Novel CSF Biomarkers in the HAART era

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Novel CSF Biomarkers in the HAART era

• Magnus Gisslén

Department of Infectious Diseases Sahlgrenska
University Hospital Göteborg, Sweden
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Rational

• There is a need of objective, laboratory-based
  markers
• to predict development of neurocognitive
  disorders in HIV-infected patients
• to establish the diagnosis of AIDS dementia
• to appraise disease activity
• to assess treatment responses

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CSF markers

• Immunological markers
• neopterin, MCP-1, b2-microglobulin, IgG-index
  etc.
• Virological markers
• HIV-RNA, HIV-DNA, replicative capacity,
  sequencing, heteroduplex etc.
• Neruomarkers
• tau, p-tau, b-amyloid, gangliosides (GM1, GD3
  etc), sulfatide, GFAp, S-100, NSE, NFp etc.
• Other markers
• albumine ratio etc.

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Neurofilament protein (NFp)

• A major structural element of neurons
• Mainly found in large myelinated neurons
• A triplet protein, the light subunit (NFL) is the
  essential component of the neurofilament core
• Main function to maintain the axonal calibre and
  thereby having a crucial role for morphological
  integrity and conduction velocity of nerve
  impulses

Hoffman PN et al, PNAS, 1987. 84(10)3472-6
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NFL ELISA
Detection limit 125 ng/L Normal CSF NFLlt250
ng/L
van Geel WJ et al, J Immunol Methods, 2005. 296
179-85
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Neurofilament protein

• The light subunit of neurofilament protein (NFL)
  is a sensitive marker of axonal disruption.
• Increased CSF NFL concentrations are principally
  thought to reflect injury to myelinated axons.
• CSF NFL elevated in a number of neurodegenerative
  disorders

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CSF-NFLinfarct volume
Rosengren L, unpublished
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Cardiac arrest CSF-NFL and GFAp
Rosén H et al, J Neurol Sci 2004. 221 19-24
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Cardiac arrest CSF-NFL
Rosén H et al, J Neurol Sci 2004. 221 19-24
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Amateur Boxing
Zetterberg H et al, Arch Neurol 2006. 631277-80
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ALS
CSF-NFL levels according to clinical subtype
reference level
Rosengren L et al, J Neurochem. 1996
Nov67(5)2013-8
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CSF-NFL and multiple sclerosis
Norgren, N. et al. Neurology 2004631586-1590
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Studahl M et al, J Neurol 2000. 247 636-42
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(No Transcript)
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HIV

• Neurofilament protein
• Cross-sectional
• Pre-ADC
• HAART
• Treatment interruption

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Cross sectional

• n211
• no ongoing antiretroviral treatment
• ADC n56
• CNS OI n44
• Neuro-asymptomatic n95
• PHI n16

Abdulle S et al, J Neurol. 2007 Apr 10 Epub
ahead of print
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CSF NFL in HIV




Abdulle S et al, J Neurol. 2007 Apr 10 Epub
ahead of print
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CSF NFL in ADC

Abdulle S et al, J Neurol. 2007 Apr 10 Epub
ahead of print
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Active vs inactive ADC
CSF NFL
n69
n7
Brew BJ et al, 2007. unpublished
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CSF NFL in CNS OIs
Abdulle S et al, J Neurol. 2007 Apr 10 Epub
ahead of print
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CSF NFL in neuro-asymptomaticHIV-infected
subjects
Abdulle S et al, J Neurol. 2007 Apr 10 Epub
ahead of print
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Could ADC be predicted by elevated CSF NFL
concentrations in asymptomatic subjects?

• Longitudinal cohort study
• Retrospective
• Cases
• ADC and LP performed in asymptomatic stage within
  2 years prior to presentation
• n9
• Controls
• HIV-infected with no neurological symptoms
• CD4 cell matched
• n27

Gisslen M et al, J Infect Dis 2007. in press
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Could ADC be predicted by elevated CSF NFL
concentrations in asymptomatic subjects?

• Longitudinal cohort study
• Retrospective
• Cases
• CSF NFL 954 (429-1550) ng/L
• 7/9 gt250 ng/L
• Controls
• CSF NFL 146 (lt125-422) ng/L
• 9/27 gt250 ng/L

Gisslen M et al, J Infect Dis 2007. in press
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Gisslen M et al, J Infect Dis 2007. in press
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Gisslen M et al, J Infect Dis 2007. in press
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Effect of HAART on CSF NFL

• 21 patients with increased CSF NFL
• 9/21 ADC

Mellgren Å et al, 2007. submitted
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Effect of HAART on CSF NFL
Abdulle S et al, J Neurol. 2007 Apr 10 Epub
ahead of print
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Effect of HAART on CSF NFL
Price RW et al, unpublished
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CSF NFLduring treatment interruption
CSF NFL increased in 3/8 patients
Gisslen M et al, AIDS Res Therapy 2005,26
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Summary

• CSF NFL
• markedly increased in ADC and CNS-OI
• correlates with severity of ADC
• negative in inactive ADC
• decrease after treatment initiation
• increase occasionally after treatment
  interruption
• increased levels before ADC presentation

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Conclusions

• NFL is a good CSF marker of active HIV-related
  neurodegeneration
• Further studies needed to define its utility in
  clinical practice and clinical trial settings

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Acknowledgement
CSF Consortium RW Price, San Francisco BJ Brew,
Sydney P Cinque, Milano L Hagberg, Göteborg L
Rosengren, Göteborg K Blennow, Göteborg Å
Mellgren, Göteborg S Abdulle, Göteborg H
Zetterberg, Göteborg S Spudich, San Francisco SG
Deeks, San Francisco L Pemberton, Sydney

• Sponsors
• NIH (NINDS NIMH)
• NHMRC (Australia)
• Scandinavian Society of Antimicrobial
  Chemotherapy
• The Research Foundation of Swedish Physician
  Against AIDS
• The Sahlgrenska Academy of Göteborg University
• Instituto Superiore di Sanità, AIDS Program, Italy