Effect of Mediterranean Diet and Probiotics in Adults With Mild Cognitive Impairment

Study Overview
=================
Brief Summary
-----------------
Manipulation of the gut microbiota through dietary modification affects brain function, with improvement in patients with cognitive disorders. Combined effect of nutritional intervention with Mediterranean diet and probiotics with potentially healthy growth of germ, affect the evolution of mild cognitive impairment, by the modulation of components related with the axis microbiota-gut-brain: neuropeptides, short-chain fatty acids, markers for oxidative stress and inflammation.

Official Title
-----------------
A 24 Weeks Double-blind Latin-square Trial of Effect of Mediterranean Diet and Probiotics in Adults With Mild Cognitive Impairment

Conditions
-----------------
Mild Cognitive Impairment

Intervention / Treatment
-----------------
* Dietary Supplement: Mediterranean diet
* Dietary Supplement: Healthy diet (WHO recommendations)
* Dietary Supplement: Placebo
* Dietary Supplement: Biopolis-MIX42


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age> = 60 years with mild cognitive impairment (Clinical Dementia Rating (CRD) 0.5; Mini Mental Examiantion de Folstein (MMSE)> 23; Repeatable Battery for the Asessment of Neuropsychological Status (RBANS) <= 85) Drugs with a stable dose from a minimum of 4 weeks prior to screening (excluding psychopharmaceuticals and any other that could affect alertness and cognitive ability) Geriatric depression scale score <6 Sufficient visual and auditory abilities to carry out the neuropsychological tests. Good health without diseases that prevent the completion of the study. A minimum educational training established for 6 years or similar work history. A familiar informant or close caregiver with a minimum contact with the patient established in 10 hours per week that can accompany the participant to the clinical visits Exclusion Criteria: Any uncontrolled medical or neurological condition that, in the opinion of the researcher, could contribute to the subject's cognitive impairment (for example, substances abuse, vitamin B12 deficiency, abnormal thyroid function, stroke, or other Cerebral vascular disease, Lewy body dementia, frontotemporal dementia, TBI). A clinically significant psychiatric illness (eg, major depression, schizophrenia, or bipolar affective disorder) in the 6 months prior to screening. Transient ischemic attack or cerebrovascular accident or any unexplained loss of consciousness in 1 year before selection (in case of vascular deficit with cognitive sequelae that may still be reversible). Poorly controlled diabetes mellitus, due to a glycosylated haemoglobin (HbA1c) value of 8% in the selection. History of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class 3 or 4), or clinically significant conduction disorders (unstable atrial fibrillation) within 1 year prior to screening. Uncontrolled hypertension defined as the mean of 3 measures of systolic blood pressure / diastolic blood pressure> 165/100 mmHg, and persistent systolic blood pressure / diastolic blood pressure > 180/100 mmHg in the 3 months prior to randomization which were considered by the researcher as an indicative of chronic uncontrolled hypertension. History of seizures in the 10 years prior the selection. Recent history (within 1 year of screening) of alcohol or substance abuse with positive urine test (looking for non-prescription drugs), alcohol or cannabinoids. Patients with chronic diseases will be excluded: severe psychiatric, chronic processes in need of treatment such as chronic kidney failure, chronic liver disease, neoplasms under treatment, chronic obstructive pulmonary disease, endocrinopathies susceptible to decompensation and digestive tract diseases.

Ages Eligible for Study
-----------------
Minimum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: 50 men and women with mild cognitive impairment and more than 60 years will follow three dietary intervention periods of 24 weeks each, with a randomized crossover design. Dietary periods will be: 1.- Healthy diet (WHO recommendations) + placebo; 2.- Mediterranean diet + placebo and ; 3.- Mediterranean diet plus (Mediterranean diet + Biopolis-MIX42 (a capsule containing 10^9 colony forming units of Lactobacillus rhamnosus and Bifidobacterium longum)).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Healthy diet Arm<br>Healthy diet (WHO recommendations) + placebo | Dietary Supplement: Healthy diet (WHO recommendations)<br>* Recommendations according to WHO<br>Dietary Supplement: Placebo<br>* Placebo<br>|
| Placebo Comparator: Mediterranean diet Arm<br>Mediterranean diet + placebo | Dietary Supplement: Mediterranean diet<br>* Mediterranean diet: 22% Monounsaturated fat, 6% Polyunsaturated fat, 7% Saturated fat, 15% Protein, 50% Carbohydrates<br>Dietary Supplement: Placebo<br>* Placebo<br>|
| Active Comparator: Mediterranean diet plus Arm<br>Mediterranean diet + Biopolis-MIX42 (1 capsule per day containing 10^9 colony forming units of Lactobacillus rhamnosus and Bifidobacterium long). | Dietary Supplement: Mediterranean diet<br>* Mediterranean diet: 22% Monounsaturated fat, 6% Polyunsaturated fat, 7% Saturated fat, 15% Protein, 50% Carbohydrates<br>Dietary Supplement: Biopolis-MIX42<br>* Biopolis-MIX42: a capsule containing 10^9 colony forming units of Lactobacillus rhamnosus and Bifidobacterium longum.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive change | Cognitive change in Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog- Plus). The total ADAS-Cog-plus score ranges from 0-70 with higher scores suggesting greater impairment. | Baseline and 24 weeks after each dietary intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microbiota pattern | Changes in the percentage of different families of Microbiota will be analysed during the study | Baseline and 24 weeks after each dietary intervention | 
| Endotoxemia levels | Changes in the endotoxemia levels will be analysed during the study | Baseline and 24 weeks after each dietary intervention | 
| Change in inflammatory marker | At time 0 and after 24 weeks of each intervention period and follow-up, the levels of high sesitivity C-reactive protein (hs-CRP) were determined in plasma in mg/dL. | Baseline and 24 weeks after each dietary intervention | 
| Change in oxidative stress parameters | At time 0 and after 24 weeks of each intervention period and follow-up, the levels of advanced glycation end products (AGEs) were determined in serum in ug/mL: methylglioxal (MG) and N-carboxymethyllysine (CML). Likewise, carbonilated proteins in nmol/mg and lipid peroxidation levels in plasma in ug/mL. | Baseline and 24 weeks after each dietary intervention | 
| Neurofunctional change | At time 0 and after 24 weeks of each intervention period and follow-up, neurofunctional changes were measured by emission tomography with 2-deoxy-2-[fluorine-18]fluoro- D-glucose (18F-FDG-PET) | Baseline and 24 weeks after each dietary intervention | 
| Modulation of Microbiota-gut-nervous system | Changes in the plasma levels of molecules with activity on the nervous system were analysed during the study. At time 0 and after 24 weeks of each intervention period and follow-up, Gamma-Aminobutiric acid (GABA) in ng/mL and short-chain fatty acids (acetate, propionate and butirate) in ng/mL were determined in plasma. | Baseline and 24 weeks after each dietary intervention | 
| Change in cytokine levels | At time 0 and after 24 weeks of each intervention period and follow-up, the levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) were determined in plasma in pg/mL. | Baseline and 24 weeks after each dietary intervention | 
| Neuropeptides modulation | Changes in the plasma levels of molecules with activity on the nervous system were analysed during the study. At time 0 and after 24 weeks of each intervention period and follow-up, Substance P (SP), Y Peptide (PYY), beta-amyloid in pg/mL were determined in plasma. | Baseline and 24 weeks after each dietary intervention | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Mild Cognitive Impairment, Probiotics, Microbiota, Mediterranean diet