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Myelination, Remyelination and Multiple Sclerosis

Part 1: Myelination, Remyelination and Multiple Sclerosis

00:00:12.10 Welcome to this iBiology seminar, my name is Mikael Simons.
00:00:16.11 And I will speak about myelination, remyelination, and multiple
00:00:20.23 sclerosis. So this seminar is divided into two parts, I will start
00:00:27.01 and give an overview about progressive multiple sclerosis, myelination,
00:00:30.16 and remyelination. And Christine Stadelmann will then take over
00:00:35.09 and talk about the neuropathology of multiple sclerosis.
00:00:39.21 So, just to remind you, multiple sclerosis is an autoimmune disease
00:00:45.13 that leads to an inflammatory attack probably against the myelin sheath
00:00:48.12 that results in multifocal inflammatory lesions that you can see
00:00:53.12 here in the MRI by these white spots. These hyperintense lesions are then
00:00:57.20 highlighted in the neuropathological images, and you can see here
00:01:01.21 the three hallmarks of M.S. The first is inflammation, so there is
00:01:07.06 infiltration of B-cells and T-cells, and in particular, macrophages.
00:01:12.03 The second hallmark is demyelination, you can see myelin in blue
00:01:15.13 and the completely demyelinated area in white. The third hallmark
00:01:21.09 is axonal loss, so in the lesion there's also partial axonal damage
00:01:27.20 or injury. The typical MS clinical course is shown here, so typically it
00:01:34.16 starts as a relapsing remitting disease, where patients develop symptoms and then
00:01:39.10 they recover from these relapses at least partially, and this is
00:01:44.05 repeated over and over again. Until the one or two decades or so,
00:01:50.12 when the disease then converts into secondary progressive MS.
00:01:56.02 There are two extreme forms of this, one is relapsing remitting MS
00:02:01.01 without progression into secondary progressive MS, and the other extreme is
00:02:08.01 primary progressive MS, where there is no relapses and the patients
00:02:12.15 immediately start with the progressive phase. So in this progressive phase,
00:02:16.15 the symptoms that the patient develops are irreversible. Now while there are good
00:02:21.10 treatment options for relapsing remitting MS, the treatment for secondary progressive
00:02:25.15 MS, or primary progressive MS, is not possible. So therefore,
00:02:31.02 it is important to understand how progressive MS develops.
00:02:35.19 So if you look at the pathology, then the acute focal lesions decrease
00:02:40.16 gradually over time. However, there is a second pathology which
00:02:46.19 increases. This is the global or diffuse pathology. And this consists of
00:02:51.00 widespread neurodegeneration or a diffuse inflammation. Now a key question is
00:02:58.19 to understand how the focal pathology can convert into a global
00:03:03.12 diffuse pathology. So how this really happens is not known.
00:03:08.16 I can just present a few ideas here of how the pathology spreads.
00:03:13.12 So the white box here is the brain, and you have four inflammatory
00:03:19.13 lesions within this brain. Now some of these lesions may resolve
00:03:25.04 inflammation, may disappear over time, while in other lesions, the inflammation
00:03:30.23 may persist. And this can serve as the nucleus where immune cells may
00:03:34.09 enter or infiltrate the brain. In addition, the immune cells from the
00:03:38.17 periphery may enter the brain from the edges of the meninges into the brain.
00:03:42.11 So at the end you have a focal inflammation which converts into
00:03:48.02 a diffuse inflammation which may have different components, one which is the
00:03:52.04 cells from the periphery which have entered the brain and the other might be
00:03:56.20 the microglia, the resident macrophages of the brain, that have become activated.
00:04:01.24 Now not only inflammation is likely to spread but also the tissue damage.
00:04:09.19 So in the green spots again are areas where the lesions are formed.
00:04:13.20 Where you have focal tissue injury. Some of these lesions may recover by
00:04:19.03 remyelination, this is the process where new myelin sheaths are
00:04:22.23 formed again. However, in some of the lesions the damage may persist.
00:04:27.09 Now because the cells in the brain are highly connected and they depend on each
00:04:32.17 other, the damage to the myelin sheath may lead to secondary axonal
00:04:37.09 damage, this again might affect other neurons and spread within the
00:04:41.03 brain. So then, at the end you have a focal tissue injury which
00:04:46.10 have become more diffuse and widespread. Now the brain is
00:04:50.19 at risk for spreading of diseases because the cells are highly connected,
00:04:56.11 and the cells depend on each other. So all the dendrocytes depend on
00:05:00.00 neurons, and the neurons depend on the oligodendrocytes.
00:05:05.06 Now if this is really proven -- it's not known, this is just the hypothesis
00:05:10.01 for how the focal disease can be converted to a global disease. Now is
00:05:17.01 remyelination failing in MS? Now this is a brain here, stained in blue is myelin
00:05:22.03 sheath, and with light arrows you see chronically demyelinated plaques
00:05:27.13 in white, so most of the plaques in fact are not remyelinated. But with
00:05:34.00 red arrows, you see two plaques where remyelination was successful and
00:05:39.08 you can see this light blue staining which indicates local plaques
00:05:45.06 where remyelination has taken place. So if you quantify this
00:05:48.21 over different many patients and brains, then the number is around that
00:05:54.24 20% of the lesions can recover and remyelinate, while 80% fail to do
00:06:00.08 so. So indeed, there is a failure of remyelination, at least in great parts.
00:06:05.04 Now, this failure of remyelination could contribute to the spread of
