Investigating Brain Insulin Resistance in Alzheimer Disease with Intra-Nasal Insulin Administration: a Multimodal Neuroimaging Study
Overview
- Phase
- Not Applicable
- Intervention
- Insulin
- Conditions
- Alzheimer Disease
- Sponsor
- Erasme University Hospital
- Enrollment
- 120
- Primary Endpoint
- Effects of INI administration on FMRI data in the 3 groups
- Status
- Withdrawn
- Last Updated
- last year
Overview
Brief Summary
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 .
Detailed Description
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.
Investigators
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.
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 \[MINI\])
Arms & Interventions
Intranasal Insulin then Placebo
First day , participant will receive Intranasal Insulin (100IU insulin/ml) 2 spray representing 0.8 ml in each nostril to achieve 1.6 ml (total dose =160UI) Second day participant will receive Placebo Intranasal , witch is saline solution (Nacl 0.9%). 2 spray representing 0.8 ml in each nostril to achieve 1.6 ml
Intervention: Insulin
Placebo then Intranasal Insulin
First day ,participant will receive Placebo Intranasal , witch is saline solution (Nacl 0.9%). 2 spray representing 0.8 ml in each nostril to achieve 1.6 ml Second day, participant will receive Intranasal Insulin (100IU insulin/ml) 2 spray representing 0.8 ml in each nostril to achieve 1.6 ml (total dose =160UI)
Intervention: Placebo
Outcomes
Primary Outcomes
Effects of INI administration on FMRI data in the 3 groups
Time Frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
For brain fRMI data: BOLD signal variation (Arbitrary Unit from a percent change from baseline).
Effects of INI administration on EEG Frequency band data in the 3 groups
Time Frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Spectrum analysis of the power (Power of the EEG signal(µV²/Hz) plotted against frequency band in Hz)
Effects of INI administration on PET-FDG regional standardized data in the 3 groups
Time Frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
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
Effects of INI administration on PET-FDG global data in the 3 groups
Time Frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
For brain PET-FDG: Statistical Parametric Mapping analysis (SPM) for voxel-wise groups comparison and multiple correlations (t-score)
Effects of INI administration on EEG connectivity data in the 3 groups
Time Frame: end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition)
Connectivity changes (SmallWorldness index σ , a quantitative method for determining canonical network equivalence,)
Secondary Outcomes
- Impact of gender on Intranasal insulin administration responses(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(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(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(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(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(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.(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(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(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(end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition))