Calorie Restriction and Brain Function in Mild Cognitive Impairment
Кључне речи
Апстрактан
Опис
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.
Датуми
| Последња верификација: | 04/30/2019 |
| Фирст Субмиттед: | 03/10/2019 |
| Предвиђена пријава послата: | 03/10/2019 |
| Прво објављено: | 03/12/2019 |
| Послато последње ажурирање: | 05/07/2019 |
| Последње ажурирање објављено: | 05/08/2019 |
| Стварни датум почетка студије: | 05/07/2019 |
| Процењени датум примарног завршетка: | 12/30/2020 |
| Предвиђени датум завршетка студије: | 12/30/2020 |
Стање или болест
Интервенција / лечење
Dietary Supplement: Intermittent Calorie Restriction + Dietary Counseling
Behavioral: Dietary Counseling
Фаза
Групе руку
| Арм | Интервенција / лечење |
|---|---|
| Experimental: Intermittent Calorie Restriction + Dietary Counseling 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. | Dietary Supplement: Intermittent Calorie Restriction + Dietary Counseling 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. |
| Active Comparator: Dietary Counseling A Registered Dietitian of Nutrition (RDN) will consult with subjects about dietary modifications to induce moderate weight loss. Participants will utilize these recommendations. |
Критеријуми
| Узраст подобан за студирање | 70 Years До 70 Years |
| Полови подобни за студирање | All |
| Прихвата здраве волонтере | да |
| Критеријуми | Inclusion Criteria: 1. Years of age 70-85; 2. Body Mass Index => 28 and < 40 and weight < 350 pounds; 3. Mini-Mental State Examination >= 24; 4. A subjective memory concern from the participant, caregiver/informant, or a clinician; 5. 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); 6. A Clinical Dementia Rating - sum of boxes = 0.5; 7. No deficits in activities of daily living; 8. Consensus confirmation of MCI by senior investigators; 9. An informant/caregiver that is informed about the study and will be present at study visits. Exclusion Criteria: 1. A history of a major cardiovascular event(e.g., heart attack); 2. A history of cerebrovascular or other neurological disorders (e.g., stroke, epilepsy, multiple sclerosis, etc.); 3. A history of substance abuse in the past 6 months; 4. A history of eating disorders; 5. A history of clinically significant endocrine disorders (e.g., hypothyroidism); 6. A history of mood and anxiety disorders (e.g., Major Depressive Disorder, Generalized Anxiety Disorder, Bipolar disorder, etc.); 7. Taking insulin; 8. Current use of systemic corticosteroids; 9. Current use of Warfarin; 10. Having smoked tobacco products in the last 3 months; 11. Contraindications for MRI (pacemakers, ferrous metal implants or shrapnel about the face or eyes, etc.); 12. Other medical history that, in the opinion of the investigators, would constitute risk for subject participation; 13. Hypertension, defined by a diastolic/systolic blood pressure of > 160/110; 14. No current use of memantine or other Alzheimer's disease drugs. |
Исход
Примарне мере исхода
1. Body Weight [16 weeks]
Секундарне мере исхода
1. Resting Metabolic Rate (ml/kg/min) [16 weeks]
2. Body Fatness (%) [16 weeks]
3. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) [16 weeks]
4. Functional Magnetic Resonance Imaging memory task activation [16 weeks]
5. Functional Magnetic Resonance Imaging executive function task activation [16 weeks]
6. Cerebral blood flow [16 weeks]
7. Neural network functional connectivity [16 weeks]
8. Mini-Mental State Examination [16 weeks]
9. NIH EXAMINER Dysexecutive Errors Composite Score [16 weeks]
10. NIH EXAMINER Executive Function Factor [16 weeks]
11. California Verbal Learning Test [16 weeks]
12. Wechsler Memory Scale IV Logical Memory I and II/A and B [16 weeks]
Остале мере исхода
1. Brain volume [16 weeks]
2. White matter tract integrity [16 weeks]
3. Appetitive hormones [16 weeks]
4. Pro- and anti-inflammatory immune markers [16 weeks]
5. Ketone body production [16 weeks]
6. Lean Muscle Mass (%) [16 weeks]
7. NIH EXAMINER Verbal Fluency 1 [16 weeks]
8. NIH EXAMINER Verbal Fluency 2 [16 weeks]
9. NIH EXAMINER Categorical Fluency 1 [16 weeks]
10. NIH EXAMINER Categorical Fluency 2 [16 weeks]
11. NIH EXAMINER Insight [16 weeks]
12. NIH EXAMINER Spatial 1-Back Task [16 weeks]
13. NIH EXAMINER Spatial 2-Back Task [16 weeks]
14. NIH EXAMINER Saccades and Anti-Saccades [16 weeks]
15. NIH EXAMINER Continuous Performance Task [16 weeks]
16. NIH EXAMINER Dot Counting [16 weeks]
17. NIH EXAMINER Set-Shifting [16 weeks]
18. NIH EXAMINER Unstructured Task [16 weeks]
19. NIH EXAMINER Flanker [16 weeks]
20. NIH EXAMINER Social Norms Questionnaire [16 weeks]
21. NIH EXAMINER Behavior Rating Scale [16 weeks]
22. Trails A [16 weeks]
23. Trails B [16 weeks]
24. Digit-Span Forward and Backward [16 weeks]
25. Digit Substitution [16 weeks]
26. Benton Visual Retention Test [16 weeks]
27. Activities of Daily Living [16 weeks]
28. Montreal Cognitive Assessment [16 weeks]
29. Clinical Dementia Rating [16 weeks]
30. NIH EXAMINER Fluency Factor [16 weeks]
31. NIH EXAMINER Cognitive Control Factor Score [16 weeks]
32. NIH EXAMINER Working Memory Factor Score [16 weeks]
