James D. Bowen, MD
Medical Director, Multiple Sclerosis Center
Swedish Neuroscience Institute
Seattle, Washington

• 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

• 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

RRMS
SPMS
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.

• 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

• 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

• 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 .

• N = 224
– 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
Time EDSS 4−6
Time EDSS 4−7
Time EDSS 6−7
23.1
5.7
12.1
3.3
7.1
5.4
12.0
4.0
Without Relapse
(yrs)
With Relapse
(yrs)
SPMS onset
PPMS onset
Time EDSS 4−6
Time EDSS 4−7
Time EDSS 6−7
Time EDSS 4−6
Time EDSS 4−7
Time EDSS 6−7
4.0
7.8
2.6
5.5
12.4
4.0
Abbreviations: PPMS, primary-progressive MS; SPMS, secondary-progressive MS.
Confavreux C. N Engl J Med . 2000;343:1430-1438.
4.4
10.0 ( P = .04)
4.3 ( P = .002)
5.4
11.3
3.6

Patients with CIS have changes in :
• Atrophy (corpus callosum) 1
• Magnetization transfer 2
• NAA on MR spectroscopy 1
– 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
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.

MS max
Logical Reasoning
Orbitofrontal Cortex fMRI MS >Control (P <.05)
M12 min max
M12 min
NeuroCog
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)
Control
Mean perceived effort: P <.01
MS = 5.6, Control = 3.3
C03 Slide courtesy of Dr. James D. Bowen.

Incomplete Control with Immune
Therapies
Attacks
MRI
EDSS
50
40
30
20
10
0
100
90
80
70
60
A
A
28
83
13
B
B
29
33
10.54
C
C
32
51
27
D
D
32
78
10
E
68
92
54
F
65
7.9
E F
EDSS
Attacks
MRI
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.

• ~80% stable at 3 years 1
• 63% stable at 6 years 2
• 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.

Atrophy/symptoms
Primary process, loss of myelin
Sufficient antigen release to activate immune system
MRI
Slide courtesy of Dr. James D. Bowen.

Ultimate goal
• Preserve brain function
• Lessen disability

• 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)

• 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.

• Magnetization transfer
• MR spectroscopy
• Diffusion tensor imaging (DTI)
• Functional MRI (fMRI)

Magnetization Transfer
Free water
+
+
Bound water
Narrow resonant frequency Saturate at broad nonresonant frequency
Broad resonant frequency
Measure free water at that frequency
+
Free water
+
Bagnato F, Frank JA. Curr Neurol Neurosci Rep . 2003;3:238-245.
Slide courtesy of Dr. James D .
Bowen.

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.

+
+
Bagnato F, Frank JA. Curr Neurol Neurosci Rep . 2003;3:238-245.
Slide courtesy of Dr. James D. Bowen.
+

Slide courtesy of Dr. James D. Bowen.

20/80 OD
20/50 OS
Abbreviations: OD, oculus dexter; OS, oculus sinister.
Slide courtesy of Dr. James D. Bowen.

• Study of 7 MS patients, 4 controls 1
– 7T MRI: MS patients have lower T2* values
(higher iron content) in dentate, red nucleus, substantia nigra and globus pallidus
• 1.5T MRI followed longitudinally 2
– 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.

2A
• Proinflammatory and neurodegenerative properties
• PET scan using adenosine A
2A
-receptor specific
[ 11 C]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.

• 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.

• Produced by neurons or activated astrocytes 1
• Plays a role in axonal growth, modulation of neuronal activity, activity-dependent synaptic and dendritic plasticity 1,2
• Correlates with MRI T2 burden 3
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.

• Promotes
– Neurotransmitter synthesis 1
– Neurite outgrowth 1
• Protective role in myelin oligodendrocyte glycoprotein (MOG)-induced EAE 2
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.

• 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.

• Stabilizes microtubules 1
• 158 patients 2
– 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.

• Plays role in differentiating precursors into neurons 1
• CSF specimens from 56 patients with MS,
19 patients with noninflammatory neurologic disorders 2
– 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.

• Preservation of brain and function demonstrated
– Due to neuroprotection or immune effects of the treatment?
• Effects on regeneration/remyelination less certain

• Clinical preservation
– Expanded Disability Status Scale (EDSS) 1
 Significant delay in time to sustained EDSS progression
• MRI 1,2
 Decreased T1 black holes
 Slowing of atrophy (brain parenchymal fraction)
• Increases brain-derived neurotrophic factor production 3
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.

• Clinical preservation
– Significantly more patients had improved
Expanded Disability Status Scale at 2 years compared with placebo patients 1
• MRI
– Black hole formation reduced compared with placebo 2
1. Johnson KP, et al. Neurology.
1995;45:1268-1276.
2. Filippi M. Neurology.
2001;57:731-733.

• Glatiramer acetate (GA) increases brain-derived neurotrophic factor 1
• GA increases insulin-like growth factor-1 production by
Th2 lymphocytes in mice 2
• 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-2 3
• GA increases neuroprogenitor proliferation, migration, and differentiation 4
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.

70
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

• Clinical preservation 1
– Significantly reduced progression of sustained disability
• MRI 1
– Decreased T1 black hole formation
– Decreased atrophy in year 2
1. Miller DH, et al. Neurology.
2007;68:1390-1401.

• Decreases oxidative stress
• Increases nuclear factor-E2-related factor 2
Horssen S, et al. Neurology.
2011;76:A136.

• Increases levels of brain-derived neurotrophic factor (BDNF) 1-3
• Increased transcripts for insulin-like growth factor 1 x 20 4
• Increased transcripts for BDNF x 3 4
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.

• Mesenchymal stem cell transplants
• Olesoxime
• Teriflunomide

The patient decided to continue her interferon disease-modifying therapy in order to decrease inflammatory disease activity and possibly neurodegeneration

• Neuronal protection important in MS
• Measuring it is challenging
– MRI
– Biomarkers (brain, blood, CSF)
• Some therapies possibly have neuroprotective effects

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