Cognitive neuropsychology of HIV-associated neurocognitive disorders.
ABSTRACT: Advances in the treatment of the human immunodeficiency virus (HIV) have dramatically improved survival rates over the past 10 years, but HIV-associated neurocognitive disorders (HAND) remain highly prevalent and continue to represent a significant public health problem. This review provides an update on the nature, extent, and diagnosis of HAND. Particular emphasis is placed on critically evaluating research within the realm of cognitive neuropsychology that aims to elucidate the component processes of HAND across the domains of executive functions, motor skills, speeded information processing, episodic memory, attention/working memory, language, and visuoperception. In addition to clarifying the cognitive mechanisms of HAND (e.g., impaired cognitive control), the cognitive neuropsychology approach may enhance the ecological validity of neuroAIDS research and inform the development of much needed novel, targeted cognitive and behavioral therapies.
Project description:Cognitive decline is a severe concern of patients with mild cognitive impairment. Also, in patients with temporal lobe epilepsy, memory problems are a frequently encountered problem with potential progression. On the background of a unifying hypothesis for cognitive decline, we merged knowledge from dementia and epilepsy research in order to identify biomarkers with a high predictive value for cognitive decline across and beyond these groups that can be fed into intelligent systems. We prospectively assessed patients with temporal lobe epilepsy (N?=?9), mild cognitive impairment (N?=?19), and subjective cognitive complaints (N?=?4) and healthy controls (N?=?18). All had structural cerebral MRI, EEG at rest and during declarative verbal memory performance, and a neuropsychological assessment which was repeated after 18 months. Cognitive decline was defined as significant change on neuropsychological subscales. We extracted volumetric and shape features from MRI and brain network measures from EEG and fed these features alongside a baseline testing in neuropsychology into a machine learning framework with feature subset selection and 5-fold cross validation. Out of 50 patients, 27 had a decline over time in executive functions, 23 in visual-verbal memory, 23 in divided attention, and 7 patients had an increase in depression scores. The best sensitivity/specificity for decline was 72%/82% for executive functions based on a feature combination from MRI volumetry and EEG partial coherence during recall of memories; 95%/74% for visual-verbal memory by combination of MRI-wavelet features and neuropsychology; 84%/76% for divided attention by combination of MRI-wavelet features and neuropsychology; and 81%/90% for increase of depression by combination of EEG partial directed coherence factor at rest and neuropsychology. Combining information from EEG, MRI, and neuropsychology in order to predict neuropsychological changes in a heterogeneous population could create a more general model of cognitive performance decline.
Project description:The discipline of cognitive neuropsychology has been important for informing theories of cognition and describing the nature of acquired cognitive disorders, but its applicability in a developmental context has been questioned. Here, we revisit this issue, asking whether the cognitive neuropsychological approach can be helpful for exploring the nature and causes of developmental disorders and, if so, how. We outline the key features of the cognitive neuropsychological approach, and then consider how some of the major challenges to this approach from a developmental perspective might be met. In doing so, we distinguish between challenges to the methods of cognitive neuropsychology and those facing its deeper conceptual underpinnings. We conclude that the detailed investigation of patterns of both associations and dissociations, and across both developmental and acquired cases, can assist in describing the cognitive deficits within developmental disorders and in delineating possible causal pathways to their acquisition.
Project description:Nearly 50% of adults with HIV have some form of HIV-associated neurocognitive disorder (HAND), ranging from subtle to symptoms that interfere with everyday functioning and quality of life. HAND is diagnosed when a person performs more than 1 standard deviation below his or her normative mean on standardized measures in two or more cognitive domains (e.g., attention, speed of processing, verbal memory, executive functioning). As adults age with HIV, they are more likely to develop comorbidities such as cardiovascular disease, hypertension, and insulin resistance that may further contribute to poorer cognitive functioning and HAND. Certain computerized cognitive training programs may be able to improve specific cognitive domains in those with HIV. Such programs may be effective in changing the diagnosis of HAND in cognitively vulnerable adults. In this article, we describe the design and methods of TOPS-the Training On Purpose Study. In this on-going experimental study, 146 older adults (50+) with HAND are randomized to either: (i) an Individualized-Targeted Cognitive Training group, or (ii) a no-contact control group. This study targets those cognitive domains in which participants experience a deficit and trains participants with the corresponding computerized cognitive training program for that domain. An Individualized Targeted Cognitive Training approach using cognitive-domain-specific cognitive training programs may offer symptom relief to those individuals diagnosed with HAND, which may actually reverse this diagnosis. Given that these cognitive training programs are commercially available, this approach represents a potential paradigm shift in how HAND is considered and treated.
