A multimodal neuroimaging study of brain abnormalities and clinical correlates in post treatment Lyme disease.

Lyme disease is the most common vector-borne infectious disease in the United States. Post-treatment Lyme disease (PTLD) is a condition affecting 10-20% of patients in which symptoms persist despite antibiotic treatment. Cognitive complaints are common among those with PTLD, suggesting that brain changes are associated with the course of the illness. However, there has been a paucity of evidence to explain the cognitive difficulties expressed by patients with PTLD. This study administered a working memory task to a carefully screened group of 12 patients with well-characterized PTLD and 18 healthy controls while undergoing functional MRI (fMRI). A subset of 12 controls and all 12 PTLD participants also received diffusion tensor imaging (DTI) to measure white matter integrity. Clinical variables were also assessed and correlated with these multimodal MRI findings. On the working memory task, the patients with PTLD responded more slowly, but no less accurately, than did controls. FMRI activations were observed in expected regions by the controls, and to a lesser extent, by the PTLD participants. The PTLD group also hypoactivated several regions relevant to the task. Conversely, novel regions were activated by the PTLD group that were not observed in controls, suggesting a compensatory mechanism. Notably, three activations were located in white matter of the frontal lobe. DTI measures applied to these three regions of interest revealed that higher axial diffusivity correlated with fewer cognitive and neurological symptoms. Whole-brain DTI analyses revealed several frontal lobe regions in which higher axial diffusivity in the patients with PTLD correlated with longer duration of illness. Together, these results show that the brain is altered by PTLD, involving changes to white matter within the frontal lobe. Higher axial diffusivity may reflect white matter repair and healing over time, rather than pathology, and cognition appears to be dynamically affected throughout this repair process.

Characterization of basal ganglia volume changes in the context of HIV and polysubstance use.

HIV and psychoactive substances can impact the integrity of the basal ganglia (BG), a neural substrate of cognition, motor control, and reward-seeking behaviors. This study assessed BG gray matter (GM) volume as a function of polysubstance (stimulant and opioid) use and HIV status. We hypothesized that comorbid polysubstance use and HIV seropositivity would alter BG GM volume differently than would polysubstance use or HIV status alone. We collected structural MRI scans, substance use history, and HIV diagnoses. Participants who had HIV (HIV +), a history of polysubstance dependence (POLY +), both, or neither completed assessments for cognition, motor function, and risk-taking behaviors (N = 93). All three clinical groups showed a left-lateralized pattern of GM reduction in the BG relative to controls. However, in the HIV + /POLY + group, stimulant use was associated with increased GM volume within the globus pallidus and putamen. This surpassed the effects from opioid use, as indicated by decreased GM volume throughout the BG in the HIV-/POLY + group. Motor learning was impaired in all three clinical groups, and in the HIV + /POLY + group, motor learning was associated with increased caudate and putamen GM volume. We also observed associations between BG GM volume and risk-taking behaviors in the HIV + /POLY- and HIV-/POLY + groups. The effects of substance use on the BG differed as a function of substance type used, HIV seropositivity, and BG subregion. Although BG volume decreased in association with HIV and opioid use, stimulants can, inversely, lead to BG volume increases within the context of HIV.

Microglial activation is inversely associated with cognition in individuals living with HIV on effective antiretroviral therapy.

OBJECTIVE: Despite viral suppression, HIV-associated cognitive impairment persists and may be partially due to persistent immune signalling by cells of the myeloid-lineage. Here, we aimed to understand the contribution of activated microglia located in vulnerable brain regions (e.g. frontal, subcortical) of HIV-infected, virally suppressed (HIV+VS) individuals in relation to cognitive and motor function. DESIGN: Twenty-one HIV+VS individuals underwent PET with [11C]DPA-713 to image the translocator protein 18 kDa (TSPO), a marker of microglial activation, and completed a comprehensive neuropsychological test battery. METHODS: Multivariable linear regressions were used to examine the contribution of [11C]DPA-713 binding to cognitive performance. RESULTS: Higher [11C]DPA-713 binding was associated with lower cognition among HIV+VS individuals. [11C]DPA-713 binding in middle frontal gyrus/frontal cortex, hippocampus/temporal cortex and occipital cortex was inversely associated with performance on a number of cognitive domains, including verbal memory, processing speed/attention/concentration, executive function, working memory and motor function. [C]DPA-713 binding in parietal cortex, cerebellum and thalamus was associated with only specific cognitive domains including visual construction and verbal memory. Binding was not associated with global cognitive performance. CONCLUSION: The findings add to the growing body of evidence that immune-mediated brain injury may contribute to domain specific, HIV-associated, cognitive vulnerabilities despite viral suppression.

