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出境医 / 临床实验 / Prevention of Cognitive Decline in ApoE4 Carriers With Subjective Cognitive Decline After EGCG and a Multimodal Intervention ((PENSA))

Prevention of Cognitive Decline in ApoE4 Carriers With Subjective Cognitive Decline After EGCG and a Multimodal Intervention ((PENSA))

Study Description
Brief Summary:
Alzheimer's disease (AD) neuropathology is characterized by deposits of insoluble amyloid β-peptide (Aβ) in extracellular plaques and aggregated tau protein, which is found largely in the intracellular neurofibrillary tangles. Current knowledge, has allowed a shift in the definition of AD from a syndromal to a biological construct, based on biomarkers that are proxies of pathology. However, little is known about mechanisms underlying the disease progression at its early stages. The loss of dendritic spines, the primary locus of excitatory synaptic transmission in the mammalian central nervous may be linked to cognitive and memory impairment in AD: A multimodal lifestyle change intervention (dietary, physical activity and cognition) combined with epigallocatechin gallate (EGCG) will slow down cognitive decline and improve brain connectivity in a population of participants with subjective cognitive decline (SCD). In humans, alterations in functional connectivity (FC) have been observed in early AD stages, subjective cognitive decline (SCD) and mild cognitive impairment (MCI). A hyper-synchronized anterior network and a posterior network characterized by a decrease in FC are the spatial features. These disruptions also seen in AD indicate that FC alterations appear very early in the course of the disease . Experimental research strongly suggests that in order to increase our cerebral reserves, we have to follow a lifestyle that takes into account many factors. Clinical studies provided evidence that individuals with more cerebral reserves are those who have a high level of education, who maintain regular physical activity and who eat in a healthy way. The environmental enrichment (EE) animal models confirmed that the experience plays a key role in increasing brain plasticity phenomena .There is a growing understanding that a valid therapeutic emerging approach in AD is prevention. A large number of modifiable risk factors for AD have been identified in observational studies, many of which do not appear to exert effects through amyloid or tau. This suggests that primary prevention studies focusing on risk reduction and lifestyle modification may offer additional benefits. The therapeutic approach proposed in the present project aims at improving synaptic plasticity and functional connectivity in early stages of AD, and specifically in SCD in the context of a personalized medicine approach that includes a multimodal intervention (nutritional, physical, cognitive and medical) looking at improving person-centered outcomes. In this context the proposed clinical trial design will evaluate the efficacy of EGCG in the context of a personalized medicine approach that includes a multimodal intervention (nutritional, physical, cognitive and medical) looking at improving person-centered outcomes. Early phase I studies in Down syndrome young adults showed that while subjects were under EGCG, improvements in cognition were observed but these vanished when treatment was discontinued. Phase II studies combining EGCG with cognitive training showed improvements in cognitive performance and adaptive functionality but interestingly sustained effects after treatment discontinuation. Observations made in humans are in agreement with preclinical studies showing that EGCG combined with environmental enrichment resulted in an improvement of age-related cognitive decline. These observations are in favor of the option of combining EGCG with a personalized multimodal intervention. The personalized multimodal intervention will take into account medical comorbidities (i.e. metabolic syndrome, T2DM), diet (including nutritional status), physical exercise, and will incorporate cognitive training and a behavioral intervention to aid subject's adherence and empowerment to the intervention proposed. This will be in-line with other clinical studies in AD showing the superiority of multimodal interventions vs. a single life style intervention (i.e. single nutrient, physical activity). Hypothesis: A multimodal lifestyle change intervention (dietary, physical activity and cognition) combined with epigallocatechin gallate (EGCG) will slow down cognitive decline and improve brain connectivity in a population of participants with subjective cognitive decline (SCD).

Condition or disease Intervention/treatment Phase
Alzheimer Disease Nutritional Intervention Cognitive Function Dietary Supplement: EGCG Dietary Supplement: Placebo EGCG Other: Personalized intervention Other: Lifestyle recommendations Not Applicable

Detailed Description:

Study Design: Randomized, double-blind, personalized clinical trial with 200 subjects with subjective cognitive decline (SCD) of both genders, with 4 arms of treatment Duration of the Study:The total duration of the study is expected to be 24 months (subject recruitment, baseline period, treatment period, follow-up, data analysis and study report).

Primary Objective(s):To evaluate the efficacy of a multimodal intervention (dietary, physical activity and cognition) combined with epigallocatechin gallate (EGCG) in slowing down cognitive decline.

Secondary Objective(s): To evaluate several underlying mechanisms that could explain the efficacy of the intervention in preventing the progression of cognitive decline: (i) changes in gut microbiota composition and in the metabolome derived by the action of microorganisms, (ii) changes in AD biomarkers (iii) changes in biomarkers of oxidation/inflammation Target Population: Subjects (approximately 200) diagnosed of Subjective Cognitive Decline (SCD), carriers of the Apolopoprotein E4 allele, fulfilling at least 3 additional SCD plus score (at least 5 criteria) recruited either from Hospital del Mar and its primary care provider or from Barcelona Beta Brain Research Centre.

Preselection criteria i.Adults aged 60-80 years with a BMI ≥18.5 and <32 kg/m2. ii.Subjective Cognitive Decline Questionnaire (SCD-Q) items 1 and 3 positive. (BBRC) iii.Subjects willing to participate and to perform all study procedures, including Apolipoprotein E4 genotyping iv.Subject has one informant partner who, in the investigator's judgment has frequent and sufficient contact with the subject as to be able to provide accurate information about subject's cognitive and functional abilities.

