African American Alzheimer's Progression Markers - CSF and Neuro-Imaging

Mild Cognitive Impairment Clinical Trial

— A3PM  

Official title:

Biomarkers for Alzheimer's Disease and Mild Cognitive Impairment in African Americans and Caucasians

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02089555
• Other study ID #: IRB00066145
• Secondary ID: R21AG043885
• Status: Completed
• Phase: N/A
• First received: March 14, 2014
• Last updated: June 21, 2016
• Start date: September 2013
• Est. completion date: June 2016

Study information

• Verified date: June 2016
• Source: Emory University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial Summary

African Americans are twice as likely to develop Alzheimer's disease as white Americans, but few African Americans are enrolled in large Alzheimer's biomarker studies. The current proposal aims to determine the influence of Alzheimer's disease and vascular disease on memory and aging in African Americans through modern biomarkers (spinal fluid, MRI, and amyloid imaging), and how these may differ between African Americans and white Americans in preparation for a large multi-center study of aging in African American.

Description:

African Americans represent about 10% of the population in the US, but are under-represented in biomarker-related aging studies such as the Alzheimer's Disease Neuro-imaging Initiative (ADNI) and World Wide ADNI. Epidemiologic studies show that, compared to non-Hispanic white (NHW) Americans, African Americans (AA) are more likely to develop mild cognitive impairment (MCI) and Alzheimer's disease (AD), have different genetic risks of developing AD, and experience different rates of cognitive decline after cognitive symptoms develop. All these point to the existence of an MCI/AD endophenotype for AA, although few of these epidemiological studies involve modern chemical or imaging biomarkers associated with AD pathology and progression. Preliminary studies using AA subjects who have undergone CSF analysis (n=36) show that AA MCI subjects are more likely to have normal CSF AD biomarkers than NHW MCI subjects, yet at the same time greater hippocampal atrophy on MRI. The investigators hypothesize that endothelial dysfunction is an alternate mechanism which independently contributes to cognitive impairment in AA subjects with sub-threshold AD pathology in a race-independent fashion, and endothelia dysfunction further enhances the neurotoxicity of AD-associated brain changes in a race-dependent fashion. The investigators propose to build on their success in recruiting AA volunteers into memory and aging studies at the Emory's Registry for Remembrance to recruit a cross-sectional cohort of 75 AA subjects along with 75 NHW subjects with normal cognition, MCI, or mild AD. They will test this hypothesis through two aims. In Aim 1, they will determine whether endothelial dysfunctions independently contribute to cognitive decline in AA and NHW subjects by measuring cerebrospinal fluid (CSF) levels of AD, endothelial, and inflammatory markers. Each subject will also undergo MRI analysis for total area of white matter hyperintensities as an imaging marker of endothelial dysfunction. Based on the hypothesis, they predict that AA MCI/AD subjects are more likely than NHW MCI subjects to have normal CSF AD biomarkers, abnormal CSF endothelial markers, and greater number and area of white matter hyperintensities on MRI. In Aim 2, the investigators will determine if an endothelial marker - intercellular adhesion molecule 1 or ICAM-1 - gene variant unique to AA enhances AD neurotoxicity to explain the greater hippocampal atrophy among AA MCI subjects. The Lys56Met ICAM1 gene variant associated with low ICAM-1 levels is uniquely found in 16-20% of AA, and these subjects may have impaired downstream activation of neprilysin, an Abeta-degrading enzyme. If the hypothesis is true, AA subjects with the Lys56Met gene variant will be more likely to have hippocampal atrophy, temporal-parietal cerebral hypoperfusion, and cerebral amyloid deposition than AA subjects and NHW subjects without the gene variant. This may occur in the setting of CSF Abeta2 pseudo-normalization if low neprilysin levels lead to increased Abeta42 levels. Successful completion of the current proposal will confirm the preliminary finding of a unique AA endophenotype within the broader AD-spectrum disorders, directly examine whether endothelial dysfunctions additively and synergistically lead to cognitive decline in AD among AA in a cross-sectional cohort, and help power and design a future a multi-center, multi-racial longitudinal biomarker study to validate these cross-sectional findings.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 135
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 60 Years to 85 Years

Eligibility

Inclusion Criteria:

• Ages 60-85.

• Has normal cognition, a diagnosis of mild cognitive impairment, or a diagnosis of Alzheimer's disease or mild cognitive impairment.

• Self-reported race of African American or non-Hispanic white.

• Able to undergo neuropsychological testing, lumbar puncture, and MRI.

• English speaking.

Exclusion Criteria:

• History of stroke.

• Diagnosis of Parkinson's disease, amyotrophic lateral sclerosis, or another progressive neurological disorder which may spare cognition.

• Mini-Mental State Examination (MMSE) < 17

Study Design

Observational Model: Case Control, Time Perspective: Prospective

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease
• Cognition Disorders
• Mild Cognitive Impairment

Intervention

Procedure:
• Lumbar puncture
Cerebrospinal fluid (CSF) will be collected via lumbar puncture. During lumbar puncture, a needle is inserted between two lumbar bones (vertebrae) to remove a sample of cerebrospinal fluid. The procedure involves inserting a thin, hollow needle between the two lower vertebrae (lumbar region), through the spinal membrane (dura) and into the spinal canal and extracting a small amount of fluid. The procedure takes about 45 minutes.
• Blood draw
One tube of blood will be collected in an ethylenediaminetetraacetic acid (EDTA)-K2 plasma tube for DNA analysis.
• Magnetic Resonance Imaging (MRI)
Each participant will undergo Magnetic Resonance Imaging (MRI) analysis using a modified Alzheimer's Disease Neuroimaging Initiative (ADNI) protocol with a 3 Tesla (3T) MRI Scan. The exam takes approximately 20 minutes.

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia

Sponsors (2)

Lead Sponsor	Collaborator
Emory University	National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	CSF endothelial marker levels		one time only	No
Primary	CSF Alzheimer's biomarker levels		one time only	No
Secondary	MRI evidence of small vessel disease		one time only	No
Secondary	MRI evidence of brain atrophy		one time only	No

External Links

•   Emory Alzheimer's Disease Research Center