00:06:10.20 axonal damage. So I will start now by giving you a bit of background about
00:06:16.17 myelination. So about oligodendrocytes and about myelin sheath
00:06:21.01 function and structure, the development of myelin, before discussing
00:06:24.23 how myelin supports axons. And then talking about remyelination in MS.
00:06:28.22 This is the first drawing of an oligodendrocyte by Hortega. And you can
00:06:35.15 see in this drawing the cell body and then these many, many different
00:06:39.10 fine processes. So each of these fine processes ends up in a
00:06:42.19 myelin sheath. And around 50 or so myelin sheaths are formed by one
00:06:49.00 oligodendrocyte in a human brain. So damage to one of these cells has
00:06:53.12 of course big consequences, because you lose many different myelin
00:06:58.07 sheaths on different axons. This is how myelin looks in an
00:07:03.08 electron microscopy image. So you can see in a cross section this
00:07:07.18 different layers are very tightly connected, there's almost no
00:07:11.15 cytoplasm in between. And only at the edges of the myelin segments,
00:07:16.04 the myelin loses this compound structure, parallel loops are formed and
00:07:21.13 both are tightly attached to the axons. These areas in between the myelin
00:07:26.03 segments are called nodes of ranvier. They are shown here, so these are
00:07:30.12 where the sodium channels are clustered, where action potentials are
00:07:33.21 generated. And this action potential jumps from one node to the other.
00:07:38.08 And this is the base of saltatory nerve conduction, which speeds up
00:07:41.20 nerve transmission by a factor of 100, compared to unmyelinated
00:07:46.14 axons. It also saves energy because the neuron doesn't need to
00:07:53.12 make the action potential, only at the nodes of ranvier.
00:07:58.02 A second important function of myelin as has been established by
00:08:03.20 Klaus Nave and Jeff Rothstein is the metabolic support of axons.
00:08:07.06 So the oligodendrocyte produces glycolytic products like lactate
00:08:11.23 and pyruvate, and these products can then diffuse through the
00:08:15.20 oligodendrocyte, through the myelin sheath, into the axon.
00:08:18.21 So, to say that oligodendrocytes fuel the axons with energy products.
00:08:24.06 Another important function is the modulation of neuronal networks by myelin.
00:08:31.04 So there is evidence that some tasks that have been learned associate with
00:08:36.21 forming new myelin sheath. For example, shown by MRI studies, piano playing
00:08:42.09 can lead to changes in the white matter and possibly correlate
00:08:47.16 with myelin sheath. So myelin is also important to change the behavior
00:08:53.01 to function of neuronal networks. I will now talk about how myelin is formed.
00:09:00.21 I will start with normal development before going to MS. So you see here
00:09:05.06 in these pictures, blue is the myelin stain and you can see how it starts in one area
00:09:11.22 and then spreads within the brain. So the most intense phase of
00:09:15.17 producing myelin is in the first year of the human, and then it goes on for
00:09:19.20 several more years until large areas of the brain have been filled with myelin. Later
00:09:24.19 stages would be the front part, which is the frontal cortex, the more
00:09:27.24 complex areas are myelinated the latest. So myelination is a multistep
00:09:34.11 process, and I will divide this into four different parts. So the first part is the
00:09:40.11 specification of oligodendrocyte precursor cells. This is now a spinal cord
00:09:44.20 cross section of a mouse, and the blue areas are the areas where OPCs are
00:09:50.14 born, are specified. And they distribute within the spinal cord and the red area is
00:09:57.03 the second wave of OPCs that are formed in a more dorsal area.
00:10:01.24 That also distribute within the spinal area. The same principle holds true for the brain,
00:10:07.04 where you have different centers where OPCs are specified and
00:10:10.17 distributed within the brain. This is how it looks like in the brain,
00:10:18.07 so in white you have the OPCs, they are born in these areas close
00:10:22.13 to the ventricles. And these cells then migrate into the brain,
00:10:27.12 they proliferate, and they settle in the evenly spaced distance
00:10:33.22 to each other. At the end there's a dense network of OPCs that are
00:10:38.02 kept into adulthood. Now the third phase is the differentiation of some of these
00:10:45.01 precursors cells. This occurs in different steps, so first you have the
00:10:48.18 precursor cell, then the pre-myelinating cell that we still have difficulty
00:10:52.09 to recognize, but then a mature myelinating oligodendrocyte. And there are many
00:10:57.11 factors that can regulate this differentiation process. I will not go into details,
00:11:01.18 just mention that they're intrinsic and extrinsic factors. So the intrinsic
00:11:05.06 factors are transcription factors that need to be turned on in a different
00:11:10.11 manner, and extrinsic factors come from the environment, from other
00:11:15.14 cells. For example, Wnt signaling needs to be turned off or electric
00:11:20.03 activity of axons promotes the differentiation process. The last
00:11:26.03 process is the generation of the myelin sheath. So when the cells
00:11:30.03 have differentiated, they send out the process. And this process
00:11:33.15 has to recognize now the axons to be myelinated, the recognition
00:11:37.09 process molecules have not been identified so far. Once their
00:11:42.00 recognition attachment is established, then this membrane
00:11:46.11 moves around the axon in a particular way. How it moves around, I will
00:11:51.05 show in this video. So in green you have the axon, in the left
00:11:56.02 corner you have an oligodendrocyte that will send out the process.
