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Ketogentic diet-induced changes in the cerebrospinal fluid: biomarkers and mechanisms

Award Number: R15NS066392
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2010
PERIOD OF PERFORMANCE END DATE: 06/30/2018

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Ketogentic diet-induced changes in the cerebrospinal fluid: biomarkers and mechanisms - ¿ DESCRIPTION (provided by applicant): 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2015	TRINITY COLLEGE	300 SUMMIT ST	HARTFORD	CT	06106	CAPITOL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	9/16/2018	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $351,991 )
2015	2015	TRINITY COLLEGE	SUMMIT STREET	HARTFORD	CT	06106	CAPITOL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/29/2015	COMPETING CONTINUATION	$351,991
														Subtotal = $351,991

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2010	TRINITY COLLEGE	SUMMIT STREET	HARTFORD	CT	06106	CAPITOL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/17/2013	NEW	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $230,656 )
2010	2010	TRINITY COLLEGE	SUMMIT STREET	HARTFORD	CT	06106	CAPITOL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/23/2010	NEW	$230,656
														Subtotal = $230,656

Grand Total All Awards = $582,647

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Ketogentic diet-induced changes in the cerebrospinal fluid: biomarkers and mechanisms

Award Number: R15NS066392

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2010

PERIOD OF PERFORMANCE END DATE: 06/30/2018

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