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Multiple Sclerosis
From neuroscience to treatment
Dr Rosie Jones
The Brain Centre, Southmead Hospital
Spring 2015
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Characteristics of MS
“Autoimmune mediated inflammation (causing
damage) triggered by unknown factors in
susceptible individuals and resulting in”:
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Patchy damage to myelin / loss of Oligodendrocytes (?)
Failure of nerve conduction
Axonal damage
Axonal/nerve cell degeneration
Reduced brain Volume
Development of scarring
In the CNS
Spring 2015
MS Research Unit
This session
• Understanding MS
– Demographics
– Pathology
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Immuno-pathology
Myelin damage
Axonal damage
Routes to designing treatment
– Possible CNS repair mechanisms
– Some examples of MS Symptoms
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MS Demographics
• Prevalence between 10/100,000 and 170/100,000 (around
100,000 in the UK , 3 million world wide)
• Most common in temperate latitudes
• 2:1 women:men
• Diagnosed in early adulthood (teens to 30s, range “x” to 70
years) Childhood MS now acknowledged.
• Familial (genetic) susceptibility + unidentified factors
• Significantly more common in Caucasian populations
• Multiple symptoms-sensory and motor
• Progressive with or without relapses
Relapse Remitting, Primary Progressive Secondary Progressive
(RR PP SP)
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POPULATION STUDIES
Some examples of prevalence figures
world-wide:
UK 99-178/100,000 (Orkney 287/100,00?)
France 50/100,000
Italy 35-50/100,000
USA 70-165/100,000 (New Mexico 22/100/000)
Australia 11-40/100,000
New Zealand 24-77/100,000
Middle East 20 -50/100,000 (?)
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Environment: MIGRATION STUDIES
Studies of migration from high prevalence
area to low prevalence area:
• South Africa and Israel are both low
prevalence areas.
• Europeans migrating to these areas retain
high prevalence risk unless they migrate
before the age of 15 years.
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Environment: EXPOSURE
• Levels of sunlight/Vit. D
– Temperate latitudes, lack of exposure to sun
• Exposure to chemicals
– Solvents, fuel pollution, smoking
• Exposure to (viral) infections
– Measles, hepatitis, herpes etc. Vaccinations
• Exposure to stress/trauma
– MS may occur/worsen after giving birth, physical injury
traumatic life events
• Dietary differences
• High saturated fat levels-lack of polyunsaturated fats in diet.
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MULTIPLE SCLEROSIS
Spring
Spring2012
2015
MS Research Unit
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EDSS expanded disability status scale
Spring 2015
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Kurtzke JF (1983) Neurology 33 (11): 1444–52.
Progression of Disability
Occurrence, Extent of Severity
MS Courses as Redefined by MRI
SPMS
Clinical Impairment
MRI-Defined Plaque Burden
Late
RRMS
Enhancements
Early
RRMS
Time
Spring 2015
Adapted with permission from Dr. J.S. Wolinsky.
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Natural History of MS
• Relapse remitting phase- intermittent clinical
events 1 to 4/year - 5 to 20 years
• Secondary progressive phase-few or no
relapses, steady progression in disability levelling
off by about 20 years after diagnosis
• Primary progressive – steady increase in
disability with or without relapses.
• Severe - very rare. Fast progression to
wheelchair/bed-bound/death in 3 to 10 years
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Pathology
Development of an MS Plaque
Inflammation, Demyelination
Axonal damage
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Characteristics of MS pathology
“Autoimmune mediated inflammation
resulting in”:
• Damage to/loss of myelin/or loss of
Oligodendrocytes?
• Axonal damage
• Axonal degeneration
• Loss of brain bulk
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Myelin and Nerve Conduction
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Demyelination: Myelin and
Oligodendrocytes in the CNS
• Myelination in the CNS is by
Oligodendrocytes-(peripheral nervous system
myelin is produced by Schwann cells-not present in
CNS and not affected by MS)
• Each Oligodendrocyte produces myelin
extensions that wrap around several nerve
axons
• What happens to Oligodendrocytes in MS?
