Real-world impact of neurocognitive deficits in acute and early HIV infection

The acute and early period of HIV-1 infection (AEH) is characterized by neuroinflammatory and immunopathogenic processes that can alter the integrity of neural systems and neurocognitive functions. However, the extent to which central nervous system changes in AEH confer increased risk of real-world functioning (RWF) problems is not known. In the present study, 34 individuals with AEH and 39 seronegative comparison participants completed standardized neuromedical, psychiatric, and neurocognitive research evaluations, alongside a comprehensive assessment of RWF that included cognitive symptoms in daily life, basic and instrumental activities of daily living, clinician-rated global functioning, and employment. Results showed that AEH was associated with a significantly increased risk of dependence in RWF, which was particularly elevated among AEH persons with global neurocognitive impairment (NCI). Among those with AEH, NCI (i.e., deficits in learning and information processing speed), mood disorders (i.e., Bipolar Disorder), and substance dependence (e.g., methamphetamine dependence) were all independently predictive of RWF dependence. Findings suggest that neurocognitively impaired individuals with AEH are at notably elevated risk of clinically significant challenges in normal daily functioning. Screening for neurocognitive, mood, and substance use disorders in AEH may facilitate identification of individuals at high risk of functional dependence who may benefit from psychological and medical strategies to manage their neuropsychiatric conditions.     

Substance use is a risk factor for neurocognitive deficits and neuropsychiatric distress in acute and early HIV infection

The acute and early stages of HIV infection (AEH) are characterized by substantial viral replication, immune activation, and alterations in brain metabolism. However, little is known about the prevalence and predictors of neurocognitive deficits and neuropsychiatric disturbances during this period. The present study examined the impact of demographic, HIV disease, and substance use factors on HIV-associated neurocognitive impairment and self-reported neuropsychiatric distress among 46 antiretroviral-naive adults with median duration of infection of 75 days relative to a sample of 21 HIV seronegative (HIV?) adults with comparable demographics and risk factors. Participants were administered a brief neurocognitive battery that was adjusted for demographics and assessed executive functions, memory, psychomotor speed, and verbal fluency, as well as the Profile of Mood States, a self-report measure of neuropsychiatric distress. Odds ratios revealed that AEH participants were nearly four times more likely than their seronegative counterparts to experience neurocognitive impairment, particularly in the areas of learning and information processing speed. Similarly, AEH was associated with a nearly fivefold increase in the odds of neuropsychiatric distress, most notably in anxiety and depression. Within the AEH sample, HIV-associated neurocognitive impairment was associated with problematic methamphetamine use and higher plasma HIV RNA levels, whereas neuropsychiatric distress was solely associated with high-risk alcohol use. Extending prior neuroimaging findings, the results from this study indicate that HIV-associated neurocognitive impairment and neuropsychiatric distress are highly prevalent during AEH and are associated with high-risk substance use.     

An active lifestyle is associated with better neurocognitive functioning in adults living with HIV infection

Studies of healthy adults show that engagement in physical, social, and mental activities is associated with better cognitive outcomes, suggesting that these activities may increase cognitive reserve. Given the prevalence and real-world impact of HIV-associated neurocognitive disorders (HAND), the present study examined the association between neurocognitive outcomes and self-reported proxies for physical exercise, social activity, and mental activity (employment was used as a proxy for mental activity) among 139 HIV-infected adults (M _age = 48.7; 48 % age 50+). Participants completed a neuromedical and neuropsychological battery and were classified based on the number of self-reported active lifestyle factors (ALFs; 0 to 3), including physical exercise, social activity, and current employment. The association between ALFs and both demographically adjusted average neuropsychological T-scores and HAND diagnoses was examined. Results revealed that an increased number of ALFs were associated with better global neurocognitive performance as well as a lower prevalence of HAND. These cross-sectional findings suggest that an active engagement in life may bolster neurocognitive functioning, perhaps by enhancing cognitive and/or brain reserve. However, an alternative explanation might be that persons with better neurocognitive functioning are more inclined and able to engage in these life activities. Future studies should utilize neuroimaging methodology, longitudinal data, and interventional approaches to establish cause–effect relationships and uncover the neural mechanisms whereby physical, social, and mental stimulation may protect neurocognition via cognitive reserve among those living with HIV.     