Older individuals with HIV infection have greater memory deficits than younger individuals.

The prevalence of HIV-associated neurocognitive disorder (HAND) remains persistently high in the era of combination antiretroviral therapy. We aimed to characterize the pattern of neurocognitive dysfunction in older subjects with HAND in particular amnestic versus non-amnestic impairment. One hundred six subjects from the Johns Hopkins University NIMH Clinical Outcomes cohort underwent standardized neuropsychological (NP) testing between November 2006 and June 2010. We examined performance in seven cognitive domains (memory, attention, speed of processing,visuospatial, language, motor, and executive). Older subjects were defined as age >50 years at the time of NP testing.Subjects were diagnosed with HAND according to established criteria and dichotomized into amnestic cognitive impairment or non-amnestic cognitive impairment with deficit defined as z scores <−1.5 for the verbal and nonverbal memory domains.There were 32 older subjects with a mean age (SD) of 54.2 (2.8) years and 74 younger subjects, 43.7 (4.3) years. Older age was associated with a 4.8-fold higher odds of memory deficits adjusted for potential confounders (p =0.035) identified a priori. With age modeled as a continuous covariate,every 1 year increase in age was associated with a 1.11-fold higher odds of memory deficit (p =0.05). There was a higher proportion of amnestic cognitive impairment among older subjects than younger subjects with HIV infection. Neurodegenerative processes other than those directly due to HIV maybe increasingly important as individuals with chronic HIV infection and HAND survive into older age.

Evaluating sleep and cognition in HIV.

OBJECTIVE: To examine the relationship between measures of sleep quality and cognitive performance in HIV-positive individuals stable on combination antiretroviral therapy. DESIGN: Multimethod assessments of sleep quality, patterns, and cognitive performance were assessed in a predominantly black HIV-positive cohort. METHODS: Sleep quality and patterns were characterized in 36 subjects by polysomnogram, 2-week actigraphy monitoring, and validated sleep questionnaires. Cognitive performance was assessed with a battery of neuropsychological tests. RESULTS: The majority of participants were cognitively impaired [based on Frascati (75%) criteria]. Self-reported mean scores on the Pittsburgh sleep quality index and the insomnia severity scale suggested poor sleep quality. Better cognitive performance, particularly on tasks of attention, frontal/executive function, and psychomotor/motor speed, was associated with polysomnogram sleep indices (ie, reduced wake after sleep onset, greater sleep efficiency, greater sleep latency, and greater total sleep time). Thirty-seven percent of participants had sleep patterns suggestive of chronic partial sleep deprivation, which was associated with significantly worse performance on the digit symbol test (P = 0.006), nondominant pegboard (P = 0.043), and verbal fluency tests (P = 0.044). CONCLUSIONS: Our results suggest that compromised sleep quality and duration may have a significant impact on cognitive performance in HIV-positive individuals. Future studies are warranted to determine the utility of sleep quality and quantity indices as potential predictive biomarkers for development and progression of future HIV-associated neurocognitive disorder.

CCL3L1 gene copy number in individuals with and without HIV-associated neurocognitive disorder.

