High-fidelity intravoxel incoherent motion parameter mapping using locally low-rank and subspace modeling.

PURPOSE: Intravoxel incoherent motion (IVIM) is a quantitative magnetic resonance imaging (MRI) method used to quantify perfusion properties of tissue non-invasively without contrast. However, clinical applications are limited by unreliable parameter estimates, particularly for the perfusion fraction (f) and pseudodiffusion coefficient (D*). This study aims to develop a high-fidelity reconstruction for reliable estimation of IVIM parameters. The proposed method is versatile and amenable to various acquisition schemes and fitting methods. METHODS: To address current challenges with IVIM, we adapted several advanced reconstruction techniques. We used a low-rank approximation of IVIM images and temporal subspace modeling to constrain the magnetization dynamics of the bi-exponential diffusion signal decay. In addition, motion-induced phase variations were corrected between diffusion directions and b-values, facilitating the use of high SNR real-valued diffusion data. The proposed method was evaluated in simulations and in vivo brain acquisitions in six healthy subjects and six individuals with a history of SARS-CoV-2 infection and compared with the conventionally reconstructed magnitude data. Following reconstruction, IVIM parameters were estimated voxel-wise. RESULTS: Our proposed method reduced noise contamination in simulations, resulting in a 60%, 58.9%, and 83.9% reduction in the NRMSE for D, f, and D*, respectively, compared to the conventional reconstruction. In vivo, anisotropic properties of D, f, and D* were preserved with the proposed method, highlighting microvascular differences in gray matter between individuals with a history of COVID-19 and those without (p = 0.0210), which wasn't observed with the conventional reconstruction. CONCLUSION: The proposed method yielded a more reliable estimation of IVIM parameters with less noise than the conventional reconstruction. Further, the proposed method preserved anisotropic properties of IVIM parameter estimates and demonstrated differences in microvascular perfusion in COVID-affected subjects, which weren't observed with conventional reconstruction methods.

Single-shell NODDI using dictionary-learner-estimated isotropic volume fraction.

Neurite orientation dispersion and density imaging (NODDI) enables the assessment of intracellular, extracellular, and free water signals from multi-shell diffusion MRI data. It is an insightful approach to characterize brain tissue microstructure. Single-shell reconstruction for NODDI parameters has been discouraged in previous studies caused by failure when fitting, especially for the neurite density index (NDI). Here, we investigated the possibility of creating robust NODDI parameter maps with single-shell data, using the isotropic volume fraction (fISO ) as a prior. Prior estimation was made independent of the NODDI model constraint using a dictionary learning approach. First, we used a stochastic sparse dictionary-based network (DictNet), which is trained with data obtained from in vivo and simulated diffusion MRI data, to predict fISO . In single-shell cases, the mean diffusivity and raw T2 signal with no diffusion weighting (S0 ) was incorporated in the dictionary for the fISO estimation. Then, the NODDI framework was used with the known fISO to estimate the NDI and orientation dispersion index (ODI). The fISO estimated using our model was compared with other fISO estimators in the simulation. Further, using both synthetic data simulation and human data collected on a 3 T scanner (both high-quality HCP and clinical dataset), we compared the performance of our dictionary-based learning prior NODDI (DLpN) with the original NODDI for both single-shell and multi-shell data. Our results suggest that DLpN-derived NDI and ODI parameters for single-shell protocols are comparable with original multi-shell NODDI, and the protocol with b = 2000 s/mm2 performs the best (error ~ 5% in white and gray matter). This may allow NODDI evaluation of studies on single-shell data by multi-shell scanning of two subjects for DictNet fISO training.

Whole-brain computational modeling reveals disruption of microscale brain dynamics in HIV infected individuals.