Low peripheral mitochondrial DNA copy number during manic episodes of bipolar disorders is associated with disease severity and inflammation

Mitochondria (Mt) are intra-cellular components essential for cellular energy processes whose dysfunction may induce premature cellular senescence and/or inflammation, both observed in bipolar disorders (BD). We investigated mitochondrial DNA copy number (mtDNAcn) levels in patients with BD being in manic, depressive or euthymic phase and in healthy controls (HC) both characterized for the levels of blood-based inflammatory markers and stigma of pathogens.312 patients with BD were compared to 180 HC. mtDNAcn were measured using a digital droplet PCR. Serum levels of 14 inflammatory molecules and 3 anti-infectious IgG stigma were respectively evaluated by electro-chemiluminescence, ELISA and dedicated immunoassays. The statistical analyses were performed using Spearman’s correlation, Wilcoxon signed-rank and Kruskal-Wallis rank sum tests. P-values were adjusted for multiple testing with Benjamini-Hochberg method.We found low levels of mtDNAcn in BD patients as compared to HC (P = 0.008) especially during manic episodes (P = 0.0002). We also observed that low levels of mtDNAcn are negatively correlated with mood and psychotic scales (PANSS, YMRS and CGI) (adjusted P (Adj P) = 0.02, 0.003 and 0.05 respectively) and positively with the GAF severity scale (Adj P = 0.002). They were also correlated with high levels of both intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 (Adj P = 0.003 and 0.001) along with a trend toward increased IL-2, IL-10 and B2M circulating levels (Adj P = 0.05).Here, we report correlations between marker of mitochondria functioning and both clinical scales and inflammatory markers in BD patients experiencing manic episodes. If replicated, these finding might allow to predict transition between disease phases and to design accurate therapeutic options.     

Peripheral blood lymphocyte HIV DNA levels correlate with HIV associated neurocognitive disorders in Nigeria

Mononuclear cells play key roles in the pathogenic mechanisms leading to HIV-associated neurocognitive disorders (HANDs). We examined the association between HIV DNA within peripheral blood mononuclear cell (PBMC) subsets and HAND in Nigeria. PBMCs were collected at baseline from 36 antiretroviral naive participants. CD14+ cells and T&B lymphocyte fractions were isolated by, respectively, positive and negative magnetic bead separation. Total HIV DNA within CD14+ and T&B cells were separately quantified using real-time PCR assay targeting HIV LTR-gag and cell input numbers determined by CCR5 copies/sample. Utilizing demographically adjusted T scores obtained from a 7-domain neuropsychological test battery, cognitive status was determined by the global deficit score (GDS) approach, with a GDS of ≥0.5 indicating cognitive impairment. In a linear regression adjusting for plasma HIV RNA, CD4 and lymphocyte count, Beck’s depression score, and years of education, there was 0.04 lower log₁₀ HIV DNA copies within T&B lymphocytes per unit increase in global T score (p = 0.02). Adjusting for the same variables in a logistic regression, the odds of cognitive impairment were 6.2 times greater per log₁₀ increase in HIV DNA within T&B lymphocytes (p = 0.048). The association between cognitive impairment and HIV DNA within CD14+ monocytes did not reach statistical significance. In this pretreatment cohort with mild cognitive dysfunction, we found a strong association between levels of HIV DNA within the lymphocyte subset and HAND independent of plasma HIV RNA. These findings likely reflect the neurologic impact of a larger HIV reservoir and active viral replication.     

