Wednesday, October 26, 2016

A biomarker for epileptogenesis?

After a child has an unprovoked seizure, the burning question in everyone's mind is: Does this mean this child is going to have more seizures?  Unfortunately, there is currently no reliable way to answer this question. Dr. Louis Manganas, an Assistant Professor of Pediatric Neurology at Stony Brook University, aims to improve this situation by identifying a biomarker of epileptogenesis.
In many and perhaps all cases, epileptic seizures are caused by the presence of aberrant re-entrant circuits in neural networks. The fact has been known for several decades that epileptic seizures lead to accelerated proliferation of neural progenitor cells (NPCs), which are the mitotically active neuroblasts that give rise to new neurons. Following a single seizure, the newly generated cells may integrate into existing neural circuits, disrupt them, and induce subsequent seizures. This may represent one of the mechanisms underlying epileptogenesis.

Thus, the accelerated NPC proliferation following an unprovoked seizure may have the harmful effect of inducing subsequent epilepsy. It follows that the presence and concentration of NPCs following an unprovoked seizure could serve as a biomarker of epileptogenesis. But, how to detect the NPCs?

Nine years ago, while he was a postdoctoral fellow at Cold Spring Harbor Laboratories, Dr. Manganas and his co-workers discovered that NPCs can be detected by magnetic resonance spectroscopy (MRS). Probably because of their uniquely high concentration of saturated fatty acids and monounsaturated fatty acids, NPCs can be detected as a 1.28 ppm peak on MRS. The identity and origin of this peak are unknown. However, the amplitude of this peak is proportional to the concentration of NPCs. He published his findings in the journal Science.

Dr. Manganas has hypothesized that the aberrant proliferation of NPCs following a single seizure may act as a nidus for epileptogenesis and that the amplitude of this peak on MRS may correlate with the risk of subsequent epilepsy. Following his discovery of the MRS peak associated with NPCs, Dr. Manganas has completed a residency in child neurology and a fellowship in epilepsy. Now, nine years later, Dr. Manganas is conducting the study that tests his hypothesis. As the 2016 recipient of the Pediatric Epilepsy Research Foundation (PERF) grant, Dr. Manganas is examining whether the NPC peak is greater in patients who have had a single seizure than in controls and whether the amplitude of the NPC peak following a single seizure correlates with the risk of developing subsequent epilepsy.

"I am grateful to PERF for providing these funds. The PERF grant is currently my sole source of funding for this research, which I have been planning since 2007."

Daniel J. Bonthius, MD
From CNS Connections Fall/Annual Meeting 2016

Manganas LN, Zhang X, Li Y, Hazel RD, Smith SD, Wagshul ME, Henn F, Benveniste
H, Djuric PM, Enikolopov G, Maletic-Savatic M. Magnetic resonance spectroscopy
identifies neural progenitor cells in the live human brain. Science. 2007 Nov


The identification of neural stem and progenitor cells (NPCs) by in vivo brain imaging could have important implications for diagnostic, prognostic, and therapeutic purposes. We describe a metabolic biomarker for the detection and quantification of NPCs in the human brain in vivo. We used proton nuclear magnetic resonance spectroscopy to identify and characterize a biomarker in which NPCs are enriched and demonstrated its use as a reference for monitoring neurogenesis. To detect low concentrations of NPCs in vivo, we developed a signal processing method that enabled the use of magnetic resonance spectroscopy for the analysis of the NPC biomarker in both the rodent brain and the hippocampus of live humans. Our findings thus open the possibility of investigating the role of NPCs and neurogenesis in a wide variety of human brain disorders.

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