00:12:00.03 And you see how this process now attaches to the axon, and wraps
00:12:05.17 around it and then at the same time, there's an extension through the layers
00:12:10.19 inside. So the inner layer is the one that actually moves around
00:12:13.17 the axon. Now in multiple sclerosis lesion, these different steps
00:12:19.10 are recapitulated, or some of these steps. So you see in acute lesion
00:12:24.08 here, myelin has been removed, you only see the axons in green now.
00:12:28.04 And the oligodendrocyte precursor cells are now recruited into the
00:12:33.06 lesion, which signals exactly as during development, it's not completely
00:12:37.20 known. But probably also signals from microglia and macrophages
00:12:41.21 will contribute. Once they have settled in the lesion, the second step is the
00:12:49.00 differentiation of these cells. So they will now become more complex
00:12:52.02 and send out different processes that will attach to the axons
00:12:55.21 and wrap the membrane around the axon. Now not all lesions
00:13:02.04 are successful in remyelinating. And in fact, the minority only.
00:13:06.22 The majority of lesions look like this. Where you have the lesion, myelin has been removed,
00:13:11.10 you have some oligodendrocyte precursor cells in the surrounding of the
00:13:15.13 lesion, they have not made it into the lesion, instead you have
00:13:19.00 now astrocytes that have formed a scar. There is also extracellular
00:13:23.09 matrix components which have been deposited within the lesion.
00:13:27.15 Now it would be important within individual patients to see which
00:13:33.17 lesions can remyelinate and which lesions remain as chronic
00:13:38.15 lesions which are unable to remyelinate. So MRI would be the ideal
00:13:44.09 measurements, but unfortunately, there's not a specific sequence where we can
00:13:48.04 recognize myelin. But progress has been made with 7 Tesla MRI studies.
00:13:53.01 And I will show you a study performed by Daniel Reich, where they
00:13:58.13 looked at different patients and looked at these lesions for more than
00:14:03.08 one year. And looked at evolution of the lesions. For simplicity,
00:14:06.10 I will show you cartoons of this and not the actual MRIs.
00:14:10.23 So the upper row, which you see in red, is the immune cells that
00:14:15.12 have formed in this acute lesion. Now some of these immune cells
00:14:20.06 will resolve and there will be a rim that can be seen in MRIs,
00:14:24.23 a paramagnetic rim of immune cells at the edges. Now if this rim
00:14:29.19 persists and it correlates with poor recovery, so with no remyelination.
00:14:35.07 So this was shown in an autopsy where one of these lesions was
00:14:41.14 basically analyzed. And you can see in blue the myelin stain again,
00:14:45.09 and you can see the completely demyelinated lesion, and at the edges
00:14:49.05 is this inflammatory rim. And if you focus into these cells, you see macrophages
00:14:53.21 loaded with iron. So this is an indication of poor recovery of a
00:15:00.06 lesion. Not all lesions develop like this, so there were also lesions which were
00:15:06.00 able to recover by MRI criteria. Again, red is the inflammation, and you see this
00:15:12.11 paramagnetic ring, but now this ring does not persist. The transient
00:15:18.16 ring. And this correlates with better recovery. If you now plot these different
00:15:25.22 types of lesions for different patients, then an interesting pattern emerges.
00:15:30.15 So the young patients, or those with a transient paramagnetic rim,
00:15:35.00 so have good recovery, and the older patients are those which have
00:15:39.21 poor recovery. Now why does remyelination fail in MS?
00:15:48.05 So one hypothesis in the field is that there is a differentiation block
00:15:51.21 in the lesion. So OPCs are somehow recruited to the edges of the lesion,
00:15:55.15 but signals are missing that would instruct the cells to differentiate
00:16:02.04 into myelinating oligodendrocytes. So efforts have been made to
00:16:06.13 identify compounds that can promote differentiation of T-cells, and different
00:16:12.03 high throughput screens have been performed, and some of these
00:16:15.21 drugs are now entering first clinical trials. In hope, of course, that
00:16:20.22 we will have some remyelination therapies in the future.
00:16:25.00 So why is remyelination important? I mentioned that remyelination
00:16:31.00 is probably important to preserve the axon in the long run.
00:16:35.07 So the structure of the axon, but also to provide the axon
00:16:39.01 with metabolites for structure and support. Not only loss of
00:16:44.24 myelin could be a problem, but also myelin dysfunction. So here you have a
00:16:49.03 myelinated sheath, and if you focus into this myelin sheath, there are
00:16:53.00 areas where there is some cytoplasm. And these cytoplasmic areas are
00:16:56.12 important for the metabolism of the myelin sheath and also to get
00:17:00.12 metabolites across the myelin sheath to the axon probably. And we
00:17:04.19 know that this function of the cytoplasmic channel is associated with
00:17:09.04 late onset axon degeneration. If this occurs in MS is unknown, but
00:17:14.10 this is a second possibility that myelin dysfunction can also lead
00:17:18.07 to axonal damage. At the end I want to summarize the main points,
00:17:22.21 so in MS, progressive MS, there is a focal pathology which has been
00:17:27.23 spread to a more global pathology. We know that remyelination
00:17:33.04 is insufficient in MS, so most lesions are in fact not remyelinated.
00:17:38.01 Remyelination is a process that recapitulates many of the steps
00:17:42.15 that occur in development, and remyelination is important
00:17:47.05 probably to preserve the long term survival of the axons.
00:17:52.17 And I will end here, thank you very much for your attention.