Increased cell-free mitochondrial DNA is a marker of ongoing inflammation and better neurocognitive function in virologically suppressed HIV-infected individuals

Cell-free mitochondrial DNA (mtDNA) is a highly immunogenic molecule that is associated with several inflammatory conditions and with neurocognitive impairment during untreated HIV infection. Here, we investigate how cell-free mtDNA in cerebrospinal fluid (CSF) is associated with inflammation, neuronal damage, and neurocognitive functioning in the context of long-term suppressive antiretroviral therapy (ART). We quantified the levels of cell-free mtDNA in the CSF from 41 HIV-infected individuals with completely suppressed HIV RNA levels in blood plasma (<50 copies/mL) by droplet digital PCR. We measured soluble CD14, soluble CD163, interferon γ-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α), neopterin, and neurofilament light chain (NFL) by immunoassays in CSF supernatant or blood plasma. Higher levels of mtDNA in CSF were associated with higher levels of MCP-1 (r = 0.56, p < 0.01) in CSF and TNF-α (r = 0.43, p < 0.01) and IL-8 (r = 0.44, p < 0.01) in blood plasma. Subjects with a previous diagnosis of AIDS showed significantly higher levels of mtDNA (p < 0.01) than subjects without AIDS. The associations between mtDNA and MCP-1 in CSF and TNF-α in blood remained significant after adjusting for previous diagnosis of AIDS (p < 0.01). Additionally, higher levels of mtDNA were associated with a lower CD4 nadir (r = ?0.41, p < 0.01) and lower current CD4% (r = ?0.34, p = 0.03). Paradoxically, higher levels of mtDNA in CSF were significantly associated with better neurocognitive performance (r = 0.43, p = 0.02) and with less neuronal damage (i.e. lower NFL). Higher cell-free mtDNA is associated with inflammation during treated HIV infection, but the impact on neurocognitive functioning and neuronal damage remains unclear and may differ in the setting of suppressive ART.     

Blood-based inflammation biomarkers of neurocognitive impairment in people living with HIV

Inflammation in people living with HIV (PLWH) correlates with severity of HIV-associated neurocognitive disorders. The objective of this study is to identify blood-based markers of neurocognitive function in a demographic balanced cohort of PLWH. Seven neurocognitive domains were evaluated in 121 seropositive Black/African American, Non-Hispanic White, and White Hispanic men and women using computerized assessments. Associations among standardized neurocognitive function and HIV-related parameters, relevant sociodemographic variables, and inflammation-associated cytokines measured in plasma and cellular supernatants were examined using multivariate and univariate regression models. Outlier and covariate analyses were used to identify and normalize for education level, CD4 T cell count, viral load, CNS and drug abuse comorbidities, which could influence biomarker and neurocognitive function associations. Plasma levels of chemokine (C-C motif) ligand (CCL) 8 significantly associated with memory, complex attention, cognitive flexibility, psychomotor speed, executive function, and processing speed. Plasma tissue inhibitor of metalloproteinases 1 associated with the aforementioned domains except memory and processing speed. In addition, plasma interleukin-23 significantly associated with processing speed and executive function. Analysis of peripheral blood cell culture supernatants revealed no significant markers for neurocognitive function. In this cohort, CD4 T cell count and education level also significantly associated with neurocognitive function. All identified inflammatory biomarkers demonstrated a negative correlation to neurocognitive function. These cytokines have known connections to HIV pathophysiology and are potential biomarkers for neurocognitive function in PLWH with promising clinical applications.

     

Striatum morphometry is associated with cognitive control deficits and symptom severity in internet gaming disorder

Internet gaming disorder (IGD), identified in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) Section III as a condition warranting more clinical research, may be associated with impaired cognitive control. Previous IGD-related studies had revealed structural abnormalities in the prefrontal cortex, an important part of prefrontal-striatal circuits, which play critical roles in cognitive control. However, little is known about the relationship between the striatal nuclei (caudate, putamen, and nucleus accumbens) volumes and cognitive control deficit in individuals with IGD. Twenty-seven adolescents with IGD and 30 age-, gender- and education-matched healthy controls participated in this study. The volume differences of the striatum were assessed by measuring subcortical volume in FreeSurfer. Meanwhile, the Stroop task was used to detect cognitive control deficits. Correlation analysis was used to investigate the relationship between striatal volumes and performance in the Stroop task as well as severity in IGD. Relative to controls, the IGD committed more incongruent condition response errors during the Stroop task and showed increased volumes of dorsal striatum (caudate) and ventral striatum (nucleus accumbens). In addition, caudate volume was correlated with Stroop task performance and nucleus accumbens (NAc) volume was associated with the internet addiction test (IAT) score in the IGD group. The increased volumes of the right caudate and NAc and their association with behavioral characteristics (i.e., cognitive control and severity) in IGD were detected in the present study. Our findings suggest that the striatum may be implicated in the underlying pathophysiology of IGD.     

