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NCT Number: NCT03978052

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

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).

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Key information

Conditions

Alzheimer Disease Behavior Brain Diseases Central Nervous System Diseases Cognition Disorders Cognitive Decline Cognitive Dysfunction Dementia Mental Disorders Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases Risk Reduction Behavior Tauopathies

Age range

60 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Barcelonabeta Brain Research Center, Barcelona, Barcelona, Spain, Spain

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About this study

Study Design: Randomized, double-blind, personalized clinical trial with 150 subjects with subjective cognitive decline (SCD) of both genders, with 3 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): 1 To evaluate the safety of the interventions 2 To evaluate several underlying mechanisms that could explain the efficacy of the intervention in preventing the progression of cognitive decline: (i) Changes in brain connectivity, (ii) changes in AD biomarkers, (iii) changes in biomarkers of oxidation/inflammation, (iv) changes in gut microbiota composition and the metabolome derived by the action of microorganisms, v) changes in biological aging predictors.

Target Population: Subjects diagnosed with Subjective Cognitive Decline (SCD) criteria including cognitive performance within normal values (Normal scoring on psychometric evaluation, adjusted for age and education), carriers of the Apolipoprotein E4 allele, recruited either from either the Parc de Salut Mar and its primary care providers, from Barcelona Beta Brain Research Centre or through a web-based system.

Preselection criteria i.Adults aged 60-80 years with a BMI ≥18.5 and <32 kg/m2. ii. Ad-hoc Subjective Cognitive Decline Questionnaire (SCD-Q) item "do you perceive memory or cognitive difficulties?" positive.

iii. Subjects willing to participate and perform all study procedures, including Apolipoprotein E4 genotyping iv. The subject has one informant partner who, in the investigator's judgment has frequent and sufficient contact with the subject to provide accurate information about the subject's cognitive and functional abilities.

Study Arm(s):

  • Arm I: EGCG and multimodal intervention (n=50)
  • Arm II: Placebo EGCG and multimodal intervention (n=50)
  • Arm III: Healthy lifestyle recommendations (n=50) Duration of Patient Participation: The total duration of patient participation is expected to be 17 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 500 mg/day will be administered to subjects for 12 months or a matched placebo Multimodal intervention (12 months): 1) Social stimulation, ten 90-120 minutes guided group activities; 2) Cognitive training, trice per week, 30-minute sessions; 3) Psychoeducational support groups, 10 sessions, 4) personalized diet 8 sessions, 5) personalized physical activity.

End point: modified Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC), including additional tests of executive functions: the PACC-exe.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

i. Meet all selection criteria and no exclusion criteria. ii. Fulfill SCD criteria (Jessen et al. 2014) including cognitive performance within normal values (Normal scoring on psychometric evaluation, adjusted for age and education).

iii. Age between 60 and 80 with a BMI ≥18.5 and <35 kg/m2. iv. Carrying the APOE-ɛ4 allele. v. Participants are willing to participate and perform all study procedures.

Exclusion criteria

i. Inability or unwillingness to give written informed consent or communicate with study staff or illiteracy.

ii. Clinically significant unstable psychiatric disorder that may affect cognition (e.g. major depression disorder, schizophrenia, bipolar or psychotic disorder according to DSM-V).

iii. Neurological conditions that may affect cognition or may imply a prodromal stage of neurodegenerative disease other than AD (e.g., cranioencephalic trauma with permanent neurologic effects, epilepsy, multiple sclerosis, previous stroke, extrapyramidal signs at physical exploration, history of brain tumor...).

iv. 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, anticonvulsant medications (except gabapentin and pregabalin for non-seizure indications) corticosteroids or immunosuppressive therapies that may affect inflammatory parameters).

v. Any contraindication to perform brain MRI (e.g. pacemaker, MRI-incompatible aneurysm clips).

vi. Clinically significant abnormalities in laboratory test or MRI scan results at screening unless acceptable by the investigator (e.g. mild/moderate kidney failure, benign tumor that does not require surgical intervention…).

vii. Any medical condition that may affect the study assessments in the opinion of the principal investigators or medical advisors.

viii. Current intake of vitamin supplements, catechins, or products containing EGCG (i.e. TEAVIGO, Mega Green Tea Capsules Life Extension, or Font-UP Grand Fontaine Laboratories) for at least 3 months previous to the screening visit.

ix. History within the last 2 years of treatment for primary or recurrent malignant disease, excluding non-melanoma skin cancers, resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or situ prostate cancer with normal prostate-specific antigen post-treatment.

