mri: t2-hypertense lesions and t1-hypointense. the first one are demyelinating lesions and appear brighter than the surroundings in t2-mri. the t1-hypointense are areas less dense than the surrounding naw, and appear black on t1-mri. they are mainly axonal degeneration areas. because their black appearance they are sometimes known as black holes. they seem to appear as a sequel after a strong demyelinating lesion. bbb disruption is normally shown using gadolinium. it is a contrast that cannot cross the bbb except when it is dysfunctional. therefore, in active lesions with bbb implication the contrast enters the brain and appears in the mri. before bbb disruption, some brain tissues which present normal aspect under t1 and t2 mri (normal appearing white matter, nawm and normal appearing grey matter, nagm), can show several abnormalities under special mri technologies: 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. diffusion tensor mri or magnetic transfer mri are two options to enhance mri-hidden abnormalities discovery. this is currently an active field of research with no definitive results, but it seems that these two technologies are complementary. other methods of mri allow us to get a better insight of the lesions structure. recently mp-rage mri has shown better results than psir and dir for gray matter lesions. susceptibility weighted imaging (swi-mri) has shown iron (hemosiderin) deposition in lesions, and helps to detect otherwise invisible lesions. abnormalities in the gray matter (diffusion tensor mri alterations) of the brain parenchyma are present early in the course of multiple sclerosis normal appearing brain tissues using several texture analysis technologies, it is possible to classify white matter areas into three categories: normal, normal-appearing and lesions. currently, it is possible to detect lesions before they present demyelination, and they are called pre-active lesions. a fourth area called dawm (diffusely abnormal white matter) has been proposed and can help to differentiate ppms and spms. abundant extracellular myelin in the meninges of patients with multiple sclerosis has been found brain tissues with mri-hidden problems are usually named normal appearing. exploring the normal-appearing corpus callosum has been found a possible primary hypoperfusion, according with other findings in this same direction. also iron (in hemosiderin deposits and as well as in ferritin-like structures inside the macrophage) accumulation has been reported several findings in these areas have been shown. post-mortem studies over nawm and nagm areas (normal appearing white and gray matters) 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, and oxidative injury of oligodendrocytes and neurons could be associated with active demyelination and axonal injury. nawm in ms has been reported to be similar to nawm in leukoaraiosis, though nawm damage in ms is inflammatory and special microscopic techniques like cars microscopy show that the cns of ms patients may be globally altered, and both lesions and nawm are just manifestations of another underlying problem. the nawm is specially abnormal close to the ventricles, which may indicate a pathogenic mechanism mediated via the csf or ependyma. non-lesional white matter most of the brain in ms is unaffected. though obviously normal white matter appears normal under mri, so does the nawm white matter described in the next section. to establish a difference, normal white matter is named non-lesional white matter (nlwm) this normal white matter is reported to be around 56% of the total wm of the patients. normal appearing white matter the white matter with hidden but mri-visible damage is known as "normal-appearing white matter" (nawm) and is where lesions appear. the nawm is considered a non-visible kind of lesion, produces disability and it is responsive to natalizumab the pathology of the nawm differs from areas near the lesions or near the cortex. close to wm lesions, axonal pathology and microglial activation may explain subtle mri changes. distant from lesions, microglial activation associated with proximity to cortical lesions might underlie mri abnormalities. the nawm precedes the lesions. it has been shown that the apparent diffusion coefficient (adc) precedes the development of new plaques. later increases during bbb breakdown (gadolinium enhancement) and finally decays after the enhancement. bbb disruption takes place on nawm areas. this can be read in different ways. maybe some hidden changes in white matter structure trigger the bbb disruption, or maybe the same process that creates the nawm areas disrupts the bbb after some time. pre-active lesions are lesions in an early stage of development. they resolve sometimes without further damage, and not always develop into demyelinating lesions. they present clusters of activated microglia in otherwise normal-appearing white matter. oligodendrocyte abnormalities appear to be crucially involved. the earliest change reported in the lesions examined is widespread oligodendrocyte apoptosis in which t cells, macrophages, activated microglia, reactive astrocytes, and neurons appear normal. this observation points to some change in the local environment (nawm) to which oligodendrocytes are especially susceptible and which triggers a form of apoptosis. water diffusivity is higher in all nawm regions, deep gray matter regions, and some cortical gray matter region of ms patients than normal controls. 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. this would be consistent again with cases of chronic cerebrospinal venous insufficiency. 