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| ID | Type | Description | Link |
|---|---|---|---|
| 2023-508203-20-00 | EU Trial (CTIS) Number |
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Not realisable on time planned and with the academic funds
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intranasal Insulin then Placebo | Experimental | 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 |
|
| Placebo then Intranasal Insulin | Active Comparator | 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) |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Insulin | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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). | 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 | 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) | 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,) | 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) | end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition) |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition) |
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Inclusion Criteria:
For the young subject group (group 1):
For the MCI/AD group (group 2):
For the group 2 - matched controls (group 3):
Exclusion Criteria:
Exclusion criteria related to trimodal neuroimaging data acquisition:
Exclusion criteria related to demographic data:
Exclusion criteria related to the use of INI as IMP:
Criteria susceptible to postpone study inclusion:
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| Name | Affiliation | Role |
|---|---|---|
| Gil Leurquin-Sterk, MD,PhD | Nuclear Medicine department of H.U.B. site Erasme. | Principal Investigator |
| Xavier De Tiège, MD,PhD | Laboratoire de Neuroanatomie et Neuroimagerie translationnelles Université Libre de Bruxelles | Study Chair |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31375134 | Background | DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer's disease. Mol Neurodegener. 2019 Aug 2;14(1):32. doi: 10.1186/s13024-019-0333-5. | |
| 29653606 | Background | Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R; Contributors. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018 Apr;14(4):535-562. doi: 10.1016/j.jalz.2018.02.018. |
| Label | URL |
|---|---|
| The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends | View source |
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All data will be shared on the CTIS database.
Data will be available Before the study start , being registered in CTIS database
Publicly available
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D007328 | Insulin |
| ID | Term |
|---|---|
| D011384 | Proinsulin |
| D061385 | Insulins |
| D010187 | Pancreatic Hormones |
| D036361 | Peptide Hormones |
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| Placebo | Drug | 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. |
|
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| 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) |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | end of acquisition for each group (each group of 30 subject estimated at 12 weeks after first subjet acquisition) |
| 25681666 | Background | Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer's disease. Alzheimers Dement. 2015 Sep;11(9):1007-14. doi: 10.1016/j.jalz.2014.11.009. Epub 2015 Feb 11. |
| 33585904 | Background | Dhana K, Aggarwal NT, Rajan KB, Barnes LL, Evans DA, Morris MC. Impact of the Apolipoprotein E epsilon4 Allele on the Relationship Between Healthy Lifestyle and Cognitive Decline: A Population-Based Study. Am J Epidemiol. 2021 Jul 1;190(7):1225-1233. doi: 10.1093/aje/kwab033. |
| 15750215 | Background | Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? J Alzheimers Dis. 2005 Feb;7(1):63-80. doi: 10.3233/jad-2005-7107. |
| 29957442 | Background | Tian S, Huang R, Han J, Cai R, Guo D, Lin H, Wang J, Wang S. Increased plasma Interleukin-1beta level is associated with memory deficits in type 2 diabetic patients with mild cognitive impairment. Psychoneuroendocrinology. 2018 Oct;96:148-154. doi: 10.1016/j.psyneuen.2018.06.014. Epub 2018 Jun 22. |
| 24843720 | Background | Gudala K, Bansal D, Schifano F, Bhansali A. Diabetes mellitus and risk of dementia: A meta-analysis of prospective observational studies. J Diabetes Investig. 2013 Nov 27;4(6):640-50. doi: 10.1111/jdi.12087. Epub 2013 Apr 26. |
| 10599761 | Background | Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology. 1999 Dec 10;53(9):1937-42. doi: 10.1212/wnl.53.9.1937. |
| 19885299 | Background | de la Monte SM, Wands JR. Alzheimer's disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol. 2008 Nov;2(6):1101-13. doi: 10.1177/193229680800200619. |
| 36219990 | Background | Nijssen KMR, Mensink RP, Joris PJ. Effects of Intranasal Insulin Administration on Cerebral Blood Flow and Cognitive Performance in Adults: A Systematic Review of Randomized, Placebo-Controlled Intervention Studies. Neuroendocrinology. 2023;113(1):1-13. doi: 10.1159/000526717. Epub 2022 Aug 24. |
| 36834685 | Background | Shpakov AO, Zorina II, Derkach KV. Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium. Int J Mol Sci. 2023 Feb 7;24(4):3278. doi: 10.3390/ijms24043278. |
| 37379265 | Background | Wu S, Stogios N, Hahn M, Navagnanavel J, Emami Z, Chintoh A, Gerretsen P, Graff-Guerrero A, Rajji TK, Remington G, Agarwal SM. Outcomes and clinical implications of intranasal insulin on cognition in humans: A systematic review and meta-analysis. PLoS One. 2023 Jun 28;18(6):e0286887. doi: 10.1371/journal.pone.0286887. eCollection 2023. |
| 21911655 | Background | Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38. doi: 10.1001/archneurol.2011.233. Epub 2011 Sep 12. |
| 29508509 | Background | Schmid V, Kullmann S, Gfrorer W, Hund V, Hallschmid M, Lipp HP, Haring HU, Preissl H, Fritsche A, Heni M. Safety of intranasal human insulin: A review. Diabetes Obes Metab. 2018 Jul;20(7):1563-1577. doi: 10.1111/dom.13279. Epub 2018 Apr 6. |
| 25373630 | Background | Rosenbloom MH, Barclay TR, Pyle M, Owens BL, Cagan AB, Anderson CP, Frey WH 2nd, Hanson LR. A single-dose pilot trial of intranasal rapid-acting insulin in apolipoprotein E4 carriers with mild-moderate Alzheimer's disease. CNS Drugs. 2014 Dec;28(12):1185-9. doi: 10.1007/s40263-014-0214-y. |
| 33515428 | Background | Hallschmid M. Intranasal Insulin for Alzheimer's Disease. CNS Drugs. 2021 Jan;35(1):21-37. doi: 10.1007/s40263-020-00781-x. Epub 2021 Jan 30. |
| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D003072 | Cognition Disorders |
| D006728 |
| Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |