echo T(2) relaxation. Subjects with Long-T(2) lesions had a significantly longer disease duration than subjects without this lesion subtype [cite journal |author=Laule C, Vavasour IM, Kolind SH, "et al" |title=Long T(2) water in multiple sclerosis: What else can we learn from multi-echo T(2) relaxation? |journal=J. Neurol. |volume=254 |issue=11 |pages=1579–87 |year=2007 |pmid=17762945 |doi=10.1007/s00415-007-0595-7] . It has been found that grey matter injury correlates with disability [cite journal |author=Zhang Y, Zabad R, Wei X, Metz LM, Hill MD, Mitchell JR |title=Deep grey matter 'black T2' on 3 tesla magnetic resonance imaging correlates with disability in multiple sclerosis |journal= |volume= |issue= |pages= |year=2007 |pmid=17468444 |doi=10.1177/1352458507076411] and that there is high oxidative stress in lesions, even in the old ones. [cite journal |author=Holley JE, Newcombe J, Winyard PG, Gutowski NJ |title=Peroxiredoxin V in multiple sclerosis lesions: predominant expression by astrocytes |journal= |volume= |issue= |pages= |year=2007 |pmid=17623739 |doi=10.1177/1352458507078064] . Water diffusivity is higher in all NAWM regions, deep gray matter regions, and some cortical gray matter region of MS patients than normal controls [cite journal |author=Phuttharak W, Galassi W, Laopaiboon V, Laopaiboon M, Hesselink JR |title=Abnormal diffusivity of normal appearing brain tissue in multiple sclerosis: a diffusion-weighted MR imaging study |journal=J Med Assoc Thai |volume=90 |issue=12 |pages=2689–94 |year=2007 |pmid=18386722 |doi=] .

Post-mortem studies over NAWM and NAGM areas show several biochemical alterations, like increased protein carbonylation and high levels of Glial fibrillary acidic protein (GFAP), which in NAGM areas comes together with higher than normal concentration of protein carbonyls, suggesting reduced levels of antioxidants and the presence of small lesions [cite journal |author=Bizzozero OA, DeJesus G, Callahan K, Pastuszyn A. |title=Elevated protein carbonylation in the brain white matter and gray matter of patients with multiple sclerosis |journal= |volume= |issue= |pages= |year= |pmid=16007681 |doi=] . The amount of interneuronal Parvalbumin is lower than normal in brain's motor cortex areas [cite journal |author=Clements RJ, McDonough J, Freeman EJ. |title=Distribution of parvalbumin and calretinin immunoreactive interneurons in motor cortex from multiple sclerosis post-mortem tissue |journal= |volume= |issue= |pages= |year= |pmid=18297277 |doi=] . Citrullination appears in SPMS [cite journal |author=Nicholas AP, Sambandam T, Echols JD, Tourtellotte WW. |title=Increased citrullinated glial fibrillary acidic protein in secondary progressive multiple sclerosis |journal= |volume= |issue= |pages= |year= |pmid=15067723 |doi=] . It seems that a defect of sphingolipid metabolism modifies the properties of normal appearing white matter [David Wheeler, Veera Venkata Ratnam Bandaru, Peter A. Calabresi, Avindra Nath and Norman J. Haughey, A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis [http://brain.oxfordjournals.org/cgi/content/full/awn190v1] ]

NAWM shows a decreased perfusion which does not appear to be secondary to axonal loss. The reduced perfusion of the NAWM in MS might be caused by a widespread astrocyte dysfunction, possibly related to a deficiency in astrocytic beta(2)-adrenergic receptors and a reduced formation of cAMP, resulting in a reduced uptake of K(+) at the nodes of Ranvier and a reduced release of K(+) in the perivascular spaces [cite journal |author=De Keyser J, Steen C, Mostert JP, Koch MW. |title=Hypoperfusion of the cerebral white matter in multiple sclerosis: possible mechanisms and pathophysiological significance |journal= |volume= |issue= |pages= |year=2008 |pmid=18594554 |doi=] .

