Ketones and brain function: possible link to polyunsaturated fatty acids and availability of a new brain PET tracer,...

Area of Science:

• Neuroscience
• Biochemistry
• Metabolic Disorders

Background:

• Ketogenic diet (KD) is used for seizure control, but its precise mechanisms, particularly the role of polyunsaturated fatty acids (PUFA) and ketone body uptake, are not fully understood.
• Changes in brain PUFA metabolism (arachidonic acid [ARA] and docosahexaenoic acid [DHA]) in children and rats on KD suggest potential alternative pathways for seizure management.
• The necessity of persistent ketonemia or elevated brain ketone uptake for KD effectiveness in intractable epilepsy remains an open question.

Purpose of the Study:

• To investigate the direct brain uptake of ketones in humans and animals using a novel PET tracer.
• To explore whether elevated brain ketone uptake is essential for the clinical efficacy of the ketogenic diet in epilepsy.
• To assess ketone and glucose uptake in the brain during KD treatment and in aging-related neurological disorders.

Main Methods:

• Synthesis of carbon-11 labeled acetoacetate ((11)C-AcAc) for Positron Emission Tomography (PET) studies.
• Administration of (11)C-AcAc to rats on a KD for 10 days to measure brain ketone uptake.
• Paired PET scans in rats and humans using (11)C-AcAc followed by (18)fluorodeoxyglucose to compare ketone and glucose brain uptake.

Main Results:

• Brain uptake of (11)C-AcAc in rats on KD increased 7- to 8-fold compared to controls, similar to the effect of 48-hour fasting.
• This suggests that KD significantly enhances brain ketone utilization.

Conclusions:

• The study introduces a novel PET tracer ((11)C-AcAc) for direct measurement of brain ketone uptake.
• Findings indicate a substantial increase in brain ketone uptake during KD, prompting further investigation into its role in seizure control and neurological disorders.
• This research opens new avenues for understanding KD mechanisms and developing targeted therapies.