Detecting Early Alzheimer's Using MR

Recruiting

• Conditions: Alzheimer Disease
• Interventions: Other: Magnetic Resonance Imaging (MRI); Other: Blood Glucose Assessment; Other: Positron Emission Tomography (PET); Other: Cognitive Assessment

• Registration Number: NCT05614310
• Lead Sponsor: University of Aberdeen

Brief Summary

Alzheimer's disease (AD) is the most common cause of dementia, affecting approximately 10% of individuals aged ≥ 65. Most available treatments aim at controlling symptoms at an early stage rather than providing a cure. Therefore, an accurate and early diagnosis of AD with appropriate management will slow the progression of the condition. Reduced cerebral glucose levels have been observed in patients with early AD. Glucose hypometabolism can be assessed by administering a radioactive glucose analogue, 2-deoxy-2-(18F) fluoro-D-glucose (18FDG), and imaging with PET (positron emission tomography). The high cost and limited availability of PET-CT (PET - computed tomography) still hamper its general clinical application. Moreover, the use of radioactive tracers in combination with the additional ionizing radiation of CT is not suitable for repeated measurements. Therefore, currently, the provisional diagnosis of AD is still based on the combination of clinical history, neurological examination, cognitive testing over a period of time, and structural neuroimaging. This has major time and resource implications.

A radically different and highly innovative means for imaging glucose with magnetic resonance imaging (MRI) has now been established, exploiting the interaction between hydroxyl protons in glucose and the protons in water; the method is termed glucose Chemical Exchange Saturation Transfer (glucoCEST). GlucoCEST MRI is a method that has no reliance on radiolabelled glucose analogues and could become widely implemented in clinic practice. We therefore aim to investigate the potential of glucoCEST MRI in Alzheimer's disease.

Detailed Description

Alzheimer's disease (AD) is the most common cause of dementia, affecting approximately 10% of individuals aged ≥ 65. Most available treatments aim at controlling symptoms at an early stage rather than providing a cure. Therefore, an accurate and early diagnosis of AD with appropriate management will slow the progression of the condition. Reduced cerebral glucose levels have been observed in patients with early AD. Glucose hypometabolism can be assessed by administering a radioactive glucose analogue, 2-deoxy-2-(18F) fluoro-D-glucose (18FDG), and imaging with PET (positron emission tomography). The high cost and limited availability of PET-CT (PET - computed tomography) still hamper its general clinical application. Moreover, the use of radioactive tracers in combination with the additional ionizing radiation of CT is not suitable for repeated measurements. Therefore, currently, the provisional diagnosis of AD is still based on the combination of clinical history, neurological examination, cognitive testing over a period of time, and structural neuroimaging. This has major time and resource implications.

A radically different and highly innovative means for imaging glucose with magnetic resonance imaging (MRI) has now been established, exploiting the interaction between hydroxyl protons in glucose and the protons in water; the method is termed glucose Chemical Exchange Saturation Transfer (glucoCEST). GlucoCEST MRI is a method that has no reliance on radiolabelled glucose analogues and could become widely implemented in clinic practice. We believe that glucoCEST MRI has the potential to replace FDG-PET and improve patient healthcare as part of a routine clinical pathway in very early detection of AD.

The study will include 20 healthy volunteers for developing glucoCEST in the clinical 3T MRI scanner (development phase) and 20 volunteers without AD and 20 patients with clinically diagnosed AD (clinical phase). All participants will have a 3T brain MRI scan after they receive oral glucose. The participants in the clinical phase will have a 3T brain MRI scan, a brain PET scan and they will also undertake two cognitive tests.

The glucose uptake and clearance rate in the brain will be measured from PET and MRI scans and compared between groups and imaging modalities. Sensitivity and specificity of glucoCEST to detect AD will be also calculated.

Primary Objective: To estimate the sensitivity of glucose uptake as measured by glucoCEST MRI in patients with AD compared with age and sex matched controls.

Secondary objective: To investigate if the glucose uptake as measured by glucoCEST MRI is related to the glucose uptake as measured in FDG-PET.

The main aims of the study are:

1. To determine normal uptake and clearance rates of glucose in the brain as measured by dynamic glucoCEST MRI at 3T

2. To compare glucose uptake as measured by glucoCEST MRI and FDG-PET.

3. To compare glucose uptake as measured by glucoCEST MRI in patients with AD and age and sex matched controls.

Study Timeline

• Study First Submitted: 2022-11-03
• Study First Submitted QC: 2022-11-10
• Study First Posted: 2022-11-14
• Study Start: 2022-11-15
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-25
• Last Update Posted: 2025-03-30
• Primary Completion: 2025-12-31
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

Development phase:

Controls (development group) must:

• be > 18 years
• consent to the study
• not report problems with memory.