Project description:BACKGROUND:HIV-associated neurocognitive disorder (HAND) can occur in patients without prior AIDS defining illness and can be debilitating. This study aimed to evaluate the difference in the patterns of intrinsic brain activity between patients with or without HAND for deepening our understanding of HAND. METHODS:We evaluated 24 HIV-infected individuals, 12 with previously diagnosed HAND and 12 previously diagnosed without HAND, and 11 seronegative individuals. These individuals then underwent repeat NP testing and a functional brain MRI scan. For functional MRI analysis, seed-based analysis with bilateral precuneus cortex seed was applied. RESULTS:Among the 12 individuals with previously diagnosed HAND, 3 showed improvement of their neurocognitive function and 1 was excluded for worsening liver disease. Among the 12 patients who previously had normal neurocognitive function, 2 showed neurocognitive impairment. Overall, the HAND group, who had impaired cognitive function at the time of MRI scan, showed significant decrease of resting status functional connectivity between bilateral precuneus and prefrontal cortex (PFC) compared with nonHAND group, those who had normal neurocognitive function (Corrected P<0.05). The functional connectivity with the right inferior frontal operculum and right superior frontal gyrus was positively correlated with memory and learning ability. CONCLUSIONS:This cross-sectional study found a significant difference in fMRI patterns between patients with and without HAND. Decreased functional connectivity between precuneus and PFC could be possible functional substrate for cognitive dysfunction in HIV patients, which should be characterized in a longitudinal study.
Project description:<h4>Objective</h4>The aim of this study was to apply the HIV-associated neurocognitive disorders (HAND) criteria for diagnosing HAND in HIV-infected adults, in a cohort of HIV-infected youth to thus establish whether this system is able to detect a spectrum of neurocognitive disorders (ND) in HIV-infected youth.<h4>Methods</h4>We used a comprehensive pediatric neurocognitive battery, an assessment of functional competence, and the American Academy of Neurology system for diagnosing ND in a cross-sectional study of HIV-infected youth (n = 86) and HIV-negative controls (n = 34) to establish whether this system could detect a spectrum of ND in HIV-infected youth (6-16 years).<h4>Results</h4>Compared to a well-matched control group of HIV-negative youth, HIV-infected youth performed significantly more poorly on tests of Verbal IQ, Full Scale IQ, processing speed, finger tapping, verbal memory, expressive language, cognitive flexibility, and inhibition. HIV-infected youth were also more likely to have impaired total competence on the Child Behavior Checklist. Using the criteria for HAND, we found that 45.35% of the 86 HIV-infected youth could be diagnosed with an ND. Furthermore, youth with HIV encephalopathy (HIVE) were 9.4 times more likely to have a diagnosis of a major ND compared to HIV-infected youth without HIVE.<h4>Conclusions</h4>The HAND criterion designed for adults was able to identify youth with important functional cognitive impairments who do not fit criteria for HIVE and would therefore not have been identified otherwise. This has major clinical implications regarding the importance of managing HIV-infected youth.
Project description:HIV-associated neurocognitive disorder (HAND) describes a spectrum of behavioural, motor and cognitive disturbances that can occur secondary to HIV infection. Less severe forms of the disorder persist despite advances in antiretroviral medication efficacy and availability. Childhood trauma (CT) may predispose individuals to developing HAND. As genetic variation in human apolipoprotein E (ApoE) has been implicated in cognitive decline and may mediate the development of long-term health outcomes following CT, we investigated the influence of ApoE and CT on cognitive function in the context of HIV. One hundred twenty-eight HIV-positive Xhosa women completed the Childhood Trauma Questionnaire-Short Form (CTQ-SF) as well as the HIV Neurobehavioural Research Center neurocognitive test battery. rs7412 and rs429358 were genotyped using KASP assays, and this data was used to determine the ApoE isoform. Baseline differences in demographic and clinical variables according to CT exposure were calculated. Analysis of covariance was used to assess the contributions of CT and ApoE variants, as well as their interaction, to cognitive function. Eighty-eight participants reported experiencing CT. The rs7412 C allele protected against the harmful effect of CT on motor scores using an additive model. The interaction of ApoE ?4 and CT was associated with worse attention/working memory scores. ApoE ?4, alone and in combination with CT, is associated with poorer cognitive function. Further research into this gene-environment interaction may assist in identifying at-risk individuals for targeted interventions.