Study Arm(s): 1. Arm I: EGCG and a multimodal intervention (n=50) 2. Arm II: Placebo EGCG and a multimodal intervention (n=50) 3. Arm III: EGCG and healthy lifestyle recommendations (n=50) 4. Arm IV: Placebo EGCG and healthy lifestyle recommendations (n=50) Duration of Patient Participation: The total duration of the patient participation is expected to be 16 months. Run-in period (1 month): Basal assessment of cognitive performance (cognitive battery), diet and physical activity, daily living activities (self-reported tests) and mood (self-reported tests at basal assessment and EMA's). Interventions will last 12 months. Follow-up after intervention discontinuation: at least 3 months Treatment EGCG (Font-UP, laboratories Grand Fontaine), a daily dose of approximately 5-6 mg/kg up to 520 mg/day will be administered to subjects for 12 months or matched placebo Multimodal intervention (12 months): 1) Cognitive stimulation, guided group activities once per month; 2) Cognitive training, twice per week 30-45min sessions; 3) Psychoeducational support groups, 10 sessions, 4) personalized diet 8 sessions, 5) personalized physical activity.

End point The preclinical Alzheimer cognitive composite ADCS-PACC-Plus-exe

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Arm I: EGCG and a multimodal intervention (n=50) Arm II: Placebo EGCG and a multimodal intervention (n=50) Arm III: EGCG and healthy lifestyle recommendations (n=50) Arm IV: Placebo EGCG and healthy lifestyle recommendations (n=50)
Masking: Double (Participant, Investigator)
Masking Description: Randomized, double-blind clinical trial (Participant, investigator)
Primary Purpose: Prevention
Official Title: Prevention of Cognitive Decline in ApoE4 Carriers With Subjective Cognitive Decline After EGCG and a Multimodal Intervention
Actual Study Start Date : October 30, 2019
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : September 2021
Arms and Interventions
Arm Intervention/treatment
Experimental: 1

EGCG + multimodal intervention (n=50) Font-Up 49 to 98 gr Font-up (260-520mg EGCG)/day (If participant weight is ≤ 50kg will take 1 sachet each day, if participant weight is >50kg will take 2 sachets each day)

+ personalized intervention

 Dietary Supplement: EGCG

Participants that weight >50kg intake one oral dose in the morning for breakfast and a second dose in the afternoon in (266 + 266 mg/EGCG, 49 + 49 g of Font-up).

Participants that weight <50kg intake one oral dose in the morning for breakfast (266 mg/EGCG, 49 of Font-up


Other: Personalized intervention
A personalized intervention include a physical activity plan,dietary intervention, mental health promotion interventions,
Active Comparator: 2

Font-Up 49 to 98 gr Font-up (260-520mg EGCG)/day (If participant weight is ≤ 50kg will take 1 sachet each day, if participant weight is >50kg will take 2 sachets each day)

  • non personalized intervention
 Dietary Supplement: EGCG

Participants that weight >50kg intake one oral dose in the morning for breakfast and a second dose in the afternoon in (266 + 266 mg/EGCG, 49 + 49 g of Font-up).

Participants that weight <50kg intake one oral dose in the morning for breakfast (266 mg/EGCG, 49 of Font-up


Other: Lifestyle recommendations
The recommendations are to balance caloric intake and physical activity to achieve and maintain a healthy body weight; consume a diet rich in vegetables and fruits;
Placebo Comparator: 3

Placebo Font-Up 49 to 98 gr Font-up (260-520mg EGCG)/day (If participant weight is ≤ 50kg will take 1 sachet each day, if participant weight is >50kg will take 2 sachets each day)

+ personalized intervention

 Dietary Supplement: Placebo EGCG
Participants that weight >50kg intake one oral dose in the morning for breakfast and a second dose in the afternoon in (266 + 266 mg/EGCG, 49 + 49 g of Font-up)

Other: Personalized intervention
A personalized intervention include a physical activity plan,dietary intervention, mental health promotion interventions,
Sham Comparator: 4

Placebo Font-Up 49 to 98 gr Font-up (260-520mg EGCG)/day (If participant weight is ≤ 50kg will take 1 sachet each day, if participant weight is >50kg will take 2 sachets each day)

  • non personalized intervention
 Dietary Supplement: Placebo EGCG
Participants that weight >50kg intake one oral dose in the morning for breakfast and a second dose in the afternoon in (266 + 266 mg/EGCG, 49 + 49 g of Font-up)

Other: Lifestyle recommendations
The recommendations are to balance caloric intake and physical activity to achieve and maintain a healthy body weight; consume a diet rich in vegetables and fruits;
Outcome Measures
Primary Outcome Measures :
  1. Preclinical Alzheimer Cognitive Composite- Plus-exe like score (ADCS-PACC-like) [ Time Frame: Screening, 6, 12 and 15 months. ]
    Changes in Alzheimer's cognitive compound score plus a PACC-like score (ADCS-PACC). that includes The Total Recall score from the Free and Cued Selective Reminding Test (FCSRT) (which range from 0-48 words),The Delayed Recall score on the Logical Memory IIa subtest from the Wechsler Memory Scale (which range from 0-25 story units), The Digit Symbol Substitution Test score from the Wechsler Adult Intelligence Scale-Revised (which range from 0-93 symbols), The MMSE total score (which range from 0-30 points).Each of the component change scores is divided by the baseline sample standard deviation of that component, to form standardized z scores. These z scores are summed to form the composite. Thus, change off 0.5 ADCS-PACC units will be significative


Secondary Outcome Measures :
  1. Changes in Functional neuronal connectivity (assessed by a functional magnetic resonance imaging) [ Time Frame: Screening and 12 months. ]
    Changes in Maps of change in connectivity of the Default mode network Changes in Maps of change in connectivity of the Limbic network Changes in Maps of change in connectivity of the Salience network

  2. Changes in structural connectivity networks known to be affected in Alzheimer Disease [ Time Frame: Screening and 12 months. ]
    Changes in Connectivity changes of the parahippocampus/fornix Changes in Connectivity changes of the cingulum/cingulate fiber bundle Changes in connectivity changes of the caudate heads


Other Outcome Measures:
  1. Changes in the microbiota composition [ Time Frame: Baseline, and 12 months. ]
    For the analysis of microbiota biomarkers Our characterization of the microbiome of the samples will include determination of the levels of biodiversity in the samples,we will divided samples into quartiles in order to label each sample as having low (1st quartile), average (2nd and 3rd quartiles), or high diversity (4th quartile).

