Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults 55 Years Old or Older

This is an interventional basic science trial for Metabolic Syndrome focused on measuring Ketogenic, Brain Metabolism, BETA-HYDROXYBUTYRATE, Dietary Supplement, Alzheimer's Disease Read More

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Ability to provide informed consent and willingness to sign a written informed consent document
2. Male or female, age >=55 years old
3. Cognitively intact status ascertained during screening (defined as absence of significant memory or cognitive changes in the last 2 years by subjective report, Clinical Dementia Rating (CDR) of 0, and Montreal Cognitive Assessment (MoCA) >= 26)
4. Ability to take oral medications
5. Willingness to adhere to all study procedures including having MRI/MRS.

6. Presence of Metabolic Syndrome (MetS). Specifically, they should meet three of the five following MetS diagnostic criteria to be eligible:

   • Receive drug treatment for elevated triglycerides (TGs) or have serum TGs >=150mg/dL (1.7 mmol/L)
   • Receive drug treatment for low HDL-cholesterol or have serum HDL-cholesterol<40 mg/dL (1.0 mmol/L) in males; <50 mg/dL (1.3 mmol/L) in females
   • Receive drug treatment for high Blood Pressure (BP) or have BP>=130/85 mmHg
   • Receive drug treatment for high blood glucose or have fasting plasma glucose>=mg/dL
   • Central obesity, defined as a waist circumference cm (40 in) in men and>=88cm (35 in) in women.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Previously diagnosed with a condition causing clinically significant cognitive impairment, such as MCI, AD or other type of dementia (such as vascular dementia, Lewy body dementia and frontotemporal dementia).
2. History of clinically significant brain disorders, such as stroke, multiple sclerosis, Parkinson s disease or other movement disorders, brain tumors, history of meningitis or encephalitis, history of moderate or severe traumatic brain injury (defined as Glasgow Coma Scale of 12 or less), epilepsy. Certain common neurological disorders not considered relevant (e.g. migraine, essential tremor) or incidental neuroimaging findings that are common and of uncertain clinical significance (e.g. mild-moderate microvascular changes on MRI) may be allowed.
3. Chronic and significant psychiatric conditions (e.g. history of bipolar disorder, schizophrenia, PTSD, moderate to severe depression or treatment-resistant depression. Unipolar depression or anxiety disorder may be allowed if mild or if successfully treated with single anti-depressant or anti-anxiety agents.
4. Positive urine drug screen (and no prescription medication accounting for the positive test).
5. Positive HIV, HBV or HCV status during screening.
6. Contraindications for MRI (pregnancy, pacemakers or other implanted devices, ferrous metal implants or shrapnel in or around the head etc.).
7. Anemia (defined as HGB < 12 for men or < 11 g/dl for women)
8. Poor venous access.

9. Lactation or Pregnancy (positive urine pregnancy test. Pregnancy tests will not be done on post-menopausal women defined as one of the below criteria:

   1. prior bilateral oophorectomy
   2. Amenorrhea for 12 months or more
10. Known severe allergic reactions to the KE drinks or other ketogenic supplement or stevia products.
11. Following high fat/low carb diet (ketogenic) diet or very low calorie (<500 calories) diet or taking other ketogenic supplements (such as Medium Chain Triglycerides (MCTs), Ketone Salts) or fasting intermittently and unwilling to stop it while on the KE drink/Placebo.
12. Very high or severe hypertriglyceridemia >=886mg/dL or 10.0 mmol/L)
13. Severe Hypertension (systolic blood pressure >=180mmHg and/or diastolic blood pressure >=120mmHg)
14. Weight >=300 lbs (MRI scanner weight limit)
15. Diabetes Mellitus (type 1 or 2)
16. Taking the drug metformin.
17. Non-English speakers (given staffing constraints for cognitive testing administration and need for decreased variability in testing procedures for a small N study).
18. Participant has any concurrent medical condition, so that participation in the clinical study would not be in her/his best interest, in the PI s judgement.
19. To be eligible to consent for optional thigh MRI: Individuals with joint replacements that may be affected by the defined exercise protocol or which may prevent MRI analysis or any condition, in the opinion of the investigator, that would prevent successful completion of the exercise protocol such as, but not limited to reported osteoarthritis, rheumatoid arthritis and/or fibromyalgia.

5.3 INCLUSION OF VULNERABLE PARTICIPANTS

• Children: No inclusion is planned. This study aims to investigate the effects of aging 55 years old) on brain metabolism, therefore inclusion of children is inappropriate with respect to the purpose of the research.
• Pregnant Women, Fetuses, or Neonates: No inclusion is planned. We will exclude women, fetuses or neonates with respect to the health of participants, specifically, due to the risk associated with the MRI procedure and the unknown effects of the ketone ester supplement.
• Prisoners: No inclusion is planned. This study involves several visits to the NIA Clinical Unit, which prisoners are unable to perform. Therefore, inclusion of prisoners is inappropriate with respect to the purpose of the research.
• Decisionally Impaired Adults: No inclusion is planned. Cognitive intact status will be ascertained at baseline based on Clinical Dementia Rating (CDR) of 0, and Montreal Cognitive Assessment (MoCA) > 26, since the main objective of the study is to study a population of cognitively intact individuals. Therefore, inclusion of decisionally impaired adults is inappropriate with respect to the purpose of the research. Moreover, participants are not expected to become decisionally impaired over the course of the study.
• NIH Employees: We intend to include NIH staff (to include NIH contractors and special volunteers, guest researchers and trainees) in this study. The staff will be invited to participate through standard recruitment efforts. Participation will be voluntary and neither participation nor refusal to participate will have an effect, either beneficial or adverse, on the participant s employment or position at NIH. We will follow the Guidelines for the Inclusion of Employees in NIH Research Studies and will give each employee a copy of the NIH information sheet on Staff Research Participation per NIH OHSRP SOP 14F.4: Research Involving NIH Staff as Subjects.
• Neither participation nor refusal to participate will have an effect, either beneficial or adverse, on the participant s employment or work situation.
• The NIH information sheet regarding NIH employee research participation will be distributed to all potential subjects who are NIH employees.
• The employee subject s privacy and confidentiality will be preserved in accordance with NIH Intramural policies, which define the scope and limitations of the protections.
• Subjects that are employees/staff will be consented in the usual manner. The inclusion of employees or staff is not anticipated to affect the research outcome; therefore, if the subject is a co-worker (including a supervisor, subordinate or coworker) the subject may be consented by another co-worker and/or subordinate.The study PI will not be involved in the consenting of employees or staff.
• Other vulnerable populations: No inclusion is planned.