The 'COmorBidity in Relation to AIDS' (COBRA) cohort: Design, methods and participant characteristics

BACKGROUND: Persons living with HIV on combination antiretroviral therapy (cART) may be at increased risk of the development of age-associated non-communicable comorbidities (AANCC) at relatively young age. It has therefore been hypothesised that such individuals, despite effective cART, may be prone to accelerated aging. OBJECTIVE: The COmorBidity in Relation to AIDS (COBRA) cohort study was designed to investigate the potential causal link between HIV and AANCC, amongst others, in a cohort of middle-aged individuals with HIV with sustained viral suppression on cART and otherwise comparable HIV-negative controls. METHODS: Longitudinal cohort study of HIV-positive subjects ≥45 years of age, with sustained HIV suppression on cART recruited from two large European HIV treatment centres and similarly-aged HIV-negative controls recruited from sexual health centres and targeted community groups. Both HIV-positive and HIV-negative subjects were assessed at study entry and again at follow-up after 2 years. RESULTS: Of the 134 HIV-positive individuals with a median (IQR) age of 56 (51, 62) years recruited, 93% were male, 88% of white ethnicity and 86% were men who have sex with men (MSM). Similarly, the 79 HIV-negative subjects had a median (IQR) age of 57 (52, 64) and 92% were male, 97% of white ethnicity and 80% were MSM. CONCLUSIONS: The results from the COBRA study will be a significant resource to understand the link between HIV and AANCC and the pathogenic mechanisms underlying this link. COBRA will inform future development of novel prognostic tools for earlier diagnosis of AANCC and of novel interventions which, as an adjunct to cART, may prevent AANCC

Validation of a Novel Multivariate Method of Defining HIV-Associated Cognitive Impairment

Background: The optimum method of defining cognitive impairment in virally suppressed people living with HIV is unknown. We evaluated the relationships between cognitive impairment, including using a novel multivariate method (NMM), patient- reported outcome measures (PROMs), and neuroimaging markers of brain structure across 3 cohorts. // Methods: Differences in the prevalence of cognitive impairment, PROMs, and neuroimaging data from the COBRA, CHARTER, and POPPY cohorts (total n = 908) were determined between HIV-positive participants with and without cognitive impairment defined using the HIV-associated neurocognitive disorders (HAND), global deficit score (GDS), and NMM criteria. // Results: The prevalence of cognitive impairment varied by up to 27% between methods used to define impairment (eg, 48% for HAND vs 21% for NMM in the CHARTER study). Associations between objective cognitive impairment and subjective cognitive complaints generally were weak. Physical and mental health summary scores (SF-36) were lowest for NMM-defined impairment (P <.05).There were no differences in brain volumes or cortical thickness between participants with and without cognitive impairment defined using the HAND and GDS measures. In contrast, those identified with cognitive impairment by the NMM had reduced mean cortical thickness in both hemispheres (P <.05), as well as smaller brain volumes (P <.01). The associations with measures of white matter microstructure and brain-predicted age generally were weaker. // Conclusion: Different methods of defining cognitive impairment identify different people with varying symptomatology and measures of brain injury. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer self-reported health status. This may be due to the statistical advantage of using a multivariate approach

No evidence for accelerated ageing-related brain pathology in treated HIV: longitudinal neuroimaging results from the Comorbidity in Relation to AIDS (COBRA) project

Background: Despite successful antiretroviral therapy people living with HIV (PLWH) experience higher rates of age-related morbidity, including abnormal brain structure, brain function and cognitive impairment. This has raised concerns that PLWH may experience accelerated ageing-related brain pathology. Methods: We performed a multi-centre longitudinal study of 134 virologically-suppressed PLWH (median age = 56.0 years) and 79 demographically-similar HIV-negative controls (median age = 57.2 years). To measure cognitive performance and brain pathology, we conducted detailed neuropsychological assessments and multi-modality neuroimaging (T1-weighted, T2-weighted, diffusion-MRI, resting-state functional-MRI, spectroscopy, arterial spin labelling) at baseline and after two-year follow-up. Group differences in rates of change were assessed using linear mixed effects models. Results: 123 PLWH and 78 HIV-negative controls completed longitudinal assessments (median interval = 1.97 years). There were no differences between PLWH and HIV-negative controls in age, sex, years of education, smoking, alcohol use, recreational drug use, blood pressure, body-mass index or cholesterol levels. At baseline, PLWH had poorer global cognitive performance (P0.1). Cognitive performance was stable across the study period in both groups. Conclusions: Our finding indicate that when receiving successful treatment, middle-aged PLWH are not at increased risk of accelerated ageing-related brain changes or cognitive decline over two years, when compared to closely-matched HIV-negative controls

Cognitive function and drivers of cognitive impairment in a European and a Korean cohort of people living with HIV

