People with PPMS also tend to have more lesions in the spinal cord than in the brain. In the relapsing forms, women are affected two to three times as often as men; in PPMS, the numbers of women and men are approximately equal. People with PPMS tend to experience more problems with walking and more difficulty remaining in the workforce. In general, people with PPMS may also require more assistance with their everyday activities.
The National MS Society is pursuing all promising research paths and collaborating worldwide to drive progress in research in progressive MS, for which few therapies exist. Learn more about progressive MS research. Here are a few related topics that may interest you. Our MS Navigators help identify solutions and provide access to the resources you are looking for. Enhanced number and activity of mitochondria in multiple sclerosis lesions.
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Kiryu-Seo, S. Demyelination increases axonal stationary mitochondrial size and the speed of axonal mitochondrial transport. Zambonin, J.
Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis. Campbell, G. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Clonally expanded mitochondrial DNA deletions within the choroid plexus in multiple sclerosis. Tranah, G. Mitochondrial DNA sequence variation in multiple sclerosis. Neurology 85 , — Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration? Mitochondrion 10 , — Lucchinetti, C. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination.
Mitochondrial changes within axons in multiple sclerosis. Oxidative damage in multiple sclerosis lesions. Mitsumoto, A. A subset of newly synthesized polypeptides in mitochondria from human endothelial cells exposed to hydroperoxide stress. Free Radic. Talla, V. Gene therapy with mitochondrial heat shock protein 70 suppresses visual loss and optic atrophy in experimental autoimmune encephalomyelitis. Trapp, B. Axonal transection in the lesions of multiple sclerosis.
This is the first report of the profound destruction of axons within MS lesions. Pathological mechanisms in progressive multiple sclerosis.
Lancet Neurol 14 , — Mews, I. Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions. Bitsch, A. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain Pt 6 , — Sorbara, C. Pervasive axonal transport deficits in multiple sclerosis models.
Neuron 84 , — Zheng, Y. Mitochondrial transport serves as a mitochondrial quality control strategy in axons: implications for central nervous system disorders. CNS Neurosci. Joshi, D. Deletion of mitochondrial anchoring protects dysmyelinating shiverer: implications for progressive MS.
Craner, M. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1. Waxman, S.
Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis — current status. Stys, P. Paling, D. Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Raftopoulos, R. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial.
Glia 49 , — Miller, D. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology 68 , — Zivadinov, R. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology 71 , — Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Vergo, S. Acid-sensing ion channel 1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model. Arun, T. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride.
Hundehege, P. Targeting voltage-dependent calcium channels with pregabalin exerts a direct neuroprotective effect in an animal model of multiple sclerosis. Neurosignals 26 , 77—93 Daneshdoust, D. Pregabalin enhances myelin repair and attenuates glial activation in lysolecithin-induced demyelination model of rat optic chiasm. Neuroscience , — Mehta, A. Excitotoxicity: bridge to various triggers in neurodegenerative disorders. Tisell, A. Increased concentrations of glutamate and glutamine in normal-appearing white matter of patients with multiple sclerosis and normal MR imaging brain scans.
MacMillan, E. Progressive multiple sclerosis exhibits decreasing glutamate and glutamine over two years. Pitt, D. Glutamate excitotoxicity in a model of multiple sclerosis. Wang, S. Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals synaptosomes. Azbill, R. Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes.
Brain Res. Gilgun-Sherki, Y. Riluzole suppresses experimental autoimmune encephalomyelitis: implications for the treatment of multiple sclerosis. Kalkers, N. The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Killestein, J. Glutamate inhibition in MS: the neuroprotective properties of riluzole. MS-SMART trial: a multi-arm phase 2b randomised, double blind, parallel group, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis [NCT].
Sulkowski, G. Modulation of glutamate transport and receptor binding by glutamate receptor antagonists in EAE rat brain. Effects of antagonists of glutamate receptors on pro-inflammatory cytokines in the brain cortex of rats subjected to experimental autoimmune encephalomyelitis. Suhs, K. N-methyl-D-aspartate receptor blockade is neuroprotective in experimental autoimmune optic neuritis.
