Dementias and Microbiota Composition: Is Possible to Revert the Dementia Symptoms Reverting the Microbiota Composition?

Dementia is the major cause of disability and dependency among older adults worldwide affecting memory, cognitive abilities and behavior, interfering with one's ability to perform daily lives activities. Although age is the strongest known risk factor for the onset of dementia, it is not a natural or inevitable consequence of aging. Dementia not only affects older people, since up to 9% of the cases appear before 65 years. The impact of dementia is highly important in financial terms also in human costs to countries, societies and individuals.

Dementia is an umbrella term for several diseases, being Alzheimer's disease (AD) the most common form, contributing to 60-70% of cases. Other major forms include Lewy bodies Dementias (LBDs) and frontotemporal dementia (FTD).

The role of the gastrointestinal microbiota in human brain development and function is an area of increasing interest and research. A large number of studies suggest that the gut microbiota can influence the brain, cognition and behavior of the patients, and also modulate brain plasticity, modifying brain chemistry via various mechanisms like neural, immune and endocrine Within these last two years some studies have showed differences in the microbiota of the AD patients from healthy controls. In this sense, increasing number of studies, most of them in animal models, support the notion that probiotics have significant benefit in maintaining homeostasis of the Central Nervous System. And recent studies try to replicate this finding in AD patients with controversial results.

The main objective of DEM-BIOTA project is to improve the knowledge of the relationship between microbiota and dementia. DEM-BIOTA will explore the microbiota differences between dementias: AD, LBDs, that includes: Parkinson disease dementia (PDD) and Lewy Body Dementia (LBD) and FTD-behavioral variant, also in Mild Cognitive Impairment (MCI) to study the progression; in our context (Mediterranean diet and lifestyle) and characterize them in relation to neurocognitive and neuropsychiatric symptoms as well as patient functionality (dependency level). Moreover, the capacity of a probiotic compound in reverting or improving neurocognitive and neuropsychiatric symptoms and patient functionality in a sample of AD patients will be also studied.

Hypothesis: Currently any other study to our knowledge has studied the relationship between gut microbiota and dementia symptoms in our country. Although there are few recent studies that have explored relations between microbiota and dementia, they were conducted in Japan or USA. Taken into account the important factor of diet and lifestyle in microbiota composition and the differences between these countries (Japan and USA) and Mediterranean diet and lifestyle, it was the need of a relational study in our context. The hypothesis is that although it will be different microbiota between healthy and demented subjects, the microbiota composition of healthy subjects in Mediterranean context could significant differ from the above-mentioned studies.

In the few studies already conducted, the patients included were diagnosticated of AD or it were included patients from all type of dementias. Even though AD is the most common type of dementia, there are more types of dementias that should be considered differentially as the features are significantly different. Given the diversity through the symptoms across dementias, a characterization of the gut microbiota of different types of dementia will be described, specifically, AD, LBDs: LBD and PDD separately, and FTD-behavioral variant. Furthermore, MCI subjects will be also studied in order to explore the microbiota changes before the onset of dementia (taking into account the high percentage of MCI that progress to dementia). These studies could reveal a risk factor compositional microbiota to develop dementia. The hypothesis is that microbiota will differ through different dementias and could be related to the feature symptoms of each one, being MCI subjects between healthy and dementia patients, in terms of microbiota composition.

As pointed out in the introduction, preclinical research shows that probiotics may improve cognitive performances in animal models with impaired cognition. However, data about the effects of probiotics on cognitive performance or psychopathological symptoms in humans are scarce and controversial. This lack of agreement could due to the differences in the population studied (young adults, elderly, healthy and clinic population, neurologic and psychiatric patients), the measures (different mood scales and different cognitive assessments), the probiotic compositions and the duration of treatment (from 3 weeks to 12 weeks). Considering the lack of knowledge about the probiotics potential treating dementia symptoms, dementia AD patients will be treated with a probiotic compound (a probiotic mixture already successful in improving cognitive impairment in AD patients, but only assessed by a cognitive screening and with no analysis of microbiota). The study will be conducted in an elderly group affected from AD, with a broad type of neuropsychological, neuropsychiatric and functional measures, and microbiota characterization at 12 and 24 weeks of treatment. An improvement of dementia symptoms due to probiotic consumption is expected, not only neuropsychological but also at a neuropsychiatric and functional level and these changes will be related to the changes of microbiota composition.