MRI-based neuroimaging techniques have been used to investigate brain injury associated with HIV-infection. Whole-brain cortical mean-field dynamic modeling provides a way to integrate structural and functional imaging outcomes, allowing investigation of microscale brain dynamics. In this study, we adopted the relaxed mean-field dynamic modeling to investigate structural and functional connectivity in 42 HIV-infected subjects before and after 12-week of combination antiretroviral therapy (cART) and compared them with 46 age-matched healthy subjects. Microscale brain dynamics were modeled by a set of parameters including two region-specific microscale brain properties, recurrent connection strengths, and subcortical inputs. We also analyzed the relationship between the model parameters (i.e., the recurrent connection and subcortical inputs) and functional network topological characterizations, including smallworldness, clustering coefficient, and network efficiency. The results show that untreated HIV-infected individuals have disrupted local brain dynamics that in part correlate with network topological measurements. Notably, after 12 weeks of cART, both the microscale brain dynamics and the network topological measurements improved and were closer to those in the healthy brain. This was also associated with improved cognitive performance, suggesting that improvement in local brain dynamics translates into clinical improvement.

Surface-Based Connectivity Integration: An atlas-free approach to jointly study functional and structural connectivity.

There has been increasing interest in jointly studying structural connectivity (SC) and functional connectivity (FC) derived from diffusion and functional MRI. Previous connectome integration studies almost exclusively required predefined atlases. However, there are many potential atlases to choose from and this choice heavily affects all subsequent analyses. To avoid such an arbitrary choice, we propose a novel atlas-free approach, named Surface-Based Connectivity Integration (SBCI), to more accurately study the relationships between SC and FC throughout the intra-cortical gray matter. SBCI represents both SC and FC in a continuous manner on the white surface, avoiding the need for prespecified atlases. The continuous SC is represented as a probability density function and is smoothed for better facilitation of its integration with FC. To infer the relationship between SC and FC, three novel sets of SC-FC coupling (SFC) measures are derived. Using data from the Human Connectome Project, we introduce the high-quality SFC measures produced by SBCI and demonstrate the use of these measures to study sex differences in a cohort of young adults. Compared with atlas-based methods, this atlas-free framework produces more reproducible SFC features and shows greater predictive power in distinguishing biological sex. This opens promising new directions for all connectomics studies.

Senescent Phenotype Induced by p90RSK-NRF2 Signaling Sensitizes Monocytes and Macrophages to Oxidative Stress in HIV-Positive Individuals.

BACKGROUND: The incidence of cardiovascular disease is higher in HIV-positive (HIV+) patients than it is in the average population, and combination antiretroviral therapy (cART) is a recognized risk factor for cardiovascular disease. However, the molecular mechanisms that link cART and cardiovascular disease are currently unknown. Our study explores the role of the activation of p90RSK, a reactive oxygen species-sensitive kinase, in engendering senescent phenotype in macrophages and accelerating atherogenesis in patients undergoing cART. METHODS: Peripheral whole blood from cART-treated HIV+ individuals and nontreated HIV-negative individuals was treated with H2O2 (200 µmol/L) for 4 minutes, and p90RSK activity in CD14+ monocytes was measured. Plaque formation in the carotids was also analyzed in these individuals. Macrophage senescence was determined by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. The involvement of p90RSK-NRF2 signaling in cART-induced senescence was assessed by p90RSK-specific inhibitor (FMK-MEA) or dominant-negative p90RSK (DN-p90RSK) and NRF2 activator (NRF2A). Further, the severity of atherosclerosis was determined in myeloid cell-specific wild-type and DN-p90RSK transgenic mice. RESULTS: Monocytes from HIV+ patients exhibited higher levels of p90RSK activity and were also more sensitive to reactive oxygen species than monocytes from HIV-negative individuals. A multiple linear regression analysis involving cART, Reynolds cardiovascular risk score, and basal p90RSK activity revealed that cART and basal p90RSK activity were the 2 significant determinants of plaque formation. Many of the antiretroviral drugs individually activated p90RSK, which simultaneously triggered all components of the macrophage senescent phenotype. cART inhibited antioxidant response element reporter activity via ERK5 S496 phosphorylation. NRF2A reversed the H2O2-induced overactivation of p90RSK in cART-treated macrophages by countering the induction of senescent phenotype. Last, the data obtained from our gain- or loss-of-function mice conclusively showed the crucial role of p90RSK in inducing senescent phenotype in macrophages and atherogenesis. CONCLUSIONS: cART increased monocyte/macrophage sensitivity to reactive oxygen species- in HIV+ individuals by suppressing NRF2-ARE activity via p90RSK-mediated ERK5 S496 phosphorylation, which coordinately elicited senescent phenotypes and proinflammatory responses. As such, our report underscores the importance of p90RSK regulation in monocytes/macrophages as a viable biomarker and therapeutic target for preventing cardiovascular disease, especially in HIV+ patients treated with cART.