Simma, N. Cell Commun. Beeton, C. USA 98 , — Nave, K. Myelination and support of axonal integrity by glia. Lee, Y. Oligodendroglia metabolically support axons and contribute to neurodegeneration. This study demonstrates the relevance of oligodendrocytes for trophic axonal support. Irvine, K. Remyelination protects axons from demyelination-associated axon degeneration. Lau, L. Pathophysiology of the brain extracellular matrix: a new target for remyelination. Stoffels, J. Fibronectin aggregation in multiple sclerosis lesions impairs remyelination.
Tepavcevic, V. Early netrin-1 expression impairs central nervous system remyelination. Mi, S. LINGO-1 negatively regulates myelination by oligodendrocytes. This study identifies LINGO1, which is now being targeted with the antibody opicinumab to enhance remyelination. Tran, J. Cadavid, D. Safety and efficacy of opicinumab in acute optic neuritis RENEW : a randomised, placebo-controlled, phase 2 trial. Petrillo, J. Initial impairment and recovery of vision-related functioning in participants with acute optic neuritis from the RENEW trial of opicinumab.
Gregg, C. White matter plasticity and enhanced remyelination in the maternal CNS. Zhornitsky, S. Prolactin in combination with interferon-beta reduces disease severity in an animal model of multiple sclerosis. Neuroinflammation 12 , 55 Tourbah, A. MD high-dose biotin for the treatment of progressive multiple sclerosis: a randomised, double-blind, placebo-controlled study. Mei, F. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis.
This high-throughput study identified clemastine as a potent remyelinating agent. Green, A. Clemastine fumarate as a remyelinating therapy for multiple sclerosis ReBUILD : a randomised, controlled, double-blind, crossover trial. Rankin, K. Selective estrogen receptor modulators enhance CNS remyelination independent of estrogen receptors. Deshmukh, V. A regenerative approach to the treatment of multiple sclerosis. Moss, B. Wellness and the role of comorbidities in multiple sclerosis. Neurotherapeutics 14 , — Ontaneda, D. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives.
An important and comprehensive discussion on optimal trial design in progressive MS. Will the real multiple sclerosis please stand up? Lodygin, D. Beard, J. Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats. Lange, S. Oxygen activating nonheme iron enzymes. Todorich, B. Resolution of the inflammation, restoration of the conduction block and remyelination contribute to the clinical recovery. In contrast, chronic progressive MS is characterised by the irreversibility of the deficits due to progressive neurodegeneration [ 9 - 11 ].
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To follow the different pathological processes of MS biomarkers and surrogate markers are required to monitor and predict the disease progression [ 12 ]. Areas of focal inflammation are detected with high sensitivity as new gadolinium Gd enhancing lesions. Histological analysis at autopsy or after biopsy shows that Gd-enhancement indeed correlates with intense inflammatory activity and dense perivascular cuffs [ 13 , 14 ]. In addition, Gd-enhancement lasts for weeks similar to the duration of a typical relapse. Thus, Gd-enhancement is a useful surrogate measure of relapses and therefore frequently used as an outcome criteria in many therapeutic trials of RRMS.
Since six out of seven newly formed MRI lesions are clinically silent it is more sensitive as clinical outcome measures. However, the applicability of neuroimaging to predict long-term disability from the lesion load is not straightforward [ 16 ]. It seems that a change in the number and volume of the lesions correlates only with the concurrent change in disability at early but not at later stages of the disease. There are several MR measures available to determine neurodegeneration in MS.
The two most specific MR methods are whole-brain atrophy measurements and MR spectrometry to measure the levels of the neuronal metabolite N-acetyl aspartate NAA. Atrophy can be detected in both, the brain and the spinal cord of patients with SPMS and PPMS from the beginning of the disease and several studies have shown that atrophy correlates with disability [ 18 , 19 ].
In addition to brain spinal cord volumetric measurements, MR spectrometry of NAA levels has demonstrated diffuse neuronal loss from the earliest clinical stages of disease [ 20 - 22 ]. Additionally, cerebral spinal fluid CSF biomarkers of neuronal damage such as neurofilament autoantibodies or the degree of neurofilament phosphorylation are beginning to emerge as new valuable surrogate markers for the neurodegeneration in MS [ 23 , 24 ].