Neurocognitive impairment associated with predominantly early stage HIV infection in Abuja,Nigeria

Detailed neuropsychological testing was performed on 133 human immunodeficiency virus (HIV) seropositive (SP) and 77 HIV seronegative (SN) individuals, 86 % with early stage HIV infection in Nigeria, to determine the frequency of HIV-related neurocognitive impairment among the HIV-infected group. The tests were administered to assess the following seven ability domains: speed of information processing, attention/working memory, executive functioning, learning, memory, verbal fluency, and motor function motor. Demographically corrected individual test scores and scores for each domain or reflecting a global deficit (a global deficit score, or GDS) were compared for the SP and SN groups. SP participants were older, had fewer years of education, were more likely to be married, differed in ethnicity, and had higher depression scores than SN individuals. Within the seven ability domains, SP performed worse than SN with respect to speed of information processing, executive function, learning, memory, and verbal fluency and also on the global measure. SP were also more frequently impaired on tests of SIP, and there was a borderline increase in the frequency of global impairment. On the individual tests, SP performed worse than SN on four tests that assessed learning, verbal fluency, memory, and motor function (the Timed Gait). SP subjects, however, performed better than SN on the Finger-tapping test, also a motor task. Performance by SP subjects was not associated on the timed gait which showed a borderline statistically significant correlation with CD4 counts. However, there were significant correlations between viral load measurements and individual tests of speed of information processing, executive function, learning, and verbal fluency and with overall executive function and a borderline correlation with the GDS. Depression scores for SP were associated with impairment on only a single test of executive function. These results demonstrate the ability of these assessments to identify areas of impairment that may be specifically linked to a history of HIV infection among individuals in Nigeria. Confirmation of these findings awaits analyses using data from a larger number of control subjects.     

Disrupted reward circuits is associated with cognitive deficits and depression severity in major depressive disorder

Neuroimaging studies have demonstrated that major depressive disorder (MDD) patients show blunted activity responses to reward-related tasks. However, whether abnormal reward circuits affect cognition and depression in MDD patients remains unclear. Seventy-five drug-naive MDD patients and 42 cognitively normal (CN) subjects underwent a resting-state functional magnetic resonance imaging scan. The bilateral nucleus accumbens (NAc) were selected as seeds to construct reward circuits across all subjects. A multivariate linear regression analysis was employed to investigate the neural substrates of cognitive function and depression severity on the reward circuits in MDD patients. The common pathway underlying cognitive deficits and depression was identified with conjunction analysis. Compared with CN subjects, MDD patients showed decreased reward network connectivity that was primarily located in the prefrontal-striatal regions. Importantly, distinct and common neural pathways underlying cognition and depression were identified, implying the independent and synergistic effects of cognitive deficits and depression severity on reward circuits. This study demonstrated that disrupted topological organization within reward circuits was significantly associated with cognitive deficits and depression severity in MDD patients. These findings suggest that in addition to antidepressant treatment, normalized reward circuits should be a focus and a target for improving depression and cognitive deficits in MDD patients.     

Mitochondrial DNA haplogroups and domain-specific neurocognitive performance in adults with HIV

Journal of NeuroVirology - Neurocognitive (NC) impairment (NCI) is an important cause of morbidity in persons with HIV (PWH). In the high-energy environment of the central nervous system,...     

The association of Toxoplasma gondii infection with neurocognitive deficits in a population-based analysis

Purpose

To examine the relationship between infection with Toxoplasma gondii (toxo) and cognition.

