HIV-associated neurocognitive disorders (HAND) remain a major public health concern despite effective suppression of plasma viremia by antiretroviral therapy (ART). Although HIV dementia is now rare, less severe but prevalent forms of HAND adversely impact quality of life. Motor function and multiple cognitive domains are often impaired in HIV+ patients. Elucidating the pathogenesis of HAND is crucial to development of optimal treatments. While reduced basal ganglia volumes are a hallmark of HIV/AIDS, atrophy of the cortex is also seen in ART- treated patients today. We have preliminary data from a structural magnetic resonance imaging (MRI) study of non-demented, virally suppressed HIV+ subjects. Significant thinning of the insula and other cortical regions, as well as of subcortical and cerebellar gray matter, was associated with detectable levels of peripheral blood mononuclear cell HIV DNA. As the insula plays a key role in attention and psychomotor ability, its dysfunction has potential implications for HAND. Alterations in functional connectivity between the insula and other brain regions affected by HIV may shed light on the mechanism behind neurocognitive decline. Using a data-driven choice of insular sub-regions based on our recent work, we propose to determine their intrinsic functional connectivity with other relevant brain structures. This project will use resting-state functional MRI to: 1) relate atrophy of the insula to altered intrinsic functional connectivity between the insula and target brain regions, and assess connectivity differences between HIV+ subjects and healthy controls;2) determine the relation between resting-state functional insular connectivity and measures of neurocognitive function;and 3) explore the possible association of resting-state functional insular connectivity with HIV DNA. Changes in insular structure and function will be evaluated as potential markers of neurocognitive impairment. Structural atrophy and disrupted functional connectivity will be quantified by MRI-based morphometry and resting-state functional MRI, respectively. An imaging marker of HAND would potentially identify and monitor patients at risk or in early stages of neurocognitive decline. Therapy aimed at halting or reversing brain atrophy or disrupted functional connectivity may eventually become possible with knowledge of the underlying processes.

Public Health Relevance

A major clinical concern today is cognitive impairment that afflicts HIV-infected patients even when their viremia is suppressed by optimally effective therapy. We have preliminary data on vulnerable regions of brain cortex (such as the insula) and subcortical structures that have implications for cognitive functions impacted by HIV. Using neuroimaging to study how HIV affects the functional connections among these brain regions, we aim to clarify the mechanisms that underlie HIV-associated neurocognitive decline and thereby ultimately to contribute to improved disease management and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS080656-02
Application #
8606784
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2013-02-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$155,826
Indirect Cost
$35,871
Name
University of Hawaii
Department
None
Type
Organized Research Units
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822