  2. Change in the dietary patterns (metabolomics) Plasma samples [ Time Frame: Baseline, 6, 12 and 15 months ]
    Change in the dietary patterns (metabolomics). Plasma, samples will be collected to analyze the corresponding metabolomes, we will divided samples into quartiles in order to label each sample as having low (1st quartile), average (2nd and 3rd quartiles), or high diversity (4th quartile)

  3. Change in the dietary patterns (metabolomics) oral fluid [ Time Frame: Baseline, 6, 12 and 15 months ]
    Change in the dietary patterns (metabolomics) oral fluid will be collected to analyze the corresponding metabolomes.metabolomes.for a better understanding of the complexity of the interrelationship of metabolomics in oral fluid and mental health.

  4. Change in the dietary patterns (metabolomics). urinary samples [ Time Frame: Baseline, 6, 12 and 15 months ]
    Change in the dietary patterns (metabolomics). urinary samples will be collected to analyze the corresponding metabolomes.for a better understanding of the complexity of the interrelationship of microbiota, diet, and mental health.

  5. Exploratory [ Time Frame: At 6 and 12 months ]
    Change derived from the treatment compliance after a multimodal lifestyle change intervention metabolomes. urinary samples will be used to identify objective biomarkers of dietary intake and dietary patterns and to assess the degree of adherence to the Mediterranean diet by monitoring the levels of dietary metabolites.

  6. Changes in the semantic verbal fluency [ Time Frame: Baseline, 6, 12 and 15 months ]
    Changes in additional cognitive performance scores of: (i) Semantic verbal fluency, "animals" in one minute. (which range from 0-12 words) higher score is better outcome.

  7. changes in the Boston Naming Test [ Time Frame: Baseline, 6, 12 and 15 months ]
    Changes in additional cognitive performance scores of: (ii) naming, Boston Naming Test (BNT).: (which range from 0-15 points) higher score is better outcome.

  8. change in attention and working memory, [ Time Frame: Baseline, 6, 12 and 15 months ]
    Changes in additional cognitive performance scores of: (iii) attention and working memory,

  9. change in the Digit span subtest (WAIS IV) [ Time Frame: Baseline, 6, 12 and 15 months ]
    Changes in additional cognitive performance scores of: (iv) Digit span subtest (WAIS IV) , (which range from 0-16 points)

  10. Changes in the Olfactory function [ Time Frame: Baseline, and 12 months ]
    Changes in the Olfactory function: the University of Pennsylvania Smell Identification Test (UPSIT) is designed to test the function of an individual's olfactory system. It is the gold standard of smell identification tests. Its performance has been related to cognition and it has been widely used as a complementary assessment tool in dementia patients.( which range from 0-40)

  11. Changes in the AD biomarkers related to (amyloid-β peptide) [ Time Frame: Baseline, and 12 months ]
    Changes in the AD biomarkers related to neurodegeneration, inflammation (amyloid-β peptide)

  12. Changes in the AD biomarkers related to (Tau proteins) [ Time Frame: Baseline, and 12 months ]
    Changes in the AD biomarkers related to neurodegeneration, inflammation (Tau proteins)

  13. Changes (CSF/plasma albumin ratio). [ Time Frame: Baseline, and 12 months ]
    Changes in other CSF biomarkers related with the blood brain barrier dysfunction will be investigated (CSF/plasma albumin ratio).


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   60 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

* Meet all selection criteria and none exclusion criteria.

  • Fulfill SCD criteria (113) including cognitive performance within normal values* (adjusted for age and education). At least SCD-Q items 1 and 3 positives.
  • Age between 60 and 80 with a BMI ≥18.5 and <32 kg/m2.
  • Carrying the ApoE4 allele.*. Fulfilling 2 additional SCD plus features from the ones listed below: memory-centered*, onset of symptoms within the last 5 years*,, corroborated by an informant*, concern about cognitive decline* and perception of lower performance compared with same age group* (criteria marked with* are among those proposed features for SCD-plus syndrome which may point to participants with a greater risk of AD pathology).
  • Participants willing to participate and to perform all study procedures. *: Normal scoring on psychometric evaluation.

