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.
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. GM atrophy is independent of the MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS.Demyelination process
According to the view of most researchers, a special subset of lymphocytes, called T helper cells, specifically Th1 and Th17, 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 and in the degeneration of the axons.
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. The final result is destruction of myelin, called demyelination.
Whether BBB dysfunction is the cause or the consequence of MS is still disputed,because activated T-Cells can cross a healthy BBB when they express adhesion proteins.
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. 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, but not in the grey matter lesions. Besides, uric acid levels are lower during relapses.
The axons themselves can also be damaged by the attacks. 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.
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.
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, and it has been found with iron oxide nanoparticles how macrophages produce the BBB disruption. The BBB breakdown is responsible of monocyte infiltration and inflammation in the brain.
Normally, gadolinium enhancement is used to show BBB disruption on MRIs. 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.
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, and are supposed to be related to the mechanism of action of interferons,
Apart from that, activated T-Cells can cross a healthy BBB when they express adhesion proteins. 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[24]. Other protein also involved is CXCL12, which could be related to the behavior of CXCL13 under methylprednisolone therapy.
Haemodynamics of the lesions have been measured and distortion has been found related to plaque distribution. 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.
The importance of vascular misbehaviour in MS pathogenesis has been confirmed by seven-tesla MRI. 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. Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1alpha through Lyn kinase.
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.
Spinal cord damage
Cervical spinal cord has been found to be affected by MS even without attacks, and damage correlates with disability. In RRMS, cervical spinal cord activity is enhanced, to compensate for the damage of other tissues.
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.
Spinal cord presents grey matter lesions, that can be confirmed post-mortem and by high field MR imaging. Spinal cord grey matter lesions may be detected on MRI more readily than GM lesions in the brain, making the cord a promising site to study the grey matter demyelination.
Retina and optic nerve damage
There is axonal loss in the retina and optic nerve, which can be meassured by Optical coherence tomography or by Scanning laser polarimetry. This measure can be used to predict disease activity.
Brain tissues abnormalities
Using several texture analysis technologies it is possible classify the white matter MRI areas in three: normal, normal-appearing and lesions.
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. Other authors simplify this in three regions: intracortical, mixed gray-white matter, and juxtacortical. Others classify them as hippocampal, cortical, and WM lesions, 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.
Post-mortem authopsy reveal that gray matter demyelination occurs in the motor cortex, cingulate gyrus, cerebellum, thalamus and spinal cord. 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 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. 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.
New methods of MRI allow us to get a better classification of the lesions. Recently MPRAGE MRI has shown better results than PSIR and DIR for gray matter lesions.
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, but it seems that these two technologies are complementary. 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. It has been found that grey matter injury correlates with disability and that there is high oxidative stress in lesions, even in the old ones. Water diffusivity is higher in all NAWM regions, deep gray matter regions, and some cortical gray matter region of MS patients than normal controls.
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. The amount of interneuronal Parvalbumin is lower than normal in brain's motor cortex areas.
Citrullination appears in SPMS. It seems that a defect of sphingolipid metabolism modifies the properties of normal appearing white matter. Related to these, peptidylarginine deiminase 2 is increased in patients with MS, and is related to arginine de-imination.
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.
White matter lesions appear in NAWM areas, and their behavior can be predicted by MRI parameters as MTR (magnetization transfer ratio). This MTR parameter is related to axonal density.
Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disability. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS.
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.
Neural and axonal damage
The axons of the neurons are damaged probably by B-Cells, though currently no relationship has been established with the relapses or the attacks. It seems that this damage is primray target of the immune system, i.e. not secondary damage after attacks against myelin.
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.
Axonal degeneration at CNS can be estimated by N-acetylaspartate to creatine (NAA/Cr) ratio, both measured by with proton magnetic resonance spectroscopy.
Blood and CSF abnormalities
Since long time ago it is known that glutamate is present at higher levels in CSF during relapses 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. Also Fibroblast growth factor-2 appear higher at CSF.
Blood serum also shows abnormalities. Creatine and Uric acid levels are lower than normal, at least in women. Ex vivo CD4(+) T cells isolated from the circulation show a wrong TIM-3 (Immunoregulation) behavior, and relapses are associated with CD8(+) T Cells[77].There is a set of differentially expressed genes between MS and healthy subjects in peripheral blood T cells from clinically active MS patients. There are also differences between acute relapses and complete remissions. Platelets are known to have abnormal high levels.
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. 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. 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.
Kallikreins are found in serum and are associated with secondary progressive stage. There is evidence of Apoptosis-related molecules in blood and they are related to disease activity.
Varicella-zoster virus remains have been found in CSF of patients during relapses, but this particles are virtually absent during remissions. Plasma Cells in the cerebrospinal fluid of MS patients could also be to blame, because they have been found to produce myelin-specific antibodies.
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. Expression of some specific proteins in circulating CD4+ T cells is a risk factor for conversion from CIS to clinically defined multiple sclerosis.
Finally, B cells in CSF appear, and they correlate with early brain inflammation.
Heterogeneity of the disease
Multiple sclerosis has been reported to be heterogeneus in its behavior, in its underlaying mechanisms and recently also in its response to medication
Demyelination patterns
Also known as Lassmann patterns, 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:
- Pattern I
- The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation.
- 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.
- Pattern III
- 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. Recently some lesions have shown mitocondrial defects and this could also be a difference between types of lesions.
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 and nobody with RRMS was found with this pattern. Balo concentric sclerosis lesions have been classified as pattern III (distal oligodendrogliopathy). Neuromyelitis optica was associated with pattern II (complement mediated demyelination), though they show a perivascular distribution, at difference from MS pattern II lesions.
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, diffusion Tensor MRI, and VCAM-1 enhanced MRI 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, found correlation with CSF and progression in November 2001, and hypotheses have been made suggesting correlation between CSF findings and pathophysiological patterns. In particular, B-cell to monocyte ratio looks promising. The anti-MOG antibody has been investigated but no utility as biomarker has been found, though this is disputed. 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.
Response to therapy
It is known that 30% of MS patients are non-responsive to Beta interferon. 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, and interleukins IL12/IL10 ratio has been proposed as marker of clinical course. Besides:
- Pattern II lesions patients are responsive to plasmapheresis, while others are not.
- 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.
- People non-responsive to interferons are the most responsive to Copaxone
- In general, people non-responsive to a treatment is more responsive to other, and changing therapy can be effective.
- There are genetic differences between responders and not responders. 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
Subgroups by molecular biomarkers
Differences have been found between the proteines expressed by patients and healthy subjects, and between attacks and remissions. Using DNA microarray technology groups of molecular biomarkers can be stablished.
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.
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, 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 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.
Posts
No comments:
Post a Comment