Tanycytes in Alzheimer's Disease and Frontotemporal Dementia

Study Overview
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Brief Summary
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Metabolic and hormonal deregulations are both a risk factor and a hallmark of Alzheimer's disease (AD) and frontotemporal dementia (FTD), occurring early in the course of the disease. In FTD in particular, hyperorality and dietary changes are associated with metabolic and hormonal changes such as altered levels of the anorexigenic hormone leptin. The hypothalamus is a brain region that controls metabolism and hormonal systems. Hypothalamic function depends on its ability to sense peripheral signals. The hypothalamus sits on a circumventricular organ called the median eminence (ME) that puts it in contact with systemic blood circulation. In the ME, fenestrated capillaries allow the diffusion of bloodborne factors. However, despite the lack of blood-brain barrier at brain microvessels, diffusion is controlled by specialized ependymoglial cells, the tanycytes, which exert a barrier function between the ME and the third ventricle and controls the access of blood-borne molecules into the hypothalamus. Previous work from our laboratory and the ERC consortium has highlighted the role of tanycytes not only in the regulation of the release of neurohormones from neuroendocrine nerve terminals into the pituitary portal blood circulation, but also in the transport of circulating leptin into the hypothalamus. Hence hypothalamic dysfunction in AD and FTD can result either from dysregulation of neuroendocrine secretions, direct neuronal loss or from defective transport (and hence resistance) to hormones like leptin. This study is to demonstrate that leptin transport though tanycytes is early altered in FTD and AD and correlates

Official Title
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TANYCYTES' ROLE IN ALZHEIMER'S DISEASE AND FRONTOTEMPORAL DEMENTIA: ARE THEY THE KEY TO WELL AGING?

Conditions
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Alzheimer Disease, Frontotemporal Dementia

Intervention / Treatment
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* Biological: Lumbar puncture
* Biological: blood sample


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects able to undergo a lumbar puncture Subjects registered with the French Social Security, in agreement with the French law on biomedical experimentation To be assigned in the study subgroups, subjects will have to fulfill the specific following criteria: Group 1: Controls absence of cognitive complaint (completion of the memory complaint questionnaire) absence of significant cognitive impairment: normal MMSE according to age and education levels Subjects capable of and willing to comply with the protocol and to give their written informed consents after having received and understood the subject information Group 2: Alzheimer's Disease Diagnosis of probable Alzheimer's disease dementia according to the NIA 2011 criteria1 MMSE ≥ 16 Subjects who have a study partner. The study partner is required to complete several scales and to drive back the subject after the lumbar puncture for safety reasons. If the subjects or their study partners are not able to drive, their transport fees will be reimbursed by the promotor Subjects and his/her study partners capable of and willing to comply with the protocol and to give their written informed consents after having received and understood the subject information. According to the legal protection or the mental capacities of the subject, he/she will be accompanied by him/her legally acceptable representative during this procedure Group 3: Frontotemporal Dementia Diagnosis of probable frontotemporal dementia according to the FTDC 2011 criteria2 MMSE ≥ 16 Subjects who have a study partner. The study partner is required to complete several scales and to drive back the subject after the lumbar puncture for safety reasons. If the subjects or their study partners are not able to drive, their transport fees will be reimbursed by the promotor Subjects and his/her study partners capable of and willing to comply with the protocol and to give their written informed consents after having received and understood the subject information. According to the legal protection or the mental capacities of the subject, he/she will be accompanied by him/her legally acceptable representative during this procedure Exclusion Criteria: General exclusion criteria: Subjects with dementia caused by a non-neurodegenerative disease, including patients with severe cerebrovascular risk factor load Subjects who have contraindications to perform a lumbar puncture Subjects who have contraindications to perform a MRI scan Associated illnesses or conditions: Subjects with other neurodegenerative disease such as Lewy body dementia and Parkinson's disease Subjects with other serious neurological disorder such as brain tumor, stroke, epilepsy, hydrocephalus and any condition which contraindicates, in the investigator's judgment, entry to the study; Subjects with severe metabolic or endocrine disorder (excluding hypothyroidism under stable hormone replacement therapy, controlled type 2 diabetes or common dyslipidaemia), previously known or identified at screening Subjects under metformin treatment. Biological exclusion criteria: Subjects with known active HCV, HBV or HIV Subjects with clinical or significant laboratory abnormalities, previously known or identified at screening, in the judgment of the investigator Others: Pregnancy or breastfeeding or Women of childbearing age without effective contraception (a pregnancy test will be done) Subjects with excessive alcohol intake or drug abuse, in the judgment of the investigator Subjects who, in the opinion of the investigator, have a risk of non-compliance to the study procedures or who are otherwise not appropriate to include in this clinical trial (for example, being impossible to contact in case of emergency)