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OLIGODENDROCYTES
Oligodendrocyte in culture
(Immunofluorescence for
galactocerebroside)
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Brain Imaging
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PATHOLOGY
Not all aspects of MS
pathology are understood
• Blood brain barrier
disruption- immune cells
move into CNS.
• Complex inflammatory
responses
• Localised CNS damagedemyelination, axonal
damage
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Pathology
Local infiltration of
inflammatory cells
across blood vessel
walls requires:
• Adhesion to blood
vessel epithelium
• Transit across blood
vessel wall
• Migration into local
brain tissue
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Evidence that MS is an Autoimmune
disease. Immune activity overview
• Activated T lymphocytes appear in the blood and
CSF. Reactive to myelin proteins e.g. *MOG or
MBP
• Activated T cells and macrophages seen in MS
plaques
• Increased CD4+ (helper) to CD8+ (suppresser) T
cell ratio.
• Local IgG production seen in CSF-action of B
cells?
Possible antibody candidates:*MOG (oligodendrocyte glycoprotein), MBP
(myelin basic protein), viral infection?
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William Lindsey and Jerry Wolinsky
•
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Immune markers
Increased circulating levels of immune markers of
immune activity during MS exacerbations observed
including:
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T cell activation markers
Markers of macrophage activation
Markers of cellular adhesion
Markers of extracellular matrix breakdown
Markers of inflammatory cellular amplification
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T cell activation markers
Markers of T Helper cell (Th-1) activation
• Activated T helper cells release IL-2 (soluble IL-2
receptors detected)
• IL-4 is associated with T cell activation
• Interferon-gamma (INF) is associated with T cell
activation
• Macrophage activation follows. aTNF
IL=interleukin, TNF = tumour necrosis factor, INF=interferon
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Macrophage activation
Macrophage demyelination in vitro is mediated by
tumour necrosis factor-(TNF a) and Interferon
(INF)
• TNFa is increased in MS during relapse
• INF and TNFa act synergistically to heighten
immune responses
• TNFa damages Oligodendrocytes in vitro
Beta interferon, INF, counteracts the influence of
TNFaand INF
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Aims of Disease Modifying Drugs
DMDs are designed to break a key link or links in the
presumed pathway to tissue destruction in active
disease
Links include
• Immune cell activation (PB, CNS other?)
• Immune cell adhesion and migration (BBB)
• Immune cell clonal expansion (PB or CNS)
• Immune cell/cytokine cycle amplification
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William Lindsey and Jerry Wolinsky
•
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Autoreactive T Cells
Danger Signal
or Trigger
T
T
T
Activation, Differentiation,
Clonal Expansion
T
T
Adhesion/Attraction
T
Periphery
Transmigration
T
BBB
B
Antibodies
IFN-
T
APC
CNS
APC
M
NO
TNF-a
Local Reactivation
Release of Cytokines;
Recruitment of M
T
TNF-a
Demyelination and Axon Loss
Spring 2015
Adapted with kind permission from Prof. R. Hohlfeld.
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The Dual Nature of Inflammation in
MS
Pro-inflammatory and
Neurotoxic Factors
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Th1 cytokines
TNF-a
IL-1
Nitric oxide
Reactive oxygen species
Glutamate
Antibodies and complement
Cell-mediated neurotoxicity
TISSUE DAMAGE
Spring 2015
Anti-inflammatory and
Neuroprotective Factors
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Th2 cytokines
TGF-
IL-1
Neurotrophic factors
– BDNF
– NGF
– NT-3
– CNTF
– GDNF
TISSUE PROTECTION
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Aims of Disease Modifying Drugs
DMDs are designed to break a key link or links in the
presumed pathway to tissue destruction in active
disease
Links include
• Immune cell activation (PB, CNS other?)
• Immune cell adhesion and migration (BBB)
• Immune cell clonal expansion (PB or CNS)
• Immune cell/cytokine cycle amplification
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Clonal cell expansion-promotion of
cellular reactivity?
