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PHARMACOKINETICS AND DYNAMICS OF A KETOGENIC INTERVENTION IN ALZHEIMER'S DISEASE AND FRONTOTEMPORAL DEMENTIA

      Background

      Brain glucose hypometabolism is a prominent and early feature across neurodegenerative disorders, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Elevating brain ketones to bypass this metabolic failure is an emerging therapeutic strategy, with promising results in AD. The Medium Chain Triglyceride Intervention in AD and FTD trials (MINT-AD and MINT-FTD) are ongoing, randomized, placebo-controlled Phase 1b trials investigating the pharmacokinetics and dynamics of a ketogenic supplement in Alzheimer’s disease (AD), and exploring pilot outcome measures to support larger ketogenic trials in these disorders.

      Methods

      Patients with a clinical diagnosis consistent with mild-moderate AD (MMSE 16-26) are randomized at 1:4 to placebo or a twice daily medium chain triglyceride drink (MCT – 60% C-8, 40% C-10). A total of 5 dose groups will be recruited, with doses ranging from 5 grams twice daily up to 25 grams twice daily, for a total of 18 days (including 8-day drug titration). Primary outcome measures are safety, tolerability and pharmacodynamic effects of MCT supplementation on plasma ketones, and the pharmacokinetics of the MCT supplement. Exploratory outcome measures include cognitive function, N-acetyl aspartate and glutamine/glutamate MR spectroscopy, functional resting brain connectivity, brain blood flow (arterial spin labeling), ambulatory EEG, and circadian rhythms (actigraphy). MINT-FTD is a smaller study of 25 grams twice daily of MCT in 6 patients with the FTD subtype Primary Progressive Aphasia (PPA). Outcome measures are identical to MINT-AD, with a focus on language function.

      Results

      Preliminary data indicate expected high tolerability of 10-20 grams of MCT daily in AD patients, with plasma ketone elevations at 3-4 hours after supplement ingestion. Interim analyses from MINT-AD and MINT-FTD will include safety and tolerability, ketone pharmacokinetic data, and exploratory imaging and cognitive measures in both AD and FTD patient populations.

      Conclusions

      Ketogenic MCT supplementation is an emerging therapeutic intervention in dementia syndromes characterized by abnormal brain glucose metabolism. Detailed pharmacokinetic analysis in both AD and FTD patient populations is critical for proper dose selection in larger clinical trials in these cohorts. Novel biomarker outcome measures unique to a ketogenic intervention may further allow the use of efficient, adaptive trial design in larger future studies.