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How does Progressive MS differ from Relapsing MS?

Anne Gocke, Ph.D.

Assistant ProfessorDepartment of NeurologyJohns Hopkins University

CMSCMay 28, 2014

Types of MS• Progressive relapsing

• Progressive MS –secondary progressive (SPMS) and primary progressive (PPMS)

• SPMS: progression follows initial relapsing remitting phase

• PPMS: gradual steady and relentless functional decline from onset

• Relapsing remitting (RRMS)

• Most patients will be affected by progressive disease course at some stage

Source: Crown Copyright

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Relapsing and Progressive MS

• Unknown

– Primary trigger(s)

– Specificity of pathogenic immune cells

– Mechanism underlying progressive disability 

– Genetic contributors to progression

– Does progressive MS result from primary neurodegenerative process involving loss of oligosor axons where inflammation is secondary process?

Stys PK, Zamponi GW, van Minnen J, Geurts JJ. Will the real multiple sclerosis please stand up? Nat Rev Neurosci. 2012;13:507‐14.

AutoimmunityCytodegeneration

‘Inside-out’ model

‘Outside-in’ model

Antigenicproteins, lipids

NO, glutamate,cytokines

CN

S

Peri

pher

y

“Inside Out” or “Outside In”?

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Primary Progressive MS• More likely to affect men than other forms of the disease

• Typically begins a decade later than RRMS onset – age is important

• Shares similar genetic susceptibility and similar pathology with other forms of MS (variant of the same problem)

• Characterized by underlying neurodegenerative problem??

• Meningeal infiltrates of B and T cells particularly prominent in progressive MS and lymphoid follicles associated with underlying microglia activation and cortical plaques

• White matter plaques often neuroinflammatory at the center but microgilaand macrophages as well as evidence of ongoing axonal injury can be found (simmering and possibly concentrically expanding axonopathy)

• Diffuse low grade parenchymal inflammation with B cells, T cells, and microglia reported

• Perivascular inflammation often evident without associated disruption of blood‐brain barrier – may explain failure of current therapies

• Axonal and neuronal death may result from glutamate‐mediated excitotoxicity, oxidative injury, iron accumulation, and/or mitochondrial failure

Challenges of Progressive MS

• Current inability to develop effective therapies due to lack of understanding of underlying biology of this form of disease– Disease mechanisms driving progressive disease remain unknown

– Therapeutic options currently limited to symptomatic treatments and physiotherapy

– Currently no animal model available that accurately models this stage of disease

• Definition: gradual worsening of motor/cognitive function over time with or without superimposed attacks?

• Is evolution from relapsing to progressive MS different than PPMS?

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Proposed theories to explain pathogenesis of progressive MS

• Brain damage driven by inflammation similar to what is seen in RRMS, but behind intact BBB

• Starts as an inflammatory disease but chronic inflammation leads to neurodegeneration/disease progression independent of inflammation– Microglial activation under control of intact neurons –control might be lost as consequence of neurodegeneration

• Primarily neuro‐degenerative disease with progression amplified by inflammation in early disease

Relapsing vs. Progressive DiseaseDifferences in Pathophysiology

• Pathological hallmarks of RRMS: inflammatory demyelinating lesions in brain and spinal cord visualized by MRI – axonal damage and loss related to foci of inflammation

• PPMS: diffuse rather than focal inflammation; involves more prominent cortical demyelination (may contribute to progression of disease); diffuse axonal injury; frequent presence of microglial nodules in the brain

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Pathological Differences between RRMS and PMS

Grey matter

White matterDemyelinatinglesion

RRMS PMS

Less-prominentinvolvement of

grey matter

Marked involvementof grey matter

Inf ammation and axonalinjury occurs mostly indemyelinating lesions

Inf ammation and axonalinjury occurs diffusely

throughout thewhite matter

Figure 1 | Key pathological differences between RRMS and PMS. Inflammation and axonal injury (indicated by darker shading) occurs mostly in demyelinating lesions in RRMS, but happens diffusely throughout the white matter in PMS. The grey matter is more prominently involved in PMS than in RRMS. Abbreviations: PMS, progressive multiple sclerosis; RRMS, relapsing–remitting multiple sclerosis.

Koch MW., et al. Treatment trials in progressive MS‐ current challenges and future directions. Nat. Rev. Neurol. 9, 496‐503 (2013).   

Inflammation

• Present at all stages of MS

• Consists of perivascular and parenchymal infiltrates of lymphocytes and macrophages

• Active lesions: dominate RRMS – initial response consists mainly of CD8+ T cells, abundant macrophage recruitment/activation; secondary response includes recruitment of T cells, B cells and macrophages as consequence of myelin destruction; infiltration of inflammatory cells into CNS results in profound damage to BBB as seen by gad‐enhancing lesions on MRI

• Chronic lesions: seen in SPMS and PPMS ‐ relationship between inflammation and BBB damage less obvious (impairment can occur in presence or absence of inflammatory infiltrates); large aggregates of inflammatory cells observed in meninges display features of lymphoid follicles (T and B cell germinal centers and presence of follicular DCs); as disease progresses inflammation becomes compartmentalized behind intact BBB

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Brain. 2007 Apr;130(Pt 4):1089‐104.Meningeal B‐cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology.Magliozzi R1, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, Reynolds R, Aloisi F.

