Clinical trial NCT05614310: Detecting Early Alzheimer's Using MR
Official title: Early Detection Of Alzheimer's Disease With GlucoCEST MRI: A Feasibility Study.
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Alzheimer Disease
Keywords: Magnetic Resonance Imaging (MRI)
Glucose Chemical Exchange Saturation Transfer (CEST)
Lead sponsor: University of Aberdeen
Sponsor class: OTHER
Collaborators: name: NHS Grampian
First posted: 2022-11-14
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Target population: For the methods development phase, 20 healthy volunteers (age 18 years and above) without contra-indications to MRI will be recruited. Twenty patients with clinically diagnosed AD and 20 age-matched controls (+/- 3 years) will be recruited to test the clinical feasibility of glucoCEST.

As a feasibility study, the current work is unlikely to cover the full representative range of AD patients with diverse phenotypes. Its key purpose is to explore whether the proposed technique will show different glucose uptake between those with normal cognition and those with early AD. Further the purpose of future clinical use will be to detect AD in its early stage where clinical manifestations of AD are either subclinical or very mild. We will ensure that the sample is representative of the age range of AD patients, as well as sex balanced.

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.

Eligibility criteria: 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

Primary outcomes:
measure: PET glucose measurement
timeFrame: 2 years
measure: CEST-MRI glucose measurement
timeFrame: 2 years
measure: Sensitivity and specificity of CEST-MRI glucose measurements
timeFrame: 2 years
measure: Repeatability of CEST-MRI glucose measurement
timeFrame: 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: Aberdeen
country: United Kingdom
facility: University of Aberdeen
Study officials:
affiliation: University of Aberdeen
name: Gordon Waiter, PhD
role: STUDY_CHAIR
References:
citation: Kukull WA, Higdon R, Bowen JD, McCormick WC, Teri L, Schellenberg GD, van Belle G, Jolley L, Larson EB. Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol. 2002 Nov;59(11):1737-46. doi: 10.1001/archneur.59.11.1737.
citation: Bloudek LM, Spackman DE, Blankenburg M, Sullivan SD. Review and meta-analysis of biomarkers and diagnostic imaging in Alzheimer's disease. J Alzheimers Dis. 2011;26(4):627-45. doi: 10.3233/JAD-2011-110458.
citation: Marcus C, Mena E, Subramaniam RM. Brain PET in the diagnosis of Alzheimer's disease. Clin Nucl Med. 2014 Oct;39(10):e413-22; quiz e423-6. doi: 10.1097/RLU.0000000000000547.
citation: Tolomeo D, Micotti E, Serra SC, Chappell M, Snellman A, Forloni G. Chemical exchange saturation transfer MRI shows low cerebral 2-deoxy-D-glucose uptake in a model of Alzheimer's Disease. Sci Rep. 2018 Jun 22;8(1):9576. doi: 10.1038/s41598-018-27839-7.
citation: Wang J, Weygand J, Hwang KP, Mohamed AS, Ding Y, Fuller CD, Lai SY, Frank SJ, Zhou J. Magnetic Resonance Imaging of Glucose Uptake and Metabolism in Patients with Head and Neck Cancer. Sci Rep. 2016 Jul 27;6:30618. doi: 10.1038/srep30618.
citation: Kim M, Torrealdea F, Adeleke S, Rega M, Evans V, Beeston T, Soteriou K, Thust S, Kujawa A, Okuchi S, Isaac E, Piga W, Lambert JR, Afaq A, Demetriou E, Choudhary P, Cheung KK, Naik S, Atkinson D, Punwani S, Golay X. Challenges in glucoCEST MR body imaging at 3 Tesla. Quant Imaging Med Surg. 2019 Oct;9(10):1628-1640. doi: 10.21037/qims.2019.10.05.