Investigating Brain Insulin Resistance in Alzheimer Disease with IntraNasal Insulin : a Multimodal Neuroimaging Study

Using simultaneous multimodal neuroimaging (FDG-PET, fMRI, EEG), this research project will aim to further investigate in vivo brain insulin signalling by exploring the effects of acute INI administration on neurometabolic and neurovascular coupling, and on cortical electrical activity, both in individuals with normal cognitive function and those affected by Mild cognitive Impairment and Alzheimer's Disease .

Current pharmacological interventions mostly target symptoms. Most recently, disease-modifying therapies targeting beta-amyloid aggregation have been developed. Randomized controlled trials using these drugs (Lacenemab and Donanemab) in patients with early symptomatic AD showed a modest impact in terms of slowing cognitive decline and reducing amyloid biomarkers, associated with significant adverse effects. Yet, to date, no pharmacological intervention has been shown to reverse the loss in cognitive function associated with AD, nor to prevent the development of AD pathology. The risk of developing AD is influenced by both genetic and acquired factors, which include APOE genotype and insulin resistance. A better understanding of the association between insulin resistance and AD has important implications, both from a pathophysiological perspective and to foster the development of new therapeutic and preventive strategies. Observational studies have unambiguously demonstrated the bidirectional link between AD and type 2 diabetes mellitus (T2DM). Moreover, recent studies have shown that AD patients without T2DM have impaired insulin signalling at the brain level, which has led the field to define AD as "type 3 diabetes". Insulin is a hormone normally synthesized by the pancreas to regulate blood glucose levels and its utilization within the cells of our body, including the brain. To date, studies using intranasal insulin (INI) administration to investigate brain insulin signalling have shown significant variations in fMRI BOLD signal and improved cognition in healthy subjects. In AD patients, chronic INI administration for months showed that it significantly slowed down the progressive brain metabolism alteration as measured by positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG), and to reduce the ratio of tau on amyloids deposit levels in cerebro-spinal fluid(tau-P181 to CSF Aβ42). Taken together, these findings raise the possibility that insulin is modifying AD-related processes.However, the effects of acute INI administration on brain function and cognition in healthy and AD subjects is not fully characterized yet. Acute INI could help to identify pathophysiologic processes occurring after a single doses, mainly insulin signalling and not due to any long term exposure event (genetic expression or modulation of the receptors).

PET-FDG is a neuroimaging technique that enables the quantification of human brain metabolism. Magnetic Resonance Imaging (MRI) utilizes a magnetic field to capture high-precision structural information about the humain brain. Functional MRI (fMRI) extends the capabilities of traditional MRI by capturing information on the modulation of brain perfusion during tasks and resting state. Finally, electroencephalography (EEG) allows direct and dynamic acquisition of cortical electric activity and allow to study functional brain connectivity.

Using simultaneous multimodal neuroimaging (FDG-PET, fMRI, EEG), this research project will aim to further investigate in vivo brain insulin signalling by exploring the effects of acute INI administration on neurometabolic and neurovascular coupling, and on cortical electrical activity, both in individuals with normal cognitive function and those affected by MCI/AD.

Eligibility Criteria:
Inclusion Criteria:

For the young subject group (group 1):

* Men and women aged 21-45 years old.
* Women under effective contraception.
* For Women, the study protocol should be performed during the follicular phase of the menstrual cycle, because of ...
* Subjects must be proficient in speaking, reading and understanding French in order to be assessed with the neuropsychological tests battery.

For the MCI/AD group (group 2):

* Men and women aged 40-85 years old.
* Patients included on the registry of Neurodegeresence study in Hopital Erasme.
* Patients are capable of providing informed consent.
* Patients are proficient in speaking, reading and understanding French, in order to be assessed with the neuropsychological tests battery.
* Being diagnosed with amnestic MCI or probable mild AD, according to the core clinical criteria of the NIA and Alzheimer's Association guidelines.
* If the patient has a prescription medication acetylcholinesterase inhibitor (e.g. donepezil, rivastigmine, galantamine) and/or memantine doses has to be stable since 1 month at least.

For the group 2 - matched controls (group 3):

* Men and women aged 40-85 years old.
* Participants capable of providing informed consent
* Subjects are proficient in speaking, reading and understanding French, in order to be assessed with the neuropsychological tests battery.

Exclusion Criteria:

Exclusion criteria related to trimodal neuroimaging data acquisition:

* Dense or tight hair braiding or scalp lesions, preventing adequate EEG cap positioning.
* Pregnancy and/or breastfeeding.
* Claustrophobia.
* Metallic component (e.g. pacemaker) incompatible with the MRI acquisition.
* Participants over 120 kg for radioprotection issues.

Exclusion criteria related to demographic data:

* Any acute medical condition that required either hospitalization or surgery within the past 6 months.
* The subject has participated in a clinical trial investigation within 1 month of this study.
* Current or past psychiatric illness (according to the Mini International Neuropsychiatric Interview \[MINI\])
* For healthy participants (groups 1 and 3), having a first degree relative with dementia onset before 65 years (Alzheimer, Lewy body disease, Parkinson)
* Dementia (Mini-Mental State Examination \[MMSE\] scores ≤ 20) for group 2 and 3.
* CDR score ≥2, witch will be evaluated before inclusion by investigator for group 2 and 3.
* Current recreational drug or alcohol abuse.
* Serious systemic disease that would interfere with the conduction of the trial .
* Based on selection of Dementia from neurologic causes, Hachinski Ischemia Score \> 4 (55).

Exclusion criteria related to the use of INI as IMP:

* Being under corticosteroid treatment (non-topical treatment)
* Being under birth-control pill containing ethinyl estradiol.
* The subject has an allergy to the IMP.
* History of bleeding disorder.
* The use of anticoagulants warfarin (Coumadin) or dabigatran (Pradaxa)
* Taking a hormonal therapy (e.g., post menopausal, oncological treatment...)
* Type 1 DM or Type 2 DM treated with insulin.
* History of severe hypoglycaemia.
* Participant being under any chronic Intranasal treatment.

Criteria susceptible to postpone study inclusion:

* Clogged or runny nose.
* Current Ears Nose Throat (ENT) infection.
* Fever during the last 24 hours.
* Consumption of caffeine during the last 24 hours.
* Fasting period inferior to 12h before study visits.
* Sleep deficiency the night preceding study days as assessed by Pittsburgh Survey