HPA-axis in MS

Cortisol relates to severity and pathology of multiple sclerosis

Jeroen Melief, PhD student

The hypothalamus-pituitary-adrenal (HPA)-axis is activated in most but not all multiple sclerosis (MS) patients and is implicated in clinical progression. In a post-mortem study we investigated the relationship between HPA-axis activity, pathology and molecular mechanisms in progression of MS. In 42 MS patients, HPA-axis activity was determined by measuring cortisol levels in cerebrospinal fluid (CSF) and counting corticotropin-releasing hormone (CRH) expressing neurons in the hypothalamus. Duration of MS and time to EDSS 6 served as indicators of disease progression. Neuropathological characteristics of MS lesions were analyzed and normal appearing white matter (NAWM) was studied for glucocorticoid-related gene expression.

Cortisol levels inversely correlated with disease progression in secondary progressive MS, i.e. with duration of MS (r = 0.412, p = 0.019) and time to EDSS 6 (r = 0.397, p = 0.036), which was most pronounced in females (r = 0.556, p = 0.005 and r = 0.512, p = 0.018, respectively). Moreover, patients with low cortisol levels and fast progression had markedly elevated active lesion loads and reduced percentages of lesions with signs of remyelination.

Compared to NAWM of patients with low cortisol levels, NAWM of patients with high cortisol values showed elevated expression of glucocorticoid-responsive genes with immunosuppressive and neuroprotective effects, such as CD163, and decreased expression of pro-inflammatory genes, most notably interferon-γ.

Apparently, low CSF cortisol levels coincide with fast progression of MS and are associated with strongly elevated rates of demyelination and decreased levels of remyelination. In contrast, high CSF cortisol levels concur with less destructive types of MS pathology and prevent lesion development by promoting immunosuppressive and neuroprotective mechanisms in NAWM.