How does Progressive MS differ

How

does

Progressive

MS

differ

from

Relapsing

MS?

Anne Gocke, Ph.D.

Assistant Professor

Department of Neurology

Johns Hopkins University

CMSC

May 28, 2014

Types

of

MS

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

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

oligos

or

axons

where

inflammation

is

secondary

process?

Primary

Progressive

MS

• 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 microgila and 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

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

Disease

Differences

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

Pathological

Differences

between

RRMS

and

PMS

Inf ammation and axonal injury occurs mostly in demyelinating lesions

Inf ammation and axonal injury occurs diffusely

throughout the white 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 

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

Focal demyelination: white matter Focal remyelination: white matter Demyelination: deep grey matter nuclei Demyelination: 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

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,

■ Oxidative injury ■ Mitochondrial dysfunction ■ Inf ammation ■ Microglia activation ■ Oxidative burst Pathological changes Disease mechanisms

Evolution

of

structural

pathology

and

disease

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 remyelination

following removal of debris 

and secretion of neurotrophic

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

Ca

accumulation

and

degeneration

•

Ion

channels

could

be

targets

for

neuroprotective

therapies

in

PMS

Axon Action

potential potentialAction

Energy

suff cient def cientEnergy

Na+/ Ca2+

exchanger Glutamatereceptor VGCC

Ca2+ a Na+ ATP-dependent Na+ 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 

FIGURE 1 | M odel of p66ShcA-mediated feed forward pathway of mitochondrial ROS and neurodegeneration in M S.Under normal cellular conditions, p66ShcA is sequestered by Prx1 in an inactive form. Under the excessive cellular stressors associated w ith MS disease processes, p66ShcA is disassociated from Prx1 and is serine phosphorylated by PKC-β. Phosphorylated p66ShcA forms a complex with Pin1 isomerase, which leads to p66ShcA translocation into the intermitochondrial space (IMS). There, p66ShcA oxidizes cytochrome c and reduces oxygen to form mitochondrial ROS, w hich induces opening

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

Front. Physiol., 25 July 2013 | doi: 10.3389/fphys.2013.00169 Mitochondrial dysfunction and neurodegeneration in multiple sclerosis

Kimmy Su1,2_{, Dennis Bourdette}2,3_{and Michael Forte}1_*

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

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

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