Furthermore, new genetic approaches such as genome-wide association scans for MS have recently identified new susceptibility loci for MS [ 25 - 27 ]. Such studies may also unravel genes associated with chronic progressive courses of the disease. Evidence for neuordegeneration in MS has been reported as early as by Charcot in post-mortem histolopathological analysis.
Contemporary high-resolution laser-scanning confocal microscopy analyses have confirmed the presence of axonal pathology in MS lesions [ 28 - 30 ]. The most widely used marker for axonal dysfunction is the detection of amyloid precursor protein APP accumulations in the axons.
Why APP becomes detectable in axons of MS lesions is not completely understood, but the breakdown of axonal transport followed by the subsequent retention of APP is the most likely possibility. It is also feasible that APP synthesis increases or degradation decreases as a result of the inflammatory process.
Another immunohistochemical marker used to demonstrate axonal pathology is SMI32, an antibody that labels non-phosphorylated neurofilament in axons. The maturation of the axonal cytoskeleton is usually accompanied by increased neurofilament phosphorylation, a process that is induced by the myelinating glia and leads to an increase in axonal diameter [ 31 ]. Demyelination may trigger the dephosphorylation of neurofilaments in axons, thereby mediating structural changes within the axon. Other changes in the axonal cytoskeleton that are observed in MS lesions are the phosphorylation and aggregation of tau, a microtubule-binding protein [ 32 , 33 ].
Increased carbonylation and degradation of cytoskeleton elements within axons have also been reported [ 34 ]. All these findings show that the axonal cytoskeleton is highly vulnerable and an important target in MS. These functional changes of the axonal cytoskeleton have important consequences if they persist as they will eventually lead to alterations in the transport of cargo along the axons and to an impairment of synaptic transmission [ 35 ]. Whereas these changes in the axonal cytoskeleton may mark a transient and still reversible dysfunctional state of the axon, other neuropathological findings such as axonal transsection and axonal end-bulb formation clearly show irreversible axonal damage in MS lesions [ 29 ].
Axonal swellings and transsections are already observed early in the disease within acute demyelinating lesions. More transsected or swollen axons were found within acute, inflammatory lesions as compared to chronic, sclerotic plaques [ 10 , 36 ]. On the basis of this positive correlation between inflammation and structural changes in axons, the inflammatory process has been suggested to be responsible for the ongoing neurodegeneration in MS [ 37 ]. Besides this local, acute neuronal damage in inflammatory lesions, there is also a more widespread, diffuse neurodegeneration in the CNS of MS patients.
One possible explanation for the diffuse neuronal loss is secondary Wallerian degeneration as a result of focal axonal injury. However, there seems to be no correlation between total lesion load and the extent of neurogeneration as determined by NAA levels or brain atrophy measurement [ 12 ].
These finding raise the question whether the inflammatory attack by itself is the sole responsible factor or whether non-inflammatory mechanisms contribute to neurodegeneration in MS [ 10 ]. There are a number of different inflammatory effectors that may be responsible for the axonal pathology in MS. Under physiological conditions neurons express low amounts of MHC class I.
The presence of activated microglia is a pathological hallmark of lesions in chronic progressive MS. These cells release a number of different factors that have been shown to be cytotoxic to neurons in culture [ 44 ]. For example nitrogen monoxide NO has repeatedly been seen to be detrimental to neurons for example by modifying ion channels, inhibiting mitochondrial respiration or blocking synaptic vesicle transport [ 45 - 47 ].
Neuropathological studies reveal an activation of the inducible form of NO synthase in acute lesions of patients with multiple sclerosis [ 48 , 49 ]. Another important mediator of axonal damage seems to be glutamate as inflammatory stimuli may trigger glutamate release, which in turn induces excitotoxicity by calcium overload in neurons [ 50 , 51 ]. NMDA N-methyl-D-aspartic acid receptors are expressed on the surface of oligodendrocytes and in the myelin membrane and can, if activated abnormally, result in myelin degradation [ 53 , 54 ]. Other inflammatory responses that can induce neuronal injury are antibody- and complement mediated processes.
An interesting finding in this respect is the identification of autoantibody-mediated axonal injury by targeting neurofascin NF , a neuronal protein concentrated in the node of Ranvier [ 55 ]. A viral etiology of MS has been discussed [ 57 , 58 ] and it feasible that specific viral infection may trigger an autoimmune-response towards axonal components and thereby contribute to neurodegeneration in MS. Mitochondrial dysfunction is another factor that is likely to contribute to axonal damage in MS.