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1: Controls<br> | Biological: Lumbar puncture<br>* 5 mL of CSF<br>Biological: blood sample<br>* 6x5 mL of blood sample collected :1 dry tube, 2 EDTA tubes, 1 fluoride tube, and 2 polypropylene tubes<br>|
| Group 2: Alzheimer's Disease<br> | Biological: Lumbar puncture<br>* 5 mL of CSF<br>Biological: blood sample<br>* 6x5 mL of blood sample collected :1 dry tube, 2 EDTA tubes, 1 fluoride tube, and 2 polypropylene tubes<br>|
| Group 3: Frontotemporal Dementia<br> | Biological: Lumbar puncture<br>* 5 mL of CSF<br>Biological: blood sample<br>* 6x5 mL of blood sample collected :1 dry tube, 2 EDTA tubes, 1 fluoride tube, and 2 polypropylene tubes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean CSF-to-blood ratio (CBR) of leptin concentration. | Leptin concentration in blood and CSF (in the pg/mL range) will be measured by enzyme-linked immunosorbent assay (ELISA). | At visit 2, occurring 1 to 90 days after visit 1(Baseline) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean of the CSF-to-blood ratio (CBR) of hypothalamus-related hormones | CSF-to-blood ratio (CBR) of hypothalamus-related hormones | At visit 2, occurring 1 to 90 days after visit 1(Baseline) | 
| Blood metabolomics | Blood and CSF metabolites will be measured by LC MS/MS.Will be used a mix of targeted and untargeted approach for metabolomics using the Thermo Q-Exactive Orbitrap. | At visit 2, occurring 1 to 90 days after visit 1(Baseline) | 
| CSF metabolomics | Blood and CSF metabolites will be measured by LC MS/MS.Will be used a mix of targeted and untargeted approach for metabolomics using the Thermo Q-Exactive Orbitrap. | At visit 2, occurring 1 to 90 days after visit 1(Baseline) | 
| Correlation coefficient between leptin CBR and general cognitive functioning assessed by the Mattis Dementia Rating Scale (MDRS)6 | Correlation coefficient between leptin CBR and general cognitive functioning | At visit 2, occurring 1 to 90 days after visit 1(Baseline) | 
| Correlation coefficients between leptin CBR and performances in a neuropsychological battery assessing the function of affective and social cognition in each AD and FTD groups | Correlation coefficients between leptin CBR and performances | At visit 2, occurring 1 to 90 days after visit 1(Baseline) | 
| Correlation coefficients between leptin CBR and behavioral, and psychological symptoms of dementia | Correlation coefficients between leptin CBR and behavioral, and psychological symptoms | At visit 2, occurring 1 to 90 days after visit 1(Baseline) | 
| Correlation coefficients between leptin CBR and putative symptoms/markers of hypothalamus dysfunction | Correlation coefficients between leptin CBR and putative symptoms/markers | At visit 2, occurring 1 to 90 days after visit 1(Baseline) | 
| Correlation coefficients between leptin CBR and changes in resting metabolic activity assessed by indirect calorimetry through | Correlation coefficients between leptin CBR and changes in resting metabolic activity | At visit 2, occurring 1 to 90 days after visit 1(Baseline) | 
| Correlation coefficients between leptin CBR and the following CSF biomarkers | Correlation coefficients between leptin CBR and the following CSF biomarkers | At visit 2, occurring 1 to 90 days after visit 1(Baseline) | 
| Correlation coefficients between leptin CBR and the following MRI markers | Correlation coefficients between leptin CBR and the following MRI markers | At visit 2, occurring 1 to 90 days after visit 1(Baseline) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer disease, Frontotemporal Dementia, tanycytes, metabolism, hormone, cerebrospinal fluid, blood, hypothalamus