Diffusion Basis Spectral Imaging Detects Ongoing Brain Inflammation in Virologically Well-Controlled HIV+ Patients

Abstract

Inflammation occurs after HIV infection and persists despite highly active antiretroviral therapy (HAART). Diffusion tensor imaging (DTI), measures HIV associated white matter changes, but can be confounded by inflammation. Currently, the influence of inflammation on white matter integrity in well-controlled HIV+ patients remains unknown. We used diffusion basis Spectrum imaging (DBSI) derived cellularity to isolate restricted water diffusion associated with inflammation separated from the anisotropic diffusion associated with axonal integrity. Ninety-two virologically suppressed HIV+ patients on HAART and 66 HIV uninfected (HIV-) controls underwent neuropsychological performance (NP) testing and neuroimaging. NP tests assessed multiple domains (memory, psychomotor speed, and executive functioning). DTI and DBSI derived fractional anisotropy (FA) maps were processed with tract based spatial statistics for comparison between both groups. Cellularity was assessed with regards to age, HIV status, and NP. Within the HIV+ cohort, cellularity was compared to clinical (HAART duration) and laboratory measures of disease (e.g. CD4 cell current and nadir). NP was similar for both groups. DTI derived FA was lower in HIV+ compared to HIV- individuals. In contrast, DBSI derived FA was similar for both groups. Instead, diffuse increases in cellularity were present in HIV+ individuals. Observed changes in cellularity were significantly associated with age, but not NP, in HIV+ individuals. A trend level association was seen between cellularity and HAART duration. Elevated inflammation, measured by cellularity, persists in virologically well-controlled HIV+ individuals. Widespread cellularity changes occur in younger HIV+ individuals and diminish with aging and duration of HAART.

The Aging Brain With HIV Infection: Effects of Alcoholism or Hepatitis C Comorbidity

“…DTI has been underutilized in studying the HIV brain and thus also holds promise for clarifying the brain regions involved in HIV-associated cognitive and motor impairments and in explicating mechanisms that may contribute to dysfunction with age. Free water imaging, a DTI analysis method that improves the specificity and sensitivity of DTI by accounting for extracellular water (Pasternak et al, 2009 , 2012 ; Metzler-Baddeley et al, 2012 ), may permit a better understanding of neuroinflammatory processes in HIV (Strain et al, 2017 ) and aging. A better understanding of the aging HIV brain will help in the development of integrated healthcare approaches for these complicated patients.…”

“…Effects on DTI metrics may also depend on presence of neurological complications (Corrêa et al, 2015 ), with symptomatic individuals showing effects extending to frontal areas (Zhu et al, 2013 ). Chronic relative to initial infection often shows more substantial differences in DTI metrics related to biomarkers of infection (e.g., viral load and immune compromise), disease duration, and ART duration (Wright et al, 2015 ; Cordero et al, 2017 ; Strain et al, 2017 ), which complicates attempts to distinguish effects of age, as age is often correlated with the duration of infection and ART.…”

“…Although widespread abnormalities in white matter microstructure correlate with general cognitive compromise in HIV (Nir et al, 2014 ; Strain et al, 2017 ; Underwood et al, 2017a ; Watson et al, 2017 ), more specific microstructure/function relationships have also been reported. For example, planning deficits correlated with low FA in anterior thalamic radiations, inferior fronto-occiptal fasciculi, superior longitudinal fascicule, corpus callosum genu, and uncinate fascicule (Corrêa et al, 2015 ); motor impairments correlated with low FA in various motor tracts (Bernard et al, 2013 ); self-reported signs of peripheral neuropathy correlated with abnormally high callosal diffusivity (Pfefferbaum et al, 2009a ).…”

Aging and Apolipoprotein E in HIV Infection

“…MR diffusion tensor imaging (DTI) detected increased mean diffusivity of the genu of the corpus callosum over 1 year in a cohort of 39 clinically and cognitively stable HIV-infected subjects (mean age 47.4 years) compared to 32 SN controls (mean age 46.7 years), suggesting greater than age-related inflammatory changes occurred in that region (Chang et al 2008 ). In a subsequent study, Strain et al ( 2017 ) used diffusion basis spectral imaging (DBSI)-derived cellularity as a measure of restricted water diffusion associated with inflammation in the brain. Their study cohort included 92 virologically suppressed HIV-infected subjects on stable ART regimens (mean age 49.1 years) and 66 SN controls (mean age 38.6 years).…”

The Impact of Edema and Fiber Crossing on Diffusion MRI Metrics: DBSI vs. Diffusion ODF

“…17 DBSI differs from DTI and other models in that it separates isotropic diffusion components to discriminate between inflammation, cellularity, and cerebrospinal fluid (CSF), enabling tracking of pathologies such as multiple sclerosis, 18,20,21 cervical spondylotic myelopathy, 22,23 traumatic spinal cord injury, 24,25 epilepsy, 26 and intracranial inflammation in HIV+ patients. 27 Importantly, DBSI simultaneously resolves angle of crossing fibers and quantifies individual fiber diffusivity, a feature that neither DTI, DKI, QBI nor NODDI possesses.…”