Cognitive, Psychiatric, and Quality of Life Outcomes in Adult Survivors of Extracorporeal Membrane Oxygenation Therapy: A Scoping Review of the Literature.

OBJECTIVES: To perform a scoping literature review of cognitive, psychiatric, and quality of life outcomes in adults undergoing extracorporeal membrane oxygenation for any indication. DATA SOURCES: We searched PubMed, EMBASE, Cochrane Library, Web of Science, CINAHL, and PsycINFO from inception to June 2019. STUDY SELECTION: Observational studies, clinical trials, qualitative studies, and case series with at least 10 adult subjects were included for analysis. Outcomes of interest consisted of general or domain-specific cognition, psychiatric illness, and quality of life measures that included both mental and physical health. DATA EXTRACTION: Study selection, data quality assessment, and interpretation of results were performed by two independent investigators in accordance with the PRISMA statement. DATA SYNTHESIS: Twenty-two articles were included in this review. Six described cognitive outcomes, 12 described psychiatric outcomes of which two were qualitative studies, and 16 described quality of life outcomes. Cognitive impairment was detected in varying degrees in every study that measured it. Three studies examined neuroimaging results and found neurologic injury to be more frequent in venoarterial versus venovenous extracorporeal membrane oxygenation, but described a variable correlation with cognitive impairment. Rates of depression, anxiety, and post-traumatic stress disorder were similar to other critically ill populations and were related to physical disability after extracorporeal membrane oxygenation. Extracorporeal membrane oxygenation survivors' physical quality of life was worse than population norms but tended to improve with time, while mental quality of life did not differ significantly from the general population. Most studies did not include matched controls and instead compared outcomes to previously published values. CONCLUSIONS: Extracorporeal membrane oxygenation survivors experience cognitive impairment, psychiatric morbidity, and worse quality of life compared with the general population and similar to other survivors of critical illness. Physical disability in extracorporeal membrane oxygenation patients plays a significant role in psychiatric morbidity. However, it remains unclear if structural brain injury plays a role in these outcomes and whether extracorporeal membrane oxygenation causes secondary brain injury.

Detecting cognitive impairment in HIV-infected individuals using mutual connectivity analysis of resting state functional MRI.

It is estimated that more than 50% of the individuals affected with Human Immunodeficiency Virus (HIV) present deficits in multiple cognitive domains, collectively known as HIV-associated neurocognitive disorder (HAND). Early stages of brain injury may be clinically silent but potentially measurable via neuroimaging. A total of 40 subjects (20 HIV positive and 20 age-matched controls) volunteered for the study. All subjects underwent a standard battery of neuropsychological tests used for the clinical diagnosis of HAND. Fourteen HIV+ and five healthy subjects showed signs of neurological impairment. Connectivity was computed using mutual connectivity analysis (MCA) with generalized radial basis function neural network, a framework for quantifying non-linear connectivity as well as conventional correlation from 160 regional time-series that were extracted based on the Dosenbach (DOS) atlas. We subsequently applied graph theoretic as well as network analysis approaches for characterizing the connectivity matrices obtained and localizing between-group differences. We focused on trying to detect cognitive impairment using the subset of 29 (14 subjects with HAND and 15 cognitively normal controls) subjects. For the global analysis, significant differences (p < 0.05) were seen in the variance in degree, modularity and Smallworldness. Regional analysis revealed changes occurring mainly in portions of the lateral occipital cortex and the cingulate cortex. Furthermore, using Network Based Statistics (NBS), we uncovered an affected sub-network of 19 nodes comprising predominantly of regions of the default mode network. Similar analysis using the conventional correlation method revealed no significant results at a global scale, while regional analysis shows some differences spread across resting state networks. These results suggest that there is a subtle reorganization occurring in the topology of brain networks in HAND, which can be captured using improved connectivity analysis.