Exclusion Criteria:

  • Inability or unwillingness to give written informed consent or communicate with the study staff or illiteracy.
  • Clinically significant unstable psychiatric disorder that may affect cognition (e.g. major depression disorder, schizophrenia, bipolar or psychotic disorder according to diagnostic and statistical manual of mental disorders fifth edition )
  • Neurological conditions that may affect cognition or may imply an early stage of neurodegenerative disease other than AD (i.e. cranioencephalic trauma with permanent neurologic effects, epilepsy, multiple sclerosis, previous stroke, extrapyramidal signs at physical exploration, history of brain tumor...).
  • History or evidence of any medical condition or use of medication that in the opinion of the investigator could affect subjects' safety or interfere with the study assessments (e.g. use of neuroleptic drugs, corticosteroids or immunosuppressive therapies that may affect inflammatory parameters).
  • Any contraindication to perform Lumbar Puncture procedure (e.g. platelet count <100.000/ml, lumbar spine deformity, anticoagulant treatment).
  • Any contraindication to perform brain MRI procedure (e.g. pacemaker, MRI-incompatible aneurysm clips).
  • Current intake of vitamin supplements, catechins or products containing EGCG (i.e. , Mega Green Tea capsules Life Extension or Font-UP Grand Fontaine Laboratories) for at least 3 months previous to the screening visit.
Contacts and Locations

Locations
Layout table for location information
Spain
Barcelonabeta Brain Research Center Not yet recruiting
Barcelona, Barcelona, Spain, Spain, 08005
Contact: Karine Fauria    (+34) 93 316 09 90    kfauria@fpmaragall.org   
Contact: Carolina Minguillon,    (+34) 93 316 09 90    cminguillon@fpmaragall.org   
Principal Investigator: Jose Luis Molinuevo, MD, PhD Scientific Director         
IMIM (Institut Hospital del Mar d'Investigacions Mèdiques) Recruiting
Barcelona, Spain, 08003
Contact: Rafael De la Torre Fornell, PhD    (+34) 933160484    rtorre@imim.es   
Contact: Julian Mateus Rodriguez    (+34) 933160490    jmateus@imim.es   
Principal Investigator: Rafael de la Torre, PharmD Phd Director Programme         
Sponsors and Collaborators
Parc de Salut Mar
Fundacion IMIM
Barcelonabeta Brain Research Center, Pasqual Maragall Foundation
Tracking Information
First Submitted Date  ICMJE May 29, 2019
First Posted Date  ICMJE June 6, 2019
Last Update Posted Date March 5, 2020
Actual Study Start Date  ICMJE October 30, 2019
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 5, 2019) 		Preclinical Alzheimer Cognitive Composite- Plus-exe like score (ADCS-PACC-like) [ Time Frame: Screening, 6, 12 and 15 months. ]
Changes in Alzheimer's cognitive compound score plus a PACC-like score (ADCS-PACC). that includes The Total Recall score from the Free and Cued Selective Reminding Test (FCSRT) (which range from 0-48 words),The Delayed Recall score on the Logical Memory IIa subtest from the Wechsler Memory Scale (which range from 0-25 story units), The Digit Symbol Substitution Test score from the Wechsler Adult Intelligence Scale-Revised (which range from 0-93 symbols), The MMSE total score (which range from 0-30 points).Each of the component change scores is divided by the baseline sample standard deviation of that component, to form standardized z scores. These z scores are summed to form the composite. Thus, change off 0.5 ADCS-PACC units will be significative
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2019)
  • Changes in Functional neuronal connectivity (assessed by a functional magnetic resonance imaging) [ Time Frame: Screening and 12 months. ]
    Changes in Maps of change in connectivity of the Default mode network Changes in Maps of change in connectivity of the Limbic network Changes in Maps of change in connectivity of the Salience network
  • Changes in structural connectivity networks known to be affected in Alzheimer Disease [ Time Frame: Screening and 12 months. ]
    Changes in Connectivity changes of the parahippocampus/fornix Changes in Connectivity changes of the cingulum/cingulate fiber bundle Changes in connectivity changes of the caudate heads
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 5, 2019)
  • Changes in the microbiota composition [ Time Frame: Baseline, and 12 months. ]
    For the analysis of microbiota biomarkers Our characterization of the microbiome of the samples will include determination of the levels of biodiversity in the samples,we will divided samples into quartiles in order to label each sample as having low (1st quartile), average (2nd and 3rd quartiles), or high diversity (4th quartile).
  • Change in the dietary patterns (metabolomics) Plasma samples [ Time Frame: Baseline, 6, 12 and 15 months ]
    Change in the dietary patterns (metabolomics). Plasma, samples will be collected to analyze the corresponding metabolomes, we will divided samples into quartiles in order to label each sample as having low (1st quartile), average (2nd and 3rd quartiles), or high diversity (4th quartile)
  • Change in the dietary patterns (metabolomics) oral fluid [ Time Frame: Baseline, 6, 12 and 15 months ]
    Change in the dietary patterns (metabolomics) oral fluid will be collected to analyze the corresponding metabolomes.metabolomes.for a better understanding of the complexity of the interrelationship of metabolomics in oral fluid and mental health.
  • Change in the dietary patterns (metabolomics). urinary samples [ Time Frame: Baseline, 6, 12 and 15 months ]
    Change in the dietary patterns (metabolomics). urinary samples will be collected to analyze the corresponding metabolomes.for a better understanding of the complexity of the interrelationship of microbiota, diet, and mental health.
  • Exploratory [ Time Frame: At 6 and 12 months ]
    Change derived from the treatment compliance after a multimodal lifestyle change intervention metabolomes. urinary samples will be used to identify objective biomarkers of dietary intake and dietary patterns and to assess the degree of adherence to the Mediterranean diet by monitoring the levels of dietary metabolites.
  • Changes in the semantic verbal fluency [ Time Frame: Baseline, 6, 12 and 15 months ]
    Changes in additional cognitive performance scores of: (i) Semantic verbal fluency, "animals" in one minute. (which range from 0-12 words) higher score is better outcome.