Clinical phase

Patients must:

• be ≥ 65 years,
• able to provide informed consent to the study
• have been clinically diagnosed with AD by the mental health team.

Controls must:

• be ≥ 65 years
• able to provide consent to the study
• have a normal score in the ADAS-cog test and the Mini Mental State Examination test (MMSE)
• not report problems with memory.

Exclusion Criteria

Subjects will not be considered if they:

• have a history of diabetes,
• have history of a major stroke (mini-stroke/Transient Ischaemic Attacks or lacunar stroke are acceptable),
• have contra-indications to MRI scanning such as implantable cardiac devices
• have family history in AD, to exclude possible gene mutations associated with AD
• have advanced AD who lack the capacity to consent.
• Are pregnant (for developmental phase)
• are unable to read or speak English

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Patients (N = 20) (Clinical Phase)	Magnetic Resonance Imaging (MRI)	Patients (N = 20) will attend 2 visits up to 1 week apart. Patients will be asked to have a no-sugar diet and take no exercise for 24 hours before each visit and to avoid eating 6 hours before scan. Visit 1: Patients will undergo a positron emission tomography (PET) assessment. Before and after their PET assessment patients will be given a pinprick blood sugar test. PET assessment: Visit 2: Patients will undergo MRI assessment. Before and after their MRI scan patients will be given a pinprick blood sugar test. Healthy controls will complete cognitive assessments.
Healthy Controls (N = 20) (Clinical Phase)	Magnetic Resonance Imaging (MRI)	Healthy controls (N = 20) will attend 2 visits up to 1 week apart. Healthy controls will be age matched (+/- 3 years) and sex matched to the patient group. Healthy controls will be asked to have a no-sugar diet and take no exercise for 24 hours before each visit and to avoid eating 6 hours before scan. Visit 1: Healthy Controls will undergo a positron emission tomography (PET) assessment. Before and after their PET assessment patients will be given a pinprick blood sugar test. PET assessment: Visit 2: Healthy Controls will undergo MRI assessment. Before and after their MRI scan patients will be given a pinprick blood sugar test. Healthy controls will complete cognitive assessments.
Development Group 1 (N = 10) (Development Phase)	Blood Glucose Assessment	Development group participants (N = 10) will undergo 1 magnetic resonance imaging (MRI) sessions. Before and after their MRI scan participants will be given a pinprick blood sugar test.
Development Group 1 (N = 10) (Development Phase)	Magnetic Resonance Imaging (MRI)	Development group participants (N = 10) will undergo 1 magnetic resonance imaging (MRI) sessions. Before and after their MRI scan participants will be given a pinprick blood sugar test.
Healthy Controls (N = 20) (Clinical Phase)	Cognitive Assessment	Healthy controls (N = 20) will attend 2 visits up to 1 week apart. Healthy controls will be age matched (+/- 3 years) and sex matched to the patient group. Healthy controls will be asked to have a no-sugar diet and take no exercise for 24 hours before each visit and to avoid eating 6 hours before scan. Visit 1: Healthy Controls will undergo a positron emission tomography (PET) assessment. Before and after their PET assessment patients will be given a pinprick blood sugar test. PET assessment: Visit 2: Healthy Controls will undergo MRI assessment. Before and after their MRI scan patients will be given a pinprick blood sugar test. Healthy controls will complete cognitive assessments.
Patients (N = 20) (Clinical Phase)	Blood Glucose Assessment	Patients (N = 20) will attend 2 visits up to 1 week apart. Patients will be asked to have a no-sugar diet and take no exercise for 24 hours before each visit and to avoid eating 6 hours before scan. Visit 1: Patients will undergo a positron emission tomography (PET) assessment. Before and after their PET assessment patients will be given a pinprick blood sugar test. PET assessment: Visit 2: Patients will undergo MRI assessment. Before and after their MRI scan patients will be given a pinprick blood sugar test. Healthy controls will complete cognitive assessments.
Patients (N = 20) (Clinical Phase)	Cognitive Assessment	Patients (N = 20) will attend 2 visits up to 1 week apart. Patients will be asked to have a no-sugar diet and take no exercise for 24 hours before each visit and to avoid eating 6 hours before scan. Visit 1: Patients will undergo a positron emission tomography (PET) assessment. Before and after their PET assessment patients will be given a pinprick blood sugar test. PET assessment: Visit 2: Patients will undergo MRI assessment. Before and after their MRI scan patients will be given a pinprick blood sugar test. Healthy controls will complete cognitive assessments.
Healthy Controls (N = 20) (Clinical Phase)	Positron Emission Tomography (PET)	Healthy controls (N = 20) will attend 2 visits up to 1 week apart. Healthy controls will be age matched (+/- 3 years) and sex matched to the patient group. Healthy controls will be asked to have a no-sugar diet and take no exercise for 24 hours before each visit and to avoid eating 6 hours before scan. Visit 1: Healthy Controls will undergo a positron emission tomography (PET) assessment. Before and after their PET assessment patients will be given a pinprick blood sugar test. PET assessment: Visit 2: Healthy Controls will undergo MRI assessment. Before and after their MRI scan patients will be given a pinprick blood sugar test. Healthy controls will complete cognitive assessments.
Patients (N = 20) (Clinical Phase)	Positron Emission Tomography (PET)	Patients (N = 20) will attend 2 visits up to 1 week apart. Patients will be asked to have a no-sugar diet and take no exercise for 24 hours before each visit and to avoid eating 6 hours before scan. Visit 1: Patients will undergo a positron emission tomography (PET) assessment. Before and after their PET assessment patients will be given a pinprick blood sugar test. PET assessment: Visit 2: Patients will undergo MRI assessment. Before and after their MRI scan patients will be given a pinprick blood sugar test. Healthy controls will complete cognitive assessments.
Development Group 2 (N = 10) (Development Phase)	Magnetic Resonance Imaging (MRI)	To investigate the repeatability of MRI assessment, 10 development phase healthy volunteers will be recruited to undergo two repeated study assessments. The second visit will be between 7 and 14 days after their first visit. The second repeated study assessment will follow the same procedure as the first visit, consisting of blood glucose assessment and MRI assessment. Participants will be advised to fast from mid-night and avoid eating breakfast.
Development Group 2 (N = 10) (Development Phase)	Blood Glucose Assessment	To investigate the repeatability of MRI assessment, 10 development phase healthy volunteers will be recruited to undergo two repeated study assessments. The second visit will be between 7 and 14 days after their first visit. The second repeated study assessment will follow the same procedure as the first visit, consisting of blood glucose assessment and MRI assessment. Participants will be advised to fast from mid-night and avoid eating breakfast.
Healthy Controls (N = 20) (Clinical Phase)	Blood Glucose Assessment	Healthy controls (N = 20) will attend 2 visits up to 1 week apart. Healthy controls will be age matched (+/- 3 years) and sex matched to the patient group. Healthy controls will be asked to have a no-sugar diet and take no exercise for 24 hours before each visit and to avoid eating 6 hours before scan. Visit 1: Healthy Controls will undergo a positron emission tomography (PET) assessment. Before and after their PET assessment patients will be given a pinprick blood sugar test. PET assessment: Visit 2: Healthy Controls will undergo MRI assessment. Before and after their MRI scan patients will be given a pinprick blood sugar test. Healthy controls will complete cognitive assessments.

