Cognition and Cerebellar Dysfunction in Multiple Sclerosis are Associated with Decreased Bri2 Expres

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Cognition and Cerebellar Dysfunction in Multiple
Sclerosis are Associated with Decreased Bri2
Expression

• Pamela Good, Niamh OHara, Nara Chhua, Violaine K
  Harris, and Saud A. Sadiq

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Mechanisms of Disease Pathogenesis in MS

• Microarray and proteomic analysis of CNS tissue
  and CSF
• Investigate disease factors associated with
  benign vs aggressive disease course
• Investigate reasons for phenotypic expression of
  disease - spinal, cerebellar, cognition
• Biomarker for cerebellar and cognitive
  dysfunction

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Biomarker discovery by proteomic analysis of MS
CSF

• ProteinChip technology followed by SELDI-TOF
  mass spec proteomic analysis
• 13 control CSF
• 20 primary progressive (PPMS) CSF
• 20 secondary progressive (SPMS) CSF

2.6 kDa
2.6 kDa
2.6 kDa
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2.6 kDa protein decreased in CSF from progressive
MS

• Post-hoc Mann-Whitney test
• CON vs PPMS p0.0136
• CON vs SPMS p0.0057
• PPMS vs SPMS p0.1941

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Identification of Bri-CT peptide in CSF
Bri-CT peptide
EASNCFAIRHFENKFAVETLICS
Bri2 (ITM2b)
Furin
ADAM10
SPPL2a/b
intracellular domain
extracellular domain
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Genetic variants of Bri2 involved in FBD and FDD
familial dementias
Bri2
Bri-CT
BRICHOS
N-
-C
N-
Furin
FBD
ABri

BRICHOS
N-
-C
N-
Furin
FDD
ADan

Duplication TTTAATTTGT
BRICHOS
N-
-C
N-
Furin

• ABri and ADan mutated peptides form amyloid
  deposits in cerebral vasculature and parenchyma.

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Bri2 function

• Apoptosis
• Promotes neurite outgrowth
• Role in nerve terminals
• Regulation of Amyloid precursor protein (APP) and
  cleavage of Amyloid ? (A????and????

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Bri2 expression

• Highly expressed in hippocampus (pyramidal
  neurons) and cerebellar cortex (Purkinje cells)
• Expression increased in pathological cases
  (dystrophic neurites in AD, ischemic lesions,
  Lewy bodies and Lewy neurites, etc.)
• Axonal expression in transfected neurons
• Glial expression

Akiyama et al, Acta neuropathol 10753, 2004
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HYPOTHESIS

• Altered Bri2 (Bri-CT) expression may correlate
  with cerebellar/cognition dysfunction in MS.

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Cerebellar function scale
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Cognition function scale
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Bri-CT CSF levels decreased in MS patients with
cerebellar deficits
SPMSPPMS
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A?(1-42) CSF levels decreased in MS patients with
cerebellar deficits
Cerebellar function
p0.06 (ns)
plt0.05
SPMSPPMS
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Other biomarkers show no correlation with
cerebellar deficits in MS
Cerebellar function
Cognitive function

• Fetuin-A

• RNase-1

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Is Bri2 expression altered in MS brain?

• Examine Bri2 mRNA from MS brain samples by
  quantitative PCR
• 10 non-MS samples (hippocampus and cerebellum)
• 10 MS samples (hippocampus and cerebellum)
• Investigate levels of APP

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Bri2 mRNA levels unchanged in MS hippocampus
APP mRNA
ns
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Bri2 mRNA levels lowered in MS cerebellum
APP mRNA
Bri2 mRNA
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Control gene expression unchanged in MS
RNase1 cerebellum
RNase1 hippocampus
ns
ns
MS
Control
MS
Control
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Conclusions

• Our preliminary data shows that levels of Bri-CT
  peptide are significantly lower in CSF of MS
  patients with cerebellar and cognition
  dysfunction
• CSF A? peptide levels were also lower in patients
  with cerebellar dysfunction, albeit with less
  significance
• Bri2 mRNA expression was significantly decreased
  in cerebellum from MS patients compared to non-MS
• Our findings suggest that decreased cerebellar
  Bri2 expression may play a role in
  cognition/cerebellar dysfunction and CSF levels
  of Bri-CT may serve as a biomarker of these
  functions in MS