Treatment and study plan

EGCG

Dietary Supplement

FontUp capsules (100 mg of EGCG each)

12 months, three to five capsules per day (participant's weight ≤ 50kg: 3 capsules/day; weight >50kg: 5 capsules/day.

Placebo EGCG

Dietary Supplement

Placebo FontUp (same appearance as active).

12 months, three to five capsules per day (participant's weight ≤ 50kg: 3 capsules/day; weight >50kg: 5 capsules/day.

Healthy lifestyle recommendations

Other

Personalized advice on diet, physical activity, cognitive training, and social stimulation activities.

Multimodal lifestyle intervention

Other
  • Dietary intervention: personalized dietary recommendations based on MedDiet, 9 individual counseling sessions.
  • Physical activity intervention: Guided gymnasium (aerobic, strength, and balance activities). Minimum one class/week the first 6months, and two classes/week from month 7 to 12). Achieve a physically active lifestyle (10,000 steps/day; individuals living with disability 8,500 steps/day). Achieve moderate physical exercise in older adults (150 to 210 minutes/week or 90 to 150 minutes depending on medical history.
  • Cognitive training: NeuronUP, 3/week, 30 min sessions
  • Psychoeducation: ten 90-minute sessions
  • Social stimulation activities: ten to twelve 90-to-120-minute sessions.

Primary outcomes

  1. Modified Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC) including additional tests of executive functions: the PACC-exe

    Time frame: Screening and 12 months

    Changes in the PACC-exe, that include:

    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 Coding Test Total score from the Wechsler Adult Intelligence Scale-Revised (which range from 0-93 symbols), The Montreal Cognitive assessment (MOCA) total score (which range from 0-30 points), and additionally, the Interference score from the Stroop Colour and Word Test (SCWT) and the Five Digit Test. 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.

Secondary outcomes

  1. Safety outcome of the intervention with EGCG: AEs and SAEs

    Time frame: Baseline, 6 and 12

    evaluated by means of Incidence, nature, severity and causality of adverse events (AEs) and serious adverse events (SAEs)

  2. Safety outcome of the intervention with EGCG: Biomarkers thyroid

    Time frame: Baseline, 6 and 12

    Assessment of thyroid function parameters: both TSH and freeT4 within normal values according to the reference population

  3. Safety outcome of the intervention with EGCG: Biomarkers liver

    Time frame: Baseline, 6 and 12

    Assessment of liver function parameters: ALP and ALT within normal values according to the reference population

  4. Safety outcome of the intervention with EGCG: Biomarkers

    Time frame: Baseline, 6 and 12

    Assessment of renal function parameters: creatinine within normal values according to the reference population

  5. 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

  6. 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 outcomes

  1. Changes in Modified Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC) including additional tests of executive functions: the PACC-exe

    Time frame: Screening, 6, 12 and 15 months.

    Changes in the PACC-exe, that include:

    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 Coding Test Total score from the Wechsler Adult Intelligence Scale-Revised (which range from 0-93 symbols), The Montreal Cognitive assessment (MOCA) total score (which range from 0-30 points), and additionally, the Interference score from the Stroop Colour and Word Test (SCWT) and the Five Digit Test. 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.

  2. 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. Samples will be divided 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) 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 (SFCAs, kynurenine pathway...), we will divide samples into quartiles to label each sample as having low (1st quartile), average (2nd and 3rd quartiles), or high diversity (4th quartile)

  4. Change in the dietary patterns (metabolomics) oral fluid

    Time frame: Baseline, 6, 12 and 15 months

    Changes in the dietary patterns (metabolomics) of oral fluid will be collected to analyze the corresponding metabolomes for a better understanding of the complexity of the interrelationship of metabolomics in oral fluid and mental health.