White matter lesions appear in NAWM areas [D. E. Goodkin, MD, W. D. Rooney, PhD, R. Sloan, P. Bacchetti, PhD, L. Gee, MPH, M. Vermathen, PhD, E. Waubant, MD, M. Abundo, S. Majumdar, PhD, S. Nelson, DrrerNat and M. W. Weiner, MD A serial study of new MS lesions and the white matter from which they arise, NEUROLOGY 1998;51:1689-1697 [http://www.neurology.org/cgi/content/abstract/51/6/1689] ] , and their behavior can be predicted by MRI parameters as MTR (magnetization transfer ratio) [Filippi M, Rocca MA, Martino G, Horsfield MA, Comi G. Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis PMID 9629851] [M. Cercignani, MPhil, G. Iannucci, MD, M. A. Rocca, MD, G. Comi, MD, M. A. Horsfield, PhD and M. Filippi, MD Pathologic damage in MS assessed by diffusion-weighted and magnetization transfer MRI [http://www.neurology.org/cgi/content/abstract/54/5/1139] ] . This MTR parameter is related to axonal density [J. H. T. M. Van Waesberghe, MD et al.Axonal loss in multiple sclerosis lesions: Magnetic resonance imaging insights into substrates of disability, doi=10.1002/1531-8249(199911)46. [http://www3.interscience.wiley.com/journal/81502650/abstract?CRETRY=1&SRETRY=0] ] .

Normal brain tissues

It has been stablished that myelin basic protein (MBP) from multiple sclerosis (MS) patients contains lower levels of phosphorylation at Thr97 than normal individuals [cite journal |author=Tait AR, Straus SK. |title=Phosphorylation of U24 from Human Herpes Virus type 6 (HHV-6) and its potential role in mimicking myelin basic protein (MBP) in multiple sclerosis |journal= |volume= |issue= |pages= |year=2008 |pmid=18616943 |doi=] .

=Neural and axonal da

The axons of the neurons are damaged probably by B-Cells [Cause of nerve fiber damage in multiple sclerosis identified [http://www.physorg.com/news80230112.html] ] , though currently no relationship has been established with the relapses or the attacks [cite journal |author=Pascual AM, Martínez-Bisbal MC, Boscá I, "et al" |title=Axonal loss is progressive and partly dissociated from lesion load in early multiple sclerosis |journal=Neurology |volume=69 |issue=1 |pages=63–7 |year=2007 |pmid=17606882 |doi=10.1212/01.wnl.0000265054.08610.12] . It seems that this damage is primray target of the immune system, i.e. not secondary damage after attacks against myelin [Huizinga R, Gerritsen W, Heijmans N, Amor S. Axonal loss and gray matter pathology as a direct result of autoimmunity to neurofilaments, PMID 18804534 ]

A relationship between neural damage and N-Acetyl-Aspartate concentration has been established, and this could lead to new methods for early MS diagnostic through magnetic resonance spectroscopy [Neuer Diagnose-Ansatz zur Früherkennung von MS [http://www1.uni-bonn.de/pressDB/jsp/pressemitteilungsdetails.jsp?detailjahr=2007&detail=365] ]

Axonal degeneration at CNS can be estimated by N-acetylaspartate to creatine (NAA/Cr) ratio, both measured by with proton magnetic resonance spectroscopy [cite journal |author=Mostert JP, Blaauw Y, Koch MW, Kuiper AJ, Hoogduin JM, De Keyser J |title=Reproducibility over a 1-month period of (1)H-MR spectroscopic imaging NAA/Cr ratios in clinically stable multiple sclerosis patients |journal=Eur Radiol |volume= |issue= |pages= |year=2008 |pmid=18389250 |doi=10.1007/s00330-008-0925-x] .

Blood and CSF abnormalities

Since long time ago it is known that glutamate is present at higher levels in CSF during relapses [cite journal |author=Sarchielli P, Greco L, Floridi A, Floridi A, Gallai V. |title=Excitatory amino acids and multiple sclerosis: evidence from cerebrospinal fluid. |journal=Arch. Immunol. |year=2003 |pmid=12925363] compared to healthy subjects and to MS patients before relapses. Also a specific MS protein has been found in CSF, chromogranin A, possibly related to axonal degeneration. It appears together with clusterin and complement C3, markers of complement-mediated inflammatory reactions [cite journal |author=Stoop MP, Dekker LJ, Titulaer MK, "et al" |title=Multiple sclerosis-related proteins identified in cerebrospinal fluid by advanced mass spectrometry |journal=Proteomics |volume= |issue= |pages= |year=2008 |pmid=18351689 |doi=10.1002/pmic.200700446] . Also Fibroblast growth factor-2 appear higher at CSF [cite journal |author=cite journal |author=Stoop MP, Dekker LJ, Titulaer MK, "et al" |title=Multiple sclerosis-related proteins identified in cerebrospinal fluid by advanced mass spectrometry |journal=Proteomics |volume= |issue= |pages= |year=2008 |pmid=18351689 |doi=10.1002/pmic.200700446 |title=Fibroblast growth factor-2 levels are elevated in the cerebrospinal fluid of multiple sclerosis patients |journal=Neurosci Lett. |volume= |issue= |pages= |year=2008 |pmid=18353554 |doi=10.1002/pmic.200700446] .