Progressive brain atrophy in chronically infected and treated HIV+ individuals.

Growing evidence points to persistent neurological injury in chronic HIV infection. It remains unclear whether chronically HIV-infected individuals on combined antiretroviral therapy (cART) develop progressive brain injury and impaired neurocognitive function despite successful viral suppression and immunological restoration. In a longitudinal neuroimaging study for the HIV Neuroimaging Consortium (HIVNC), we used tensor-based morphometry to map the annual rate of change of regional brain volumes (mean time interval 1.0 ± 0.5 yrs), in 155 chronically infected and treated HIV+ participants (mean age 48.0 ± 8.9 years; 83.9% male) . We tested for associations between rates of brain tissue loss and clinical measures of infection severity (nadir or baseline CD4+ cell count and baseline HIV plasma RNA concentration), HIV duration, cART CNS penetration-effectiveness scores, age, as well as change in AIDS Dementia Complex stage. We found significant brain tissue loss across HIV+ participants, including those neuro-asymptomatic with undetectable viral loads, largely localized to subcortical regions. Measures of disease severity, age, and neurocognitive decline were associated with greater atrophy. Chronically HIV-infected and treated individuals may undergo progressive brain tissue loss despite stable and effective cART, which may contribute to neurocognitive decline. Understanding neurological complications of chronic infection and identifying factors associated with atrophy may help inform strategies to maintain brain health in people living with HIV.

Mutual connectivity analysis of resting-state functional MRI data with local models.

Functional connectivity analysis of functional MRI (fMRI) can represent brain networks and reveal insights into interactions amongst different brain regions. However, most connectivity analysis approaches adopted in practice are linear and non-directional. In this paper, we demonstrate the advantage of a data-driven, directed connectivity analysis approach called Mutual Connectivity Analysis using Local Models (MCA-LM) that approximates connectivity by modeling nonlinear dependencies of signal interaction, over more conventionally used approaches, such as Pearson's and partial correlation, Patel's conditional dependence measures, etcetera. We demonstrate on realistic simulations of fMRI data that, at long sampling intervals, i.e. high repetition time (TR) of fMRI signals, MCA-LM performs better than or comparable to correlation-based methods and Patel's measures. However, at fast image acquisition rates corresponding to low TR, MCA-LM significantly outperforms these methods. This insight is particularly useful in the light of recent advances in fast fMRI acquisition techniques. Methods that can capture the complex dynamics of brain activity, such as MCA-LM, should be adopted to extract as much information as possible from the improved representation. Furthermore, MCA-LM works very well for simulations generated at weak neuronal interaction strengths, and simulations modeling inhibitory and excitatory connections as it disentangles the two opposing effects between pairs of regions/voxels. Additionally, we demonstrate that MCA-LM is capable of capturing meaningful directed connectivity on experimental fMRI data. Such results suggest that it introduces sufficient complexity into modeling fMRI time-series interactions that simple, linear approaches cannot, while being data-driven, computationally practical and easy to use. In conclusion, MCA-LM can provide valuable insights towards better understanding brain activity.

Combination antiretroviral therapy improves cognitive performance and functional connectivity in treatment-naïve HIV-infected individuals.

