Mild Cognitive Impairment5-2CRNCT03872375
Calorie Restriction and Brain Function in Mild Cognitive Impairment
A study testing Meal-Replacement Therapy and Dietary Counseling in people with Mild Cognitive Impairment, run by Iowa State University at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 70 to 85 years
- Conditions the study is for
- Mild Cognitive Impairment
- What is being tested?
- Meal-Replacement Therapy and Dietary Counseling
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 96 participants
- Where
- 2 sitesUnited States
- Study dates
- 8 May 2019to 31 Dec 2021
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 70 to 85 years
- All sexes
- No healthy volunteers
- Older adult
Who may be able to join
- Years of age 70-85;
- Body Mass Index => 28 and < 40 and weight < 350 pounds;
- Mini-Mental State Examination >= 24;
- A subjective memory concern from the participant, caregiver/informant, or a clinician;
- An education-adjusted score for the Logical Memory II, paragraph A Wechsler Scale (16 years: 8-10; 8-15 years: 5-7; < 0-7 years: 2-3);
- A Clinical Dementia Rating - sum of boxes = 0.5;
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- No deficits in activities of daily living;
- Consensus confirmation of MCI by senior investigators;
- An informant/caregiver that is informed about the study and will be present at study visits.
Who cannot join
- A history of a major cardiovascular event(e.g., heart attack);
- A history of cerebrovascular or other neurological disorders (e.g., stroke, epilepsy, multiple sclerosis, etc.);
- A history of substance abuse in the past 6 months;
- A history of eating disorders;
- A history of clinically significant endocrine disorders (e.g., hypothyroidism);
- A history of mood and anxiety disorders (e.g., Major Depressive Disorder, Generalized Anxiety Disorder, Bipolar disorder, etc.);
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- Taking insulin;
- Current use of systemic corticosteroids;
- Current use of Warfarin;
- Having smoked tobacco products in the last 3 months;
- Contraindications for MRI (pacemakers, ferrous metal implants or shrapnel about the face or eyes, etc.);
- Other medical history that, in the opinion of the investigators, would constitute risk for subject participation;
- Hypertension, defined by a diastolic/systolic blood pressure of > 160/110;
- No current use of memantine or other Alzheimer's disease drugs.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Nutrition and Wellness Research Center
Ames, Iowa, 50011
University of Iowa Hospitals and Clinics
Iowa City, Iowa, 52242
About this study
Official title: Intermittent Calorie Restriction and Brain Function in MCI
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).
Read the 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.
- Conditions
- Mild Cognitive Impairment
- Being tested
- Meal-Replacement Therapy, Dietary Counseling
- Keywords
- Executive function, MRI, Memory, 5-2 CR
- Medical subject headings
- Cognitive Dysfunction
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Meal-Replacement TherapyDietary supplement
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.
Dietary CounselingBehavioural
A Registered Dietitian of Nutrition will provide consultation on how to induce moderate weight loss.
| Study group | Role | What they receive |
|---|---|---|
| Intermittent Calorie Restriction + Dietary Counseling | Experimental | Participants will be asked to consume a single 530 kilocalorie shake (i.e., "High Calorie" Boost shake) on a given day for two consecutive days each week. Participants will eat ad libitum during the remaining 5 days. Participants will also receive Registered Dietitian of Nutrition (RDN) consultations about dietary modifications to induce moderate weight loss. Participants will utilize these recommendations in addition to shake consumption.
Subjects are also asked to follow RDN dietary recommendations. Receives: Dietary Supplement: Meal-Replacement Therapy; Behavioral: Dietary Counseling |
| Dietary Counseling | Active comparator | A Registered Dietitian of Nutrition (RDN) will consult with subjects about dietary modifications to induce moderate weight loss. Participants will utilize these recommendations. Receives: Behavioral: Dietary Counseling |
What is being measured
The primary outcome is the main question the study is designed to answer.
Body Weight
% change in BMI (kg/m2)
Measured: 16 weeks
Secondary outcomes (9)
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
Insulin resistance measured with fasting glucose and insulin
Measured: 16 weeks
Functional Magnetic Resonance Imaging memory task activation
Regional brain activity induced by a memory task
Measured: 16 weeks
Functional Magnetic Resonance Imaging executive function task activation
Regional brain activity induced by an executive function task
Measured: 16 weeks
Cerebral blood flow
Regional cerebral blood flow assessed using Arterial Spin Labeling
Measured: 16 weeks
Neural network functional connectivity
Degree of network strength in neural networks assessed at rest using Functional Magnetic Resonance Imaging
Measured: 16 weeks
Mini-Mental State Examination
The construct for this total score is global cognitive performance, based on performance over a series of cognitive sub-domains. The unit is correct performance on a series of cognitive sub-domain tasks. The range is 0-30. A higher number is better.
Measured: 16 weeks
NIH EXAMINER Dysexecutive Errors Composite Score
The construct for this composite score is overall impairment in various executive function domains. The unit is the total number of errors committed during several NIH EXAMINER tasks (Continuous Performance Task, Fluency, Flanker, Set Shifting). The range is 0-43. A higher score is worse.