Characterization of ectopic B‐cell follicles and inflammatory 

cell infiltrates in SPMS and PPMS

Focal Plaques of Demyelination

• Plaques present in grey and white matter at all stages of disease

• Slow expansion of pre‐exisiting lesions leads to pronounced cortical demyelination associated with extensive diffuse injury throughout normal appearing white and grey matter in Progressive MS

• Cortical lesions most abundant in progressive stage of disease – most prominent in subpial cortical layers and can be linked to local inflammation in the meninges

• Activated microglia associated with active lesions

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Focal demyelination: white matterFocal remyelination: white matterDemyelination: deep grey matter nucleiDemyelination: cor tex

a c

d e f

b

*

Figure 1 | Characteristic brain pathology in secondary progressive multiple sclerosis. a | Brain section immunostained for proteolipid protein. Coloured areas indicate the locations of different lesion types. Marked atrophy with dilatation of cerebral ventricles and outer cerebrospinal fluid spaces is also evident. b | Normal-appearing white matter with microglial activation and microglial nodule, revealed by immunostaining for p22phox (brown). c | Proteolipid protein immunostaining (brown) reveals a broad band of subpial demyelination together with a small intracortical demyelinated lesion (pale regions). d | Low-power image of active demyelinating white matter lesion, showing macrophages with myelin degradation products (arrows) and reactive gliosis (arrowheads). e | Higher-magnification image of the active lesions shown in (d) reveals demyelinated axons (arrows), macrophages with myelin debris (arrowheads) and dystrophic axons (asterisk) within the myelin sheath. f | Double immunostaining for p22phox and CD8 shows activated microglia (brown) and T lymphocytes (black) accumulating in perivascular cuffs and dispersed within the lesion.

Brain pathology in SPMS

Lassmann, H. et al. Nat. Rev. Neurol. 8, 647–656 (2012); published online 25 September 

2012; doi:10.1038/nrneurol.2012.168

Brain. 2005 Nov;128(Pt 11):2705‐12. Epub 2005 Oct 17.Cortical demyelination and diffuse white matter injury in multiple sclerosis.Kutzelnigg A1, Lucchinetti CF, Stadelmann C, Brück W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H.

Focal inflammatory demyelinated plaques in the white matter dominate the pathology in acute and relapsing multiple sclerosis, 

while cortical demyelination and diffuse white matter inflammation 

are characteristic hallmarks of PPMS and SPMS

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Diffuse global tissue injury

• Brains of MS patients show widespread inflammation, microglial activation, astrogliosis, and mild demyelination and axonal loss in NAWM – loss of tissue volume also seen in cortex = brain atrophy

• Extent and severity increases with disease duration and most closely linked with PMS

• Small calibre axons most predominantly affected• Extent of diffuse injury not correlative with number, size, or destructiveness of focal lesions but correlates moderately with extent of cortical demyelination

a

Age and disease duration

RRMS RPMS SPMS PPMS

■ Trapped inf ammation■ Meningeal inf ammatory aggregates■ Slow expansion of pre-existing lesions■ Subpial cortical demyelination■ Diffuse white matter injur y■ Brain atrophy

■ Inf ammation■ New waves of lymphocytes entering the CNS■ Blood–brain barrier disturbance■ New active CNS lesions■ Initial remyelination in active lesions

b

Age and disease duration

RRMS RPMS SPMS PPMS

■ Oxidative injury■ Mitochondrial dysfunction■ Mitochondrial DNA deletions■ Iron accumulation with ageing (oligodendrocytes, microglia, axons, neurons and astrocytes)

■ Oxidative injury■ Mitochondrial dysfunction■ Inf ammation■ Microglia activation■ Oxidative burst■ Expression of NADPH oxidases■ iNOS expression

Pathological changes

Disease mechanisms

Evolution of structural pathology and disease mechanisms in MS

Lassmann, H. et al. Nat. Rev. Neurol. 8, 647–656 (2012); published online 25 September 

2012; doi:10.1038/nrneurol.2012.168

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Mechanisms of MS Pathology

• Distinct patterns of demyelination and tissue injury present in RRMS – likely due to distinct immune processes in inflammatory lesions

• Patterns of tissue injury are largely homogeneous in SPMS and PPMS – likely the result of slow expansion of existing lesions with sparse remyelination– Age‐dependent loss of trophic support from microglia or local environment in demyelinated plaques

Microglial Activation

• Active tissue injury associated with microglial activation in RRMS and PMS

• Microglial nodules seen in PMS

• Oxidative burst by activated microglia may have a major role in induction of demyelination and progressive axonal injury