Our study aimed to investigate the short-term effect of combination antiretroviral therapy (cART) on cognitive performance and functional and structural connectivity and their relationship to plasma levels of antiretroviral (ARV) drugs. Seventeen ARV treatment-naïve HIV-infected individuals (baseline mean CD4 cell count, 479 ± 48 cells/mm3) were age matched with 17 HIV-uninfected individuals. All subjects underwent a detailed neurocognitive and functional assessment and magnetic resonance imaging. HIV-infected subjects were scanned before starting cART and 12 weeks after initiation of treatment. Uninfected subjects were assessed once at baseline. Functional connectivity (FC) was assessed within the default mode network while structural connectivity was assessed by voxel-wise analysis using tract-based spatial statistics (TBSS) and probabilistic tractography within the DMN. Tenofovir and emtricitabine blood concentration were measured at week 12 of cART. Prior to cART, HIV-infected individuals had significantly lower cognitive performance than control subjects as measured by the total Z-score from the neuropsychological tests assessing six cognitive domains (p = 0.020). After 12 weeks of cART treatment, there remained only a weak cognitive difference between HIV-infected and HIV-uninfected subjects (p = 0.057). Mean FC was lower in HIV-infected individuals compared with those uninfected (p = 0.008), but FC differences became non-significant after treatment (p = 0.197). There were no differences in DTI metrics between HIV-infected and HIV-uninfected individuals using the TBSS approach and limited evidence of decreased structural connectivity within the DMN in HIV-infected individuals. Tenofovir and emtricitabine plasma concentrations did not correlate with either cognitive performance or imaging metrics. CONCLUSIONS: Twelve weeks of cART improves cognitive performance and functional connectivity in ARV treatment-naïve HIV-infected individuals with relatively preserved immune function. Longer periods of observation are necessary to assess whether this effect is maintained.

Simulation of changes in diffusion related to different pathologies at cellular level after traumatic brain injury.

PURPOSE: The goal of the current study was to investigate tissue pathology at the cellular level in traumatic brain injury (TBI) as revealed by Monte Carlo simulation of diffusion tensor imaging (DTI)-derived parameters and elucidate the possible sources of conflicting findings of DTI abnormalities as reported in the TBI literature. METHODS: A model with three compartments separated by permeable membranes was employed to represent the diffusion environment of water molecules in brain white matter. The dynamic diffusion process was simulated with a Monte Carlo method using adjustable parameters of intra-axonal diffusivity, axon separation, glial cell volume fraction, and myelin sheath permeability. The effects of tissue pathology on DTI parameters were investigated by adjusting the parameters of the model corresponding to different stages of brain injury. RESULTS: The results suggest that the model is appropriate and the DTI-derived parameters simulate the predominant cellular pathology after TBI. Our results further indicate that when edema is not prevalent, axial and radial diffusivity have better sensitivity to axonal injury and demyelination than other DTI parameters. CONCLUSION: DTI is a promising biomarker to detect and stage tissue injury after TBI. The observed inconsistencies among previous studies are likely due to scanning at different stages of tissue injury after TBI. Magn Reson Med 76:290-300, 2016. © 2015 Wiley Periodicals, Inc.

Impact of minocycline on cerebrospinal fluid markers of oxidative stress, neuronal injury, and inflammation in HIV-seropositive individuals with cognitive impairment.

Elevated cerebrospinal fluid (CSF) levels of markers of oxidative stress, neuronal injury, and inflammation and decreased neurotransmitter levels have been reported in HIV-associated neurocognitive disorders (HAND). Minocycline may have a neuroprotective effect by inhibiting inducible nitric oxide synthase, which produces nitric oxide, a compound that induces oxygen free radical production. In A5235, "Phase II, Randomized, Placebo-Controlled, Double-Blind Study of Minocycline in the Treatment of HIV-Associated Cognitive Impairment," minocycline was not associated with cognitive improvement, but the effect on the above CSF measures was not examined previously. The objective of this study was to examine the effect of minocycline on markers of oxidative stress, neuronal injury, neurotransmitter levels, and inflammation from CSF in participants in A5235. One hundred seven HIV+ individuals received either minocycline 100 mg or placebo orally every 12 h for 24 weeks. Twenty-one HIV+ individuals received the optional lumbar punctures. Lipid and protein markers of oxidative stress (e.g., ceramides and protein carbonyls), glutamate, neurotransmitter precursors, kynurenine metabolites, neurofilament heavy chain, and inflammatory cytokines were measured in the CSF before and after treatment. The 24-week change in ceramides was larger in a beneficial direction in the minocycline group compared to the placebo group. The two groups did not differ in the 24-week changes for other markers.These results suggest that minocycline may decrease lipid markers of oxidative stress (ceramides) in individuals with HAND; however, an effect of minocycline on other CSF markers was not observed. A larger sample size is needed to further validate these results.