Methods

Multivariate logistic regression was used to test the association of toxo seropositivity with indices of cognitive function among over 4,200 adults in the third National Health and Nutrition Examination Survey.

Results

Toxo-seropositive participants were more likely than seronegative participants to score in the worst quartile of the simple reaction time test (OR 1.3, 95 % CI 1.0, 1.6), symbol-digit substitution test (SDST, OR 1.5, 95 % CI 1.2, 1.9) and the serial-digit learning test (trials to criterion) (SDLTNT, OR 1.4, 95 % CI 1.1, 1.8) in models adjusted for age, race/ethnicity, gender and foreign birth. After further adjustment for all cofactors, the association between toxo seropositivity and these outcomes was no longer significant. However, seropositivity was associated with worse scores on the SDST (OR 2.9, 95 % CI 1.8, 4.8) among those in the lowest income category and the SDLTNT (OR 1.5, 95 % CI 1.1, 2.5) among those foreign born.

Conclusions

Toxo seropositivity may be associated with poor cognitive test scores in certain subgroups; however, causation cannot be established in this cross-sectional study.     

Fatigue in HIV/AIDS is associated with depression and subjective neurocognitive complaints but not neuropsychological functioning

Fatigue and depressive symptoms are common in HIV-infection. The relationship between these symptoms and neuropsychological functioning is poorly understood, particularly in symptomatic infection/AIDS. This study examined the associations among fatigue, depressive symptoms, subjective neurocognitive complaints, and objective neuropsychological performance in HIV/AIDS. Sixty-eight men with HIV-infection (27 adults with HIV-infection but not AIDS and 41 with AIDS diagnosis) completed a neuropsychological test battery and self-report measures of fatigue (Fatigue Severity Scale), depressive symptoms (Beck Depression Inventory), and subjective neurocognitive complaints (Patient's Assessment of Own Functioning). High levels of fatigue were endorsed by participants. Fatigue severity was related to depressive symptoms but not to AIDS diagnosis or medication status. Verbal learning and motor function was worse in participants with AIDS, but neuropsychological functioning was not significantly correlated with fatigue or depressive symptoms. Subjective neurocognitive complaints were predicted by both depressive symptoms and fatigue. Our results suggest that adults with fatigue and HIV-infection (with or without AIDS) should be screened for depression. Neither fatigue nor depressive symptoms appear to affect neuropsychological functioning in HIV/AIDS. Future research is needed to develop and evaluate instruments and methods to differentiate depression-related fatigue from fatigue that may reflect underlying medical disease. Such research will further the development of effective treatments for fatigue associated with HIV-infection.     

Plasma HIV RNA level is associated with neurocognitive function among HIV-1-infected patients in Nigeria

Plasma HIV RNA level has been shown to correlate with HIV disease progression, morbidity, and mortality. We examined the association between levels of plasma HIV RNA and cognitive function among patients in Nigeria. A total of 179 HIV-1-infected participants with available plasma HIV RNA results and followed longitudinally for up to 2 years were included in this study. Blood samples from participants were used for the measurement of plasma HIV RNA and CD4+ T cell count. Utilizing demographic and practice effect-adjusted T scores obtained from a seven-domain neuropsychological test battery, cognitive status was determined by the global deficit score (GDS) approach, with a GDS ≥?0.5 indicating cognitive impairment. In a longitudinal multivariable linear regression analysis, adjusting for CD4 cell count, Beck’s Depression Score, age, gender, years of education, and antiretroviral treatment status, global T scores decreased by 0.35 per log₁₀ increase in plasma HIV RNA [p?=?0.033]. Adjusting for the same variables in a multivariable logistic regression, the odds of neurocognitive impairment were 28% higher per log₁₀ increase in plasma HIV RNA (OR 1.28 [95% CI 1.08, 1.51]; p?=?0.005). There were statistically significant associations for the speed of information processing, executive, and verbal fluency domains in both linear and logistic regression analyses. We found a significant association between plasma HIV RNA levels and cognitive function in both baseline (cross-sectional) and longitudinal analyses. However, the latter was significantly attenuated due to weak association among antiretroviral-treated individuals.     

