The investigators propose a proof of concept RCT (randomized clinical trial), testing the efficacy of intranasal insulin (INI) with semaglutide, a combination therapy with strong biological plausibility to benefit impaired cognition through vascular mechanisms, in older adults with MetS (metabolic syndrome) and MCI (Mild Cognitive Impairment), who are enriched for cerebrovascular disease and at high dementia risk. The study will focus on cognitive and biological outcomes, allowing identification of relevant mechanisms.
The Specific Aims of the study are: Aim 1. To examine the ease and precision of use of the intranasal device and once daily semaglutide pill. Aim 2. To examine the adherence to the two types of treatment. Aim 3. To examine the safety profile of the combination of intranasal insulin with semaglutide. The safety profile of each has been published broadly, but the safety of their combination has not been examined. Aim 4. Although the primary goal of the pilot study is proof of concept essential to design a large combination therapy RCT, The investigators will compare the combination of intranasal insulin and semaglutide with the other three groups on a) cognition, b) cerebral blood flow (via ASL MRI), c) glucose uptake (via FDG PET), ADRD(Alzheimer's disease and related disorders)-related blood biomarkers (Aβ42/Aβ40 ratio, pTau181 and 231, NfL and GFAP), and expression of insulin signaling genes from brain derived exosomes.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
80
The medication is available in 3, 7, and 14-mg tablets for oral use. Participants will be instructed to start with an initiating dose of 3 mg once daily. If they do not experience adverse events (nausea, vomiting, and abdominal pain) then the dose will be titrated to 7 mg once daily after 30 days. Again, if the participant does not experience adverse events, the dose will be further titrated after 30 days to 14 mg once daily. This does will continue until the end of the study, at 12 months.
The study will use the ViaNase; Kurve Technology intranasal device to administer insulin intra-nasally. This device has been used in other studies of persons with AD and has shown insulin penetration into the brain via CSF studies. Through sniffing, the medication crosses the blood-brain barrier (BBB) at the top of the nasal cavity. Participants will be instructed to press a switch that will turn on the device, engaging a pump that releases a nebulized stream of insulin through a nose piece into a nostril for 20 seconds (the device includes an electronic timer), after which the device switches off. The process is then repeated in the other nostril. The investigators decided on administration of 20IU of INI twice per day as the literature suggests this as the optimal dosage.
Rybelsus semaglutide - this medicine will simulate taking the pill Rybelsus /semaglutide once a day. A pill identical to the medicine pill will be given.
The placebo used in this study is saline. The investigators will administer saline, with exactly the same methods as the INI insulin (twice per day, 20 seconds each sniff, in each nostril.
Joseph Sagol Neuroscience center, Sheba Medical Center
Ramat Gan, Israel
RECRUITINGCognitive change - The effect of the combination of Semaglutide and intranasal insulin on cognitive functioning.
The cognitive outcome is a balanced composite sum of z-scores of four executive function tests (Trails B, Digit-Symbol, and Category Fluency (animals, fruits and vegetables), four episodic memory tests (immediate and delayed recall of the word list from the ADAS-Cog, and immediate and delayed recall of Logical Memory Story I from the Wechsler Memory Test). Z-scores are reversed if necessary so that a positive value refers to good cognition. Cognitive functioning will be measured at baseline, 6 months, and 12 months follow-ups.
Time frame: 12 months
Neuroimaging outcome -- The effect of the combination of Semaglutide and intranasal insulin on cerebral blood flow (CBF).
Change in CBF will be measured using Arterial Spin Labeling (ASL) brain magnetic resonance imaging (MRI) scans. The unit of cerebral blood flow from ASL is ml/100g/min, which means the amount of blood flow into 100g of tissue in one minute. Scans will be taken at baseline and 6 months follow-up. Baseline and 6 months scans will be compared and analyzed to assess change in blood flow between the time points.
Time frame: 6 months
Neuroimaging outcome -- The effect of the combination of Semaglutide and intranasal insulin on brain glucose intake.
Brain Glucose intake will be measured by \[F18\]FDG-PET: Voxel-wise standardized uptake value ratio (SUVR) images will be created in native MRI space with the pons as reference region. \[F18\]FDG values will be extracted from ADRD-vulnerable regions of interest (dorsolateral prefrontal cortex, medial and lateral temporal lobe, and medial and lateral parietal cortex). Scans will be taken at baseline and 6 months follow-up. Baseline and 6 months scans will be compared and analyzed to assess change in glucose intake between the time points.
Time frame: 6 months
Change in specific cognitive domains - The effect of the combination of Semaglutide and intranasal insulin on executive functions and episodic memory.
Cognitive outcomes will be the domain-specific composites, for executive functions and episodic memory, by using four executive function tests (Trails B, Digit-Symbol, and Category Fluency \[animals, fruits and vegetables), and four episodic memory tests (immediate and delayed recall of the word list from the ADAS-Cog, and immediate and delayed recall of Logical Memory Story I from the Wechsler Memory Test). Cognitive outcomes will be measured at baseline, 6 months, and 12 months follow-ups
Time frame: 12 months
Neuroimaging outcomes- The effect of the combination of Semaglutide and intranasal insulin on microstructural alterations indicative of tissue injury.
