Synaptic Injury and Functional Connectivity in Alzheimer's Disease

Study Overview
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Brief Summary
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The purpose of this study is to examine cross-sectional associations between CSF markers of synaptic injury (Ng and SNAP-25) and functional connectivity in default and semantic memory networks using 3T- fMRI in individuals with MCI (i.e. the earliest clinically detectable stage of cognitive impairment) due to AD or mild AD dementia (CDR 0.5-1; n=20) and cognitively normal controls (CDR 0; n=20).

Detailed Description
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SPECIFIC AIMS: Aim 1: Investigate correlations between CSF biomarkers of synaptic injury (Ng and SNAP-25) and functional connectivity (FC) within the default mode network (DMN) using resting-state fMRI (adjusting for age, gender, apolipoprotein-E4 [APOE4] genotype, task performance, and regional brain atrophy) in MCI/AD and controls. Aim 2: Examine correlations between CSF biomarkers of synaptic injury and functional connectivity (FC) within the semantic memory network on task-activated fMRI using the Famous Name Discrimination Task (FNDT) (adjusting for age, gender, APOE4 genotype, task performance, and regional brain atrophy) in MCI/AD and controls.

Official Title
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Cerebrospinal Fluid Markers of Synaptic Injury and Functional Connectivity in Alzheimer's Disease

Conditions
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Alzheimer Disease, Late Onset

Intervention / Treatment
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* Diagnostic Test: CSF analysis
* Radiation: Functional MRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants included in the study should meet all 4 inclusion criteria: 60 years of age or older A clinical diagnosis of MCI, mild AD dementia, or normal cognition No significant medical or surgical co-morbidities No contraindications to LP or MRI. Exclusion criteria: Participants with any of the following criteria will be excluded from the study: Participants with MCI due to AD or mild AD dementia who have been treated with cholinesterase inhibitors or glutamate antagonists in the 3 months prior to study enrollment Individuals with any past history of ischemic or traumatic brain injury Individuals with imaging evidence of significant cerebrovascular disease or structural brain lesions (e.g. tumor, demyelinating disorders, infection, or congenital anomalies) Active mood disorder Active alcohol use Active use of benzodiazepines, barbiturates, anticholinergic, or anti-epileptic medications

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| MCI due to AD or mild AD dementia<br>The clinical diagnoses of amnestic MCI due to AD or mild AD dementia will be made according to standard clinical criteria as described by the National Institute of Aging -Alzheimer's Association Working Group and supported by CSF biomarker data for tau, p-tau181, and Aβ42. This includes evaluation for other systemic or neurological disorders which could account for the cognitive impairment, and inclusion of results from ancillary structural imaging (CT or structural MRI), neuro-psychometric testing, and FDG-PET imaging (when available) into the diagnostic scheme. All participants in this group will undergo clinical and cognitive evaluations, CSF analysis, and functional MRI during resting state and semantic memory tasks. | Diagnostic Test: CSF analysis<br>* CSF analysis for tau, p-tau181, Abeta42, and CSF levels of markers of synaptic injury<br>Radiation: Functional MRI<br>* Functional MRI during resting state and semantic memory task activation<br>|
| Normal controls<br>Normal cognition will be defined as cognitive performance on detailed neuropsychometric testing that falls within 1 SD of age-, gender-, and education-matched norms in all cognitive domains, and no subjective report of cognitive decline from an individual's baseline (i.e. CDR 0). All participants in this group will undergo clinical and cognitive evaluations, CSF analysis, and functional MRI during resting state and semantic memory tasks. | Diagnostic Test: CSF analysis<br>* CSF analysis for tau, p-tau181, Abeta42, and CSF levels of markers of synaptic injury<br>Radiation: Functional MRI<br>* Functional MRI during resting state and semantic memory task activation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlations between CSF biomarker measurements and fMRI measures of functional connectivity at baseline | Cross-sectional associations between CSF biomarker measurements and fMRI measures at baseline | Study duration is 3 years (36 months) for each participant, including 3 visits: one for cognitive evaluations, one for fMRI, and one for CSF collection. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CSF levels of tau, p-tau181, Abeta42, Ng, and SNAP-25 (pg/ml) | Quantification of biomarker levels in CSF | CSF collection will be performed for each participant once during the study (within 3 years of study enrollment). | 
| Functional Connectivity measures on functional MRI (r) | Functional Connectivity Measures on fMRI during resting state and task activation | fMRI will be performed for each participant once during the study (within 3 years of study enrollment). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Synaptic injury