Project description:The Human Genome Project, coupled with rapidly evolving high-throughput technologies, has opened the possibility of identifying heretofore unknown biological processes underlying human disease. Because of the opaque nature of HIV-associated neurocognitive disorder (HAND) neuropathogenesis, the utility of such methods has gained notice among NeuroAIDS researchers. Furthermore, the merging of genetics with other research areas has also allowed for application of relatively nascent fields, such as neuroimaging genomics, and pharmacogenetics, to the context of HAND. In this review, we detail the development of genetic, transcriptomic, and epigenetic studies of HAND, beginning with early candidate gene association studies and culminating in current "omics" approaches that incorporate methods from systems biology to interpret data from multiple levels of biological functioning. Challenges with this line of investigation are discussed, including the difficulty of defining a valid phenotype for HAND. We propose that leveraging known associations between biology and pathology across multiple levels will lead to a more reliable and valid phenotype. We also discuss the difficulties of interpreting the massive and multitiered mountains of data produced by current high-throughput omics assays and explore the utility of systems biology approaches in this regard.
Project description:Virtual reality (VR) represents a key technology of the 21st century, attracting substantial interest from a wide range of scientific disciplines. With regard to clinical neuropsychology, a multitude of new VR applications are being developed to overcome the limitations of classical paradigms. Consequently, researchers increasingly face the challenge of systematically evaluating the characteristics and quality of VR applications to design the optimal paradigm for their specific research question and study population. However, the multifaceted character of contemporary VR is not adequately captured by the traditional quality criteria (ie, objectivity, reliability, validity), highlighting the need for an extended paradigm evaluation framework. To address this gap, we propose a multidimensional evaluation framework for VR applications in clinical neuropsychology, summarized as an easy-to-use checklist (VR-Check). This framework rests on 10 main evaluation dimensions encompassing cognitive domain specificity, ecological relevance, technical feasibility, user feasibility, user motivation, task adaptability, performance quantification, immersive capacities, training feasibility, and predictable pitfalls. We show how VR-Check enables systematic and comparative paradigm optimization by illustrating its application in an exemplary research project on the assessment of spatial cognition and executive functions with immersive VR. This application furthermore demonstrates how the framework allows researchers to identify across-domain trade-offs, makes deliberate design decisions explicit, and optimizes the allocation of study resources. Complementing recent approaches to standardize clinical VR studies, the VR-Check framework enables systematic and project-specific paradigm optimization for behavioral and cognitive research in neuropsychology.
Project description:Older HIV-infected patients are at risk for both HIV-associated neurocognitive disorder (HAND) and Alzheimer's disease. We investigated neuroimaging and neuropsychological performance of 61 virally suppressed older adults with HAND (mean (SD) age 64.3 (3.9) years), 53 demographically matched individuals with mild cognitive impairment of the Alzheimer's type (MCI-AD; 65.0 [4.8]), and 89 healthy controls (65.0 [4.3]) cross-sectionally and over 20 months. At the baseline, both disease groups exhibited lower volumes in multiple cortical and subcortical regions compared with controls. Hippocampal volume differentiated MCI-AD from HAND. Cognitively, MCI-AD performed worse on memory and language compared with HAND. Adjusted longitudinal models revealed greater diffuse brain atrophy in MCI-AD compared with controls, whereas HAND showed greater atrophy in frontal gray matter and cerebellum compared with controls. Comparing HAND with MCI-AD showed similar atrophy rates in all brain regions explored, with no significant findings. MCI-AD exhibited more pronounced language decline compared with HAND. These findings reveal the need for further work on unique cognitive phenotypes and neuroimaging signatures of HAND compared with early AD, providing preliminary clinical insight for differential diagnosis of age-related brain dysfunction in geriatric neuroHIV.
Project description:HIV-Tat protein has been implicated in the pathogenesis of HIV-1 neurological complications (i.e., neuroAIDS), but direct demonstrations of the effects of Tat on behavior are limited. GT-tg mice with a doxycycline (Dox)-inducible and brain-selective tat gene coding for Tat protein were used to test the hypothesis that the activity of Tat in brain is sufficient to impair learning and memory processes. Western blot analysis of GT-tg mouse brains demonstrated an increase in Tat antibody labeling that seemed to be dependent on the dose and duration of Dox pretreatment. Dox-treated GT-tg mice tested in the Barnes maze demonstrated longer latencies to find an escape hole and displayed deficits in probe trial performance versus uninduced GT-tg littermates, suggesting Tat-induced impairments of spatial learning and memory. Reversal learning was also impaired in Tat-induced mice. Tat-induced mice additionally demonstrated long-lasting (up to one month) deficiencies in novel object recognition learning and memory performance. Furthermore, novel object recognition impairment was dependent on the dose and duration of Dox exposure, suggesting that Tat exposure progressively mediated deficits. These experiments provide evidence that Tat protein expression is sufficient to mediate cognitive abnormalities seen in HIV-infected individuals. Moreover, the genetically engineered GT-tg mouse may be useful for improving our understanding of the neurological underpinnings of neuroAIDS-related behaviors.