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. it also seems that myelin basic protein (mbp) from multiple sclerosis (ms) patients contains lower levels of phosphorylation at thr97 than normal individuals. nawm is the place where lesions appear and the process seems to be made by microglia, in absence of leukocyte infiltration, astrogliosis or demyelination. at the final stage of the process, these microglia develop into active demyelinating ms lesion in ppms there is evidence that nawm is affected by the same pathological processes that characterize wm lesions, namely inflammation, demyelination, axonal injury, macrophage infiltration and gliosis. some evidence suggests that wm changes predict subsequent gm abnormalities, rather than the opposite. anomalies in nawm rather than lesions have a greater impact on later gm damage. gray matter damage. normal appearing gray matter 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. epstein-barr virus could be involved, but is not likely. involvement of the deep gray matter (dgm), suggested by magnetic resonance imaging, is confirmed, and most dgm lesions involve both gm and white matter. inflammation in dgm lesions is intermediate between the destructive inflammation of white matter lesions and the minimal inflammation of cortical lesions. iron depositions appear in deep gray matter by magnetic field correlation mri differently from nawm, nagm areas are not related to the development of lesions diffusely abnormal white matter other active area of study is the diffusely abnormal white matter (dawm). it seems to be a reduction of myelin phospholipids that correlates with a reduction of the myelin water fraction. the dawm consisted of extensive axonal loss, decreased myelin density, and chronic fibrillary gliosis, all of which were substantially abnormal compared with normal-appearing wm and significantly different from focal wm lesion pathology. changes in the vasculature take place not only in focal lesions but also in dawm as detected by postmortem mri dirty appearing white matter dirty-appearing white matter (referred to as dawm like the former case) is defined as a region with ill-defined borders of intermediate signal intensity between that of normal-appearing white matter (nawm) and that of plaque on t2-weighted and proton density imaging. it is probably created by loss of myelin phospholipids, detected by the short t2 component, and axonal reduction. microglial nodules originally proposed as a biomarker, the presence of these nodules has a possible pathogenetic significance. though their role in the lesion evolution is still unclear, their presence in normal-appearing white matter have been suggested to be an early stage of lesion formation heterogeneity of the disease multiple sclerosis has been reported to be heterogeneous in its behavior, in its underlying mechanisms, in its response to medication and remarkably, also respect the response to the specific potassium channel autoantibody kir4.1. for some authors, what we call ms in reality is a heterogeneous group of diseases some independent reports take also ppms apart some others point a connection between some ms cases and peripheral neuropathies some reports propose the existence of molecular biomarkers that determine the clinical course of the disease, but the relationship to the pathological types has still not been established as of 2016. demyelination patterns four different damage patterns have been identified in patients' brain tissues. the original report suggests that there may be several types of ms with different immune causes, and that ms may be a family of several diseases. though originally was required a biopsy to classify the lesions of a patient, since 2012 it is possible to classify them by a blood test looking for antibodies against seven lipids, three of which are cholesterol derivatives. it is believed that they may correlate with differences in disease type and prognosis, and perhaps with different responses to treatment. in any case, understanding lesion patterns can provide information about differences in disease between individuals and enable doctors to make more accurate treatment decisions patterns i and ii show the classical pathological features of ms lesions with microglia and macrophages, while patterns iii and iv are considered atypical and could be separated from the ms spectrum at some point. the four identified patterns are: pattern ithe scar presents t-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation. pattern iithe 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. this pattern has been considered similar to damage seen in nmo, though aqp4 damage does not appear in pattern ii ms lesions nevertheless, pattern ii has been reported to respond to plasmapheresis, which points to something pathogenic into the blood serum. the complement system infiltration in these cases convert this pattern into a candidate for research into autoimmune connections like anti-kir4.1, anti-anoctamin-2 or anti-mog mediated ms about the last possibility, research has found antimog antibodies in some pattern-ii ms patients. sometimes autoimmunity against the human cns has been triggered by accident or medical mistake. the reactions have been diverse according to the sources of the disease but pathological confirmed ms (damage fulfills all pathological criteria of ms) is among them, and it shows pattern ii pattern ii pathogenic t cells clonally expanded were found in the cn, specifically, cd4+ th2 cells (secreting il-4, l-5, and il-13) have recently been described in pattern ii ms, and their clones have been isolated as living cells the functional characterization shows that t cells releasing th2 cytokines and helping b cells dominate the t-cell infiltrate in pattern ii brain lesions. pattern iiithe 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. for some researchers this pattern is an early stage of the evolution of the others. for others, it represents ischaemia-like