MS patients are also known to be CD46 defective, and this leads to Interleukin-10 (IL-10) deficiency, being this involved in the inflammatory reactions [cite journal |author=Astier AL |title=T-cell regulation by CD46 and its relevance in multiple sclerosis |journal=Immunology |volume= |issue= |pages= |year=2008 |pmid=18384356 |doi=10.1111/j.1365-2567.2008.02821.x] . Levels of IL-2, IL-10, and GM-CSF are lower in MS females than normal. IL6 is higher instead. These findings do not apply to men [cite journal |author=Kanabrocki EL, Ryan MD, Lathers D, Achille N, Young MR, Cauteren JV, Foley S, Johnson MC, Friedman NC, Siegel G, Nemchausky BA. |title=Circadian distribution of serum cytokines in multiple sclerosis |journal=Clin. Ter. |volume= |issue= |pages= |year=2007 |pmid=17566518 |doi=] . This IL-10 interleukin could be related to the mechanism of action of methylprednisolone, together with CCL2. Interleukin IL-12 is also known to be associated with relapses, but this is unlikely to be related to the response to steroids [cite journal |author=Rentzos M, Nikolaou C, Rombos A, Evangelopoulos ME, Kararizou E, Koutsis G, Zoga M, Dimitrakopoulos A, Tsoutsou A, Sfangos C. |title=Effect of treatment with methylprednisolone on the serum levels of IL-12, IL-10 and CCL2 chemokine in patients with multiple sclerosis in relapse |journal= |volume= |issue= |pages= |year=2008 |pmid=18657352 |doi=]

There is also an overexpression of IgG-free kappa light chain protein in both CIS and RR-MS patients, compared with control subjects, together with an increased expression of an isoforms of apolipoprotein E in RR-MS [cite journal |author=Chiasserini D, Di Filippo M, Candeliere A, Susta F, Orvietani PL, Calabresi P, Binaglia L, Sarchielli P. |title=CSF proteome analysis in multiple sclerosis patients by two-dimensional electrophoresis |journal= |volume= |issue= |pages= |year=2008 |pmid=18637954 |doi=]

Heterogeneity of the disease

Demyelination patterns

Also known as Lassmann patterns [Devic’s disease: bridging the gap between laboratory and clinic, Ralf Gold, Christopher Linington, Brain, Vol. 125, No. 7, 1425-1427, July 2002 [http://brain.oxfordjournals.org/cgi/content/full/125/7/1425] ] , it is believed that they may correlate with differences in disease type and prognosis, and perhaps with different responses to treatment. This report suggests that there may be several types of MS with different immune-related causes, and that MS may be a family of several diseases.

The four identified patterns are [http://www.neurologyreviews.com/aug02/nr_aug02_mslesion.html] :

; Pattern I : The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation. [cite web| url=http://immserv1.path.cam.ac.uk/~immuno/part1/lec10/lec10_97.html| title=Part 1B Pathology: Lecture 11 - The Complement System| accessdate=2006-05-10| first=Nick| last=Holmes| date=15 November 2001] ; Pattern II : The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, as before, but also signs of complement system activation can be found. [cite journal| url=http://brain.oxfordjournals.org/cgi/content/abstract/122/12/2279| journal=Brain| volume=122| issue=12| pages=2279–2295| month=December| year=1999| title=A quantitative analysis of oligodendrocytes in multiple sclerosis lesions - A study of 113 cases| first=Claudia| last=Lucchinetti| coauthors=Wolfgang Brück, Joseph Parisi, Bernd Scheithauer, Moses Rodriguez and Hans Lassmann| accessdate=2006-05-10| doi=10.1093/brain/122.12.2279] ; Pattern III : The scars are diffuse with inflammation, distal oligodendrogliopathy and microglial activation. There is also loss of myelin associated glycoprotein (MAG). The scars do not surround the blood vessels, and in fact, a rim of preserved myelin appears around the vessels. There is evidence of partial remyelinization and oligodendrocyte apoptosis.; Pattern IV : The scar presents sharp borders and oligodendrocyte degeneration, with a rim of normal appearing white matter. There is a lack of oligodendrocytes in the center of the scar. There is no complement activation or MAG loss.