Mechanisms for clonal expansion of autoreactive immune cells and cellular
amplification/restriction unclear
• Following BBB breach other cells follow:
In MS plaques T cells and macrophages
• Macrophage activation: e.g. TNFa,macrophage
inflammatory proteins
• Pro-inflammatory cytokines detected in lesions
– TNFa, INf-,IL-2,IL-6,Il12.
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Treatments based on modifying
immune function
• Some tested disease modifying agents
– Beta interferon- (betaseron betaferon, Avonex)
– Glatiramir acetate (Copaxone, copolymer 1)
– Natalizumab (Antegren)-affects adhesion
molecules
– Campath H (Alemtuzumab) acts against CD52
lymphocytes
– Cell proliferation modulation?
– Stem cells??
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BBB Action of Adhesion Molecules
Peripheral
circulation
Basement
membrane
Matrix degrading enzymes e.g.
matrix metallo-proteinases
T cells express
adhesion molecules
e.g. LFA-1 VLA-4
CNS Blood
vessel
Blood vessels express
Adhesion molecules e.g.
E-Selectin
LFA- Leukocyte function associated antigen-1 VLA Very late antigen-4
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Current drug trials
Cladribine
Oral
x5x2mo
Depletes resting and
dividing lymphocytes
Lymphocytes and
monocytes
Alemtuzumab
ivx5dx
12mo
CD52+ Lymphocytes
Ablation lymphocytes
and monocytes
Rituximab
Ivx2
rep
CD20+B lymphocytes
Depletes naïve and
memory B cells
Aticept
sc
BlysS and APRIL
Affects B lymphocyte
activation
Daclizumab
ivxmo
CD25+ Lymphocytes
Expansion of CD2 56
and NK clones – takes
out activated l’cytes
Fingolimod
Oral daily
SIP Receptors
Sequesters lymphocytes
in lymph tissue
Laquinomod
Oral
3xd
Enhances Th11 responses
Immunomodulatory
Teriflunomide
Oral daily
Blocks pyrmidine synthesis
immunomodulatory
BG00012
Oral
3xd
Enhances Th11 responses
imunomodulatory
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Clinical outcome of some DMDs
• Reduction in number of relapses in early RR MS
• Reduction in new MRI (enhancing) CNS lesions in
early RR MS
• Reduction in progression of disease by 9 to 12
months
• Changes broadly reverse when treatments stops.
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Current treatments
• Inflammatory phase-steroids
• Non–acute phases
– General immunosuppressant agents
– Possible non-drug immuno-suppressants
• e.g. diet, lifestyle changes
• Statins?
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Damage to axons and nerve cells
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Myelin damage and axonal loss in
MS
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Fate of axons and nerve cells
It is now clear that axonal loss and damage are
major features of MS
• Presence of NAA (N-acetyle aspartate) in MR
spectroscopy
• Loss of brain bulk
• Increasing disability
• Alterations in physiological measures
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Neuronal/axonal damage
Axonal damage thought to be secondary to myelin
damage. Loss of trophic support or direct injury to
axon
BUT
In some models of MS axonal damage appears early
with or without evidence of demyelination.
AND
Reduction in CNS bulk continues in absence of
demyelination episodes (e.g. Progressive MS)
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Possible causes of axonal loss
Damage by
• Proteases
• Inflammatory cytokines
• Nitric oxide
• Glutamate/Glutamine
Evidence of up-regulation of all these possible
mechanisms seen in active MS.
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Possible mechanisms of repair
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Remyelination
Remyelination
requires:
• Viable myelin making cells
(oligodendrocytes)
• Intact nerve processes
• Suitable environment for
cellular survival and
activation
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Oligodendrocyte - development
Oligodendrocyte (OD) progenitor
OD precursor
Pre-OD
Adult OD progenitor
?
Immature OD
Mature OD
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Features of Oligodendrocytes
• Progenitor cells +ve for 04 mabs. Present
throughout CNS. Undifferentiated.