Diffusion-Weighted Imaging Reveals Impaired Glymphatic Clearance in Idiopathic Intracranial Hypertension.

BACKGROUND AND PURPOSE: The pathophysiology underlying idiopathic intracranial hypertension (IIH) remains incompletely understood. While one theory postulates impaired cerebral glymphatic clearance in IIH, there is a paucity of methods to quantify glymphatic activity in human brains. The purpose of this study was to use advanced diffusion-weighed imaging to evaluate the glymphatic clearance of IIH patients and how it may relate to clinical severity. MATERIALS AND METHODS: DWI was used to separately evaluate the diffusivity along the cerebral perivascular spaces and lateral association and projection fibers, with the degree of diffusivity used as a surrogate for glymphatic function (diffusion tensor image analysis along the perivascular space. Patients with IIH were compared with normal controls. Glymphatic clearance was correlated with several clinical metrics, including lumbar puncture opening pressure and Frisen papilledema grade (low grade: 0-2; high grade: 3-5). RESULTS: In total, 99 patients with IIH were identified and compared with 6 healthy controls. Overall, patients with IIH had significantly lower glymphatic clearance based on DWI-derived diffusivity compared with controls (P = .005). Additionally, in patients with IIH, there was a significant association between declining glymphatic clearance and increasing Frisen papilledema grade (P = .046) but no correlation between opening pressure and glymphatic clearance (P = .27). Furthermore, healthy controls had significantly higher glymphatic clearance compared with patients with IIH and low-grade papilledema (P = .015) and high-grade papilledema (P = .002). Lastly, patients with IIH and high-grade papilledema had lower glymphatic clearance compared with patients with IIH and low-grade papilledema (P = .005). CONCLUSIONS: Patients with IIH possess impaired glymphatic clearance, which is directly related to the extent of clinical severity. The DWI-derived parameters can be used for clinical diagnosis or to assess response to treatment.

Brain elastography in aging relates to fluid/solid trendlines.

The relatively new tools of brain elastography have established a general trendline for healthy, aging adult humans, whereby the brain's viscoelastic properties 'soften' over many decades. Earlier studies of the aging brain have demonstrated a wide spectrum of changes in morphology and composition towards the later decades of lifespan. This leads to a major question of causal mechanisms: of the many changes documented in structure and composition of the aging brain, which ones drive the long term trendline for viscoelastic properties of grey matter and white matter? The issue is important for illuminating which factors brain elastography is sensitive to, defining its unique role for study of the brain and clinical diagnoses of neurological disease and injury. We address these issues by examining trendlines in aging from our elastography data, also utilizing data from an earlier landmark study of brain composition, and from a biophysics model that captures the multiscale biphasic (fluid/solid) structure of the brain. Taken together, these imply that long term changes in extracellular water in the glymphatic system of the brain along with a decline in the extracellular matrix have a profound effect on the measured viscoelastic properties. Specifically, the trendlines indicate that water tends to replace solid fraction as a function of age, then grey matter stiffness decreases inversely as water fraction squared, whereas white matter stiffness declines inversely as water fraction to the 2/3 power, a behavior consistent with the cylindrical shape of the axons. These unique behaviors point to elastography of the brain as an important macroscopic measure of underlying microscopic structural change, with direct implications for clinical studies of aging, disease, and injury.

Tensor-valued diffusion MRI detects brain microstructure changes in HIV infected individuals with cognitive impairment.