  5. 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.

  6. Exploratory

    Time frame: At 6 and 12 months

    Change in metabolomes derived from the treatment compliance after a multimodal lifestyle change intervention. Urinary samples (24h) 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 (i.e. hydroxytyrosol metabolism, biomarkers of alcohol consumption...).

  7. 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.

  8. 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.

  9. 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,

  10. 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)

  11. 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)

  12. Changes in the AD biomarkers

    Time frame: Baseline, and 12 months

    Changes in the AD biomarkers related to neurodegeneration (NfL), neurotoxicity (GFAP),Tau proteins amyloid-β peptides

  13. Changes in biological aging

    Time frame: Baseline and 12 months

    Blood sample will be collected for further analysis on biological age biomarkers assessed by epigenetics (biological ageing). The difference between chronological age and biological age, defined as average age acceleration (Δage), will be used to determine individual aging.

  14. Changes in physical activity/fitness: VREM

    Time frame: Screening, 6, 12 and 15 months

    Changes in physical activity as measured by the Spanish Short Version of the Minnesota Leisure Time Physical Activity Questionnaire (Comellas et al., 2012). It reports energy expenditure during leisure time and allows individuals to be classified into activity categories.

  15. Changes in physical activity/fitness: RAPA

    Time frame: Screening, 6, 12 and 15 months

    Changes in physical activity as measured by the Rapid Assessment of Physical Activity (RAPA). Designed for quickly assessing the level of physical activity of older adults.

  16. Changes in physical activity/fitness: SPPB

    Time frame: Screening, 6, 12 and 15 months

    Changes in physical performance as measured by The Short Physical Performance Battery (SPPB), a validated measure of physical function in older adults. The SPPB represents the sum of results from three component tests of functional relevance: standing balance, 4-meter gait speed (4MGS), and five-repetition sit-to-stand motion (5STS)

  17. Changes in physical activity/fitness: SFT

    Time frame: Screening, 6, 12

    Changes in physical performance as measured by the The Senior Fitness Test battery evaluating balance (flamingo test), lower limb strength (chair stand test), upper limb strength (arm curl test), lower limb flexibility (chair sit-and-reach test), upper limb flexibility (back scratch test), agility (8-foot up-and-go test), speed (brisk walking test) and resistance (6-minute walk test).

  18. Changes in physical activity/fitness: grip strength

    Time frame: Screening, 6, 12 and 15 months

    Changes in physical performance as measured by the grip strength with a dynamometer, which measures the maximum isometric strength of the hand and forearm muscles.

  19. Changes in physical activity/fitness: Fitbit steps

    Time frame: Screening, 6, 12 and 15 months or continuous measures (Fitbit measures and EMAs)

    Changes in physical activity as measured by the number of steps

  20. Changes in physical activity/fitness: Fitbit physical activity

    Time frame: Continuous measure

    Changes in physical activity as measured by the physical activity estimation. Each minute is classified as being sedentary, light, moderate or vigorous activity, based on metabolic equivalent (METs), which are indicators for exercise intensity. After 10 minutes of continuous moderate to intense activity, equivalent for activities at or above 3 METs, such minutes are considered "active minutes".

  21. Changes in physical activity/fitness: Fitbit floors climbed

    Time frame: Continuous measure

    Changes in physical activity as measured by the number of floors climbed

  22. Changes in physical activity/fitness: Fitbit active minutes

    Time frame: Continuous measure

    Changes in physical activity as measured by the number of active minutes

  23. Changes in physical activity/fitness: Fitbit heart rate

    Time frame: Continuous measure

    Changes in physical activity as measured by the heart rate

  24. Changes in quality of sleep: Fitbit sleep

    Time frame: Continuous measure

    Changes in sleep as measured by the sleep duration

  25. Changes in quality of sleep: Pittsburg Sleep Quality Index

    Time frame: Screening, 6, 12 and 15 months

    Changes in sleep measured by the Pittsburg Sleep Quality Index: provides a global index of sleep quality over the previous one-month interval. It is a generic, 19 items self-rated scale designed to measure overall sleep problems

  26. Changes in quality of sleep: Epworth sleepines scale

    Time frame: Screening, 6, 12 and 15 months

    Changes in sleep Epworth sleepiness scale (ESS): The ESS assesses daytime sleepiness. It is a four-grade scale (0, no napping; 3, high likelihood of napping), with eight questions, with a maximum of 24 points; a score >10 is considered to be excessive sleepiness.