• Precursor cells +ve for Galacto-cerebroside (GalC).
Earliest OG specific marker to be expressed.
Large pale nucleus.
• May produce myelin processes.
• Mature cell +ve for myelin oligodendrocyte
glycoprotein MOG. Small dense nucleus.
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Possibilities for promoting
remyelination
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Stimulate cell activity/differentiation
Block progenitor cell inhibitory factors
Block agents that kill myelin-making cells
Transplant new OG cells-stem cells
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Oligodendrocytes and myelin
Extensive remyelination does not occur
despite presence of intact axons and
GalC+ve cells in the same lesion area.
• GalC +ve cells do not appear to mature into MOG +ve cells to
form new myelin
– Cells appear quiescent. Die before they can mature?
• GalC and MOG +ve cells appear to be destroyed in long term
plaques
– MOG+ve (mature) cells are destroyed selectively
• Possibilities for treatmentstimulate cell activity/differentiation
block inhibitory/cytotoxic factors
Induce/transplant new OG cells?
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Nerve cell repair
Loss of axonal capability to repair may be :
• Intrinsic-no mechanism in mature CNS
• Due to Nogo-A mediated damage-Block or ablate.
• Lack of access to or response to nerve growth
factors
• Hostile cytotoxic soup-too many factors to control
Neurotrophic support may be developed e.g. CNTF
ciliary neurotrophic factor.
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Stem cells
Can stem cells be used to effect repair in MS?
• Types of possible stem cells
– Resident/introduced oligodendrocyte precursor
cells.
• Used in early repair? Depleted?
– Embryonic stem cells
• ethical and cross reactivity issues. Tumours
– Other stem cells-e.g. haematopoietic
• Autologous and relatively easy to obtain
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C. What is known about adult stem cell differentiation?
Figure 2. Hematopoietic and stromal stem cell differentiation. Click here for larger image.
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Symptoms in MS
Multiple symptoms both motor and sensory
• Muscle weakness, fatigue, stiffness
(spasticity) contracture
• Sensory changes pain, burning/
tightness/numbness. Vision. Joint position.
• Loss of motor control-ataxia tremor
• Continence problems
• Cognitive changes
• Other behavioural and mood changes
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Physical fatigue
Neuromuscular
fatigue and
weakness
Illustrated as
change in force
output with time.
Loss of force may be
due to central or
peripheral (muscle)
fatigue.
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10
8
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2
0
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Force Control
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Force MS
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Neuromuscular Fatigue in MS
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Symptom Treatment
• Spasticity. Muscle stiffness and spasmsloss of central inhibition of spinal
motoneurones. Baclofen
• Loss of bladder control spinal lesions block
descending and ascending pathways. Urine
retention is most dangerous-can lead to
kidney damage.
• Pain. Neuropathic pain, very difficult to
treat. Pain from muscle contractures.
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Fatigue Statements
• “Fatigue is one of the worst symptoms”
“Having to
use a wheel chair is a big change but it’s not as
bad as the fatigue”.
•
-”like having a really bad ‘Flu” “You feel weak and
unable to get about. It comes on without warning
and is one of the hardest things to deal with”
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Mental Fatigue
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Runs out of steam
Cannot make effort
May need to rest or sleep
May feel depressed or frustrated
Usually worse when hot or under
stress
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Mental Fatigue
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Loss of concentration
Ability to think through/solve problems
Reduced motivation
Over whelming need to rest or sleep
Affects up to 90% of people with MS
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Intention Tremor
Definition-An increase in tremor amplitude
towards the termination of a visually guided
goal-directed movement.
• 30% of the MS population are estimated to
have upper limb tremor
• Causes dependence in daily activities
• Subjects with severe tremor have a high
level of disability and loss of independence.
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Figure of 8: Control subject
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Example of figure of 8 data collection
(severe tremor)
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Measurement of Tremor
• Second example: reach-retrieve (functional) test