Calorie Restriction and Brain Function in Mild Cognitive Impairment
Condition: Mild Cognitive Impairment
MeSH terms: Cognitive Dysfunction
Study type: Interventional

Summary: 
      Problems with blood sugar metabolism (i.e., metabolic dysfunction) progressively develop
      through old age, which is primarily due to obesity and lack of physical activity. Metabolic
      dysfunction increases the risk for Alzheimer's disease (AD) and negatively impacts memory and
      related brain function. There is intense interest in developing interventions, particularly
      non-drug therapies, to combat AD. Recent clinical trials have found that intranasal insulin,
      which facilitates glucose metabolism in the brain, is able to maintain memory in participants
      with Mild Cognitive Impairment (MCI), the precursor to AD. While intranasal insulin is a
      useful, proof-of-concept intervention, it does not affect visceral fat mass and therefore
      metabolic dysfunction will persist in a given person.

      The investigators wish to engage participants with MCI in intermittent calorie restriction
      (CR), to reduce metabolic dysfunction and improve glucose metabolism. Intermittent calorie
      restriction in this case refers to eating whatever one wants for 5 days, followed by 2
      consecutive days of consuming 530 calories via one protein shake with sufficient nutrients to
      sustain the person. This results in reliable weight loss, which itself improves glucose
      metabolism in the body and has a wealth of other benefits. (It should be mentioned here that
      weight maintenance has been shown in studies when participants restrict to 1 day/week).
    

Detailed description: 
      AD diagnosis is projected to increase from approximately 5 million to 13.8 million Americans
      by 2050. The Alzheimer's Association estimates that healthcare costs for AD by 2050 could be
      1.2 trillion dollars per year for Americans aged 65 years or older. There is marked focus on
      treating AD during the MCI phase, which precedes AD.

      In the brain, insulin normally facilitates microvascular blood flow, glucose uptake, and
      glucose oxidation for adenosine triphosphate (ATP) generation. Insulin resistance (IR) is
      defined as a reduced cellular responsiveness to insulin, characterized by higher insulin
      levels needed to maintain glucose regulation in the periphery and certain brain areas. IR is
      found in MCI and AD patient brains. AD-related neuropathology, such as amyloid
      beta-containing plaques, progressive atrophy, and glucose hypometabolism first occur in brain
      areas that also have a high density of insulin receptors. Such areas include medial temporal
      lobe (MTL) and prefrontal cortex (PFC). Furthermore, as illustrated in the literature and
      previous work of the investigators, peripheral IR is associated with AD-like changes in MTL
      and PFC, including: 1) brain atrophy; 2) less glucose uptake; 3) accumulation of
      amyloid-beta, a hallmark of AD; and 4) increased phosphorylation of tau fibrils, another
      hallmark of AD. Finally, higher IR is related to deficits in memory performance and executive
      function.

      These cognitive deficits can be ameliorated with 40 IU of intranasal insulin, which increases
      insulin processing in the brain with minimal peripheral effects, where MCI and AD patients
      show stable visuospatial working memory, as well as declarative learning and memory. One
      limitation of intranasal insulin is that it does not change obesity, which causes IR, and may
      therefore be only temporarily effective. As such, the investigators are interested in dietary
      regimens that can lower IR and may have long-term beneficial effects on AD neuropathology and
      cognitive output. Critically, intermittent calorie restriction (CR) diets reliably decrease
      body weight and IR in human adults. Intermittent CR protects neurons against dysfunction and
      degeneration in AD models. The underlying cellular and molecular mechanisms involve improved
      cellular bioenergetics and up-regulation of protein chaperones and antioxidant pathways in
      neurons. For example, 5-2 CR, a diet consisting of 5 days ad libitum followed by 2
      consecutive days consuming 500-600 kcal, decreases IR beyond what is achieved with daily CR,
      and has a compliance rate of 83% versus 55% even by 6 months. It is also important to mention
      that no serious Adverse Events have occurred during past 5-2 CR studies.
    

Intervention name(s): Meal-Replacement Therapy; Dietary Counseling
Intervention type(s): Dietary Supplement; Behavioral
Intervention description(s): The meal replacement shake, consumed once per day on two consecutive days, will over a given week lead to negative energy balance and induce weight loss.; A Registered Dietitian of Nutrition will provide consultation on how to induce moderate weight loss.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Dietary Supplement: Meal-Replacement Therapy
To examine the effect of meal-replacement therapy on weight loss, behavior, and brain outcomes in overweight to obese aged adults with mild cognitive impairment.
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Executive function; MRI; Memory; 5-2 CR