  • changes in the Boston Naming Test [ Time Frame: Baseline, 6, 12 and 15 months ]
    Changes in additional cognitive performance scores of: (ii) naming, Boston Naming Test (BNT).: (which range from 0-15 points) higher score is better outcome.
  • change in attention and working memory, [ Time Frame: Baseline, 6, 12 and 15 months ]
    Changes in additional cognitive performance scores of: (iii) attention and working memory,
  • change in the Digit span subtest (WAIS IV) [ Time Frame: Baseline, 6, 12 and 15 months ]
    Changes in additional cognitive performance scores of: (iv) Digit span subtest (WAIS IV) , (which range from 0-16 points)
  • Changes in the Olfactory function [ Time Frame: Baseline, and 12 months ]
    Changes in the Olfactory function: the University of Pennsylvania Smell Identification Test (UPSIT) is designed to test the function of an individual's olfactory system. It is the gold standard of smell identification tests. Its performance has been related to cognition and it has been widely used as a complementary assessment tool in dementia patients.( which range from 0-40)
  • Changes in the AD biomarkers related to (amyloid-β peptide) [ Time Frame: Baseline, and 12 months ]
    Changes in the AD biomarkers related to neurodegeneration, inflammation (amyloid-β peptide)
  • Changes in the AD biomarkers related to (Tau proteins) [ Time Frame: Baseline, and 12 months ]
    Changes in the AD biomarkers related to neurodegeneration, inflammation (Tau proteins)
  • Changes (CSF/plasma albumin ratio). [ Time Frame: Baseline, and 12 months ]
    Changes in other CSF biomarkers related with the blood brain barrier dysfunction will be investigated (CSF/plasma albumin ratio).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Prevention of Cognitive Decline in ApoE4 Carriers With Subjective Cognitive Decline After EGCG and a Multimodal Intervention
Official Title  ICMJE Prevention of Cognitive Decline in ApoE4 Carriers With Subjective Cognitive Decline After EGCG and a Multimodal Intervention
Brief Summary Alzheimer's disease (AD) neuropathology is characterized by deposits of insoluble amyloid β-peptide (Aβ) in extracellular plaques and aggregated tau protein, which is found largely in the intracellular neurofibrillary tangles. Current knowledge, has allowed a shift in the definition of AD from a syndromal to a biological construct, based on biomarkers that are proxies of pathology. However, little is known about mechanisms underlying the disease progression at its early stages. The loss of dendritic spines, the primary locus of excitatory synaptic transmission in the mammalian central nervous may be linked to cognitive and memory impairment in AD: A multimodal lifestyle change intervention (dietary, physical activity and cognition) combined with epigallocatechin gallate (EGCG) will slow down cognitive decline and improve brain connectivity in a population of participants with subjective cognitive decline (SCD). In humans, alterations in functional connectivity (FC) have been observed in early AD stages, subjective cognitive decline (SCD) and mild cognitive impairment (MCI). A hyper-synchronized anterior network and a posterior network characterized by a decrease in FC are the spatial features. These disruptions also seen in AD indicate that FC alterations appear very early in the course of the disease . Experimental research strongly suggests that in order to increase our cerebral reserves, we have to follow a lifestyle that takes into account many factors. Clinical studies provided evidence that individuals with more cerebral reserves are those who have a high level of education, who maintain regular physical activity and who eat in a healthy way. The environmental enrichment (EE) animal models confirmed that the experience plays a key role in increasing brain plasticity phenomena .There is a growing understanding that a valid therapeutic emerging approach in AD is prevention. A large number of modifiable risk factors for AD have been identified in observational studies, many of which do not appear to exert effects through amyloid or tau. This suggests that primary prevention studies focusing on risk reduction and lifestyle modification may offer additional benefits. The therapeutic approach proposed in the present project aims at improving synaptic plasticity and functional connectivity in early stages of AD, and specifically in SCD in the context of a personalized medicine approach that includes a multimodal intervention (nutritional, physical, cognitive and medical) looking at improving person-centered outcomes. In this context the proposed clinical trial design will evaluate the efficacy of EGCG in the context of a personalized medicine approach that includes a multimodal intervention (nutritional, physical, cognitive and medical) looking at improving person-centered outcomes. Early phase I studies in Down syndrome young adults showed that while subjects were under EGCG, improvements in cognition were observed but these vanished when treatment was discontinued. Phase II studies combining EGCG with cognitive training showed improvements in cognitive performance and adaptive functionality but interestingly sustained effects after treatment discontinuation. Observations made in humans are in agreement with preclinical studies showing that EGCG combined with environmental enrichment resulted in an improvement of age-related cognitive decline. These observations are in favor of the option of combining EGCG with a personalized multimodal intervention. The personalized multimodal intervention will take into account medical comorbidities (i.e. metabolic syndrome, T2DM), diet (including nutritional status), physical exercise, and will incorporate cognitive training and a behavioral intervention to aid subject's adherence and empowerment to the intervention proposed. This will be in-line with other clinical studies in AD showing the superiority of multimodal interventions vs. a single life style intervention (i.e. single nutrient, physical activity). Hypothesis: A multimodal lifestyle change intervention (dietary, physical activity and cognition) combined with epigallocatechin gallate (EGCG) will slow down cognitive decline and improve brain connectivity in a population of participants with subjective cognitive decline (SCD).
Detailed Description

