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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
TRIPLE
A venous line will be installed and an MRI-compatible EEG Cap (32 scalp electrodes) will be installed with conductive gel between the scalp and the electrode. Participants will receive 2 Intranasal spray. Participants will then be installed in the PET/MRI camera. At 30 min post INI administration, a continuous infusion of FDG will be started, along with dynamic PET acquisition while recording EEG and fMRI sequences. Participant will be asked to rest, eyes opened and awake to stay awake during the 55 minutes. At the end of the neuroimaging data acquisition, participants will be freed from EEG Cap and will undergo neuropsychologic evaluation.The final part of neuropsychological evaluation will be performed on week later, on the phone.. The total study time for each scanning day will be around 3h.
A venous line will be installed and an MRI-compatible EEG Cap (32 scalp electrodes) will be installed with conductive gel between the scalp and the electrode. Participants will receive 2 Intranasal spray. Participants will then be installed in the PET/MRI camera. At 30 min post INI administration, a continuous infusion of FDG will be started, along with dynamic PET acquisition while recording EEG and fMRI sequences. Participant will be asked to rest, eyes opened and awake to stay awake during the 55 minutes. At the end of the neuroimaging data acquisition, participants will be freed from EEG Cap and will undergo neuropsychologic evaluation.The final part of neuropsychological evaluation will be performed on week later, on the phone.. The total study time for each scanning day will be around 3h.
Effects of INI administration on FMRI data in the 3 groups
For brain fRMI data: BOLD signal variation (Arbitrary Unit from a percent change from baseline).
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Effects of INI administration on PET-FDG regional standardized data in the 3 groups
For brain PET-FDG: regional SUV value(standardized Uptake Ratio) .The SUV is a mathematically derived ratio of tissue radioactivity concentration at a point in time at a specific region of interest and the injected dose of radioactivity per kilogram of the patient's body weight
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Effects of INI administration on PET-FDG global data in the 3 groups
For brain PET-FDG: Statistical Parametric Mapping analysis (SPM) for voxel-wise groups comparison and multiple correlations (t-score)
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Effects of INI administration on EEG connectivity data in the 3 groups
Connectivity changes (SmallWorldness index σ , a quantitative method for determining canonical network equivalence,)
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Effects of INI administration on EEG Frequency band data in the 3 groups
Spectrum analysis of the power (Power of the EEG signal(µV²/Hz) plotted against frequency band in Hz)
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
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Impact of gender on Intranasal insulin administration responses
Co-analysis of primary endpoint: this variable will be included as covariable in group and population analysis (Male or Female)
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Impact APOE (apolipoprotein E ) genetic status on Intranasal insulin administration responses
Co-analysis of primary endpoint: this variable will be included as covariable in group and population analysis (Carrier , Homozygote , non-carrier)
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Impact of Insulino-resistance scores ( Homeostatic Model Assessment of insulin resistance Scale (HOMA-IR) ), on Intranasal insulin administration responses
Co-analysis of primary endpoint: this variable will be included as covariable in group and population analysis. higher Range of HOMA-IR indicate higher resistance to insulin. This scale is a ratio : Fasting glycaemia (mmol/L) \* Fasting Insulinemia (mui/mL)/22.5. Cut off are defined with value \<1.0 for non resistant subject. \>1.9 for insulin resistance and \>2.9 for high insulin resistance.
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Impact of intranasal insulin administration on cognition and episodic memory
Neuropsychological Data: A French-language battery for "Free Recall and Recall with Clue- 16" (RL-RI-16) The subjects get a global score from 0 to 144; a higher score means better-preserved memory function. Those score are then adjusted to existing data and deviation of the subject is calculated in statistical z-score.
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Impact of intranasal insulin administration on attention / visual scanning
Neuropsychological Data: Attention testing will be assessed with tests from a Attention Test Battery,validated in french, assessing the attention of the subject. Visual scanning a matrix-like arrangement of 5 x 5 stimuli is used, the aim being to detect whether this arrangement includes a critical stimulus or not. One reaction key is used for the answer "present" and another for the answer "not present". T Score are calculated for row and column , compared to a data base adjusted for age.
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Impact of intranasal insulin administration on attention / mental flexibility
Neuropsychological Data: This test is a "set shifting" task. A letter and a number are presented simultaneously to the right and left of the center of the screen. The subject has two reaction keys, one on the left and one on the right hand side. The task is to press the reaction key corresponding to the side on which the target stimulus appears. T Score are calculated from the reaction times, compared to a data base adjusted for age.
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Impact of intranasal insulin administration on attention / inhibition.
Neuropsychological Data: Attention testing will be assessed with tests from Attention Test Battery,validated in french, assessing the attention of the subject. Reaction times and errors are recorded in a simple Go/No-go test with two stimuli ""+"" and ""x"", of which only one (the ""x"") is critical T Score are calculated from reaction time, compared to a data base adjusted for age.
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Impact of INI Administration on Spatial Memory
Spatial memory testing will be assessed with the RUCHE-M test (Ruche Modified test). Scoring is 1 point for every square accurately reproduced in the learning phase; the same scoring will apply for the 5-time recall (total 50 points). For scoring the recognition test, 10/10 is attributed if the participant finds the correct grid. 1 point is subtracted for every failure. A lower score is attributed for lower performance in visual memory.
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Impact of INI Administration on Global Memory Performance
Score ranging from 0 to theoretically infinity, defined as how much a subject could memorize in serial information. A higher score means higher performance in sequential memory learning.
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Impact of INI Administration on Fluency
Score goes from 0 to theoretically 120; the number of names a subject can present starting with the same letter. Performance is directly reflected in the score; higher scores report higher performances.
Time frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)