Transcript Slides - Projects In Knowledge

Neuronal Preservation in MS
James D. Bowen, MD
Medical Director, Multiple Sclerosis Center
Swedish Neuroscience Institute
Seattle, Washington
Case
• 38-year-old woman
– 2008: optic neuritis
– 2009: numbness in right leg; MRI abnormal
– Diagnosed with MS and started on interferon
beta-1a SQ 3 x week
• Patient is now concerned about possible
brain atrophy and what can be done to
stop it
Dichotomy of MS Damage
• Inflammation
– Acute
– Prominent immune component
• Degeneration
– Chronic
– Little immune component
Bramow S, et al. Brain. 2010;133:2983-2988.
Acute Inflammation
Enhancement: BBB leakage
Focal tissue loss: black holes
T1 image with gadolinium
Abbreviation: BBB, blood brain barrier.
Slide courtesy of Dr. James D. Bowen.
Degeneration
Cortical atrophy
Central atrophy
Slide courtesy of Dr. James D. Bowen.
FLAIR sequence
Disease Course in MS
RRMS
SPMS
Symptoms 
Atrophy/degeneration
Clinical symptoms
MRI
Abbreviations: MRI, magnetic resonance imaging; RRMS, relapsing-remitting MS;
SPMS, secondary-progressive MS.
Spain RI, et al. BMC Med. 2009;7:74.
Slide courtesy of Dr. James D. Bowen.
Problems with This Model
• Initiation of immune attack
• Diverse immune attack
• Earliest oligodendrocyte damage
• Long-term course determined by
progression
• Progressive from the beginning
• Incomplete control with immune therapies
Initiation of Immune Attack
• Starts with macrophages, not T-cells
• Requires antigen release to begin
immune attack
• Antigens must make it to circulation or
lymph tissue
• Something must happen before immune
attack
Diverse Immune Attack
• Entire immune system activated in MS
– Innate system
– Adaptive system
 B-cells
 CD4, Th1
 CD17
– Antigen-presenting cells
• Not a single rogue component
Earliest Oligodendrocyte Damage
• 14-year-old female, 9-month history of MS
• 4th attack = brainstem; fatal within 17 hours
• Lesion: little loss of myelin, all oligodendrocytes
had apoptosis
• Macrophages, T-cells, MRP-14+ mononuclear
cells, and enlarged astrocytes absent
• Rare microglia endocytosing oligodendrocyte
nuclei
• Areas of phagocytosis had perivascular cuffing,
CD4, CD8, CD45RO+, macrophages
• 9 additional acute lesions in 6 cases identified
Barnett MH, Prineas JW. Ann Neurol. 2004;55:458-468.
Effects of Attacks on Progression
• N = 224 patients with ≥1 exacerbation
– 90 days after exacerbation
 41% had EDSS score residual deficit of ≥0.5
 30% had EDSS score residual deficit of ≥1.0
• Attacks can lead to permanent worsening
Abbreviation: EDSS, Expanded Disability Status Scale.
Lublin FD, et al. Neurology. 2003;61:1528-1532.
Effects of Attacks on Progression
Relapsing-Remitting Onset
(yrs)
Progressive Onset
(yrs)
Time onset−EDSS 4
11.4
0
Time onset−EDSS 6
23.1
7.1
Time EDSS 4−6
5.7
5.4
Time EDSS 4−7
12.1
12.0
Time EDSS 6−7
3.3
4.0
SPMS onset
PPMS onset
Without Relapse
(yrs)
With Relapse
(yrs)
Time EDSS 4−6
4.0
4.4
Time EDSS 4−7
7.8
10.0 (P = .04)
Time EDSS 6−7
2.6
4.3 (P = .002)
Time EDSS 4−6
5.5
5.4
Time EDSS 4−7
12.4
11.3
Time EDSS 6−7
4.0
3.6
Abbreviations: PPMS, primary-progressive MS; SPMS, secondary-progressive MS.
Confavreux C. N Engl J Med. 2000;343:1430-1438.
Progressive from the Beginning
Patients with CIS have changes in:
• Atrophy (corpus callosum)1
• Magnetization transfer2
• NAA on MR spectroscopy1
– Marker of neuronal dysfunction and/or loss
• Functional MRI (fMRI)3
Abbreviations: CIS, clinically isolated syndrome; NAA, N-acetylaspartate.