The meaning of this fact is controversial. For some investigation teams it means that MS is a heterogeneous disease. Others maintain that the shape of the scars can change with time from one type to other and this could be a marker of the disease evolution. Anyway, the heterogeneity could be true only for the early stage of the disease [cite journal |author=Breij EC, Brink BP, Veerhuis R, "et al" |title=Homogeneity of active demyelinating lesions in established multiple sclerosis |journal=Ann Neurol |volume=63 |issue=1 |pages=16–25 |year=2008 |pmid=18232012 |doi=10.1002/ana.21311] . Recently some lesions have shown mitocondrial defects and this could also be a difference between types of lesions [cite journal |author=Mahad D, Ziabreva I, Lassmann H, Turnbull D. |title=Mitochondrial defects in acute multiple sclerosis lesions |journal= |volume= |issue= |pages= |year=2008 |pmid=18515320 |doi=]

Correlation with clinical courses

No definitive relationship between these patterns and the clinical subtypes has been established by now, but some relations have been established. All the cases with PPMS (primary progressive) had pattern IV (oligodendrocyte degeneration) in the original study [Primary progressive multiple sclerosis [http://brain.oxfordjournals.org/cgi/content/full/125/12/2784] ] and nobody with RRMS was found with this pattern. Balo concentric sclerosis lesions have been classified as pattern III (distal oligodendrogliopathy) [(Article in Spanish) Estudio longitudinal mediante imagen de resonancia magnética (RM) del efecto de la azatioprina [http://www.fedem.org/revista/n13/actualidad.html] ] . Neuromyelitis optica was associated with pattern II (complement mediated demyelination), though they show a perivascular distribution, at difference from MS pattern II lesions [The Mystery of the Multiple Sclerosis Lesion, Frontiers Beyond the Decade of the Brain, Medscape [http://209.85.135.104/search?q=cache:xLNFPncN2OkJ:doctor.medscape.com/viewarticle/433621+the+lesion+project+neuromyelitis+optica&hl=es&gl=es&ct=clnk&cd=7&client=firefox-a] ] .

Correlation with MRI and MRS findings

The researchers are attempting this with magnetic resonance images to confirm their initial findings of different patterns of immune pathology and any evidence of possible disease “sub-types” of underlying pathologies. It is possible that such “sub-types” of MS may evolve differently over time and may respond differently to the same therapies. Ultimately investigators could identify which individuals would do best with which treatments.

It seems that Pulsed magnetization transfer imaging,cite journal
author=Smith SA, Farrell JA, Jones CK, Reich DS, Calabresi PA, van Zijl PC
title=Pulsed magnetization transfer imaging with body coil transmission at 3 Tesla: feasibility and application
journal=Magn Reson Med
volume=56
issue=4
pages=866–75
year=2006
month=October
pmid=16964602
doi=10.1002/mrm.21035
url=] diffusion Tensor MRI,cite journal
author=Goldberg-Zimring D, Mewes AU, Maddah M, Warfield SK
title=Diffusion tensor magnetic resonance imaging in multiple sclerosis
journal=J Neuroimaging
volume=15
issue=4 Suppl
pages=68S–81S
year=2005
pmid=16385020
doi=10.1177/1051228405283363
url=] and VCAM-1 enhanced MRI [http://www.admin.ox.ac.uk/po/news/2006-07/sep/24.shtml] could be able to show the pathological differences of these patterns.

Together with MRI, magnetic resonance spectroscopy will allow in the future to see the biochemical composition of the lesions.

