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

NCT06391853 | Withdrawn

• 2 other identifiers: SRB2023-1832023-508203-20-00
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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 .

Conditions

Alzheimer Disease; Mild Cognitive Impairment

Keywords

Intranasal Insulin

Outcome Measures

Primary Outcomes (5)

• 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)

Secondary Outcomes (10)

• 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 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 cognition and episodic memory

  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)

Study Arms (2)

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

Drug: Insulin

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)

Drug: Placebo

Interventions

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.

Also known as: FDG-PET, EEG, fMRI

Intranasal Insulin then Placebo

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.

Also known as: FDG-PET, EEG, fMRI

Placebo then Intranasal Insulin

Eligibility Criteria

• Age: 21 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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.
• 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).
• Being under corticosteroid treatment (non-topical treatment)
• Being under birth-control pill containing ethinyl estradiol.

Sponsors & Collaborators

• Erasme University Hospital: lead

Related Publications (16)

• 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.

  PMID: 31375134 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.

  PMID: 29653606 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.

  PMID: 25681666 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.

  PMID: 33585904 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.

  PMID: 15750215 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.

  PMID: 29957442 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.

  PMID: 24843720 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.

  PMID: 10599761 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.

  PMID: 19885299 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.

  PMID: 36219990 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.

  PMID: 36834685 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.

  PMID: 37379265 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.

  PMID: 21911655 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.

  PMID: 29508509 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.

  PMID: 25373630 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.

  PMID: 33515428 BACKGROUND

Related Links

• The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction

Interventions

Insulin

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• 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

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 8, 2024
• First Posted: April 30, 2024
• Study Start: October 1, 2024
• Primary Completion: March 1, 2026
• Study Completion (Estimated): October 1, 2026
• Last Updated: January 27, 2025

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, CSR
• Time Frame: Data will be available Before the study start , being registered in CTIS database
• Access Criteria: Publicly available