Primary Outcome Measures

Name	Time	Method
PET glucose measurement	2 years	Dynamic frames from FDG-PET will be summed and normalised to the cerebellum using MATLAB (MathWorks Inc., USA). Standardised uptake values (SUVs) from PET will then be calculated. Regions of interests (ROIs) will derived from normalisation to the standard Desikan Killiany atlas. Average SUV from PET will be calculated from each ROI in MATLAB.; Glucose uptake (maximum ΔS/So) with units of ratio.; Clearance (rate of decrease of ΔS/So) values with units of ratio.
Sensitivity and specificity of CEST-MRI glucose measurements	2 years	A neuroradiologist blinded to the diagnosis of each participant will be asked to report the scans in a similar way to an FDG-PET scan. Sensitivity and specificity of glucoCEST to detect AD by estimating the proportion of true positives and true negatives respectively will be determined. To demonstrate the feasibility of glucoCEST in differentiating AD patients from controls, group comparisons of glucose (paired samples t-tests as implemented by SPSS) uptake values between patients and controls and of glucose clearance values between patients and controls will be performed.; Sensitivity and specificity values with units of ratio.
CEST-MRI glucose measurement	2 years	Dynamic frames from CEST MRI will be summed and normalised to the cerebellum using MATLAB (MathWorks Inc., USA). Standardised uptake values (SUVs) will be calculated in regions of interests (ROIs) derived from normalisation to the standard Desikan Killiany atlas. Average SUV from each ROI, the glucose uptake (maximum ΔS/So) and clearance (rate of decrease of ΔS/So) values from patients and controls will be calculated using MATLAB.; Glucose uptake (maximum ΔS/So) with units of ratio.; Clearance (rate of decrease of ΔS/So) values with units of ratio
Repeatability of CEST-MRI glucose measurement	2 years	To investigate the repeatability of MRI assessment, 10 out of 20 development phase healthy volunteers will be recruited to undergo a second repeated study assessment visit between 7 and 14 days after their first visit.; Coefficient of variation values with units of percent.

Trial Locations

Locations (1)

University of Aberdeen; 🇬🇧 Aberdeen, United Kingdom