In fact, the number of mitochondria is not only increased in chronic active and inactive lesions in progressive MS, but also the respiratory chain complex IV activity is altered [ 59 , 60 ]. Oxidative damage to mitochondrial enzymes and DNA might be responsible for the impairment of mitochondria [ 61 ]. While it is clear that inflammation correlates with neuronal cell death in acute inflammatory lesions, permanent disability is low during the early stages of RRMS.
In fact, neurological deficits seem to accumulate at a time when Gd-enhancing lesions become less frequent and the total lesion load remains stable. One possible explanation for this discrepancy is that the MRI only maps the inflammatory lesions that are formed early in disease, but not the inflammatory infiltrates that occur later in the disease. There is indeed some evidence that the pattern of inflammation changes in the course of MS [ 62 ].
Lymph follicle-like structures in the meninges and in the perivascular space have been observed in the progressive phase of the disease [ 63 ]. In addition, while T- and B- cells are cleared from active lesions, there is a population of plasma cells that remain diffusely distributed within the brain parenchyma [ 62 ]. There is also an increasing number of microglia that are scattered throughout the brain in progressive MS [ 64 ]. It has been suggested that early inflammatory lesions trigger these changes [ 62 ] and create a new inflammatory environment with a different subset of inflammatory chemokines [ 65 ] which is formed within the CNS parenchyma.
The inflammatory cells that persist in the CNS in progressive MS may directly induce neuronal damage. There is also evidence for an increasing number of cortical lesions in chronic progressive MS [ 11 ]. These lesions differ fundamentally from the white matter lesions as they are mainly composed of activated microglia and contain a much lower number of T- and B-cells [ 66 - 68 ].
It is possible that neuronal injury in the cortex is induced by a soluble factor released by the inflammatory infiltrates within the meninges. A shift from adaptive to innate immunity with abnormally activated dendritic cells is another potential mechanism of disease progression in MS [ 9 ].
Maturation and activation of dendritic cells were found to drive a proinflammatory immune response in secondary progressive MS [ 69 ]. However, it is also possible that neuronal damage is indirect and a result of the ongoing demyelination in the brain. The loss of myelin has indeed far-reaching consequences for the axon. Demyelination does not only slow down nerve conduction, but also obliterates the axonal architecture and reduces long-term neuronal survival. The important function of myelin is highlighted in mouse mutants that are unable to form an intact myelin sheath as a result of gene deletions.
For example, Shiverer mice contain a deletion of the MBP gene, which leads to the absence of myelin sheet formation and a severe behavioural phenotype with epileptic seizures and tremor [ 70 ]. The life span of these mice is dramatically reduced demonstrating the importance of myelin for the survival of an organism. Shiverer mice display a large number of changes in the axonal cytoskeleton and in the vesicular transport system that point towards a role of myelin in the regulation of fast axonal transport [ 71 ].
The breakdown of axonal transport that is often observed in neurons within active MS lesions could thus be explained in part by the loss of myelin ensheating the axons. In addition to the role of myelin in structuring the axon, there is also evidence that myelin is essential for the long-term axonal survival [ 72 , 73 ]. Evidence for such a function, comes again from mouse mutants that lack some of the major myelin genes. Axonal swellings, transections and an impairment of axonal transport occurning in these mice are highly reminiscent to the changes found in the CNS of patients suffering from MS.
These mouse mutants provide evidence for a function of oligodendrocytes in providing trophic support for axons that is required for their maintenance into late adulthood. It will be important to identify these trophic factors and to determine whether they become limiting in chronic, progressive MS. The concentration of voltage-gated sodium channels within specific regions between the internodes, the nodes of Ranvier, is another important function of myelin. The clustering of the sodium channels, Na v 1.
The saltatory conduction does not only speed up nerve conduction several folds, but also conserves energy within the neuron. After a demyelinating event, the clustering of sodium channels in the nodes of Ranvier is lost and both, the Na v 1. This response restores the conduction of the action potential, however resulting in a much higher energy demand. In summary, there is evidence for at least two different mechanisms that contribute to neurodegeneration in MS — axonal damage by a direct inflammatory attack and as a consequence of demyelination.
