Synaptic Injury and Functional Connectivity in Alzheimer's Disease

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

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).

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease, Late Onset
• Intervention / Treatment: Diagnostic test: CSF analysis; Radiation: Functional MRI

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 35

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Participants will be recruited from the community and the Memory Disorders Clinic of The OSU Wexner Medical Center Department of Neurology. This study will include cognitively normal individuals (CDR 0; n=20), individuals with a clinical diagnosis of single-domain or multi-domain amnestic MCI due to AD or mild AD dementia (CDR 0.5 or 1; n=20).

Description

Inclusion Criteria: Participants included in the study should meet all 4 inclusion criteria:

1. 60 years of age or older
2. A clinical diagnosis of MCI, mild AD dementia, or normal cognition
3. No significant medical or surgical co-morbidities
4. No contraindications to LP or MRI.

Exclusion criteria: Participants with any of the following criteria will be excluded from the study:

1. 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
2. Individuals with any past history of ischemic or traumatic brain injury
3. Individuals with imaging evidence of significant cerebrovascular disease or structural brain lesions (e.g. tumor, demyelinating disorders, infection, or congenital anomalies)
4. Active mood disorder
5. Active alcohol use
6. Active use of benzodiazepines, barbiturates, anticholinergic, or anti-epileptic medications

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
MCI due to AD or mild AD dementia; 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; CSF analysis for tau, p-tau181, Abeta42, and CSF levels of markers of synaptic injury; Radiation: Functional MRI; Functional MRI during resting state and semantic memory task activation
Normal controls; 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; CSF analysis for tau, p-tau181, Abeta42, and CSF levels of markers of synaptic injury; Radiation: Functional MRI; Functional MRI during resting state and semantic memory task activation

What is the study measuring?

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).

Collaborators and Investigators

• Sponsor: Ohio State University
• Investigators: Principal Investigator: Rawan Tarawneh, MD, Ohio State University

Study record dates

Study Major Dates

• Study Start (Actual): February 12, 2018
• Primary Completion (Actual): September 22, 2021
• Study Completion (Actual): September 22, 2021

Study Registration Dates

• First Submitted: September 25, 2017
• First Submitted That Met QC Criteria: September 28, 2017
• First Posted (Actual): October 3, 2017

Study Record Updates

• Last Update Posted (Actual): September 28, 2021
• Last Update Submitted That Met QC Criteria: September 22, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Synaptic injury
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Disease Attributes; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Late Onset Disorders
• Other Study ID Numbers: 2017H0255

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No