Orientation in AD Patients: PET-MR Study

Study Overview
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Brief Summary
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Despite the high prevalence of Alzheimer's disease (AD), its underlying mechanisms remain poorly understood. An emerging body of evidence supports disorientation as an early marker for AD-related neurodegeneration. In this study we intend to collect, coregister and analyze Positron Emission Tomography (PET) and , functional and structural magnetic resonance imaging (MRI, fMRI) data from AD-spectrum patients to establish orientation as core disturbance in AD.

Detailed Description
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As population aging is progressively contributing to the global burden of dementia, Alzheimer's disease (AD) is gaining recognition as a health-and social-care priority. Evidence converging from recently published works as well as our own preliminary results, propose that orientation is a sensitive marker for preclinical AD-related neurodegeneration. Our behavioral results show a simple orientation test to surpass currently used neuropsychological tests in classification of patients along the AD spectrum. A subsequential fMRI study revealed the orientation task to preferentially recruit brain regions identified as susceptible to early AD-related cortical atrophy, including the posterior cingulate cortex, parietooccipital sulcus and hippocampus bilaterally, as well as to significantly overlap with the default mode network (DMN) - a set of interconnected brain regions which were independently recognized as highly perturbed in AD. In an attempt to further support the role of orientation in AD we propose to use co-registration of several modalities of neuroimaging in patients with AD, mild cognitive impairment (MCI) and healthy controls (HC): resting-state fMRI, task-fMRI, structural MRI and co-registered PET. Resting-state functional magnetic resonance (fMRI) imaging detecting temporally synchronous, spatially distributed, spontaneous low frequency blood-oxygen level-dependent signal fluctuations in task-free settings, that are further clustered into maps of functional large-scale neural networks. A major network revealed in rest is the default DMN. DMN includes the posterior cingulate (PCC), inferior parietal (IPL), lateral (LTC) and medial temporal (MTL), and medial prefrontal cortical regions (MPFC), and is known to be involved in self-referential processes including introspection, memory retrieval, daydreaming and orientation. Task fMRI - using this module we recently demonstrated that fMRI activation generated by orientation task in the person, space and time domains activated the PCC, IPL, and MPFC and MTL hubs of the DMN. This task is now to be applied in patients with AD. Structural MRI - a decrease in hippocampus volume is an early imaging finding followed by cortical atrophy as AD progresses. PET - FDG-PET (glucose metabolism) is known to show temporo-parietal hypometabolism in AD. Considered these findings alongside ongoing research at the dynamics of anatomical and functional AD associated brain dysfunction, we propose a thorough, and to the best of our knowledge, a never before attempted study aimed at linking markers for AD pathology (cortical atrophy, decrease of functional connectivity, cerebral glucose metabolism) to the disruption of specific cognitive faculties, particularly orientation in the space, time and person domains.

Official Title
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The Orientation System, the Default-network and Brain Metabolism in Patients With Early Stage Alzheimer's Disease: a Multimodal Functional Study.

Conditions
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Alzheimer Disease, Mild Cognitive Impairment

Intervention / Treatment
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* Device: Siemens Biograph mMR PET-MR (3T)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: subjects aged 50-79 years. patients suffering from memory disorder. Test score mini-mental state examinations higher than 20. Exclusion Criteria: Contraindication to MR imaging pregnant women. patients with contraindications for injection of gadolinium.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Healthy Controls<br>Age matched controls for the various clinical groups will undergo standardly used Magnetic resonance imaging (MRI) protocols, including resting state fMRI, task fMRI, T1 weighted imaging. In addition Patients will receive an intravenous injection of 2-5mCi (millicurie) of 18F (fluorodeoxyglucose) -FDG prior to PET MRI, using Biograph mMR PET-MR (3T). | Device: Siemens Biograph mMR PET-MR (3T)<br>* Standardly used Magnetic resonance imaging (MRI) protocols, including resting state fMRI, task fMRI, T1 weighted imaging. In addition Patients will receive an intravenous injection of 2-5mCi of 18F-FDG prior to PET MRI.<br>|
| Amnestic Mild cognitive impaired<br>Patients diagnosed with mild cognitive impairment, exhibiting impairment mostly in memory that is significant but does not interfere with everyday activities. Subjects will undergo standardly used Magnetic resonance imaging (MRI) protocols, including resting state fMRI, task fMRI, T1 weighted imaging. In addition Patients will receive an intravenous injection of 2-5mCi of 18F-FDG prior to PET MRI, using Biograph mMR PET-MR (3T). | Device: Siemens Biograph mMR PET-MR (3T)<br>* Standardly used Magnetic resonance imaging (MRI) protocols, including resting state fMRI, task fMRI, T1 weighted imaging. In addition Patients will receive an intravenous injection of 2-5mCi of 18F-FDG prior to PET MRI.<br>|
| Alzheimer's disease patients<br>Patients exhibiting significant loss of intellectual ability that interferes with everyday functioning that meet Alzheimer's pattern of decline, and following exclusion of alternative neurodegenerative, cerebrovascular, and metabolic etiologies. Subjects will undergo standardly used Magnetic resonance imaging (MRI) protocols, including resting state fMRI, task fMRI, T1 weighted imaging. In addition Patients will receive an intravenous injection of 2-5mCi of 18F-FDG prior to PET MRI, using Biograph mMR PET-MR (3T). | Device: Siemens Biograph mMR PET-MR (3T)<br>* Standardly used Magnetic resonance imaging (MRI) protocols, including resting state fMRI, task fMRI, T1 weighted imaging. In addition Patients will receive an intravenous injection of 2-5mCi of 18F-FDG prior to PET MRI.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Orientation performance | Evaluation of Performance in orientation task using success rate and response time. Response time and success rate would be combined into an efficacy score: success rate-response time quotient, measured in units of second^-1. A primary effort in this work is to establish a model that links all primary Outcome Measures, in an attempt to examine how pathological markers predict cognitive performance and weather there relations are modulated by fMRI activity. | 1 day | 
| Cortical atrophy | Cortical atrophy will be evaluated by applying voxel-based morphometry analysis on T1-weighted images. This outcome would be evaluated as number of voxels significantly different from from a distribution of corresponding voxels gathered from a healthy control cohort. significantly different voxels would be considered atrophic. | 1 Day | 
| Functional connectivity analysis | Functional connectivity measurements within and between functional networks. This outcome would be evaluated by using correlation values computed between single voxels/region of interest, such that correlation values reflect integrity of functional networks. | 1 Day | 
| Mental-orientation evoked fMRI activity | Contrasting mental-orientation evoked activity between controls , MCIs and AD. This outcome would be evaluated by applying a contrast between fMRI patterns of activity evoked by the mental-orientation task in clinical groups (AD and MCI) to their control counterparts, to reveal the number and location of voxels showing reduced or increased activity in mental-orientation processing. | 1 Day | 
| [18]F-fluorodeoxyglucose (FDG) uptake | [18]F-fluorodeoxyglucose glucose analog uptake is measured using positron emission tomography, and is regarded as a marker for neural activity. This outcome would be evaluated by normalizing FDG absorption values and examining voxels statistically different in their metabolic activity relative to highly validated norms. | 1 Day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Orientation, Disorientation.