1. Audoin B, et al. Mult Scler. 2007;13:41-51.
2. Fernando KT, et al. Brain. 2005;128:2911-2925.
3. Filippi M, et al. Hum Brain Mapp. 2004;21:108-117.
Right Index Tapping
max
min
MS
Control
MC and SMA MS = control (P >.05)
NeuroCog mean tapping:
MS = 55.9 taps, control = 59.0 taps (NS)
MSFC mean right 9HPT:
MS = 26 sec, control = 20 sec (NS)
Abbreviations: 9HPT, 9-hole peg test; MC, motor cortex; MSFC, MS functional composite; NS, not
significant; SMA, supplementary motor cortex.
Slide courtesy of Dr. James D. Bowen.
Logical Reasoning
Orbitofrontal Cortex
max
fMRI MS >Control (P <.05)
NeuroCog
M12 min
C03
Total mean score: P = .51
MS = 14.7, Control = 15 (NS)
Mean time to completion:
P = .32
MS = 136.6 sec
Control = 124.6 sec (NS)
max
Mean perceived effort: P <.01
MS = 5.6, Control = 3.3
M12
MS
min
C03
Control
Slide courtesy of Dr. James D. Bowen.
Incomplete Control with Immune
Therapies
A
28
83
13
Attacks
MRI
EDSS
B
29
33
10.54
C
32
51
27
D
32
78
10
E
68
92
54
F
65
7.9
100
90
% Reduction
80
70
60
EDSS
50
Attacks
40
MRI
30
20
10
0
A
B
Jacobs LD, et al. Ann Neurol. 1996;39:285-294.
IFNB MS Study Group. Neurology. 1993;43:662-667.
PRISMS Study Group. Lancet. 1998;352:1498-1504.
Johnson KP, et al. Neurology. 1995;45:1268-1276.
Polman CH, et al. N Engl J Med. 2006;354:899-910.
Hartung HP, et al. Lancet. 2002;360:2018-2025.
C
D
E
F
Autologous Stem Cell Transplant
Studies
• ~80% stable at 3 years1
• 63% stable at 6 years2
• Perhaps more effective earlier in
disease
• Perhaps more effective for RRMS
1. Reston JT, et al. Mult Scler. 2011;17:204-213
2. Bowen J, et al. Unpublished data, 2011.
Disease Model
Atrophy/symptoms
Symptoms 
Primary process, loss of myelin
Sufficient antigen release to activate immune system
MRI
Slide courtesy of Dr. James D. Bowen.
Importance of Neuronal Preservation
Ultimate goal
• Preserve brain function
• Lessen disability
Assessing Neuronal Preservation
• Disability
• MRI
• Optical Coherence Tomography (OCT)
• Biomarkers
Disability Measures
Proxy for neuronal preservation
• Expanded Disability Status Scale (EDSS)
• Multiple Sclerosis Functional Composite (MSFC)
– Paced Auditory Serial Addition Test (PASAT)
– 9-Hole Peg Test (9HPT)
– Low contrast visual acuity
– Timed 25-Foot Walk (T25-FW)
MRI Measures
• T2, FLAIR, black holes, enhancement
• Atrophy
– Brain width, ventricular width (3rd, lateral),
caudate width, corpus callosum thickness
– Whole brain volume
 Semi-manual: SABRE
 Automated: SIENA
 Brain parenchymal fraction: brain/intracranial
volume
Abbreviations: FLAIR, fluid attenuated inversion recovery; SABRE, signal amplification by
reverse exchange; SIENA, structural image evaluation, using normalization, of atrophy.
New MRI Methods
• Magnetization transfer
• MR spectroscopy
• Diffusion tensor imaging (DTI)
• Functional MRI (fMRI)
Magnetization Transfer
Narrow
resonant
frequency
+
Macromolecule
+
Broad
resonant
frequency
+
Saturate at
broad nonresonant
frequency
Measure free
water at that
frequency
+
Free water
Macromolecule
Free water
Bagnato F, Frank JA. Curr Neurol Neurosci Rep. 2003;3:238-245.
Bound water
Slide courtesy of Dr. James D. Bowen.
