Clinical evidence demonstrates dietary therapy as highly effective and even a cure for epilepsy. Specifically, children treated with a high-fat, lo-carbohydrate ketogenic diet (KD) can achieve and maintain seizure freedom even after weaning off the KD and drugs. Its potential likely extends well beyond epilepsy, with emerging research identifying benefits in other acute and chronic conditions. Yet despite continuous use since the 1920s it is still not possible to predict whether KD therapy will be successful, and its mechanism remains unknown. One of the most striking aspects of KD treatment is its proven efficacy even in medically-refractory seizures - indicating that this diet mobilizes anti-seizure mechanisms distinct from available drug treatments. To gain new insight into the mysteries of KD therapy we will leverage an exclusive opportunity to analyze a singular clinical repository. A team in Stockholm, Sweden, led by Maria Dahlin, MD, PhD, obtained cerebrospinal fluid (CSF) from each of 25 children with refractory epilepsy at two time points: 1) before and 2) at three months of maintenance on KD therapy. Clinical data and outcomes were tracked and an initial neurotransmitter analysis was performed. Due to their extremely unique and precious nature (repeated lumbar punctures in each child) these samples have been frozen and awaiting the right opportunity: novel and plausible hypotheses regarding KD efficacy, and a reliable and comprehensive analysis. Now, after several years of preparation, we propose to test our ongoing hypotheses on purinergic mechanisms of KDs and, simultaneously, perform a complete metabolic profiling of CSF obtained from humans and rats fed control vs. KD. CSF will be analyzed for more than 200 molecules by Metabolon (Durham, NC) using their most sophisticated platform. Our team is working with Metabolon regarding initial metabolomic analysis and pathway mapping of the human samples. We will continue with a detailed metabolomic and statistical analysis, collect rat CSF and blood, perform a parallel metabolic and subsequent statistical analysis on the rat samples, and proceed to detailed comparison, interpretation, hypothesis testing, and target validation. We hypothesize that these studies will 1) determine how a KD changes the metabolic signature of various pathways as well as individual metabolites; 2) determine which changes correlate with KD efficacy in children; 3) determine which baseline characteristics predict efficacy in children; 4) enable comparison between diet-mediated changes in human and rodent CSF fluid. Predicting efficacy could help identify and motivate patients who could achieve the greatest benefits. Furthermore this work will yield targets to pursue regarding key metabolic changes mobilized by a KD. Student training is included in all conceptual and proposed experimental aspects; students have been involved in the planning and initial analysis. This work represents a significant opportunity to benefit numerous disorders by revealing key mechanisms, identifying biomarkers, and validating animal models.
A high-fat low-carbohydrate `ketogenic diet' can stop seizures, and emerging evidence suggests it may treat other neurological conditions. Unfortunately it is not possible to predict if diet therapy will work and still unknown why it is effective. A comprehensive metabolic analysis of a rare repository of cerebrospinal fluid collected from children with refractory seizures prior to and at three months of ketogenic diet therapy, alongside similar analysis in animal models, could yield new insight into the success of diet-based therapy for multiple neurological disorders.
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| Boison, Detlev; Meier, Jochen C; Masino, Susan A (2017) Editorial: Metabolic Control of Brain Homeostasis. Front Mol Neurosci 10:184 |
| Ruskin, David N; Fortin, Jessica A; Bisnauth, Subrina N et al. (2017) Ketogenic diets improve behaviors associated with autism spectrum disorder in a sex-specific manner in the EL mouse. Physiol Behav 168:138-145 |
| Ruskin, David N; Murphy, Michelle I; Slade, Sierra L et al. (2017) Ketogenic diet improves behaviors in a maternal immune activation model of autism spectrum disorder. PLoS One 12:e0171643 |
| Kawamura, Masahito Jr; Ruskin, David N; Masino, Susan A (2016) Metabolic Therapy for Temporal Lobe Epilepsy in a Dish: Investigating Mechanisms of Ketogenic Diet using Electrophysiological Recordings in Hippocampal Slices. Front Mol Neurosci 9:112 |
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| Blaise, J Harry; Ruskin, David N; Koranda, Jessica L et al. (2015) Effects of a ketogenic diet on hippocampal plasticity in freely moving juvenile rats. Physiol Rep 3: |
| Kawamura Jr, Masahito; Ruskin, David N; Geiger, Jonathan D et al. (2014) Ketogenic diet sensitizes glucose control of hippocampal excitability. J Lipid Res 55:2254-60 |
| Masino, Susan A; Kawamura Jr, Masahito; Ruskin, David N (2014) Adenosine receptors and epilepsy: current evidence and future potential. Int Rev Neurobiol 119:233-55 |
| Ruskin, David N; Svedova, Julia; Cote, Jessica L et al. (2013) Ketogenic diet improves core symptoms of autism in BTBR mice. PLoS One 8:e65021 |
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