  27. Treatment compliance/adherence: EGCG

    Time frame: Screening, 6 and 12 months

    As a biomarker of EGCG ingestion compliance, EGCG will determined in plasma samples by HPLC/MS/MS at 6 and 12 months.

  28. Treatment adherence: Diet

    Time frame: Screening, 6 and 12 months

    Compliance/adherence with diet will be assessed by means of 3-day food diaries

  29. Treatment compliance/adherence: mental health

    Time frame: Screening, 6 and 12 months

    Adherence to mental health interventions will be assessed through means of: (i) monitoring the attendance to the psychoeducational group sessions, (ii) monitoring the attendance to the monthly cognitive stimulation activities, and (iii) monitoring the attendance to the scheduled cognitive training sessions (NeuronUp).

  30. Treatment compliance/adherence: MedDiet-index

    Time frame: Screening, 6 and 12 months

    Compliance/adherence with diet will be assessed by means of the 14-item Mediterranean Diet adherence screener (Martínez-González MA et al. 2012)

  31. Treatment compliance/adherence: Diet MNA

    Time frame: Screening, 6 and 12 months

    Compliance/adherence diet as assessed by the Mini Nutritional Assessment test (MNA), a single, rapid assessment of nutritional status in elderly patients in outpatient clinics, hospitals, and nursing homes. The MNA test is composed of simple measurements and brief questions that can be completed in about 10 min. The sum of the MNA score distinguishes between elderly patients with: 1) adequate nutritional status, MNA > or = 24; 2) protein-calorie malnutrition, MNA < 17; 3) at risk of malnutrition.

  32. Changes in adaptive behaviour: ABAS-2

    Time frame: Screening, 6, 12 and 15 months

    Changes in adaptive behavior as measured by the Adaptive Behavior Assessment System - Second Edition -ABAS-II- for adults. The ABAS-II tool for adults (ages 16 to 89) includes 5 subscales which assess the individual's competence (in terms of behavior frequency) in 10 different skill areas: communication abilities, community use, functional academics, home living, health and safety, leisure, self-care, self-direction, social interaction and working/labor skills

  33. Changes in Quality of Life: EQ-5D-5L

    Time frame: Screening, 6, 12 and 15 months

    Changes in quality of Life as measured by the EuroQol 5 dimensions 5 levels (EQ-5D-5L) the most used econometric instrument in the world. It is a generic instrument, applicable both in the general population and in patients with different conditions. It contains 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. It generates a single score that incorporates society's preferences for health states (utilities), suitable for cost-utility analysis by calculating quality-adjusted life years (QALYs). The health index range from 1 (perfect health) to negative values (for those states considered worse than death), 0 being the value assigned to death. The EQ-5D-5L has been validated in the Spanish population

  34. Changes in quality of life: WHOQOL-BREF

    Time frame: Screening, 6, 12 and 15 months

    Changes in quality of life measured by the the World Health Organization brief generic questionnaire (WHOQOL-BREF), a cross-cultural instrument to assess quality of life. It assesses the following broad domains: physical health, psychological health, social relationships, and environment

Sponsors and collaborators

Lead sponsor

Parc de Salut Mar

Other

Collaborators

  • Barcelonabeta Brain Research Center, Pasqual Maragall Foundation
  • Hospital del Mar Research Institute

Registry information

Acronym: (PENSA)

Important dates

Study start
2019
Primary completion
2023
Study completion
2023
First posted
Jun 6, 2019
Registry last updated
Mar 15, 2024

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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