Part 2: Neuropathology of Multiple Sclerosis

00:00:12.17 Hello everybody, welcome to my iBiology presentation.
00:00:16.14 This is part 2 of a series on multiple sclerosis and remyelination.
00:00:20.26 The part 1 presentation is given by professor Mikael Simons from
00:00:26.23 the Technical University of Munich. I'm Christine Stadelmann from the
00:00:31.13 Institute of Neuropathology in Gottingen, and I'm now in the following
00:00:35.04 presentation going to talk about multiple sclerosis pathology and
00:00:39.11 also all the prospects that we see for remyelination.
00:00:43.06 MS is a disease that affects approximately 2.5 million people
00:00:52.10 worldwide. It is a disease that normally starts in young adulthood.
00:00:57.16 And that is quite the complex pathogenesis. Now it is believed
00:01:03.01 that there is a genetic predisposition for the disease, but that
00:01:06.16 it is complimented by environmental factors. These factors
00:01:11.02 together lead to an aberrant or destructive immune response
00:01:14.19 that targets the central nervous system. With regards to the
00:01:19.02 genetic predisposition, we know now that polymorphisms in
00:01:21.28 immune regulatory genes are relevant for the predisposition
00:01:25.24 to get the disease. On the other hand, environmental factors
00:01:29.25 such as EBV, vitamin D, and smoking affect the risk of attracting
00:01:37.28 -- or contracting the disease. With regard to the disease course, MS
00:01:44.05 is quite special. In that it basically changes its face. At the beginning,
00:01:50.29 MS normally presents as a relapsing remitting disease with almost
00:01:55.19 full recovery between the relapses. However, after several years
00:02:00.26 of disease, many patients, around 70%, convert into a secondary progressive
00:02:07.10 disease phase where this ability accumulation basically occurs
00:02:12.02 without superimposed relapses. So basically, without seemingly
00:02:16.28 peripheral immune activation. On the contrary, brain volume changes
00:02:24.12 occur basically right from the very start. And that's with reduction
00:02:28.29 in brain, and the decrease may be a real issue with regards to the
00:02:34.08 development of the secondary progressive disease phase.
00:02:37.01 What about the pathology of multiple sclerosis? Here what you see
00:02:42.08 is a fixed brain section with the very prominent periventricular
00:02:48.12 brain lesions that you see here. And these grayish areas
00:02:52.06 are very prominent, very clear, you see them on both sides
00:02:55.29 here. On both hemispheres of the brain. And these represent
00:02:59.10 fully demyelinated multiple sclerosis lesions. Apart from this
00:03:04.14 periventricular area, other predilection sites are the optic nerves,
00:03:08.17 the subpial cortical area that I will come to a bit later, the spinal
00:03:13.02 cord, the brainstem, and also the cerebellum.
00:03:16.19 What are now the key features of MS pathology?
00:03:20.10 One the one hand, clearly the focal demyelinated lesions
00:03:24.07 that we will discuss in depth in the next minute, but also the
00:03:29.29 diffuse brain pathology seems to be more and more important.
00:03:34.08 Especially with increased disease duration. And this includes
00:03:39.13 meningeal and parenchymal T cell infiltration, diffuse
00:03:42.10 microglia activation, neuroaxonal damage and loss, and also
00:03:47.02 then brain atrophy that is probably the cause of all those.
00:03:52.26 So in this presentation, I'll mainly focus on the focal lesion
00:03:59.08 pathology that is observed in MS. This is a typical chronic
00:04:05.20 demyelinated lesion, you see the myelin in blue, you see the
00:04:10.13 demyelinated lesion in rose, you also see that this lesion is
00:04:15.17 periventricular localized, so very characteristic for an established
00:04:19.04 MS lesion. You see a very sharp lesion edge. You see basically
00:04:24.16 that the lesion is hypocellular in the lesion center, and you don't
00:04:28.24 see accumulation of cells at the lesion edge. So this
00:04:34.08 seemingly is more or less a scar with very little or no
00:04:39.10 ongoing disease activity. Quite different from what I've shown you before,
00:04:46.06 is this chronic active or so called "smoldering" lesion. There just
00:04:50.13 by almost bare eye in this slide here, you see that there is an
00:04:55.20 excentration of cells here at the lesion border around this
00:04:59.28 lesion area here. And if you do some immunohistochemistry,
00:05:04.18 and look at the slide in more detail, you see that there is
00:05:07.13 accumulation basically of myeloid cells. Of macrophages and
00:05:11.00 activated microglia. And what is also very important, nuclear
00:05:14.17 at the lesion center, there practically no microglia activation. Also no
00:05:18.23 phagocyte recruitment is found. This microglia activation, phagocyte
00:05:26.06 recruitment, myeloid cell activation, is very much accompanied by
00:05:30.20 acute axonal damage. And the image that you see here is right
00:05:35.10 from this lesion border. So from this smoldering lesion border,
00:05:40.22 with apparently some residual demyelinated activity.
00:05:45.02 And what you really look at in this APP immunohistochemistry
00:05:48.10 is disturbance of axonal transport, so you look at accumulated
00:05:53.18 APP here in the axons. And what we know from animal studies
00:05:57.06 and studies in brain trauma, that this APP protein stays there for
00:06:02.29 around three weeks. So basically, this means that these axons
00:06:07.13 have been damaged or demyelinated within the last three weeks.
00:06:10.24 Or it means that they are persistently functionally impaired.
00:06:15.17 And all this is of course really relevant for our understanding of
00:06:19.00 progressive disease. And this is just a schematic illustration