Although cognitive impairments are still prevalent in the current antiretroviral therapy era, limited investigations have compared the prevalence of cognitive disorder in people living with HIV (PLWH) and its determinants in different regions and ethnicities. We compared cognitive performance across six domains using comparable batteries in 134 PLWH aged ≥45 years from the COBRA study (Netherlands, UK), and 194 PLWH aged ≥18 years from the NeuroAIDS Project (South Korea). Cognitive scores were standardized and averaged to obtain domain and global T-scores. Associations with global T-scores were evaluated using multivariable regression and the ability of individual tests to detect cognitive impairment (global T-score ≤45) was assessed using the area-under-the-receiver-operating-characteristic curve (AUROC). The median (interquartile range) age of participants was 56 (51, 62) years in COBRA (88% white ethnicity, 93% male) and 45 (37, 52) years in NeuroAIDS (100% Korean ethnicity, 94% male). The rate of cognitive impairment was 18.8% and 18.0%, respectively (p = 0.86). In COBRA, Black-African ethnicity was the factor most strongly associated with cognitive function (11.1 [7.7, 14.5] lower scores vs. white ethnicity, p < 0.01), whereas in NeuroAIDS, age (0.6 [0.1, 1.3] per 10-year, p<0.01) and education (0.7 [0.5, 0.9] per year, p<0.01) were significantly associated with cognitive function with anemia showing only a weak association (−1.2 [−2.6, 0.3], p=0.12). Cognitive domains most associated with cognitive impairment were attention (AUROC = 0.86) and executive function (AUROC = 0.87) in COBRA and processing speed (AUROC = 0.80), motor function (AUROC = 0.78) and language (AUROC = 0.78) in NeuroAIDS. Two cohorts of PLWH from different geographical regions report similar rates of cognitive impairment but different risk factors and cognitive profiles of impairment

Grey and white matter abnormalities in treated HIV-disease and their relationship to cognitive function

BACKGROUND: Long-term comorbidities such as cognitive impairment remain prevalent in otherwise effectively treated people-living-with-HIV. We investigate the relationship between cognitive impairment and brain structure in successfully treated patients using multi-modal neuroimaging from the Co-morBidity in Relation to AIDS (COBRA) cohort. METHODS: Cognitive function, brain tissue volumes and white matter microstructure were assessed in 134 HIV-positive patients and 79 controls. All patients had suppressed plasma HIV RNA at cohort entry. In addition to comprehensive voxelwise analyses of volumetric and diffusion tensor imaging, we used an unsupervised machine learning approach to combine cognitive, diffusion and volumetric data, taking advantage of the complementary information they provide. RESULTS: Compared to the highly comparable control group, cognitive function was impaired in four out of the six cognitive domains tested (median global T-scores: 50.8 vs. 54.2, p<0.001). Patients had lower grey but not white matter volumes, observed principally in regions where structure generally did not correlate with cognitive function. Widespread abnormalities in white matter microstructure were also seen, including reduced fractional anisotropy with increased mean and radial diffusivity. In contrast to the grey matter, these diffusion abnormalities correlated with cognitive function. Multivariate neuroimaging analysis identified a neuroimaging phenotype associated with poorer cognitive function, HIV-infection and systemic immune activation. CONCLUSIONS: Cognitive impairment, lower grey matter volume and white matter microstructural abnormalities were evident in HIV-positive individuals despite fully suppressive antiretroviral therapy. White matter abnormalities appear to be a particularly important determinant of cognitive dysfunction seen in well-treated HIV-positive individuals

Effect of spinal manipulation on sensorimotor functions in back pain patients: study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Low back pain (LBP) is a recognized public health problem, impacting up to 80% of US adults at some point in their lives. Patients with LBP are utilizing integrative health care such as spinal manipulation (SM). SM is the therapeutic application of a load to specific body tissues or structures and can be divided into two broad categories: SM with a high-velocity low-amplitude load, or an impulse "thrust", (HVLA-SM) and SM with a low-velocity variable-amplitude load (LVVA-SM). There is evidence that sensorimotor function in people with LBP is altered. This study evaluates the sensorimotor function in the lumbopelvic region, as measured by postural sway, response to sudden load and repositioning accuracy, following SM to the lumbar and pelvic region when compared to a sham treatment.</p> <p>Methods/Design</p> <p>A total of 219 participants with acute, subacute or chronic low back pain are being recruited from the Quad Cities area located in Iowa and Illinois. They are allocated through a minimization algorithm in a 1:1:1 ratio to receive either 13 HVLA-SM treatments over 6 weeks, 13 LVVA-SM treatments over 6 weeks or 2 weeks of a sham treatment followed by 4 weeks of full spine "doctor's choice" SM. Sensorimotor function tests are performed before and immediately after treatment at baseline, week 2 and week 6. Self-report outcome assessments are also collected. The primary aims of this study are to 1) determine immediate pre to post changes in sensorimotor function as measured by postural sway following delivery of a single HVLA-SM or LVVA-SM treatment when compared to a sham treatment and 2) to determine changes from baseline to 2 weeks (4 treatments) of HVLA-SM or LVVA-SM compared to a sham treatment. Secondary aims include changes in response to sudden loads and lumbar repositioning accuracy at these endpoints, estimating sensorimotor function in the SM groups after 6 weeks of treatment, and exploring if changes in sensorimotor function are associated with changes in self-report outcome assessments.</p> <p>Discussion</p> <p>This study may provide clues to the sensorimotor mechanisms that explain observed functional deficits associated with LBP, as well as the mechanism of action of SM.</p> <p>Trial registration</p> <p>This trial is registered in ClinicalTrials.gov, with the ID number of <a href="http://www.clinicaltrials.gov/ct2/show/NCT00830596">NCT00830596</a>, registered on January 27, 2009. The first participant was allocated on 30 January 2009 and the final participant was allocated on 17 March 2011.</p

