Brain Insulin Resistance in Mild Cognitive Impairment

NCT06116188 | Unknown

• 1 other identifier: 57 /1801/2022
• Study Type: observational
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Alzheimer´s disease (AD) is the most common cause of dementia. The most important risk factor for AD is old age; modifiable risk factors for AD include metabolic risk factors, i.e. diabetes, and obesity. Insulin resistance seems to be associated with AD pathology and cognitive decline. Previous studies suggest that AD and mild cognitive impairment (MCI) due to AD, a stage between normal cognition and AD dementia, would be associated with central nervous system (CNS) insulin resistance. Insulin resistance can be measured using a sophisticated hyperinsulinemic-euglycemic clamp technique. Insulin-stimulated glucose uptake of muscles and adipose tissue is known to be reduced in an insulin resistant subject compared to healthy insulin sensitive subjects. Central nervous system insulin resistance, however, is more difficult to assess, while a clear-cut definition is thus far lacking. Previous studies have demonstrated that whole-body insulin resistance in obese subjects is accompanied with higher brain glucose-uptake (BGU) during the insulin clamp, compared to lean controls, and that BGU increases from the fasting to the insulin clamp state. On the contrary, there is no difference in BGU under fasting conditions between obese subjects and healthy lean controls. No previous studies have evaluated brain glucose uptake in clamp conditions in subjects with MCI or early AD. The aim of this study is to evaluate if brain glucose uptake is increased in MCI/ early AD subjects in a similar manner as in morbidly obese subjects in an insulin-stimulated state (during a hyperinsulinemic clamp) when compared to the fasting state, and when compared to controls. The investigators hypothesize that MCI subjects would have CNS insulin resistance that could, in time, contribute to the pathological process of AD. The investigators will recruit altogether 20 MCI subjects from the local memory clinic, and healthy controls through advertisements. All participants will undergo two \[18F\]-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans (one in the fasting state and one during the hyperinsulinemic clamp), a magnetic resonance image scan for structural changes, blood sampling, and comprehensive cognitive testing. The participants will also undergo a \[11C\]PIB-PET scan to measure brain amyloid accumulation. Understanding the metabolic changes in the brain preceding AD could help in developing disease-modifying treatments in the future.

Conditions

Alzheimer Disease; Mild Cognitive Impairment; Positron Emission Tomography

Outcome Measures

Primary Outcomes (1)

• Brain glucose uptake

  Differences in brain glucose uptake (umol/100ml/min) measured during insulin clamp conditions between the two groups.

  0 months

Secondary Outcomes (1)

• [11C]PIB-PET brain uptake

  0 months

Study Arms (2)

Patients with Mild cognitive impairment

20 study volunteers with a diagnosis of MCI due to AD or early AD or episodic memory decline during the last 6 months from the local memory clinics and by contacting doctors who treat and diagnose memory disorders. Patients with Alzheimer´s dementia - i.e. cognitive impairment severe enough to cause problems in activities of daily living - will not be included in the study due to the study protocol which requires co-operation and the ability to lie still in the PET scanner for approximately 60 minutes.

Diagnostic Test: FDG-PET study

Healthy controls

We will also recruit 20 cognitively unimpaired controls, matched for age and gender for the patients group. Inclusion criteria for the cognitively unimpaired group for the present study are: i) no subjective cognitive complaints ii) CERAD (consortium to establish a registry for Alzheimer´s Disease) test battery at screening visit: CERAD total score within the normal range iii) clinical dementia rating (CDR) = 0, based on an interview with the study volunteer´s spouse or close relative iv) age 55 to 80 years

Diagnostic Test: FDG-PET study

Interventions

FDG-PET study DIAGNOSTIC_TEST

Hyperinsulinemic, euglycemic clamp technique will be used to promote tissue glucose uptake and measure insulin sensitivity. Two cannulas will be inserted, one in a radial or an antecubital vein for PET tracer injection and infusion of glucose and insulin, another in the opposite radial or antecubital vein for blood sampling. In the clamp study subjects are administered intravenous insulin at a steady rate of 40 mU/m2/min and normoglycemia is maintained using a variable rate infusion of 20% glucose based on plasma glucose measurements, which are performed every 5min from arterialized venous blood. We will also collect samples to determine plasma insulin, serum free fatty acid and metabolic biomarkers during the study. The clamp will be performed together with \[18F\]-FDG-PET/CT.

Healthy controls; Patients with Mild cognitive impairment

Eligibility Criteria

• Age: 55 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

The investigators will recruit 20 volunteers with a diagnosis of MCI due to AD or early AD or episodic memory decline during the last 6 months from the local memory clinics and by contacting doctors who treat and diagnose memory disorders. Recruitment will also be performed via. Inclusion will be made at the first screening visit. Patients with Alzheimer´s dementia - i.e. cognitive impairment severe enough to cause problems in activities of daily living - will not be included in the study due to the study protocol which requires co-operation and the ability to lie still in the PET scanner for approximately 60 minutes. The investigators will also recruit 20 cognitively unimpaired controls.

You may qualify if:

• diagnosis of MCI due to AD or early AD based on a neurologist's or a geriatrician's clinical examination and/ or cognitive testing showing either a decline during at least a 6 month follow-up or a slight decline in episodic memory
• clinical dementia rating (CDR) = 0,5, based on an interview with the patient's spouse or close relative
• age 55 to 80 years
• no subjective cognitive complaints
• consortium to establish a registry for Alzheimer´s Disease (CERAD) test battery at screening visit within the normal range
• clinical dementia rating (CDR) = 0, based on an interview with the study volunteer´s spouse or close relative
• age 55 to 80 years

You may not qualify if:

• diabetes (type 1 or type 2)
• overweight or obesity (BMI \> 26 kg/m2)
• BMI \< 18 kg/m2
• impaired fasting glucose of impaired glucose tolerance in the 2-hour oral glucose tolerance test, performed at the screening visit
• other major neurological disease than MCI (such as a major stroke, multiple sclerosis, Parkinson's disease). Volunteers with minor neurological diseases such as migraine and a previous transient ischemic attack (TIA) can participate
• major psychiatric illness such as schitzophrenia, bipolar disorder or major depression
• conditions that affect the ability to participate in PET or MRI scanning (cancer diagnosis/ treatment within the last five years, claustrophobia, metal object in the body)
• amyloid negative PET scan (during the study or performed previously in the clinic or normal beta-amyloid42 or beta-amyloid42/40 ratio in CSF (measured previously in the clinic) (to exclude patients with cognitive decline due to some other pathological process than AD)

Sponsors & Collaborators

• Turku University Hospital: lead

Study Sites (1)

Turku PET Centre

Turku, 20520, Finland

RECRUITING

Biospecimen

Retention: NONE RETAINED

Plasma and urine samples for measurements

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction

Condition Hierarchy (Ancestors)

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

Study Officials

• Laura Ekblad, MD

  Turku PET Centre

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Laura Ekblad, MD

CONTACT

02 3130000; llekbl@utu.fi

Pirjo Nuutila, MD

CONTACT

02 3130000; pirjo.nuutila@utu.fi

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Target Duration: 1 Year
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 17, 2023
• First Posted: November 3, 2023
• Study Start: October 12, 2023
• Primary Completion: October 10, 2025
• Study Completion: October 10, 2025
• Last Updated: November 3, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

FI (1)