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HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter

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Abstract

The hypothalamus–pituitary–adrenal (HPA) axis is activated in most, but not all multiple sclerosis (MS) patients and is implicated in disease progression and comorbid mood disorders. In this post-mortem study, we investigated how HPA axis activity in MS is related to disease severity, neurodegeneration, depression, lesion pathology and gene expression in normal-appearing white matter (NAWM). In 42 MS patients, HPA axis activity was determined by measuring cortisol in cerebrospinal fluid (CSF) and counting hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons. Degree of neurodegeneration was based on levels of glutamate, tau and neurofilament in CSF. Duration of MS and time to EDSS 6 served as indicators of disease severity. Glutamate levels correlated with numbers of CRH-expressing neurons, most prominently in primary progressive MS patients, suggesting that neurodegeneration is a strong determinant of HPA axis activity. High cortisol levels were associated with slower disease progression, especially in females with secondary progressive MS. Patients with low cortisol levels had greater numbers of active lesions and tended towards having less remyelinated plaques than patients with high cortisol levels. Interestingly, NAWM of patients with high cortisol levels displayed elevated expression of glucocorticoid-responsive genes, such as CD163, and decreased expression of pro-inflammatory genes, such as tumor necrosis factor-α. Thus, HPA axis hyperactivity in MS coincides with low inflammation and/or high neurodegeneration, and may impact on lesion pathology and molecular mechanisms in NAWM and thereby be of great importance for suppression of disease activity.

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Acknowledgments

This study was financed by Dutch MS Research foundation Grant MS 03-525 and MS 03-525ext. We thank the NBB team for their excellent services (http://www.brainbank.nl).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Neuroimmunology, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA, Amsterdam, The Netherlands

    Jeroen Melief, Corbert G. van Eden & Inge Huitinga

  2. Department of Psychiatry, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    Stella J. de Wit

  3. Department of Clinical Chemistry, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    Charlotte Teunissen

  4. Department of Experimental Immunology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Jörg Hamann

  5. Department of Neurology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    Bernard M. Uitdehaag

  6. Department of Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA, Amsterdam, The Netherlands

    Dick Swaab

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  1. Jeroen Melief
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Correspondence to Jeroen Melief or Inge Huitinga.

Electronic supplementary material

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401_2013_1140_MOESM1_ESM.tif

Supplementary Fig. 1 Immunostaining for CRH in the periventricular nucleus (PVN) of the hypothalamus in a subject with only low (left panel) and high (right panel) numbers of positive neurons. Sections are taken from identical levels in the PVN (TIFF 8775 kb)

401_2013_1140_MOESM2_ESM.tif

Supplementary Fig. 2 Non-regulated genes in NAWM of MS patients. Gene expression was determined by qPCR analysis (TIFF 1215 kb)

401_2013_1140_MOESM3_ESM.xlsx

Supplementary Table 1 Characteristics of patients included for study of gene expression in normal-appearing white matter. RIN = RNA integrity number; IQR = interquartile range (XLSX 45 kb)

Supplementary Table 2 Sequences of primers used for qPCR (XLSX 45 kb)

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Melief, J., de Wit, S.J., van Eden, C.G. et al. HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter. Acta Neuropathol 126, 237–249 (2013). https://doi.org/10.1007/s00401-013-1140-7

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  • DOI: https://doi.org/10.1007/s00401-013-1140-7

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