症状严重程度比认知缺损更与精神分裂症住院患者的社会功能状况密切相关(英文)

背景以往研究表明精神分裂症患者的神经认知缺损和精神病性症状会导致其职业和社会功能降低。目的评估中国精神分裂症男性住院患者的神经认知和精神病性症状与社会心理功能之间的关系。方法选取上海市精神卫生中心的51例住院男性精神分裂症患者,其中40例患者最终完成了个体和社会功能量表(Personal and Social Performance Scale,PSP)中文版、临床疗效总评量表-病情严重程度量表(Clinical Global Impression-Severity,CGI-S)、阳性和阴性症状量表(Positive and Negative Symptom Scale,PANSS)、字母-数字排序以及香港文字记忆学习测试等项目的评定。结果患者PANSS量表的3个临床分量表的分值和社会功能总体评估(PSP总分和CGI-S分值)之间存在明显负相关。患者的神经认知测定结果与症状或社会功能状况均无关。结论对于急性期住院精神分裂症患者而言,临床症状的严重度—而非神经认知缺损程度,与其社会功能水平密切相关。     

AIDS myelopathy is not associated with elevated HIV viral load in cerebrospinal fluid

ARTICLE ABSTRACT: The pathogenesis of AIDS-associated myelopathy is unknown. Elevated HIV-1 viral load in CSF has been associated with cognitive impairment. The authors investigated if a similar association exists in patients with myelopathy. The authors evaluated levels of HIV-1 RNA in the CSF of 16 individuals with AIDS myelopathy and in 16 nonmyelopathic HIV-infected control subjects. There was no correlation between levels of HIV-1 RNA and the presence or severity of myelopathy.     

Neurogenic inflammation is associated with development of edema and functional deficits following traumatic brain injury in rats

The present study has used capsaicin-induced neuropeptide depletion to examine the role of neurogenic inflammation in the development of edema and functional deficits following traumatic brain injury (TBI). Adult, male rats were treated with capsaicin (neuropeptide-depleted) or equal volume vehicle (controls) 14 days prior to induction of moderate/severe diffuse TBI. Injury in vehicle treated control animals resulted in acute (4-5 h) edema formation, which was confirmed as being vasogenic in origin by diffusion weighted magnetic resonance imaging and the presence of increased permeability of the blood-brain barrier (BBB) to Evans blue dye. There was also a significant decline in brain magnesium concentration, as assessed by phosphorus magnetic resonance spectroscopy, and the development of profound motor and cognitive deficits. In contrast, capsaicin pre-treatment resulted in a significant reduction in post-traumatic edema formation (p < 0.001), BBB permeability (p < 0.001), free magnesium decline (p < 0.01) and both motor and cognitive deficits (p < 0.001). We conclude that neurogenic inflammation may play an integral role in the development of edema and functional deficits following TBI, and that neuropeptides may be a novel target for development of interventional pharmacological strategies.     

Cognitive and emotional deficits in early stages of HIV infection: An event-related potentials study

1. 1. In order to inventory different Event-Related Potentials (ERP) modifications in HIV-infection the authors have evaluated 23 HIV-positive subjects and 12 HIV-negative subjects. ERP were recorded during an auditory oddball task.

2. 2. Electrophysiological results showed that the latency of the N100 component of the ERP was significantly increased in HIV-positive subjects compared to the HIV-negative subjects. The latency of the N200 component of the ERP showed a similar tendency which just failed to reach significance when considering HIV-positive subjects vs HIV negative subjects. This result was in agreement with the literature which reported increased latencies in HIV infection.

3. 3. Considering all subjects the authors have observed a correlation between the amplitude of the P300 and the emotional deficit. This correlation was stronger in subjects who presented an emotional deficit and was independent of any other psychopathological symptom.

4. 4. The use of ERP appeared to be a sensitive technique to detect subclinical manifestations in HIV asymptomatic subjects and therefore would help to identify subjects at higher risk for developing cognitive impairments.