00:06:24.05 of this smoldering lesion activity. Basically, that is a hallmark
00:06:29.07 really of multiple sclerosis and is the most common lesion type
00:06:33.02 observed in patients with progressive disease. What about the
00:06:38.23 very early lesion? I want to say that one rarely has the chance
00:06:42.11 to even see early lesions because a regular typical MS
00:06:46.11 patient does not undergo brain biopsy, of course. So you
00:06:50.02 really see that only under the certain circumstances, especially when
00:06:54.02 the clinical presentation or the MRI presentation was not
00:06:58.01 entirely clear. What you see here is the same staining as before,
00:07:04.08 with PAS histochemistry, and again the myelin in blue. And again the
00:07:07.19 lesion is rose. You see a hypercellularity there, you see all this
00:07:13.28 hypercellularity is even increased at the lesion edge. And if you
00:07:19.00 do some immunohistochemistry and you look at the macrophage
00:07:21.28 and all the activated microglia, you again see clearly accentuated
00:07:26.18 lesion edge here. Again, speaking for the centrifugal lesion evolution
00:07:34.18 basically. But of course here in this quite early lesion, you see
00:07:40.11 also that the lesion is filled with macrophages in the lesion center.
00:07:43.18 With regards to astrocytes, you may see beginning astrocyte
00:07:51.04 reaction, reactive astrogliosis in the lesion itself, as well as at the
00:07:55.08 lesion edge. And this is quite important with regard to the animal
00:07:59.18 model lesion that I'm going to show you in a minute. With regards
00:08:02.28 to T cell infiltration, this may be very scarce in this early lesion
00:08:08.22 that I've just shown you. If you look here, this is CD8-positive
00:08:13.23 cells that we're looking at here. If you look at the CD3s, you might have
00:08:17.04 about twice the number that I'm showing here. So quite scarce.
00:08:21.11 But getting a bit more with lesion evolution. With regard to
00:08:27.12 our final goal in a lesion remyelination, of course the assessment of
00:08:31.23 mature oligodendrocytes, oligodendrocyte precursors, is very relevant
00:08:35.26 in the lesions. And this is for example here, a staining immunohistochemistry
00:08:39.25 for NogoA, for mature oligodendrocytes. And as it looks, the mature
00:08:45.24 oligodendrocytes do not seem to be very much impaired here by this
00:08:51.25 lesion formation. You see a bit of a reduction here in the active
00:08:55.19 lesion edge, but not very much so. It even seems that the protein
00:08:59.16 is upregulated in the lesion, compared to the clear white matter.
00:09:04.04 What we very much like to do in our research, but also in within clinical
00:09:11.02 practice, is to really stage our demyelinated lesions with regards
00:09:15.26 to demyelinated activity. To be able to compare lesions between patients
00:09:21.02 and also lesions between different diseases. To compare basically
00:09:25.24 equal stages of lesion formation. What we use for the purposes
00:09:29.29 in the one hand, the presence of myelin degradation products in
00:09:33.00 macrophages. We use major and minor myelin proteins and with the
00:09:37.06 concept that the major myelin proteins need longer to be
00:09:40.24 digested. So if you find still minor myelin proteins, such as MOGs,
00:09:44.29 cAMP, MAG, in the macrophages. This basically indicates
00:09:48.01 a more recent lesion. What also proves very, very useful
00:09:52.25 is some macrophage activation markers, such as MRP14.
00:09:57.08 That really highlight recently invaded monocytes from the blood
00:10:02.20 stream. So it's a very useful marker used for lesion age determination
00:10:07.04 in our setting. When do which lesions occur? When are they
00:10:14.13 most prominent? And there I think what is very important for you is
00:10:19.24 that on the one hand, the green lesions that are depicted here,
00:10:22.07 these are the actively demyelinating lesions. They occur in
00:10:25.29 monophasic disease, they occur in relapsing remitting disease,
00:10:29.23 they also occur still a bit in the more chronic disease forms, such
00:10:35.10 as a secondary progressive and primary progressive MS.
00:10:38.02 But in these later lesion stages, it's really the chronic
00:10:42.22 smoldering or the chronic active lesions that predominate
00:10:45.25 also of course the inactive, so called burned out lesions. And
00:10:49.19 also in part, the shadow plaques. And the shadow plaques are
00:10:52.12 here really indicated in rose. So just for comparison, my plan here is
00:11:03.26 to also show you a bit at least of NMO lesion pathology.
00:11:08.05 To have a comparison with MS and to look at the myelin
00:11:12.13 pathology that may be different in this clinical setting. So these
00:11:18.13 are really spinal cord sections from a neuromyelitis optica patient.
00:11:23.04 And just by looking here at the LFB/PAS and also the macrophage
00:11:27.13 immunohistochemistry, you see a huge lesion in the dorsal
00:11:31.19 funiculus and also of the ventrolateral spinal cord area here.
00:11:36.07 And just from looking at the macrophage staining, you might
00:11:40.06 say that from the density that you see, that the ventrolateral
00:11:44.02 lesion is much younger, much more recent. Importantly,
00:11:49.07 in 2004, Vanda Lennon has demonstrated that NMO,
00:11:53.25 neuromyelitis optica, is not a spectrum disease like multiple sclerosis
00:11:58.26 or a variant of multiple sclerosis, but really a completely different disease
00:12:04.01 entity. And that she demonstrated that anti-AQP4 antibodies
00:12:08.10 are really a clear serum signature of the disease. Neuromyelitis
00:12:13.28 optica is basically a disease characterized by spinal and optical