• Microglia may also have neuroprotective functions and could promote remyelinationfollowing removal of debris and secretion of neurotrophicmolecules

Surg Neurol Int 2011, 2:107  Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy‐A unifying hypothesisRussell L Blaylock1, Joseph Maroon

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Altered axonal ion homeostasis

• Aberrant expression of Na+

channels, acid sensing Na+

channels, glutamate receptors, and voltage‐gated calcium channels detected in demyelinated axons

• Alterations in expression or activity could result in intra‐axonal Ca2+ accumulation and degeneration

• Ion channels could be targets for neuroprotectivetherapies in PMS

Axon

Actionpotential

Actionpotential

Energysuff cient

Energydef cient

Na+/ Ca2+

exchangerGlutamatereceptor

VGCC

Ca2+

a

Na+

ATP-dependentNa+ pump

Na+

Ca2+ Ca2+

Na+

Lassmann, H. et al. Nat. Rev. Neurol. 8, 647–656 (2012); published online 25 September 

2012; doi:10.1038/nrneurol.2012.168

Mitochondrial Injury

• Energy deficiency or “virtual hypoxia” may have a pathogenic role in MS

• Impaired NADH dehydrogenase activity and increased complex IV activity in mitochondria in MS lesions

• Mitochondrial injury may reflect oxidative damage in areas of initial tissue injury

• Accumulation of mitochondrial DNA deletions in progressive MS could partly explain increased susceptibility to neurodegeneration in SPMS and PPMS

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FIGURE 1 | Model of p66ShcA-mediated feed forward pathway ofmitochondrial ROS and neurodegeneration in MS. Under normalcellular conditions, p66ShcA is sequestered by Prx1 in an inactive form.Under the excessive cellular stressors associated w ith MS diseaseprocesses, p66ShcA is disassociated from Prx1 and is serinephosphorylated by PKC-β. Phosphorylated p66ShcA forms a complexwith Pin1 isomerase, which leads to p66ShcA translocation into theintermitochondrial space (IMS). There, p66ShcA oxidizes cytochrome cand reduces oxygen to form mitochondrial ROS, which induces opening

of the mitochondrial PTP. PTP opening subsequently induces the influxof solutes into the mitochondrial matrix resulting in loss ofmitochondrial membrane potential and equilibrium of ionic gradients,which can prevent ATP synthesis, and promote matrix expansion,mitochondrial swelling, and membrane rupture leading to release ofcytochrome c into the axoplasm and eventual neuronal death.Importantly, p66ShcA is part of a positive feed-forward signalingpathway that further elevates oxidative stress levels and activatesmitochondria-mediated neuronal death.

Front. Physiol., 25 July 2013 | doi: 10.3389/fphys.2013.00169Mitochondrial dysfunction and neurodegeneration in multiple sclerosisKimmy Su1,2, Dennis Bourdette2,3 and Michael Forte1*

Oxidative Stress

• Oxidative stress drives mitochondrial dysfunction via several different mechanisms..

• Free radicals disrupt mitochondrial enzyme function

• Modify mitochondrial proteins and accelerate their degeneration

• Interfere with de novo synthesis of respiratory chain components and induce mitochondrial DNA damage

• Oxidative injury pronounced in progressive MS lesions despite low levels of inflammation and may be driven by factors other than inflammatory process in PMS

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Iron Accumulation

• Iron accumulates in aging brain where it is predominantly stored in oligodendrocytes and detoxified by binding to ferritin

• Intracytoplasmic accumulation of iron in oligos may explain high susceptibility of these cells to degeneration under conditions of oxidative stress

• In MS lesions, iron is taken up by activated macrophages and microglia – which become dystrophic and undergo fragmentation and cellular degeneration

• Process is age‐dependent and likely to be more pronounced in PMS patients

Disease‐specific molecular events in cortical multiple sclerosis lesions.Fischer MT, Wimmer I, Höftberger R, Gerlach S, Haider L, Zrzavy T, Hametner S, Mahad D, Binder CJ, Krumbholz M, Bauer J, Bradl M, Lassmann H.Brain. 2013 Jun;136(Pt 6):1799‐815.

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Conclusions

• Absence of definitive disease mechanism in both RRMS and PMS• Current evidence indicates a number of interlinking pathways which 

contribute to disease pathogenesis• Inflammation mediated by T cells, B cells, and macrophages drives 

demyelination and degeneration in all forms of the disease• In progressive MS, inflammation, characterized by lymphoid follicles in 

meninges, becomes trapped behind intact BBB making anti‐inflammatory treatment unsuccessful

• Tissue injury may be affected by microglia activation, oxidative injury and mitochondrial damage

• In PMS, liberation of iron may amplify oxidative damage resulting in  increased neurodegeneration

• Accumulation of tissue damage leads to exhaustion of functional reserve capacity of the brain, which may accelerate clinical deterioration with slow progressive tissue injury

• A great need exists for better models of PMS to aid the development of effective disease‐modifying therapies for this devastating form of the disease