Food for Thought: The Ketogenic Diet and Neurological Diseases

Prècis

Agenda

Participants

Travel Information

Periodically the James S. McDonnell Foundation (JSMF) organizes small workshops on important problems where existing and new information could benefit from a multi-perspective discussion. The organizing topic for the November 2017 JSMF workshop is the therapeutic uses of the ketogenic diet (KD) and other metabolism-based interventions in the context of neurological diseases. JSMF is convening a small group of experts in intermediary metabolism and in metabolic approaches to the management of complex diseases to review what is known and what is not yet known about the possible mechanisms of action by which the KD exerts changes in neurological function.

Background: Introduced in 1920, the ketogenic diet (KD) is still considered a useful treatment option for controlling seizures in children with intractable epilepsy. While numerous clinical studies have documented the anticonvulsant effect of the KD, the mechanisms of its actions remain incompletely understood. Still, the tight coupling of metabolism and function and the intricate compartmentation of metabolism in the different cell populations comprising brain tissue continues to fuel the idea that dietary-based interventions could have ameliorative benefits across a wide range of neurological disorders including neurodegenerative diseases, neuropsychiatric illnesses, metabolic disorders (e.g. insulin induced hypoglycemia in type 1 diabetes), and brain tumors. As a result, there is great clinical interest in using or considering the use the KD as a treatment option for a wide variety of pediatric and adult neurological patient populations. Many patients, including brain tumor patients, are choosing to put themselves on the KD or KD-like diets because of information provided by media outlets. The uneven scientific rigor of these clinical “experiments” makes interpretation of the results problematic.

Unfortunately, without a clear mechanistic understanding of how the KD alters cerebral metabolism and function it is difficult to determine when, how or why the KD is likely to be an effective (or not) therapeutic approach. A detailed understanding of what components of the KD account for its physiological effects under what conditions is essential for considering how the KD, a diet that can be unpalatable for patients and risks high rates of non-compliance in adult populations, could be modified without jeopardizing its effectiveness.

To date, a complete understanding of the impact of the KD and other metabolic interventions on human brain metabolism and function has been stymied by:

• An attempt to study mechanism in in vitro cell models that do not recapitulate the in vivo context including the highly interdependent metabolism of neurons and glial cells.
• Studies with model organisms lacking human context and often designed to test a priori assumptions rather than determine the physiologic effects of an altered diet.
• Experimental data that results in claims about the differential use of ketones as oxidative substrates for isolated cell populations non-conforming with what characterizes metabolism in the heterogeneous, interdependent cellular environment of the intact human brain.
• Failures to account for the full impact of KD and metabolic alterations on an organism’s physiology and metabolism and the influences exerted on brain physiology and metabolism.
• Inconsistent terminology in the literature as to what it is that contributes to the therapeutic effects of ketogenic diets. In the literature (sometimes in the same paper) the beneficial effects of the KD are attributed to ketogenesis per se, calorie restriction, energy restriction/imbalance, or other physiological changes (e.g. changes in fatty acid metabolism). Clinical progress requires that researchers and clinicians agree to strict physiological definitions used consistently. The understanding of in vivo mechanisms will help guide the determination of the critical physiological parameters that should be measured.

At one time cell systems and the post-mortem analysis with animal-model experiments were the primary options available for probing the mechanisms by which the KD might affect neural metabolism. The development of modern PET, MRS/MRI, optical imaging, and other emerging “neuro-technologies” together with “omics” and data analytics creates the ability to pursue key mechanistic questions in physiologically-intact pre-clinical models and, most importantly, in humans. However, even with the capabilities offered by new technologies, the limited resources in both research funding and patient availability/willingness mandates that clinical experiments be reasonably constrained by the development of clear testable hypotheses.

The motivation of this workshop is not to debate the clinical effectiveness of the KD. Rather, the workshop discussions will focus on the physiological and metabolic consequences of the KD – concentrating as much as possible on data acquired from human subjects (or where data could be acquired from human subjects) – with the aim of building a mechanistic understanding of the impact of KD on brain metabolism and function in health and disease and thus how, where and when dietary approaches like KD can be used in an informed way to advance the clinical care of patients with neurological diseases.

By bringing experts on the use of the KD in epilepsy together with experts on brain metabolism, neurological diseases, neuroprotection, neuro-inflammation, and systems neuroscience, JSMF believes the workshop discussions will advance the potential of using meso-scale metabolic interventions for complex brain disorders. The workshop will also include input from experts in systemic alterations in metabolism known to have neurological effects (e.g. diabetes) as their experiences managing patients with altered physiological metabolisms are highly relevant.

Participation in the workshop is limited. JSMF expects all participants to be actively involved. The workshop is organized into sessions comprised of a few comprehensive talks for “stage-setting” and generous time for discussions that continue through the social activities.