00:12:17.25 nerve involvement. And of course, not all patients with these
00:12:20.29 clinical signs and symptoms have anti-AQP4 antibodies.
00:12:24.22 But those who have, are designated then anti-AQP4 autoimmunity
00:12:31.18 and if you perform an indirect immunofluorescence assay in
00:12:35.19 these patients. For example on their cerebellar section, you would
00:12:39.24 see exactly what I show you here on this side. That is, you would
00:12:43.25 see a clear and very nice and fine delineation of the pial surface
00:12:49.28 on the one hand, and of the capillaries, as seen here on this right
00:12:55.24 brain section. Indicating that with the anti-APQ4 antibodies, you basically
00:13:01.14 label the astrocyte food processors that are in the brain capillaries.
00:13:07.28 Now knowing that basically an anti-astrocyte immune response is
00:13:19.11 causative of NMO and looking at the lesion morphology that you see
00:13:26.07 in the brain, you would probably expect a completely different
00:13:30.08 type of pathology. However, looking at the lesion here on the LFB
00:13:34.06 PAS histochemistry, you might really get the diagnosis wrong
00:13:39.06 and diagnose an MS lesion. If you don't look carefully enough.
00:13:43.18 However, going a bit deeper and looking at astrocytes, for example,
00:13:48.01 using GFAP immunohistochemistry. You see that astrocytes are not
00:13:51.28 usually destroyed in the lesion center, towards the lower right.
00:13:56.07 They are preserved at the upper left border here, where the
00:14:02.18 peri plaque white matter is situated. Going then further and really
00:14:08.02 staining for AQP4 itself, you see that this immunoreactivity is even
00:14:12.07 further decreased, compared to the structure protein GFAP.
00:14:16.23 Again, as an evidence that AQP4 antibodies here play a role in the
00:14:23.20 disease. If you then look at oligodendrocytes or mature and
00:14:28.12 oligodendrocyte precursor cells in the lesions using NogoA and
00:14:33.00 Olig2 as markers, as we did here. You see that oligodendrocytes
00:14:36.20 are largely absent from these acute lesions, completely destroyed
00:14:41.22 due to early lesion forming process in anti-APQ4 positive
00:14:46.24 neuromyelitis optica spectrum disorder. Looking then at the myelin
00:14:53.23 protein pathology a bit more closely, you see that major myelin
00:15:00.02 proteins, such as MBP and also PAP, are largely preserved
00:15:04.11 in these early lesions. And you would not be easily diagnosed
00:15:08.29 by demyelination here. Whereas if you look at MAG or CMP,
00:15:14.08 you'll find a total decrease or loss of these myelin proteins in the lesion.
00:15:19.16 So very indicative here of distinct pathological demyelinated process
00:15:27.22 going on. And what one might conclude from that, that there are at least
00:15:32.17 two principle mechanisms of demyelination. On the one hand,
00:15:36.00 a mechanism whereby the oligodendrocyte suffers from a primary
00:15:40.20 damage from oligodendroglial cell death. And the myelin sheath then
00:15:44.22 degenerates secondarily. And on the other hand, disease
00:15:49.04 settings of pathological circumstances, whether primary
00:15:52.23 target of the immune response is the myelin sheath. And
00:15:57.20 either is then removed by the macrophages concomitantly with the
00:16:02.14 oligodendrocyte. Or even the oligodendrocytes appear preserved
00:16:07.02 to a certain extent. In the next part, I would very much like
00:16:12.20 to come a bit back to what Mika has already discussed,
00:16:18.10 namely disease progression in multiple sclerosis.
00:16:21.07 And certainly, this is one of the characteristic features of the
00:16:24.20 disease. And again, as I said already, very special and so far,
00:16:29.22 also unresolved puzzle. And for decades now, neuropathologists
00:16:33.29 have tried to really establish the correlation of progressive disease
00:16:38.07 in their materials. What is very prominent in late stage MS patients is
00:16:44.22 certainly cortical pathology. And there especially, subpial cortical
00:16:48.18 demyelination, as delineated here with the arrows. Very characteristic
00:16:54.05 for chronic disease, very widespread in chronic patients. And
00:16:57.23 of course, as you may know, not detected by MR imaging.
00:17:02.17 So really, escaping our clinical pathological correlations
00:17:07.29 normally. Importantly, however, what should be mentioned is that
00:17:13.16 cortical demyelination is not only a feature of late stage
00:17:17.07 disease, but also occurs early in disease and may even
00:17:21.12 be present really right at the first disease bout, basically.
00:17:28.11 What may really contribute to the importance in chronic disease is
00:17:35.25 however, that ongoing remyelination that is very efficient in the
00:17:40.19 cortex may decrease with disease duration. And thus, leave
00:17:46.02 completely demyelinated subpial cortical areas that are of course
00:17:50.14 then very easy to visualize as seen here in this image.
00:17:56.17 This slide really serves two purposes. So the right hand scheme on
00:18:02.17 the one side, shows you the discrepancy between white matter
00:18:06.23 demyelination in green, and here mainly periventricular, as shown
00:18:11.04 here. And cortical demyelination shown in orange here, that really
00:18:17.08 outnumbers the volume of white matter demyelination here
00:18:21.01 by far. On the other hand, what is also easily visible on this
00:18:26.16 frontal brain section, and mainly seen on the left hand scheme here, is the
00:18:31.16 important brain atrophy that is found in quite a proportion of chronic
00:18:35.23 MS patients that also already starts early in the disease. And
00:18:40.12 maybe, a very first sign even. There I'm thinking mainly about
00:18:44.19 the MRI data on cortical atrophy, as in early sign of patients