Study Design: Randomized, double-blind, personalized clinical trial with 200 subjects with subjective cognitive decline (SCD) of both genders, with 4 arms of treatment Duration of the Study:The total duration of the study is expected to be 24 months (subject recruitment, baseline period, treatment period, follow-up, data analysis and study report).

Primary Objective(s):To evaluate the efficacy of a multimodal intervention (dietary, physical activity and cognition) combined with epigallocatechin gallate (EGCG) in slowing down cognitive decline.

Secondary Objective(s): To evaluate several underlying mechanisms that could explain the efficacy of the intervention in preventing the progression of cognitive decline: (i) changes in gut microbiota composition and in the metabolome derived by the action of microorganisms, (ii) changes in AD biomarkers (iii) changes in biomarkers of oxidation/inflammation Target Population: Subjects (approximately 200) diagnosed of Subjective Cognitive Decline (SCD), carriers of the Apolopoprotein E4 allele, fulfilling at least 3 additional SCD plus score (at least 5 criteria) recruited either from Hospital del Mar and its primary care provider or from Barcelona Beta Brain Research Centre.

Preselection criteria i.Adults aged 60-80 years with a BMI ≥18.5 and <32 kg/m2. ii.Subjective Cognitive Decline Questionnaire (SCD-Q) items 1 and 3 positive. (BBRC) iii.Subjects willing to participate and to perform all study procedures, including Apolipoprotein E4 genotyping iv.Subject has one informant partner who, in the investigator's judgment has frequent and sufficient contact with the subject as to be able to provide accurate information about subject's cognitive and functional abilities.

Study Arm(s): 1. Arm I: EGCG and a multimodal intervention (n=50) 2. Arm II: Placebo EGCG and a multimodal intervention (n=50) 3. Arm III: EGCG and healthy lifestyle recommendations (n=50) 4. Arm IV: Placebo EGCG and healthy lifestyle recommendations (n=50) Duration of Patient Participation: The total duration of the patient participation is expected to be 16 months. Run-in period (1 month): Basal assessment of cognitive performance (cognitive battery), diet and physical activity, daily living activities (self-reported tests) and mood (self-reported tests at basal assessment and EMA's). Interventions will last 12 months. Follow-up after intervention discontinuation: at least 3 months Treatment EGCG (Font-UP, laboratories Grand Fontaine), a daily dose of approximately 5-6 mg/kg up to 520 mg/day will be administered to subjects for 12 months or matched placebo Multimodal intervention (12 months): 1) Cognitive stimulation, guided group activities once per month; 2) Cognitive training, twice per week 30-45min sessions; 3) Psychoeducational support groups, 10 sessions, 4) personalized diet 8 sessions, 5) personalized physical activity.

End point The preclinical Alzheimer cognitive composite ADCS-PACC-Plus-exe
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
Arm I: EGCG and a multimodal intervention (n=50) Arm II: Placebo EGCG and a multimodal intervention (n=50) Arm III: EGCG and healthy lifestyle recommendations (n=50) Arm IV: Placebo EGCG and healthy lifestyle recommendations (n=50)
Masking: Double (Participant, Investigator)
Masking Description:
Randomized, double-blind clinical trial (Participant, investigator)
Primary Purpose: Prevention
Condition  ICMJE
  • Alzheimer Disease
  • Nutritional Intervention
  • Cognitive Function
Intervention  ICMJE
  • Dietary Supplement: EGCG

    Participants that weight >50kg intake one oral dose in the morning for breakfast and a second dose in the afternoon in (266 + 266 mg/EGCG, 49 + 49 g of Font-up).

    Participants that weight <50kg intake one oral dose in the morning for breakfast (266 mg/EGCG, 49 of Font-up

  • Dietary Supplement: Placebo EGCG
    Participants that weight >50kg intake one oral dose in the morning for breakfast and a second dose in the afternoon in (266 + 266 mg/EGCG, 49 + 49 g of Font-up)
  • Other: Personalized intervention
    A personalized intervention include a physical activity plan,dietary intervention, mental health promotion interventions,
  • Other: Lifestyle recommendations
    The recommendations are to balance caloric intake and physical activity to achieve and maintain a healthy body weight; consume a diet rich in vegetables and fruits;
Study Arms  ICMJE
  • Experimental: 1

    EGCG + multimodal intervention (n=50) Font-Up 49 to 98 gr Font-up (260-520mg EGCG)/day (If participant weight is ≤ 50kg will take 1 sachet each day, if participant weight is >50kg will take 2 sachets each day)

    + personalized intervention

    Interventions:
    • Dietary Supplement: EGCG
    • Other: Personalized intervention
  • Active Comparator: 2

    Font-Up 49 to 98 gr Font-up (260-520mg EGCG)/day (If participant weight is ≤ 50kg will take 1 sachet each day, if participant weight is >50kg will take 2 sachets each day)

    • non personalized intervention
    Interventions:
    • Dietary Supplement: EGCG
    • Other: Lifestyle recommendations
  • Placebo Comparator: 3

    Placebo Font-Up 49 to 98 gr Font-up (260-520mg EGCG)/day (If participant weight is ≤ 50kg will take 1 sachet each day, if participant weight is >50kg will take 2 sachets each day)

    + personalized intervention

    Interventions:
    • Dietary Supplement: Placebo EGCG
    • Other: Personalized intervention
  • Sham Comparator: 4

    Placebo Font-Up 49 to 98 gr Font-up (260-520mg EGCG)/day (If participant weight is ≤ 50kg will take 1 sachet each day, if participant weight is >50kg will take 2 sachets each day)