These two different modes of actions may damage the axon at different stages of the disease. It is tempting to speculate that immune-mediated axonal injury occurs in active lesions and is responsible for an acute form of neurodegeneration, whereas demyelination induces late-onset neurodegeneration. In fact, available data indicate that axons do not to degenerate immediately after demyelination, but only when compensatory mechanisms fail and a threshold of damaging insults have occurred [ 72 ].
These different mechanisms of neurodegeneration have to be taken into account when designing neuroprotective treatment strategies for MS. There has been tremendous progress in the treatment of RRMS over the past years. Several disease-modifying immunomodulatory or immunosuppressive drugs have already been approved and many more are currently in the last phases of clinical trials with promising outcomes [ 84 ]. So far, there is no proven or licensed disease-modifying drug to slow the progression of PPMS [ 85 ].
Progressive multiple sclerosis: from pathogenic mechanisms to treatment | Brain | Oxford Academic
In fact, the outcome of most clinical trials evaluating the effect of immunomodulatory or immunosuppressive drugs in PPMS has been disappointing. By now the largest trial performed in patients with PPMS patients was carried out with the immunomodulatory drug, glatiramer acetate GA [ 86 ]. Whereas GA has been proven to be efficient in the treatment of RRMS, the trial with PPMS patients had to be terminated prematurely as an interim analysis showed no discernible effect in the disease progression after two years.
Only a post hoc analysis suggested that GA may slow disease progression in a subset of patients. Trials with the immunomodulatory drug, interferon beta IFN beta , in patients with PPMS have been of smaller size, but the outcome was similarly disappointing. Two small, single-centred, placebo controlled trials patients did not reveal any reduction of disability progression in PPMS patients [ 87 , 88 ]. Although these studies were underpowered, to allow a definite conclusion on the efficacy of IFN beta the negative outcome did not encourage the initiation of larger trials. Recently, a single-center, phase two pilot study with interferon beta-1b on primary progressive showed no effect on sustained disability assessed by EDSS, but surprisingly revealed statistically significant differences for the Multiple Sclerosis Functional Composite score and for T1 and T2 lesion volume [ 89 ].
Again no benefit was detected of treatment on time to sustained disease progression [ 90 ].
For example, the humanized monoclonal antibody, alemtuzumab Campath-1H , which induces the cytolysis of CD52 positive cells leading to a T cell depletion and is highly effective in reducing relapse rate, MRI lesion load and disease progression in RRMS [ 91 ], does not seem to protect from disease progression once patients that have progressed to SPMS [ 92 ].
Another example is the immunosuppressant drug cladribine, which was not effective in modifying the disease progression in a placebo-controlled trial with patients suffering from SPMS or PPMS, even though it produced and sustained significant reduction in the number and volume of Gd-enhanced lesions on MRI [ 93 ]. These and other trials indicate that there is a critical window of therapeutic opportunity in the treatment of MS with immunomodulating or immunosuppressive drugs [ 92 ].
The analysis of the study population revealed that the patients in the European trial were younger with a higher pre-study relapse rate, suggesting that the reason for the different outcomes lies in the more active inflammatory disease in the European trial. Furthermore, mitoxantrone has been shown to slow down the progression of disease progression in patients with active and rapidly progressive SPMS [ 97 ].
Again, predictive parameters of mitoxantrone effectiveness seem to be the number of relapses within the past year before treatment indicating that the inflammatory activity determines treatment response [ 98 ]. More recent trials with the B cell depleting monoclonal antibody rituximab showed an impact on disease activity in RRMS and neuromyelitis optica, but no efficacy in PPMS [ 99 - ].
Even the aggressive treatment with autologous haematopoetic stem cell transplantation failed to suppress demyelination, neurodegeneration and clinical progression in the chronic progressive phase of the disease [ ]. All of these studies indicate that the available approved therapies are most effective early in the disease when the pathophysiology is dominated by the inflammatory and not the degenerative component.
The studies also suggest that most immunomodulatory and immunosuppressive therapies are unlikely to have any substantial effect once the disease has progressed into the chronic progressive phase of the disease.