00:18:51.04 that really, really convert into secondary progressive disease.
00:18:54.13 What is really underlying features that contribute to this atrophy
00:19:02.22 of the MS brain? And mainly to the cortical atrophy. And there
00:19:07.10 during the last years, really the notion appeared in neuropathology
00:19:12.12 that it's not really that neuropathological damage or damage to
00:19:17.14 neurons and axons. It's not only related to focal lesions. And does not
00:19:21.24 even correlate well with focal lesions, but rather is a diffuse
00:19:25.16 phenomenon. And there is work by Doron Merkler that very much
00:19:30.04 contributes. Where they show a spine loss in multiple sclerosis
00:19:33.17 cortex, independent of focal demyelination. What could now
00:19:40.16 remyelination add to our picture of multiple sclerosis?
00:19:43.28 Remyelination in MS has been discussed for decades.
00:19:48.12 And especially prominent was John Prineas delineating
00:19:53.02 the morphology of remyelination in the MS brain, as shown here
00:19:57.25 in this Annuals of Neurology paper, which very nicely showed
00:20:01.04 the axons with a thin myelin sheath that indicate remyelination
00:20:08.07 here in this MS plaque. To the left hand side, what you really see
00:20:12.02 is a fully remyelinated shadow plaque. And I think this is really
00:20:15.25 the goal, this is where we would like to go. This is what we
00:20:20.13 would like to achieve for all the lesions, for all of our patients.
00:20:23.20 So have them fully remyelinated after a certain time.
00:20:28.04 Is that goal that is useful in any way? And Mikael has already
00:20:34.28 discussed that remyelination very much seems to be the most
00:20:38.25 or is maybe the most axonal protective therapy that we may
00:20:43.01 have. However, I think some further work needs to be done
00:20:47.19 to really formally demonstrate that, especially in vivo in the patient.
00:20:51.11 We did a bit of work in that direction, and showing here, for example,
00:20:56.16 that the axonal density is higher in remyelinated compared to
00:21:00.18 demyelinated lesion areas. However, of course, one has to be
00:21:04.26 conscious here, what is the hen and what is the egg.
00:21:07.02 It may also be that remyelination just occurred much more
00:21:10.08 easily in lesion areas that were in much less damaged and
00:21:14.22 probably at a higher axonal and probably also higher OPC
00:21:18.18 density here. But still, remyelinated areas in general look much
00:21:23.08 better than demyelinated areas. What about oligodendroglia
00:21:28.22 that we certainly need if we want to induce and stimulate
00:21:32.10 remyelination? Are they there in chronic lesions? When are they
00:21:36.20 lost? Part of these questions are still open. And we tried to
00:21:41.25 get closer to some of these aspects in recent work, where we looked at
00:21:47.24 oligodendroglial density in cortical demyelinated lesions. And where we
00:21:51.25 saw that really in the chronic cortical demyelination setting, the
00:21:57.10 NogoA positive cells, as well as the Olig2 positive cells, went
00:22:02.22 very much down. However, in earlier lesions, oligodendroglia
00:22:07.07 densities were much better, and even better than normal.
00:22:13.11 So even a stimulation of oligodendroglia densities. However,
00:22:18.17 I think we're still lacking the knowledge about the modes and also the
00:22:22.26 timing of cell death. And probably our therapies should not
00:22:27.17 wait too long, but rather target earlier lesions if possible.
00:22:35.22 A huge step forward with regard to our aim of stimulating
00:22:42.02 pro-remyelinative therapies is certainly detection of remyelination
00:22:47.17 of myelin in vivo. And there, I think in the last years, the important
00:22:52.06 advances have been made with PET imaging. And this is a study hereby
00:22:58.11 Bruno Stankoff that I'm showing here from Paris, who follows up
00:23:02.10 the patients and then identifies individual lesions and identifies
00:23:06.16 basically myelin repair, remyelination in these patients. And I think this will
00:23:13.02 be very useful for the future. On the one hand, to establish
00:23:17.17 the neuron and axon protective effect of remyelination, and
00:23:22.19 on the other hand, as an in vivo readout for our pro-remyelinative
00:23:26.18 therapies. So to sum up what I've said, MS is pathologically very
00:23:35.06 characteristic. It shows a characteristic centrifugal lesion. We still have to
00:23:41.07 identify what really underlies this specific lesion, or pattern of lesion
00:23:45.29 formation. In addition, however, they are substantially diffuse and non-focal
00:23:50.12 pathology. And also inflammatory and noninflammatory correlates
00:23:54.19 of progressive disease, and they are not yet fully understood.
00:23:58.06 And we really need to know more about that to fully be able
00:24:02.13 to treat this aspect of disease in our patients. Also the pathomechanisms
00:24:07.19 of myelin damage and oligodendrocyte death are not yet fully understood.
00:24:11.05 And, as Mika also mentioned, remyelination is efficacious in only
00:24:16.23 a small proportion, approximately 20%, of patients.
00:24:20.26 So, I would clearly identify as research goals to further improve
00:24:27.08 our understanding of MS pathogenesis and lesion evolution.
00:24:30.02 To also formally demonstrate the neuroprotective effect of
00:24:33.29 remyelination, ideally in vivo using the new imaging technologies.
00:24:37.28 And then also from the cell biological side, to identify means to
00:24:43.16 protect and stimulate OPCs in evolving and established MS
00:24:48.06 lesions. With that of course, I'd like to thank all the people who contributed
00:24:53.08 this work, and you for listening. Thanks a lot.