Correlation with CSF findings

Teams in Oxford and Germany, [http://brain.oxfordjournals.org/cgi/content/abstract/124/11/2169] cite journal
author=Cepok S, Jacobsen M, Schock S, "et al"
title=Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis
journal=Brain
volume=124
issue=Pt 11
pages=2169–76
year=2001
month=November
pmid=11673319
doi=
url=http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11673319] found correlation with CSF and progression in November 2001, and hypothesis have been made suggesting correlation between CSF findings and pathophysiological patterns [Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11673319&query_hl=8&itool=pubmed_docsum] ] . In particular, B-cell to monocyte ratio looks promising. The anti-MOG antibody has been investigated but no utility as biomarker has been found [MOG antibodies in pathologically proven multiple sclerosis [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17294606&query_hl=13&itool=pubmed_docsum] ] , though this is disputed [Recognition and degradation of myelin basic protein peptides by serum autoantibodies: novel biomarker for multiple sclerosis, Belogurov AA Jr, Kurkova IN, Friboulet A, Thomas D, Misikov VK, Zakharova MY, Suchkov SV, Kotov SV, Alehin AI, Avalle B, Souslova EA, Morse HC 3rd, Gabibov AG, Ponomarenko NA [http://www.ncbi.nlm.nih.gov/pubmed/18178866?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum] ] . High levels of anti-nuclear antibodies are found normally in patients with MS. Antibodies against Neurofascin–186 could be involved in a subtype of MS [Early research into a treatment for progressive MS [http://www.mssociety.org.uk/news_events/news/research/linington_resear.html] ]

Response to therapy

It is known that 30% of MS patients are non-responsive to Beta interferon [HLA class II and response to interferon-beta in multiple sclerosis. [http://www.ncbi.nlm.nih.gov/pubmed/16281922?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum] ] . The heterogeneous response to therapy can support the idea of hetherogeneous aetiology. It has also been shown that IFN receptors and interleukins in blood serum predicts response to IFN therapy [Pharmacogenomics of Interferon-ss Therapy in Multiple Sclerosis: Baseline IFN Signature Determines Pharmacological Differences between Patients, van Baarsen LG, Vosslamber S, Tijssen M, Baggen JM, van der Voort LF, Killestein J, van der Pouw Kraan TC, Polman CH, Verweij CL. PLoS ONE. 2008 Apr 2 [PMID 18382694] ] [cite journal |author=Wiesemann E, Deb M, Hemmer B, Radeke HH, Windhagen A. |title=Early identification of interferon-beta responders by ex vivo testing in patients with multiple sclerosis |journal= |volume= |issue= |pages= |year=2008 |month= |pmid=18539537 |doi= |url=] , and interleukins IL12/IL10 ratio has been proposed as marker of clinical course [cite journal |author=Carrieri PB, Ladogana P, Di Spigna G, Fulvia de Leva M, Petracca M, Montella S, Buonavolonta L, Florio C, Postiglione L. |title=Interleukin-10 and Interleukin-12 Modulation in Patients with Relapsing-Remitting Multiple Sclerosis on Therapy with Interferon-beta 1a: Differences in Responders and Non Responders. |journal= |volume= |issue= |pages= |year=2008 |month= |pmid=18686100 |doi= |url=] . Besides:

* Pattern II lesions patients are responsive to plasmapheresis, while others are not [http://www.neurologyreviews.com/mar00/nr_mar00_MSpatients.html] [http://www.nationalmssociety.org/Research-2005Aug19.asp] [http://www.medicalnewstoday.com/medicalnews.php?newsid=29100] .
* The subtype associated with macrophage activation, T cell infiltration and expression of inflammatory mediator molecules may be most likely responsive to immunomodulation with interferon-beta or glatiramer acetate.cite journal
author=Bitsch A, Brück W
title=Differentiation of multiple sclerosis subtypes: implications for treatment
journal=CNS Drugs
volume=16
issue=6
pages=405–18
year=2002
pmid=12027786
doi=
url=]
*People non-responsive to interferons are the most responsive to Copaxone [http://www.msworld.org/Resource_Center/news/n03switch.htm] [http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17956447&ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum]
* In general, people non-responsive to a treatment is more responsive to other [cite journal |author=Carrá A, Onaha P, Luetic G, "et al" |title=Therapeutic outcome 3 years after switching of immunomodulatory therapies in patients with relapsing-remitting multiple sclerosis in Argentina |journal=Eur. J. Neurol. |volume=15 |issue=4 |pages=386–93 |year=2008 |pmid=18353125 |doi=10.1111/j.1468-1331.2008.02071.x]
* There are genetic differences between responders and not responders.cite journal
author=Byun E, Caillier SJ, Montalban X, "et al"
title=Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis
journal=Arch. Neurol.
volume=65
issue=3
pages=337–44
year=2008
month=March
pmid=18195134
doi=10.1001/archneurol.2008.47
url=] Though the article points to heterogeneous metabolic reactions to interferons instead of disease heterogeneity, it has been shown that most genetic differences are not related to interferon behavior [cite journal |author=Vandenbroeck K, Matute C |title=Pharmacogenomics of the response to IFN-beta in multiple sclerosis: ramifications from the first genome-wide screen |journal=Pharmacogenomics |volume=9 |issue=5 |pages=639–45 |year=2008 |month=May |pmid=18466107 |doi=10.2217/14622416.9.5.639 |url=]