Despite advancements, the prevalence of HIV-associated neurocognitive impairment remains at approximately 40%, attributed to factors like pre-cART (combination antiretroviral therapy) irreversible brain injury. People with HIV (PWH) treated with cART do not show significant neurocognitive changes over relatively short follow-up periods. However, quantitative neuroimaging may be able to detect ongoing subtle microstructural changes. This study aimed to investigate the sensitivity of tensor-valued diffusion encoding in detecting such changes in brain microstructural integrity in cART-treated PWH. Additionally, it explored relationships between these metrics, neurocognitive scores, and plasma levels of neurofilament light (NFL) chain and glial fibrillary acidic protein (GFAP). Using MRI at 3T, 24 PWH and 31 healthy controls underwent cross-sectional examination. The results revealed significant variations in b-tensor encoding metrics across white matter regions, with associations observed between these metrics, cognitive performance, and blood markers of neuronal and glial injury (NFL and GFAP). Moreover, a significant interaction between HIV status and imaging metrics was observed, particularly impacting total cognitive scores in both gray and white matter. These findings suggest that b-tensor encoding metrics offer heightened sensitivity in detecting subtle changes associated with axonal injury in HIV infection, underscoring their potential clinical relevance in understanding neurocognitive impairment in PWH.

Brain white matter pathways of resilience to chronic back pain: a multisite validation.

Chronic back pain (CBP) is a global health concern with significant societal and economic burden. While various predictors of back pain chronicity have been proposed, including demographic and psychosocial factors, neuroimaging studies have shown that brain characteristics can serve as robust predictors of CBP. However, large-scale, multisite validation of these predictors is currently lacking. In two independent longitudinal studies, we examined white matter diffusion imaging data and pain characteristics in patients with subacute back pain (SBP) over six- and 12-month periods. Diffusion data from individuals with CBP and healthy controls (HC) were analyzed for comparison. Whole-brain tract-based spatial statistics analyses revealed that a cluster in the right superior longitudinal fasciculus (SLF) tract had larger fractional anisotropy (FA) values in patients who recovered (SBPr) compared to those with persistent pain (SBPp), and predicted changes in pain severity. The SLF FA values accurately classified patients at baseline and follow-up in a third publicly available dataset (Area under the Receiver Operating Curve ~ 0.70). Notably, patients who recovered had FA values larger than those of HC suggesting a potential role of SLF integrity in resilience to CBP. Structural connectivity-based models also classified SBPp and SBPr patients from the three data sets (validation accuracy 67%). Our results validate the right SLF as a robust predictor of CBP development, with potential for clinical translation. Cognitive and behavioral processes dependent on the right SLF, such as proprioception and visuospatial attention, should be analyzed in subacute stages as they could prove important for back pain chronicity.

Patterns of white matter injury in HIV infection after partial immune reconstitution: a DTI tract-based spatial statistics study.

HIV-infected individuals with severe immune suppression are more likely to develop HIV-associated neurocognitive disorders than those with preserved immune function. While partial immune reconstitution occurs in those with severe immune suppression after starting combined antiretroviral therapy, it is not established whether improvement in immune function reverses or prevents injury to the central nervous system (CNS). To address this question, 50 participants (nadir CD4 counts ≤ 200 cells/mm(3), on a stable antiretroviral regimen for at least 12 consecutive weeks prior to study) and 13 HIV negative participants underwent a comprehensive neurological evaluation followed by diffusion tensor imaging (DTI). Eighty-four percent of the 50 HIV participants were neurologically asymptomatic (HIVNA) and 16 % had mild cognitive impairment (HIVCI). Tract-based spatial statistics (TBSS) on DTI data revealed that mean diffusivity (MD) increased significantly in the posterior aspect of both hemispheres in HIVNA compared to controls. In HIVCI, compared to controls and HIVNA, increased MD extended to prefrontal areas. Fractional anisotropy decreased only in HIVCI, compared to either controls or HIVNA. Furthermore, DTI showed significant correlations to duration of HIV infection and significant associations with multiple cognitive domains. This study highlights that in partial immune reconstitution, injury to the CNS is present even in those that are neurologically asymptomatic and there are discrete spatial patterns of white matter injury in HIVNA subjects compared to HIVCI subjects. Our results also show that quantitative analysis of DTI using TBSS is a sensitive approach to evaluate HIV-associated white matter disease and thus valuable in monitoring central nervous system injury.