Videos in this Talk
  • Part 1: Myelination, Remyelination and Multiple Sclerosis
    Part 1: Myelination, Remyelination and Multiple Sclerosis
    Audience:
    • Student
    • Researcher
    • Educators of Adv. Undergrad / Grad
  • Part 2: Neuropathology of Multiple Sclerosis
    Part 2: Neuropathology of Multiple Sclerosis
    Audience:
    • Student
    • Researcher
    • Educators of Adv. Undergrad / Grad
Speakers: Christine Stadelmann, Mikael Simons
Total Duration: 0:43:40
Recorded: January 2017
All Talks in Human Disease

Talk Overview

Multiple sclerosis (MS) is a debilitating autoimmune disease in which immune cells infiltrate the central nervous system and attack the myelin sheath surrounding axons.  Dr. Simons explains that myelin is necessary for signal conduction by nerve cells and for the metabolic support of axons. Demyelination results in axonal loss and formation of lesions in the brain. A small percentage of MS lesions are capable of remyelination following steps similar to axonal myelination during normal development.  Since lesion remyelination correlates with reduced neurodegeneration, Simons and his colleagues strive to understand why remyelination occurs in only a small number of MS patients and to identify drugs that may promote it.

MS begins as a disease of intermittent episodes with recovery in between. With time, however, MS changes to a progressive disease with increasing disability.  In her talk, Dr. Stadelmann explains that studies of MS brain lesions have identified specific changes that occur with disease progression. For example, chronic MS lesions contain many fewer oligodendrocytes than do early lesions.  Since oligodendrocytes produce the myelin sheath that surrounds axons, drugs that stimulate the migration and establishment of oligodendrocytes in lesions may increase axonal remyelination and improve the prognosis of MS patients. Stadelmann also explains that brain lesions can be caused by conditions other than MS, such as neuromyelitis optica.  Improved studies will help to correctly diagnose and treat these distinct diseases.

Speaker Bio

Christine Stadelmann

Christine Stadelmann

Dr. Stadelmann is a Professor and Deputy Director of the Institute for Neuropathology at the University of Göttingen Medical Center.  Her studies focus on inflammatory diseases of the central nervous system including multiple sclerosis and neuromyelitis optica. She is particularly interested in understanding which pathological events correlate with disease progression. Learn more about Dr. Stadelmann’s… Continue Reading

Mikael Simons

Mikael Simons

Dr. Simons’ research focuses on developing new ways to promote remyelination of damaged axons in demyelinating diseases such as multiple sclerosis (MS). To reach this goal, his lab strives to better understand the cellular processes underlying myelin formation in normal development. Simons received his MD from the University of Heidelberg and did his residency in… Continue Reading

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