Changes in White matter hyperintensity (WMH) volume: Total WMH volume of presumed ischemic origin will be quantified from 3D T2-FLAIR brain MRI using the Lesion Segmentation Tool. T1-weighted volumetric scans will be used to derive intracranial volume. Scans will be taken at baseline and 6 months follow-up. Baseline and 6 months scans will be compared and analyzed to assess change in WMH volume between the time points.
Time frame: 6 months
Neuroimaging outcomes- The effect of the combination of Semaglutide and intranasal insulin on gray matter and hippocampal volume.
Changes in gray matter (GM) and hippocampal volumes: neurodegeneration will be measured using T1-weighted scans brain MRI scans. Regional cortical GM and hippocampal volumes will be extracted using FreeSurfer 7.1.1. and FSL. Scans will be taken at baseline and 6 months follow-up. Baseline and 6 months scans will be compared and analyzed to assess change in GM and hippocampal volumes between the time points.
Time frame: 6 months
Functional outcome - The effect of the combination of Semaglutide and intranasal insulin on functional performance.
Change in functional performance will be measured by the Clinical Dementia Rating (CDR) Scale Sum of Boxes (SB). The CDR-SB summarizes cognitive impairment in 6 domains (memory, orientation, judgment/problem-solving, community affairs, home/hobbies, and personal care) based on subject and informant interviews. Possible scores on the CDR are 0 (no impairment), 0.5 (very mild), 1 (mild), 2 (moderate), and 3 (severe). A maximal CDR-SB score is -18. CDR will be measured at baseline, 6 months, and 12 months follow-ups.
Time frame: 12 months
Functional outcome - The effect of the combination of Semaglutide with intranasal inulin on change in functional performance as measured by IADL (instrumental activities of daily living) questionnaires.
Functional Activities will be based on subject and informant interviews. Both ADLs (activities of daily living) and IADLs (instrumental ADLs) refer to key life tasks that need to be accomplish daily. ADLs, are more basic tasks that are essential to independent living. IADLs, are more complex tasks that are still a necessary part of everyday life. The study subjects are MCI, so mostly independent in ADLs. Therefore, the IADL questionnaire used in the "ADCS Prevention Instrument Project" will be used. IADL will be assessed at baseline, 6 months and 12 months. The range score is 0-45; a higher score means that the subject is more independent.
Time frame: 12 months
Functional outcome - The effect of the combination of Semaglutide and intranasal insulin on physical capacity
Physical capacity (PC) assessment (aerobic, balance, strength) includes grip strength, 6-m walk (6MWT), timed up and go (TUG), Berg balance testing (BBS), 30 Seconds Sit To Stand Test (STS), Four Square Step Test (FSST) and the Fried frailty scale. Based on the collected data, individuals will be categorized and assigned to 1 of 3 categories: low PC (LPC), medium PC (MPC), or normal PC (NPC). Participants will receive an LPC score if either standardized 6MWT/STS/Grip score is ≤ -2 standard deviation or BBS score ≤36 or TUG score between 21-30 or FSST score \> 15 seconds or deemed as frail assessed by the Fried scale. Participants will have an MPC score if either the standardized 6MWT/STS/Grip score is between -2 and -1.5 or BBS score is between 37-45 or the TUG score is between 15-20 or FSST score is between 10.14-14.59 or determined as pre-frail by Fried scale. All other participants will be categorized as NPC. Physical capacity will be measured at baseline and 6 months follow-up.
Time frame: 6 months
Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- Aβ.
A lower amyloid beta (Aβ) 42/Aβ 40 ratio in plasma is associated with a higher risk of dementia. Aβ 42/Aβ 40 plasma ratio will be measured at baseline and 6 months followup and will be compared to assess change in ADRD-blood biomarkers between the time points.
Time frame: 6 Months
Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- P-tau181.
A higher rate of P-tau181 in plasma is associated with a higher risk of dementia. Change in rate of plasma tau proteins in blood plasma from baseline to 6 months will be assessed.
Time frame: 6 Months
Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers-P-tau231.
A higher rate of P-tau231associated with a higher risk of dementia. Change in rate of plasma P-tau231 proteins from baseline to 6 months will be examined.
Time frame: 6 Months
Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- T-tau.
A higher rate of T-tau associated with a higher risk of dementia. Change in rate of plasma T-tau proteins in blood plasma from baseline to 6 months will be examined.
Time frame: 6 Months
Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- Neurofilament light (NfL).
A higher rate of neurofilament light (NfL) is associated with a higher risk of dementia. Change in rate of plasma tau proteins in blood plasma from baseline to 6 months will be examined.
Time frame: 6 Months
Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- glial fibrillary acidic protein (GFAP).
A higher rate of glial fibrillary acidic protein (GFAP) is associated with a higher risk of dementia. Change in rate of plasma GFAP in blood plasma from baseline to 6 months will be examined.
Time frame: 6 Months
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