    • non personalized intervention
    Interventions:
    • Dietary Supplement: Placebo EGCG
    • Other: Lifestyle recommendations
Publications *
  • Skaper SD, Facci L, Zusso M, Giusti P. Synaptic Plasticity, Dementia and Alzheimer Disease. CNS Neurol Disord Drug Targets. 2017;16(3):220-233. doi: 10.2174/1871527316666170113120853. Review.
  • López-Sanz D, Bruña R, Garcés P, Martín-Buro MC, Walter S, Delgado ML, Montenegro M, López Higes R, Marcos A, Maestú F. Functional Connectivity Disruption in Subjective Cognitive Decline and Mild Cognitive Impairment: A Common Pattern of Alterations. Front Aging Neurosci. 2017 Apr 21;9:109. doi: 10.3389/fnagi.2017.00109. eCollection 2017.
  • Mandolesi L, Gelfo F, Serra L, Montuori S, Polverino A, Curcio G, Sorrentino G. Environmental Factors Promoting Neural Plasticity: Insights from Animal and Human Studies. Neural Plast. 2017;2017:7219461. doi: 10.1155/2017/7219461. Epub 2017 Jun 14. Review.
  • Galvin JE. Prevention of Alzheimer's Disease: Lessons Learned and Applied. J Am Geriatr Soc [Internet]. 2017 Oct [cited 2018 Jun 20];65(10):2128-33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28766695
  • De la Torre R, De Sola S, Pons M, Duchon A, de Lagran MM, Farré M, Fitó M, Benejam B, Langohr K, Rodriguez J, Pujadas M, Bizot JC, Cuenca A, Janel N, Catuara S, Covas MI, Blehaut H, Herault Y, Delabar JM, Dierssen M. Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans. Mol Nutr Food Res. 2014 Feb;58(2):278-88. doi: 10.1002/mnfr.201300325. Epub 2013 Sep 14.
  • de la Torre R, de Sola S, Hernandez G, Farré M, Pujol J, Rodriguez J, Espadaler JM, Langohr K, Cuenca-Royo A, Principe A, Xicota L, Janel N, Catuara-Solarz S, Sanchez-Benavides G, Bléhaut H, Dueñas-Espín I, Del Hoyo L, Benejam B, Blanco-Hinojo L, Videla S, Fitó M, Delabar JM, Dierssen M; TESDAD study group. Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Jul;15(8):801-810. doi: 10.1016/S1474-4422(16)30034-5.
  • Pons-Espinal M, Martinez de Lagran M, Dierssen M. Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1A. Neurobiol Dis. 2013 Dec;60:18-31. doi: 10.1016/j.nbd.2013.08.008. Epub 2013 Aug 20.
  • Catuara-Solarz S, Espinosa-Carrasco J, Erb I, Langohr K, Notredame C, Gonzalez JR, Dierssen M. Principal Component Analysis of the Effects of Environmental Enrichment and (-)-epigallocatechin-3-gallate on Age-Associated Learning Deficits in a Mouse Model of Down Syndrome. Front Behav Neurosci. 2015 Dec 11;9:330. doi: 10.3389/fnbeh.2015.00330. eCollection 2015.
  • McEwen SC, Siddarth P, Rahi B, Kim Y, Mui W, Wu P, Emerson ND, Lee J, Greenberg S, Shelton T, Kaiser S, Small GW, Merrill DA. Simultaneous Aerobic Exercise and Memory Training Program in Older Adults with Subjective Memory Impairments. J Alzheimers Dis. 2018;62(2):795-806. doi: 10.3233/JAD-170846. Erratum in: J Alzheimers Dis. 2019;67(3):1107.
  • Prince M, Comas-Herrera A, Knapp M, Guerchet M, Karagiannidou M. World Alzheimer Report 2016 Improving healthcare for people living with dementia. Coverage, Quality and costs now and in the future. Alzheimer's Disease International (ADI). London; 2016.
  • Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J, Cooper C, Fox N, Gitlin LN, Howard R, Kales HC, Larson EB, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N. Dementia prevention, intervention, and care. Lancet. 2017 Dec 16;390(10113):2673-2734. doi: 10.1016/S0140-6736(17)31363-6. Epub 2017 Jul 20. Review.
  • Buckley RF, Maruff P, Ames D, Bourgeat P, Martins RN, Masters CL, Rainey-Smith S, Lautenschlager N, Rowe CC, Savage G, Villemagne VL, Ellis KA; AIBL study. Subjective memory decline predicts greater rates of clinical progression in preclinical Alzheimer's disease. Alzheimers Dement. 2016 Jul;12(7):796-804. doi: 10.1016/j.jalz.2015.12.013. Epub 2016 Feb 4.
  • Ngandu T, Lehtisalo J, Solomon A, Levälahti E, Ahtiluoto S, Antikainen R, Bäckman L, Hänninen T, Jula A, Laatikainen T, Lindström J, Mangialasche F, Paajanen T, Pajala S, Peltonen M, Rauramaa R, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H, Kivipelto M. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015 Jun 6;385(9984):2255-63. doi: 10.1016/S0140-6736(15)60461-5. Epub 2015 Mar 12.
  • Crous-Bou M, Minguillón C, Gramunt N, Molinuevo JL. Alzheimer's disease prevention: from risk factors to early intervention. Alzheimers Res Ther. 2017 Sep 12;9(1):71. doi: 10.1186/s13195-017-0297-z. Review.
  • Vellas B, Carrie I, Gillette-Guyonnet S, Touchon J, Dantoine T, Dartigues JF, Cuffi MN, Bordes S, Gasnier Y, Robert P, Bories L, Rouaud O, Desclaux F, Sudres K, Bonnefoy M, Pesce A, Dufouil C, Lehericy S, Chupin M, Mangin JF, Payoux P, Adel D, Legrand P, Catheline D, Kanony C, Zaim M, Molinier L, Costa N, Delrieu J, Voisin T, Faisant C, Lala F, Nourhashémi F, Rolland Y, Van Kan GA, Dupuy C, Cantet C, Cestac P, Belleville S, Willis S, Cesari M, Weiner MW, Soto ME, Ousset PJ, Andrieu S. MAPT STUDY: A MULTIDOMAIN APPROACH FOR PREVENTING ALZHEIMER'S DISEASE: DESIGN AND BASELINE DATA. J Prev Alzheimers Dis. 2014 Jun;1(1):13-22.
  • Andrieu S, Guyonnet S, Coley N, Cantet C, Bonnefoy M, Bordes S, Bories L, Cufi MN, Dantoine T, Dartigues JF, Desclaux F, Gabelle A, Gasnier Y, Pesce A, Sudres K, Touchon J, Robert P, Rouaud O, Legrand P, Payoux P, Caubere JP, Weiner M, Carrié I, Ousset PJ, Vellas B; MAPT Study Group. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol. 2017 May;16(5):377-389. doi: 10.1016/S1474-4422(17)30040-6. Epub 2017 Mar 27.
  • Moll van Charante EP, Richard E, Eurelings LS, van Dalen JW, Ligthart SA, van Bussel EF, Hoevenaar-Blom MP, Vermeulen M, van Gool WA. Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. Lancet. 2016 Aug 20;388(10046):797-805. doi: 10.1016/S0140-6736(16)30950-3. Epub 2016 Jul 26.
  • Kivipelto M, Solomon A, Ahtiluoto S, Ngandu T, Lehtisalo J, Antikainen R, Bäckman L, Hänninen T, Jula A, Laatikainen T, Lindström J, Mangialasche F, Nissinen A, Paajanen T, Pajala S, Peltonen M, Rauramaa R, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER): study design and progress. Alzheimers Dement. 2013 Nov;9(6):657-65. doi: 10.1016/j.jalz.2012.09.012. Epub 2013 Jan 17.
  • Valls-Pedret C, Lamuela-Raventós RM, Medina-Remón A, Quintana M, Corella D, Pintó X, Martínez-González MÁ, Estruch R, Ros E. Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk. J Alzheimers Dis. 2012;29(4):773-82. doi: 10.3233/JAD-2012-111799.
  • Martínez-Lapiscina EH, Clavero P, Toledo E, San Julián B, Sanchez-Tainta A, Corella D, Lamuela-Raventós RM, Martínez JA, Martínez-Gonzalez MÁ. Virgin olive oil supplementation and long-term cognition: the PREDIMED-NAVARRA randomized, trial. J Nutr Health Aging. 2013;17(6):544-52. doi: 10.1007/s12603-013-0027-6.
  • Valls-Pedret C, Sala-Vila A, Serra-Mir M, Corella D, de la Torre R, Martínez-González MÁ, Martínez-Lapiscina EH, Fitó M, Pérez-Heras A, Salas-Salvadó J, Estruch R, Ros E. Mediterranean Diet and Age-Related Cognitive Decline: A Randomized Clinical Trial. JAMA Intern Med. 2015 Jul;175(7):1094-1103. doi: 10.1001/jamainternmed.2015.1668. Erratum in: JAMA Intern Med. 2018 Dec 1;178(12):1731-1732.
  • Morris MC, Tangney CC, Wang Y, Sacks FM, Barnes LL, Bennett DA, Aggarwal NT. MIND diet slows cognitive decline with aging. Alzheimers Dement. 2015 Sep;11(9):1015-22. doi: 10.1016/j.jalz.2015.04.011. Epub 2015 Jun 15.
  • Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer's disease. Alzheimers Dement. 2015 Sep;11(9):1007-14. doi: 10.1016/j.jalz.2014.11.009. Epub 2015 Feb 11.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 5, 2019) 		200
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2021
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

