Intermittent Calorie Restriction, Insulin Resistance, and Biomarkers of Brain Function
Condition: Alzheimer's Disease; Obesity; Diabetes Mellitus
MeSH terms: Alzheimer Disease; Insulin Resistance
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      - Insulin removes sugar from the blood to use for energy. Insulin resistance means that cells
      may not respond to insulin normally. It can lead to serious diseases. Researchers want to see
      how diet affects insulin resistance, weight, and brain chemicals related to Alzheimer s
      disease.

      Objectives:

      - To compare two forms of diet and their effects on insulin resistance and the brain.

      Eligibility:

      - Women ages 55 70 with insulin resistance.

      Design:

        -  This study requires 6 clinic visits over 9 12 weeks. Participants must fast before
           visits.

        -  Visit 1, screening:

        -  Medical history, physical exam, and blood and urine tests.

        -  Participants will get a wrist device to wear for 4 days.

        -  Visit 2:

        -  Weight and waist measurement.

        -  Blood drawn.

        -  Questionnaires and thinking tests.

        -  Lumbar puncture. Skin will be numbed and a needle inserted between bones in the back
           will remove <TAB>fluid.

        -  Participants will drink a nutrition shake. Blood will be taken 12 times over 4
           <TAB>hours through a thin tube in <TAB>the arm.

        -  Brain MRI. Participants will lie on a table that slides in and out of a cylinder in a
           strong magnetic field. <TAB>They will have a coil on their head and may do tasks.

        -  Participants will get advice about healthy eating and be randomly put in one of 2
           groups. One group will get <TAB>nutrition shakes to drink.

        -  Visits 3 5:

        -  Weight and waist measurements, vital signs, blood draw, and questionnaires.

        -  Between visits, participants will get a call or email to check how they are doing.

        -  Visit 6: Repeat of visit 1.

        -  Participants will wear the wrist device for 4 more days, have a follow-up contact, then
           the study is finished.
    

Detailed description: 
      Being overweight or obese can cause insulin resistance (IR), which is defined as reduced
      responsiveness to insulin by the cells of various tissues or organs. IR at midlife increases
      the risk of developing Alzheimer s disease (AD). We recently discovered novel biomarkers of
      brain IR (altered Tyr and Ser phosphorylated forms of insulin receptor substrate 1; IRS-1) in
      plasma exosomes enriched for neuronal origin. Moreover, IR is associated with AD biomarkers
      including deficits in resting state brain activity and cognitive performance. Calorie
      restriction is defined as consuming fewer calories than what is considered normal without a
      lack of nutrients. A certain type of calorie restriction, in which one consumes 500-600
      calories a day for two consecutive days, followed by non-restricted eating for 5 days (5-2
      CR), has been shown to lower peripheral insulin resistance effectively. Effects of CR and
      lowering peripheral IR on brain IR and cognition are unknown. The goal of this exploratory
      pilot study is to provide proof-of-concept that 5-2 CR at midlife can reverse brain IR, lower
      peripheral IR, improve cognitive performance, and increase brain activation at rest and
      during tasks. Specifically, we will study the effects of 8 weeks of 5-2 CR versus a control
      dietary intervention on brain and peripheral IR, memory and executive function, resting state
      default mode network activity, brain metabolism, and AD biomarkers. Forty overweight to obese
      women and men (between 55 and 70 years of age) will be randomized 1:1 into 5-2 CR and control
      groups. In the 5-2 CR group, participants will be offered healthy living dietary counseling
      at baseline, which they will be instructed to implement for five days/week. For each of the
      other two consecutive days/week, they will consume two shakes (Boost , CWI Medical),
      providing a total of 480 Kcal/day. In the control group, participants will be offered healthy
      living dietary counseling at baseline, which they will be asked to implement for every day of
      the week. Participants will undergo screening including a history and physical examination,
      calculation of Body Mass Index (BMI, which must be greater than or equal to 27) and a blood
      draw for insulin and glucose to determine whether they have insulin resistance. If
      participants meet eligibility criteria, they will continue with a baseline visit involving
      anthropometric measures, questionnaires, tests of cognitive function, brain MRI, blood draws
      for plasma and peripheral blood mononuclear cells, and lumbar puncture for cerebrospinal
      fluid biomarkers of AD. After 8 weeks, we will collect the same measures. To assess and
      reinforce compliance with their respective diet, participants will come into the clinic every
      2 weeks to discuss compliance, measure their body weight and perform blood draws for
      measurement of ketones to objectively confirm energy restriction for the 5-2 CR group. We
      will also contact participants every week to further ensure compliance. To assess the effects
      of the diets on physical activity, participants will be asked to wear an accelerometer for 96
      hours before and after they are on the diet.
    

Intervention name(s): Boost (R) 5-2 diet; Healthy Living Diet
Intervention type(s): Other; Other
Intervention description(s): Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.; Counseling and educational material on diet portion, consistency
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Biomarkers; Diabetes; Obesity; Dementia of the Alzheimer Type; Functional Magnetic Resonance Imaging (fMRI)