BACKGROUND: CCL3L1 copy number variation has been implicated as a marker for susceptibility and immunity to human immunodeficiency virus (HIV)-1 infection and its pathogenic sequelae. Some of these findings have been confirmed in several, but not all, subsequent independent cohort studies. A three-fold risk for the development of HIV-associated dementia was reported in individuals possessing a CCL3L1 copy number below the ethnic group median combined with a detrimental CCR5 genotype. With the availability of antiretroviral therapy since 1996, there has been a significant decline in HIV-associated dementia, and milder forms of HIV-associated neurocognitive impairment (HAND) are now most prevalent. Moreover, patients are living longer with HIV-1 infection and it is recognized that aging may be a contributory factor to the development of cognitive disorder. Thus, the need for biomarkers that can be used in clinical practice to identify and provide optimal treatment for those at increased risk for HAND is great. HAND affects 20%-30% of HIV-infected individuals, and several genetic loci which have been shown to confer susceptibility to HIV infection may also modulate the development of neurocognitive disorder. The aim of this study was to determine whether CCL3L1 chemokine gene copy number in self-defined ethnic groups could differentiate HIV-infected individuals with and without HAND. METHODS: Genomic DNA was isolated from buccal swabs or peripheral blood mononuclear cells obtained from HIV-infected patients with or without a diagnoses of neurocognitive dysfunction in the Northeast AIDS Dementia Cohort and National NeuroAIDS Tissue Consortium. To maintain a uniform standard, a quantitative polymerase chain reaction design similar to previous studies using Taqman probes and fixed input DNA between 2 ng and 10 ng was used to determine a CCL3L1 copy number. Standard curves with two-fold dilutions from 25 ng to 1.56 ng were generated. CCL3L1 copy number was determined in triplicate in 262 subjects using quantitative polymerase chain reaction and the relative quantitation method. Data were analyzed using analysis of variance, with significance defined as P < 0.05 and Bonferroni post hoc tests. RESULTS: Significant differences as determined by analysis of variance in CCL3L1 copy number between African-Americans and Caucasians (P < 0.0001) were found, highlighting ethnic group differences in the copy number of this gene. However, there were no differences in CCL3L1 copy number across the neurocognitive groups within each ethnic group. The median CCL3L1 copy number in African-Americans of two and Caucasians of one in this study was significantly lower than the previously reported ethnic group means of two and four copies, respectively. A higher prevalence of abnormal cognition with a relative risk of four was seen in African-Americans versus Caucasians. CONCLUSION: Based on this nested case-control study, CCL3L1 copy number alone may not be useful for distinguishing between individuals at risk for mild or severe neurocognitive disorder. Additional larger cohort studies are required to determine whether CCL3L1 copy number in combination with polymorphisms in other genes known to contribute to HIV risk will be useful in identifying those at increased risk for HAND.

Relationship of depression and catastrophizing to pain, disability, and medication adherence in patients with HIV-associated sensory neuropathy.

Few studies have examined how patients with chronic HIV infection cope with pain and how pain relates to medication adherence. Pain coping strategies such as catastrophizing are often associated with increased pain and disability and may also influence adherence to medications. The goal of our study is to assess the relationship of catastrophizing and depression to pain, disability, and medication adherence through questionnaires administered to a cross-section of patients with HIV-associated sensory neuropathy. In our study, 46 HIV-seropositive subjects completed questionnaires evaluating neuropathic pain severity, pain catastrophizing, pain-related disability, depressive symptoms, severity of antiretroviral therapy (ART) side effects, and common reasons for medication nonadherence. Hierarchical regression analysis indicated that pain catastrophizing correlated with severity of neuropathic pain independent of depressive symptoms. Furthermore, depressive symptoms were not associated with multiple factors independent of pain catastrophizing such as severity of neuropathic pain and pain-related disability. Pain catastrophizing, but not depressive symptoms, correlated with increased pain disability even after controlling for the effects of age and neuropathic pain. We also found that poor adherence attributed to fear of side effects or forgetfulness was associated with increased severity of neuropathic pain, while depressive symptoms but not catastrophizing correlated with ART side effects. These findings suggest that both catastrophizing and depressive symptoms are important factors to consider in the management of pain from HIV neuropathy and adherence to ART.

A comparison of performance-based measures of function in HIV-associated neurocognitive disorders.

