Neurofilament light chain: A possible fluid biomarker in the intrahippocampal kainic acid mouse model for chronic epilepsy?

Abstract

ObjectiveIn the management of epilepsy, there is an ongoing quest to discover new biomarkers to improve the diagnostic process, the monitoring of disease progression, and the evaluation of treatment responsiveness. In this regard, biochemical traceability in biofluids is notably absent in contrast to other diseases. In the present preclinical study, we investigated the potential of neurofilament light chain (NfL) as a possible diagnostic and response fluid biomarker for epilepsy.MethodsWe gained insights into NfL levels during the various phases of the intrahippocampal kainic acid mouse model of temporal lobe epilepsy—namely, the status epilepticus (SE) and the chronic phase with spontaneous seizures. To this end, NfL levels were determined directly in the cerebral interstitial fluid (ISF) with cerebral open flow microperfusion as sampling technique, as well as in cerebrospinal fluid (CSF) and plasma. Lastly, we assessed whether NfL levels diminished upon curtailing SE with diazepam and ketamine.ResultsNfL levels are higher during SE in both cerebral ISF and plasma in kainic acid‐treated mice compared to sham‐injected mice. Additionally, ISF and plasma NfL levels are lower in mice treated with diazepam and ketamine to stop SE compared with the vehicle‐treated mice. In the chronic phase with spontaneous seizures, higher NfL levels could only be detected in ISF and CSF samples, and not in plasma. No correlations could be found between NfL levels and seizure burden, nor with immunohistological markers for neurodegeneration/inflammation.SignificanceOur findings demonstrate the translational potential of NfL as a blood‐based fluid biomarker for SE. This is less evident for chronic epilepsy, as in this case higher NfL levels could only be detected in ISF and CSF, and not in plasma, acknowledging the invasive nature of CSF sampling in chronic epilepsy follow‐up.

Fluid Biomarkers of Neuro-Glial Injury in Human Status Epilepticus: A Systematic Review

“…An important advantage of NfL is its reliability in measurement in serum/blood. Additionally, two studies on humans [63,65] and a preclinical study [60] have demonstrated a close and optimal correlation between the peripheral and central compartments.…”

“…However, it is important to emphasize that the data obtained in preclinical animal models are mainly derived from the observation of alterations in different biomarkers on tissue and not on biological fluids, with some exceptions [30,60,78]. In this sense, on the one hand, it is important to be cautious in formulating parallels between humans and data in the animal.…”

“…In a recent study using the intrahippocampal kainic acid mouse model of SE, Custers et al [60] demonstrated higher levels of NfL in both cerebral interstitial fluid and plasma during SE compared to sham-injected mice. Additionally, mice treated with diazepam and ketamine to stop SE showed lower NfL levels than vehicle-treated mice.…”