Grants Awarded

Principal Investigator
Jan-Inge Henter MD, PhD
Karolinska Institutet – Stockholm, Sweden

Date of Award
December 2007

Amount of Award
$50,000
Total amount paid by the Histiocytosis Association of Canada

Layperson Summary
Problem formulation: Langerhans cell histiocytosis (LCH) is a disease of unknown cause and a remarkably variable clinical course. It may present as a discrete or intense rash, or as one or multiple lytic bone lesions that may resolve spontaneously, but it may also develop into a potentially lethal disease involving specific risk organs, defined as the lungs, liver, spleen and the hematopoietic system.

During recent years it has become obvious that the risk of developing late sequelae is one main concern in LCH, and it may affect as many as 40-60% of all survivors. One major concern is the risk of developing progressive degeneration of the brain, often referred to as Central Nervous System-LCH (CNS-LCH). The CNS may be affected already at the diagnosis of LCH, then most commonly involving the hormonal function that may result in diabetes insipidus, growth hormone deficiency and sometimes also more extended hormone deficiencies.

Of particular concern is the development of cerebral dysfunctions, and clinical CNS complications has been reported to affect at least 10% of all LCH patients. Notably, these CNS complications can be both pronounced and severe, and result in severe neuromotor deficiencies, behavioral disturbances, as well as severe cognitive dysfunctions and death. It is also alarming that this neurodegeneration appear to be progressive, and neurological sequelae may appear as late as 20 years after the initial diagnosis. Imaging with Magnetic Resonance Imaging (MRI) is today considered the best way to diagnose neurodegeneration in LCH.

Obviously, there is a desire to reduce the clinical development of CNS-LCH. However, in order to evaluate potential therapies there is a need to be able to monitor the disease course in the CNS, and since the clinical deterioration and the development of radiological findings are slow processes, it is presently difficult to evaluate the effects of various therapeutic attempts. Therefore, it would be beneficial to be able to evaluate present, ongoing CNS disease activity.

Specific Aim: To identify and evaluate biomarkers of present, ongoing CNS-LCH activity.

Work proposed: In a cohort of patients with MRI-verified CNS-LCH, we perform lumbar puncture (a clinical routine procedure) in order to obtain cerebrospinal fluid (CSF) samples. We analyze these CSF samples to evaluate the potential value of CSF biomarkers used to evaluate other neurodegenerative disorders. These markers are called glial fibrillary acid protein (GFAp), neurofilament protein, light chain (NF-L), and total tau protein. We then aim to correlate these CSF biomarker levels with clinical and neuroradiological findings.

Preliminary data: We have evaluated NF-L, tau and GFAp levels in a set of CNS-LCH patients and noticed that all these children had elevated levels of at least one of these markers. Notably, the patient with the most severe clinical and neuroradiological CNS-LCH also displayed the highest levels of NF-L and GFAp. Similarly, three patients with non-active disease at the time of evaluation had low tau levels and normal or only slightly elevated NF-L. Moreover, the tau levels also correlated with the systemic disease activity.