The objectives of this study are to compare the results of newer performance-based functional assessments in the study of HIV-associated neurocognitive disorders (HAND) and to correlate these functional assessments with specific levels of severity of HAND. One hundred fourteen HIV+ subjects in an existing cohort were evaluated with a medical history, neurological exam, neuropsychological test battery as well as subjective and novel objective measures of functional abilities. Self-reported measures of functional performance included the Karnofsky Performance Scale, a questionnaire for instrumental activities of daily living, and a questionnaire for physical quality of life measures. The newer objective functional performance assessments included the Columbia Medication Management and the San Diego Finances tests. These newer performance-based measures of function were assessed for their ability to predict level of HAND. The two objective measures of functional performance, The Columbia Medication Management Scale and the San Diego Finances Test, were both associated with levels of severity of HAND. The Karnofsky Performance Scale and the questionnaires for role and physical quality of life were subjective measures that were also associated with specific levels of HAND. Newer measures of functional performance can be used to objectively evaluate functional impairment in HAND and validate different levels of HAND.

Comparison of scales to evaluate the progression of HIV-associated neurocognitive disorder.

AIM: First, to compare the characterization of neurocognitive deficits in milder stages of HIV-associated neurocognitive disorder (HAND) derived from existing dementia rating scales of the American Academy of Neurology (AAN) and Memorial Sloan Kettering (MSK) with the 2007 consensus ('Frascati') classification. Second, to identify potential sociodemographic and clinical predictors of HAND progression during 1-year follow-up. METHODS: 104 HIV-infected subjects in an existing cohort system were evaluated with a medical history, exam, neuropsychological test battery and functional assessments. The degree of HAND was rated using the AAN, MSK and Frascati scales. The degree of concordance among these scales was determined. In addition, 45 subjects were reassessed for changes in their neurocognitive status at 1-year follow-up. Associations between age, education, sex, depression ratings, substance abuse, race, hepatitis C serostatus, CD4 count and progression of HAND were examined. RESULTS: There was excellent concordance (gamma > 0.8) among the Frascati, MSK and AAN ratings. Subjects rated as having minor cognitive motor disorder on the AAN scale (n = 45) were evenly split between Frascati rating of asymptomatic neurocognitive impairment (n = 24) and mild neurocognitive disorder (n = 21). At 1-year follow-up of 45 subjects, 31% had worsened, 13% had improved and 56% were stable. Predictors of progression included age older than 50 years (odds ratio: 5.57; p = 0.013) and female gender (odds ratio: 3.13; p = 0.036). CONCLUSION: The Frascati HAND rating scale has excellent concordance with previous neurocognitive rating scales and can be used to better characterize milder stages of cognitive impairment. Older individuals and women appeared to be more likely to show neurocognitive progression.

Diagnostic utility of the subjective peripheral neuropathy screen in HIV-infected persons with peripheral sensory polyneuropathy.

A retrospective analysis of the Johns Hopkins University HIV neurology database was performed to assess the sensitivity and specificity of the Subjective Peripheral Neuropathy Screen (SPNS) for detecting HIV-associated neuropathies. The SPNS, a 3-item scale that evaluates lower extremity neuropathic symptoms, was administered to 75 patients from the HIV neurology outpatient clinic. Patients graded the severity of each symptom on a scale of 1 to 10, and the sensitivity, specificity, and diagnostic efficiency of the SPNS were calculated for each symptom. The results showed that the SPNS had a sensitivity of 47%, a specificity of 83%, a positive predictive value of 70%, and a diagnostic efficacy of 67%. The SPNS appears to be a useful screening tool for HIV-associated sensory neuropathies; it has a high specificity and a good positive predictive value.

Construct validity of the relationship profile test: a self-report measure of dependency-detachment.

This study evaluated the construct validity of the Relationship Profile Test (RPT; Bornstein & Languirand, 2003), a 30-item self-report measure of dependency-detachment that yields three subscale scores: (a) destructive overdependence, (b) dysfunctional detachment, and (c) healthy dependency. Scores on the RPT subscales generally showed the expected patterns of intercorrelations and gender differences, and comparison of RPT scores with scores on other tests supported the convergent and discriminant validity of each RPT subscale. Results of internal and retest reliability analyses were generally supportive as well, and suggested that the three RPT subscales assess aspects of the traits they purport to measure