General objective: The main objective of DEM-BIOTA is to confirm the relationship between microbiota and dementia in our model of diet and lifestyle, improving the knowledge of the relationship between microbiota and dementias. This means to explore the possible differences between dementias in relation to microbiota in our context (Mediterranean diet and style of life) and characterize them in relation to neurocognitive and neuropsychiatric symptoms as well as patient functionality (dependency level). Moreover, the capacity of a probiotic compound in reverting or improving neurocognitive and neuropsychiatric symptoms and patient functionality will be studied.

This objective will be achieved through a multidisciplinary study considering microbiota composition and deep study of the dementia symptoms taking into account the personal characteristics of each patient. The final issue is to draw a relational map about the microbiota composition and dementia symptoms and the identification of the microbiota strains that are a risk factor of produce a deficit in metabolites. The project proposes to finally study how can a probiotic mixture improve AD symptoms, and study in deep the microbiota composition changes along with the changes (or not) of dementia symptoms.

This main objective will be carried out by combining our previous knowledge, partly of the collaboration with European Union partners, with data provided by literature on international studies on human population.

The aim match with the activities addressed in 1st Challenge identified in the Spanish Strategy for R+D+I Targeted to Societal Challenges "Health, Geographical change and Well-being": 1.1.2. Understanding disease; 1.2.1. Development of effective prevention and detection programs and improvement of disease propensity assessment.

1.3. SPECIFIC OBJECTIVES

1. - Protocol revision and preparation. Revision of the all tests and scales, writing down all the protocols, alignment the study protocols with the hospitals' procedures, timetables, sample collection protocols, etc.
2. - Study the microbiota composition (from stool samples of the patients) of AD patients in our context (Mediterranean lifestyle).

   Describe the microbiota composition from AD patients in relation with their healthy controls.

   To what extent does it differ from their controls and from the AD patient's composition of other countries?
3. - Study microbiota composition differences (from stool samples of the patients) between some of the most known dementias: AD, PDD, LBD, FTD-behavioral variant

   Describe and compare microbiota composition between some of the most known dementias: AD, PDD, LBD, FTD-behavioral variant.

   Describe and compare microbiota composition between MCI patients and AD patients.

   Describe and compare microbiota composition between MCI patients and PDD, LBD, FTD-behavioral variant patients.

   Are there any relations between the microbiota composition of all experimental groups with neuropsychological, neuropsychiatric and functional characteristics present in these dementias and in these patients? All these relations could be modulated by life stressors and diet (adherence to Mediterranean diet)?
4. - Study the effects of a probiotic compound in AD patients. In relation to AD symptoms: neuropsychological, neuropsychiatric and functional In relation to microbiota composition (analyzed from the stool samples of the patients) Until what extend and how the microbiota composition explains the AD symptoms? Can this probiotic compound improve the symptoms and is in general a good treatment/complement to the nowadays treatment?
5. - Dissemination and formation. Dissemination of results at scientific (open access journals, congresses and other national and international meetings) and social level disclosure (newspapers, research group web, webs of the hospitals and Alzheimer association, conferences to general public, radio, television, etc.), as well as formation to patients, professionals and general public.

Eligibility Criteria:
Inclusion Criteria:

Study 1, microbiota composition study- AD, PD, LBD, FTD-behavioral variant or MCI-amnesic

* diagnosed by the neurology service (or healthy subjects, without any of these diagnostics).
* more than 60 years

Study 2-probiotic intervention,:

* AD diagnosed by the neurology service;
* more than 65 years.

Exclusion Criteria:

Study 1, microbiota study:

* Comorbidity with other significant neurology disease,
* Infectious treatment with antibiotics in the previous 6 months prior to providing the stool sample,
* corticosteroid use,
* immunosuppressors or immunostimulants treatment,
* illnesses of the Gastro Intestinal tract,
* large doses of commercial probiotics consumed (greater than or equal to 10 elevated to 8 colony forming unit per organisms per day).

Study 2-probiotic intervention:

* Comorbidity with other significant neurology disease,
* Infectious treatment with antibiotics in the previous 6 months prior to providing the stool sample,
* corticosteroid use,
* immunosuppressors or immunostimulants treatment,
* illnesses of the GI tract,
* large doses of commercial probiotics consumed (greater than or equal to 10 elevated to 8 cfu per organisms per day).