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Defining and Evaluating HIV-Related Neurodegenerative Disease and Its Treatment Targets: A Combinatorial Approach to Use of Cerebrospinal Fluid Molecular Biomarkers

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Abstract

There are a number of reasons that the accomplishments of clinical trials related to HIV-related neurodegenerative disease (HRND) and the AIDS dementia complex (ADC) have had such limited impact on clinical practice. These include: rapid evolution and progress in the treatment of systemic HIV infection that has quickly outpaced neurological efforts and has markedly reduced disease incidence; ethical constraints that (rightly) demand neurologically compromised patients receive the best available treatment before experimental therapeutics; complicated backgrounds and comorbidities of patients now most susceptible to HRND; and reluctance of general AIDS clinicians and drug companies to look beyond systemic or pivotal outcomes. However, the field has also been slow to adopt methods that better exploit advances in understanding of the pathogenesis of central nervous system (CNS) infection and brain injury, and that might circumvent some of these constraints. Using a simple model of pathogenesis, we propose an approach to characterizing patients, selecting treatment targets, and evaluating outcomes that emphasize a combination of cerebrospinal fluid (CSF) markers. This model begins by using three markers related to cardinal components of HRND: CNS HIV infection (measurement of CSF HIV RNA), intrathecal immunoactivation (CSF neopterin), and brain injury [CSF light chain neurofilament (NFL)]. Careful analysis of this and other marker combinations promises more rational trial design and more rapid progress in managing CNS HIV infection and HRND using both antiviral and adjuvant treatment approaches.

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Acknowledgements

This study was supported by grants from National Institutes of Health (R01 NS043103, R01 NS37660, R01 MH62701, and MO1-RR00083), from the Medical Faculty of Göteborg University (ALFGBG-2874), and from the Research Foundation of Swedish Physicians against AIDS.

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Authors and Affiliations

  1. Department of Infectious Diseases, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden

    Magnus Gisslen & Lars Hagberg

  2. Department of Neurology, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden

    Lars Rosengren

  3. Department of Neurology, St. Vincent’s Hospital, University of New South Wales, Sydney, Australia

    Bruce J. Brew

  4. Clinic of Infectious Diseases, San Raffaele Hospital, Milan, Italy

    Paola Cinque

  5. Department of Neurology, University of California San Francisco, Neurology Service, Rm. 4M62, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, CA, 94117, USA

    Serena Spudich & Richard W. Price

Authors
  1. Magnus Gisslen
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  2. Lars Hagberg
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  3. Lars Rosengren
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  4. Bruce J. Brew
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  5. Paola Cinque
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  6. Serena Spudich
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  7. Richard W. Price
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Correspondence to Richard W. Price.

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Gisslen, M., Hagberg, L., Rosengren, L. et al. Defining and Evaluating HIV-Related Neurodegenerative Disease and Its Treatment Targets: A Combinatorial Approach to Use of Cerebrospinal Fluid Molecular Biomarkers. Jrnl Neuroimmune Pharm 2, 112–119 (2007). https://doi.org/10.1007/s11481-006-9035-1

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  • DOI: https://doi.org/10.1007/s11481-006-9035-1

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