Overview

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

Eligibility

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)