Relative Proton Concentration
MR Spectroscopy
4.0
3.0
2.0
1.0
0.0
ppm
Abbreviations: Cho, choline; Cr, creatinine; NAA, N-acetylaspartate; ppm, parts per million.
Bagnato F, Frank JA. Curr Neurol Neurosci Rep. 2003;3:238-245.
Slide courtesy of Dr. James D. Bowen.
Diffusion Tensor Imaging
Axon
++
+
+
Bagnato F, Frank JA. Curr Neurol Neurosci Rep. 2003;3:238-245.
Slide courtesy of Dr. James D. Bowen.
+
Diffusion Tensor Imaging
Slide courtesy of Dr. James D. Bowen.
Optical Coherence Tomography
20/80 OD
20/50 OS
Abbreviations: OD, oculus dexter; OS, oculus sinister.
Slide courtesy of Dr. James D. Bowen.
Brain Biomarkers—Iron
• Study of 7 MS patients, 4 controls1
– 7T MRI: MS patients have lower T2* values
(higher iron content) in dentate, red nucleus,
substantia nigra and globus pallidus
• 1.5T MRI followed longitudinally2
– Susceptibility-weighted imaging (SWI)
showed no changes over 1 year—caution
needed on claiming iron quantification with
SWI
1. Pawate S, et al. Presented at 63rd AAN; April 9-16, 2011; Honolulu, Hawaii.
2. Khan O, et al. Neurology. 2011;76:A393.
Brain Biomarkers—Adenosine
A2A-Receptor
• Proinflammatory and neurodegenerative
properties
• PET scan using adenosine A2A-receptor specific
[11C]TMSX of 4 patients with SPMS and 5
controls
• Increased uptake, widespread in white matter
• Binding associated with widespread white matter
pathology
Abbreviations: PET, positron emission tomography; SPMS, secondary-progressive MS.
Rissanen E, et al. Neurology. 2011;76:A172.
Brain Biomarkers—Neurofilament
Phosphorylation
• Postmortem brain studied by MTR, ELISA
• Hyperphosphorylated neurofilament heavy chain
correlated with T1 lesion load (r = 0.7) and
inversely correlated with MTR (r = -0.76)
• These changes were present in normalappearing white matter
Abbreviations: ELISA, enzyme-linked immunosorbent assay; MTR, magnetization transfer ratio.
Schmierer K, et al. Neurology. 2011;76:A358.
Blood Biomarkers—Brain-Derived
Neurotrophic Factor
• Produced by neurons or activated astrocytes1
• Plays a role in axonal growth, modulation of
neuronal activity, activity-dependent synaptic
and dendritic plasticity1,2
• Correlates with MRI T2 burden3
1. Binder DK, Scharfman HE. Growth Factors. 2004;22:123-131.
2. Linker RA, et al. Brain. 2010;133:2248-2263.
3. Frota ERC, et al. Mult Scler. 2010;16:S158.
Blood Biomarkers—Ciliary
Neurotrophic Factor
• Promotes
– Neurotransmitter synthesis1
– Neurite outgrowth1
• Protective role in myelin oligodendrocyte
glycoprotein (MOG)-induced EAE2
Abbreviation: EAE, experimental allergic encephalomyelitis.
1. Lam A, et al. Gene. 1991;102:271-276. 2. Linker RA, et al. Nat Med. 2002;8:620-624.
CSF Biomarkers—Neurofilament
Light Chain (NFL)
• An intermediate filament found in neurons;
marker of axonal damage
• 66 patients with CIS
– After 1.65 years, 39 developed MS
• Mean CSF NFL
– 979.6 converters
– 450.72 nonconverters
Tortorella C, et al. Presented at 63rd AAN; April 9-16, 2011; Honolulu, Hawaii.
CSF Biomarkers—Tau Protein
• Stabilizes microtubules1
• 158 patients2
– RRMS (n = 94), CIS (n = 39), PP (n = 25)
– Tau protein elevated in all MS patient groups
1. Weingarten MD, et al. Proc Natl Acad Sci USA. 1975;72:1858-1862.
2. Mares J, et al. Neurology. 1011;76:A597.
CSF Biomarkers—Pigment
Epithelium Derived Factor
• Plays role in differentiating precursors into
neurons1
• CSF specimens from 56 patients with MS,
19 patients with noninflammatory
neurologic disorders2
– In patients in remission, PEDF negatively
correlated with:
 Number of accumulated relapses (r = -0.66)
 Disease duration (r = -0.4)
Abbreviations: CSF, cerebrospinal fluid; MS, multiple sclerosis; PEDF, pigment epithelium derived factor.