Measured: 16 weeks
California Verbal Learning Test
The construct for this factor is Verbal Memory. There are three sub-scales of main interest with the following units: 1) the total number of correctly recalled items in a 16-item list for a given trial where that list is read, spanning 5 trials ("CVLT Trials 1-5 Total"); 2) the total number of correctly recalled items in the same 16-item list after a 5 minute delay ("CVLT Short Delay"); and 3) the total number of correctly recall items in the same 16-item list after a 20 minute delay ("CVLT Long Delay"). The ranges are 0-80 for CVLT Trials 1-5 Total, 0-16 for CVLT Short Delay, and 0-16 for CVLT Long Delay. A higher number is better.
Measured: 16 weeks
Digit Span - Forward and Backward
This construct probes working memory, a sub-domain of executive function. It requires participants to remember a list of numbers that gradually has more numbers added.
Measured: 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Mar 2019
- Study start8 May 2019
- Primary completion31 Dec 2021
- Study completion31 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Mild Cognitive ImpairmentStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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 blind
- Who is masked
- Outcomes assessor
- Enrolment
- 96 participants (actual)
Sponsor and investigators
- Lead sponsor
- Iowa State University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Responsible party
- Principal investigator, Auriel A. Willette, Iowa State University
- Investigators
- Auriel A Willette, Principal investigator, Iowa State University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03872375
- Sponsor's protocol ID
- 201612732
- Other IDs
- R00AG047282
- Acronym
- 5-2CR
- Status last verified
- Mar 2022
- First submitted
- 11 Mar 2019
- Last updated
- 31 Mar 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 31 Mar 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Intermittent Calorie Restriction and Brain Function in MCI
- ClinicalTrials.gov ID
- NCT03872375
- Acronym / sponsor ID
- 5-2CR / 201612732
- Conditions
- Mild Cognitive Impairment
- Keywords
- Executive function, MRI, Memory, 5-2 CR
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 96 participants (actual)
- Lead sponsor
- Iowa State UniversityUniversity, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Study start
- 8 May 2019 (actual)
- Primary completion
- 31 Dec 2021 (actual)
- Study completion
- 31 Dec 2021 (actual)
- First posted
- 13 Mar 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Intermittent Calorie Restriction + Dietary Counseling | Experimental | Dietary Supplement: Meal-Replacement Therapy, Behavioral: Dietary CounselingParticipants will be asked to consume a single 530 kilocalorie shake (i.e., "High Calorie" Boost shake) on a given day for two consecutive days each week. Participants will eat ad libitum during the remaining 5 days. Participants will also receive Registered Dietitian of Nutrition (RDN) consultations about dietary modifications to induce moderate weight loss. Participants will utilize these recommendations in addition to shake consumption. Subjects are also asked to follow RDN dietary recommendations. |
| Dietary Counseling | Active comparator | Behavioral: Dietary CounselingA Registered Dietitian of Nutrition (RDN) will consult with subjects about dietary modifications to induce moderate weight loss. Participants will utilize these recommendations. |
Who may qualify
- Ages
- 70 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Older adult
Key inclusion criteria (9 listed)
- Years of age 70-85;
- Body Mass Index => 28 and < 40 and weight < 350 pounds;
- Mini-Mental State Examination >= 24;
- A subjective memory concern from the participant, caregiver/informant, or a clinician;
- An education-adjusted score for the Logical Memory II, paragraph A Wechsler Scale (16 years: 8-10; 8-15 years: 5-7; < 0-7 years: 2-3);
Key exclusion criteria (14 listed)
- A history of a major cardiovascular event(e.g., heart attack);
- A history of cerebrovascular or other neurological disorders (e.g., stroke, epilepsy, multiple sclerosis, etc.);
- A history of substance abuse in the past 6 months;
- A history of eating disorders;
- A history of clinically significant endocrine disorders (e.g., hypothyroidism);
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Meal-Replacement TherapyThe 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. | Dietary supplement | Intermittent Calorie Restriction + Dietary Counseling |
| Dietary CounselingA Registered Dietitian of Nutrition will provide consultation on how to induce moderate weight loss. | Behavioural | Dietary Counseling, Intermittent Calorie Restriction + Dietary Counseling |
Primary outcome
Body Weight
Time frame: 16 weeks
% change in BMI (kg/m2)
9 secondary outcomes
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
Time frame: 16 weeks
Functional Magnetic Resonance Imaging memory task activation
Time frame: 16 weeks
Functional Magnetic Resonance Imaging executive function task activation
Time frame: 16 weeks
Cerebral blood flow
Time frame: 16 weeks
Neural network functional connectivity
Time frame: 16 weeks
Mini-Mental State Examination
Time frame: 16 weeks
NIH EXAMINER Dysexecutive Errors Composite Score
Time frame: 16 weeks
California Verbal Learning Test
Time frame: 16 weeks
Digit Span - Forward and Backward
Time frame: 16 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Mar 2022.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Auriel A Willette principal investigator
Iowa State University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Meal-Replacement Therapy and Dietary Counseling in people with Mild Cognitive Impairment, run by Iowa State University at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Body Weight (time frame: 16 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Mar 2022; AzTrials last refreshed its copy on 30 Oct 2026.