Subgroups by molecular biomarkers

Pubertal and pediatric MS

MS cases are rare before puberty, but they can happen. Whether they constitute a separate disease is still an open subject. Anyway, even this pubertal MS could be more than one disease, because early-onset and late-onset have different demyelination patterns [Chabas D, Castillo-Trivino T, Mowry EM, Strober JB, Glenn OA, Waubant E. Vanishing MS T2-bright lesions before puberty: A distinct MRI phenotype? PMID 18824673]

Discovery

The National MS society launched The Lesion Project to classify the different lesion patterns of MS.

Claudia F. Lucchinetti, MD from Mayo Clinic and collaborators from the U.S., Germany and Austria were chosen to conduct this study for their previous contributions in this area. They have amassed a large collection of tissue samples from people with MS through brain biopsies or autopsy. Claudia Lucchinetti was appointed director of this project. The group has reported promising findings on samples from 83 cases. They found four types of lesions, which differed in immune system activity. Within each person, all lesions were the same, but lesions differed from person to person.

The first article about pathophysiological heterogeneity was in 1996,cite journal
author=Lucchinetti CF, Brück W, Rodriguez M, Lassmann H
title=Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis
journal=Brain Pathol.
volume=6
issue=3
pages=259–74
year=1996
month=July
pmid=8864283
doi=
url=] and has been confirmed later by several teams. Four different damage patterns have been identified by her team in the scars of the brain tissue. Understanding lesion patterns can provide information about differences in disease between individuals and enable doctors to make more accurate treatment decisions.

According to one of the researchers involved in the original research "Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity."

Apart of this, recent achievements in related diseases, like neuromyelitis optica have shown that varieties previously suspected different from MS are in fact different diseases. In neuromyelitis optica, a team was able to identify a protein of the neurons, Aquaporin 4 as the target of the immune attack. This has been the first time that the attack mechanisme of a type of MS has been identified [The IgG autoantibody links to the aquaporin 4 channel [http://www.jem.org/cgi/content/abstract/202/4/473] ] .

The investigators are now trying to identify the types of cells involved with tissue destruction, and examining clinical characteristics of the individuals from whom these tissues were taken.

The MS Lesion Project has just been renewed with a commitment of $1.2 million for three years. It is now part of the Promise 2010 campaign.

Research

Until recently, most of the data available came from post-mortem brain samples and animal models of the disease, such as the experimental autoimmune encephalomyelitis (EAE), an autoimmune disease that can be induced in rodents, and which is considered a possible animal model for multiple sclerosis. [cite web| url=http://www.mult-sclerosis.org/experimentalautoimmuneencephalomyelitis.html| title=Experimental Autoimmune Encephalomyelitis| year=08/13/2003| publisher=All About Multiple Sclerosis| accessdate=2006-05-10] However, since 1998 brain biopsies apart from the post-mortem samples were used, allowing researchers to identify the previous four different damage patterns in the scars of the brain. [Lucchinetti, C. Bruck, W. Parisi, J. Scherhauer, B. Rodriguez, M. Lassmann, H."Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination" Ann Neurol, 2000; 47(6):707-17. PMID 10852536]

ee also

*Multiple sclerosis
*Multiple sclerosis borderline

References

External links

* [http://www.nationalmssociety.org/Research-TargetedLesion.asp The lesion project page]
* [http://www.thisisms.com Multiple sclerosis news]
* [http://msnews.acceleratedcure.org MS News at Accelerated Cure Project]

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