* Meet all selection criteria and none exclusion criteria.

  • Fulfill SCD criteria (113) including cognitive performance within normal values* (adjusted for age and education). At least SCD-Q items 1 and 3 positives.
  • Age between 60 and 80 with a BMI ≥18.5 and <32 kg/m2.
  • Carrying the ApoE4 allele.*. Fulfilling 2 additional SCD plus features from the ones listed below: memory-centered*, onset of symptoms within the last 5 years*,, corroborated by an informant*, concern about cognitive decline* and perception of lower performance compared with same age group* (criteria marked with* are among those proposed features for SCD-plus syndrome which may point to participants with a greater risk of AD pathology).
  • Participants willing to participate and to perform all study procedures. *: Normal scoring on psychometric evaluation.

Exclusion Criteria:

  • Inability or unwillingness to give written informed consent or communicate with the study staff or illiteracy.
  • Clinically significant unstable psychiatric disorder that may affect cognition (e.g. major depression disorder, schizophrenia, bipolar or psychotic disorder according to diagnostic and statistical manual of mental disorders fifth edition )
  • Neurological conditions that may affect cognition or may imply an early stage of neurodegenerative disease other than AD (i.e. cranioencephalic trauma with permanent neurologic effects, epilepsy, multiple sclerosis, previous stroke, extrapyramidal signs at physical exploration, history of brain tumor...).
  • History or evidence of any medical condition or use of medication that in the opinion of the investigator could affect subjects' safety or interfere with the study assessments (e.g. use of neuroleptic drugs, corticosteroids or immunosuppressive therapies that may affect inflammatory parameters).
  • Any contraindication to perform Lumbar Puncture procedure (e.g. platelet count <100.000/ml, lumbar spine deformity, anticoagulant treatment).
  • Any contraindication to perform brain MRI procedure (e.g. pacemaker, MRI-incompatible aneurysm clips).
  • Current intake of vitamin supplements, catechins or products containing EGCG (i.e. , Mega Green Tea capsules Life Extension or Font-UP Grand Fontaine Laboratories) for at least 3 months previous to the screening visit.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03978052
Other Study ID Numbers  ICMJE IMIM/PENSA
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Rafael de la Torre, Parc de Salut Mar
Study Sponsor  ICMJE Parc de Salut Mar
Collaborators  ICMJE
  • Fundacion IMIM
  • Barcelonabeta Brain Research Center, Pasqual Maragall Foundation
Investigators  ICMJE Not Provided
PRS Account Parc de Salut Mar
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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