Validation of a Novel Multivariate Method of Defining HIV-Associated Cognitive Impairment

Background. The optimum method of defining cognitive impairment in virally suppressed people living with HIV is unknown. We evaluated the relationships between cognitive impairment, including using a novel multivariate method (NMM), patientreported outcome measures (PROMs), and neuroimaging markers of brain structure across 3 cohorts.Methods. Differences in the prevalence of cognitive impairment, PROMs, and neuroimaging data from the COBRA, CHARTER, and POPPY cohorts (total n = 908) were determined between HIV-positive participants with and without cognitive impairment defined using the HIV-associated neurocognitive disorders (HAND), global deficit score (GDS), and NMM criteria.Results. The prevalence of cognitive impairment varied by up to 27% between methods used to define impairment (eg, 48% for HAND vs 21% for NMM in the CHARTER study). Associations between objective cognitive impairment and subjective cognitive complaints generally were weak. Physical and mental health summary scores (SF-36) were lowest for NMM-defined impairment (P&lt;.05). There were no differences in brain volumes or cortical thickness between participants with and without cognitive impairment defined using the HAND and GDS measures. In contrast, those identified with cognitive impairment by the NMM had reduced mean cortical thickness in both hemispheres (P&lt;.05), as well as smaller brain volumes (P&lt;.01). The associations with measures of white matter microstructure and brain-predicted age generally were weaker.Conclusion. Different methods of defining cognitive impairment identify different people with varying symptomatology and measures of brain injury. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer selfreported health status. This may be due to the statistical advantage of using a multivariate approach

Listening to music reduces eye movements

Listening to music can change the way that people visually experience the environment, probably as a result of an inwardly directed shift of attention. We investigated whether this attentional shift can be demonstrated by reduced eye movement activity, and if so, whether that reduction depends on absorption. Participants listened to their preferred music, to unknown neutral music, or to no music while viewing a visual stimulus (a picture or a film clip). Preference and absorption were significantly higher for the preferred music than for the unknown music. Participants exhibited longer fixations, fewer saccades, and more blinks when they listened to music than when they sat in silence. However, no differences emerged between the preferred music condition and the neutral music condition. Thus, music significantly reduces eye movement activity, but an attentional shift from the outer to the inner world (i.e., to the emotions and memories evoked by the music) emerged as only one potential explanation. Other explanations, such as a shift of attention from visual to auditory input, are discussed

Validation of a novel multivariate method of defining HIV-associated cognitive impairment

Background The optimum method of defining cognitive impairment in virally suppressed people-living-with-HIV is unknown. We evaluated the relationships between cognitive impairment, including using a novel multivariate method (NMM), patient reported outcome measures (PROMs) and neuroimaging markers of brain structure across three cohorts. Methods Differences in the prevalence of cognitive impairment, PROMs and neuroimaging data from the COBRA, CHARTER and POPPY cohorts (total n=908) were determined between HIV-positive participants with and without cognitive impairment defined using the HIV-associated neurocognitive disorders (HAND), global deficit score (GDS) and NMM criteria. Results The prevalence of cognitive impairment varied by up to 27% between methods used to define impairment (e.g. 48% for HAND vs. 21% for NMM in the CHARTER study). Associations between objective cognitive impairment and subjective cognitive complaints were generally weak. Physical and mental health summary scores (SF-36) were lowest for NMM-defined impairment (p’s<0.05). There were no differences in brain volumes or cortical thickness between participants with and without cognitive impairment defined using the HAND and GDS measures. In contrast, those identified with cognitive impairment by the NMM had reduced mean cortical thickness in both hemispheres (p’s<0.05), as well as smaller brain volumes (p<0.01). The associations with measures of white matter microstructure and brain-predicted age were generally weaker. Conclusion Different methods of defining cognitive impairment identify different people with varying symptomatology and measures of brain injury. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer self-reported health status. This may be due to the statistical advantage of using a multivariate approach