1. Houenou LJ, et al. J Comp Neurol. 1999;412:506-514.
2. Orbach R, et al. Neurology. 2011;76:A375.
Effect of Therapies on
Neuroprotection
• Preservation of brain and function
demonstrated
– Due to neuroprotection or immune effects of
the treatment?
• Effects on regeneration/remyelination less
certain
Interferons
• Clinical preservation
– Expanded Disability Status Scale (EDSS)1
 Significant delay in time to sustained EDSS
progression
• MRI1,2
 Decreased T1 black holes
 Slowing of atrophy (brain parenchymal fraction)
• Increases brain-derived neurotrophic
factor production3
1. Jacobs LD, et al. Ann Neurol. 1996;39:285-294. 2. Paty DW, et al. Neurology. 1993;43:662-667.
3. Yoshimura S, et al. Mult Scler. 2010;10:1178-1188.
Glatiramer Acetate
• Clinical preservation
– Significantly more patients had improved
Expanded Disability Status Scale at 2 years
compared with placebo patients1
• MRI
– Black hole formation reduced compared with
placebo2
1. Johnson KP, et al. Neurology. 1995;45:1268-1276.
2. Filippi M. Neurology. 2001;57:731-733.
Brain-Derived Neurotrophic & Other
Factors and Glatiramer Acetate
• Glatiramer acetate (GA) increases brain-derived
neurotrophic factor1
• GA increases insulin-like growth factor-1 production by
Th2 lymphocytes in mice2
• Experimental allergic encephalomyelitis optic neuritis in
rats—GA increases survival of retinal ganglion cells and
increases phosphorylation of neuroprotective kinases
(Akt, MAPK1, MAPK2) and bcl-23
• GA increases neuroprogenitor proliferation, migration,
and differentiation4
1. Azoulay D, et al. Mult Scler. 2005;suppl 1: S86.
2. Skihar V, et al. Mult Scler. 2005;suppl 1: S51.
3. Maier K, et al. Mult Scler. 2005;suppl 1: S51.
4. Aharoni R, et al. Mult Scler. 2005;suppl 1: S51.
Effects of Treatment on BDNF
70
BDNF ng/mL
60
50
40
30
20
10
0
Healthy
Control
RRMS
RRMS
Relapse
RRMS
Remission
GA
Abbreviations: BDNF, brain-derived neurotrophic factor; GA, glatiramer acetate;
IFN, interferon; RRMS, relapsing-remitting MS.
Slide courtesy of Dr. James D. Bowen.
Azoulay D, et al. Mult Scler. 2005;suppl 1: S86.
IFN
Natalizumab
• Clinical preservation1
– Significantly reduced progression of sustained
disability
• MRI1
– Decreased T1 black hole formation
– Decreased atrophy in year 2
1. Miller DH, et al. Neurology. 2007;68:1390-1401.
BG00012 (Dimethylfumarate)
• Decreases oxidative stress
• Increases nuclear factor-E2-related
factor 2
Horssen S, et al. Neurology. 2011;76:A136.
Laquinimod
• Increases levels of brain-derived
neurotrophic factor (BDNF)1-3
• Increased transcripts for insulin-like
growth factor 1 x 204
• Increased transcripts for BDNF x 34
1. Thone J, et al. Mult Scler. 2010;16:S310.
2. Hayardeny L, et al. Mult Scler. 2010;16:S160.
3. Bruck W, Wegner C. J Neurol Sci. 2011;306:173-179.
4. Silva C, et al. Mult Scler. 2010;16:S310.
Others
• Mesenchymal stem cell transplants
• Olesoxime
• Teriflunomide
Case Conclusion
The patient decided to continue her
interferon disease-modifying therapy in
order to decrease inflammatory disease
activity and possibly neurodegeneration
Conclusions
• Neuronal protection important in MS
• Measuring it is challenging
– MRI
– Biomarkers (brain, blood, CSF)
• Some therapies possibly have
neuroprotective effects
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