Pharmacokinetic interactions of CEP-1347 and atazanavir in HIV-infected patients.

CEP-1347 is a potent inhibitor of mixed lineage kinase (MLK), which was investigated for ameliorating HIV-associated neurocognitive disorders. CEP-1347 and atazanavir pharmacokinetics were determined when CEP-1347 50 mg twice daily was administered to HIV-infected patients (n = 20) receiving combination antiretroviral therapy including atazanavir and ritonavir (ATV/RTV, 300/100 mg) once daily continuously. Co-administration of CEP-1347 and ATV/RTV resulted with significant changes in pharmacokinetics of ATV but not RTV. Specifically, an increase in ATV accumulation ratio of 15 % (p = 0.007) and a prolongation of T(½) from 12.7 to 15.9 h (p = 0.002) were observed. The results suggested that co-administration of CEP-1347 with ATV/RTV in HIV-infected patients might result in limited impact on ATV but not on RTV pharmacokinetics.

Progressive cerebral injury in the setting of chronic HIV infection and antiretroviral therapy.

Emerging evidence suggests that CNS injury and neurocognitive impairment persist in the setting of chronic HIV infection and combination antiretroviral therapy (CART). Yet, whether neurological injury can progress in this setting remains uncertain. Magnetic resonance spectroscopy and neurocognitive and clinical assessments were performed over 2 years in 226 HIV-infected individuals on stable CART, including 138 individuals who were neurocognitively asymptomatic (NA). Concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myoinositol, and glutamate/glutamine (Glx) were measured in the midfrontal cortex (MFC), frontal white matter (FWM), and basal ganglia (BG). Longitudinal changes in metabolite levels were determined using linear mixed effect models, as were metabolite changes in relation to global neurocognitive function. HIV-infected subjects showed significant annual decreases in brain metabolite levels in all regions examined, including NAA (2.95 %) and Cho (2.61 %) in the FWM; NAA (1.89 %), Cr (1.84 %), Cho (2.19 %), and Glx (6.05 %) in the MFC; and Glx (2.80 %) in the BG. Similar metabolite decreases were observed in the NA and subclinically impaired subgroups, including subjects with virologic suppression in plasma and CSF. Neurocognitive decline was associated with longitudinal decreases in Glx in the FWM and the BG, and in NAA in the BG. Widespread progressive changes in the brain, including neuronal injury, occur in chronically HIV-infected persons despite stable antiretroviral treatment and virologic suppression and can lead to neurocognitive declines. The basis for these findings is poorly understood and warrants further study.

Antiplatelet activity of valproic acid contributes to decreased soluble CD40 ligand production in HIV type 1-infected individuals.

CD40L is a type II membrane glycoprotein of the TNF family that is found on activated T cells, B cells, and platelets. We previously reported that the soluble form of this inflammatory mediator (sCD40L) is elevated in the plasma and cerebrospinal fluid of HIV-1-infected, cognitively impaired individuals. In this study, we demonstrate that the mood-stabilizing drug valproic acid (VPA) reduces sCD40L levels in plasma samples of HIV-1-infected patients (n = 23) and in washed human platelets, which are the main source of circulating sCD40L. VPA also inhibited HIV-1 transactivator of transcription-induced release of sCD40L and platelet factor 4 in C57BL/6 mice. The mechanism by which VPA was able to do so was investigated, and we demonstrate that VPA, a known glycogen synthase kinase 3ß inhibitor, blocks platelet activating factor-induced activation of glycogen synthase kinase 3ß in platelets in a manner that alters sCD40L release from platelets. These data reveal that VPA has antiplatelet activity, and they convey important implications for the potential of VPA as an adjunct therapy not only for cognitively impaired patients with HIV-1 infection, but also numerous inflammatory diseases for which such antiplatelet therapies are currently lacking.