Behavioral and neuroimaging evidence for impaired executive function in “cognitively normal” older HIV-infected adults

Abstract

The increased prevalence of HIV among adults >50 years underscores the importance of improving our understanding of mechanisms causing HIV-associated neurocognitive disorders (HAND). Identifying novel and non-invasive diagnostic predictors of HAND prior to clinical manifestation is critical to ultimately identifying means of preventing progression to symptomatic HAND. Here using a task-switching paradigm, in which subjects were cued (unpredictably) to perform a face-gender or a word-semantic task on superimposed face and word images, we examined the behavioral and neural profile of impaired cognitive control in older HIV+ adults (N=14, 9 HIV+). Functional magnetic resonance imaging (fMRI) and behavioral data were acquired while subjects were performing the face-gender or word-semantic task. We found that, despite comparable performance in standard neuropsychology tests that are designed to probe executive deficits, HIV infected participants were significantly slower than uninfected controls in adapting to change in task demand, and the behavioral impairments can be quantitatively related to difference in fMRI signal at the dorsal anterior cingulate cortex (ACC). Due to the limited sample size of this hypothesis generating study, we should take caution with these findings and future studies with a large and better matched sample size are needed. However, these rather novel findings in this study have a few important implications: first, the prevalence of cognitive impairments in HIV+ older adults might be even higher than previously proposed; secondly, ACC (in particularly its dorsal region) might be one of the key regions underlying cognitive impairments (in particularly executive functions) in HIV; and thirdly, it might be beneficial to adopt paradigms developed and validated in cognitive neuroscience to study HAND, as these techniques might be more sensitive to some aspects of HIV-associated neurocognitive impairments than standard neuropsychology tests.

Different roles of frontal versus striatal atrophy in HIV‐associated neurocognitive disorders

“…In the present study, the CLE technique reveals evidence suggesting that the ACC might be the most consistently affected sub‐region within the frontal‐limbic‐subcortical system in HIV+ adults, even in those who performed comparable to HIV− controls on varying neurocognitive tests. Interestingly, using different imaging techniques such as functional MRI (fMRI) and positron emission tomography (PET), we (Jiang, Barasky, Olsen, Riesenhuber, & Magnus, ) and others (Garvey et al, ), respectively, have also found ACC dysfunction/injury in cognitively “normal” HIV+ adults who perform comparable to controls on standard neurocognitive tests, and the degree of injury correlate with performance. Studies using other techniques such as magnetic resonance spectroscopy (MRS) have also identified injury to ACC during primary HIV infection (Peluso et al, ).…”

“…Interestingly, using different imaging techniques such as functional MRI (fMRI) and positron emission tomography (PET), we (Jiang, Barasky, Olsen, Riesenhuber, & Magnus, 2016) and others (Garvey et al, 2014), respectively, have also found ACC dysfunction/injury in cognitively "normal" HIV+ adults who perform comparable to controls on standard neurocognitive tests, and the degree of injury correlate with performance. Studies using other techniques such as magnetic resonance spectroscopy (MRS) have also identified injury to ACC during primary HIV infection (Peluso et al, 2013).…”

“…Nevertheless, this novel neural model can make several concrete and testable predictions. First, cognitively “normal” HIV+ adults might struggle with a task that heavily involves the ACC, such as a cognitive control task (Jiang et al, ); Second, a ratio of caudate (or striatum) volume versus frontal volume might be more sensitive to detect the presence of ANI/MND than the traditionally used ratio of caudate versus total brain volume (Dal Pan et al, ; Hestad et al, ; Kieburtz et al, ); Third, learning is affected at both stages, but delayed recall might be affected more at the caudate/striatum stage; Fourth, previous studies have suggested a high concentration of virus in the subcortical regions (Kumar et al, ; Perez et al, ), therefore, a rebound in viral load is likely to be more associated with injury to the caudate/striatum than to the frontal/ACC.…”

HIV-associated executive dysfunction in the era of modern antiretroviral therapy: A systematic review and meta-analysis

“…This is consistent with our findings that larger deficits in set-shifting are found among studies with relatively high proportions of substance-dependent HIV+ participants. While measurable set-shifting deficits were not found in the majority of individual studies, neuroimaging studies have demonstrated that structural and functional brain abnormalities in the basal ganglia and medial frontal regions (e.g., dorsal anterior cingulate cortex) are associated with poorer performance on set-shifting measures in HIV+ individuals (Corrêa et al, 2016; Jiang, Barasky, Olsen, Riesenhuber, & Magnus, 2016). With regard to biomarkers, HIV-associated set-shifting deficits have been associated with magnetic resonance spectroscopy (MRS) markers of abnormal astrocytic glutamate processing, reduced oxygen and glucose metabolism in frontal white matter structures (Mohamed et al, 2010), and elevated levels of circulating cytokines (Cohen et al, 2011).…”

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

“…Visuospatial abilities are relatively spared (Cysique et al, 2006 ), but may be sensitive to age-HIV interactions (Foley et al, 2013 ). Persistent cognitive impairments post-ART have been attributed to a variety of factors (e.g., immunological, genetic, psychosocial) (e.g., Arentoft et al, 2015 ; Thaler et al, 2015 ; Hobkirk et al, 2017 ), including ART, in particular efavirenz (Ciccarelli et al, 2011 ; Romão et al, 2011 ; Funes et al, 2014 ; Ma et al, 2016 ), advancing age (e.g., Morgan et al, 2011 ; Brew and Chan, 2014 ; Jacks et al, 2015 ; Jiang et al, 2016 ; Gomez et al, 2017 ), and comorbidity for substance use (Rosenbloom et al, 2010 ; Sassoon et al, 2012 ; Míguez-Burbano et al, 2014 ) or HCV infection (Devlin et al, 2012 ).…”