Lack of neuroinflammation in the HIV-1 transgenic rat: An [18 F]-DPA714 PET imaging study

BACKGROUND: HIV-associated neuroinflammation is believed to be a major contributing factor in the development of HIV-associated neurocognitive disorders (HAND). In this study, we used micropositron emission tomography (PET) imaging to quantify neuroinflammation in HIV-1 transgenic rat (Tg), a small animal model of HIV, known to develop neurological and behavioral problems. METHODS: Dynamic [(18)F]DPA-714 PET imaging was performed in Tg and age-matched wild-type (WT) rats in three age groups: 3-, 9-, and 16-month-old animals. As a positive control for neuroinflammation, we performed unilateral intrastriatal injection of quinolinic acid (QA) in a separate group of WT rats. To confirm our findings, we performed multiplex immunofluorescent staining for Iba1 and we measured cytokine/chemokine levels in brain lysates of Tg and WT rats at different ages. RESULTS: [(18)F]DPA-714 uptake in HIV-1 Tg rat brains was generally higher than in age-matched WT rats but this was not statistically significant in any age group. [(18)F]DPA-714 uptake in the QA-lesioned rats was significantly higher ipsilateral to the lesion compared to contralateral side indicating neuroinflammatory changes. Iba1 immunofluorescence showed no significant differences in microglial activation between the Tg and WT rats, while the QA-lesioned rats showed significant activation. Finally, cytokine/chemokine levels in brain lysates of the Tg rats and WT rats were not significantly different. CONCLUSION: Microglial activation might not be the primary mechanism for neuropathology in the HIV-1 Tg rats. Although [(18)F]DPA-714 is a good biomarker of neuroinflammation, it cannot be reliably used as an in vivo biomarker of neurodegeneration in the HIV-1 Tg rat. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-015-0390-9) contains supplementary material, which is available to authorized users

STRUCTURAL ANALYSIS OF THE MAIN ROTOR BLADE FOR A LIGHT HELICOPTER - CASE OF HOVERING FLIGHT MODE

—The aerospace industry deals from the beginning with structures with special requirements as extreme lightweight and withstanding to a big number of load cases. Aerodynamics constraints lead to supplementary restrictions, the results being the complex shape to sustain the fuselage, the rotor blades or the wings skin. This paper presents a static structural analysis of the main rotor blade for the light helicopter. To simulate the mechanical behavior of the blade, a finite elements method was used. A case of hovering flight mode was considered

Diffusion tensor and volumetric magnetic resonance measures as biomarkers of brain damage in a small animal model of HIV.

There are currently no widely accepted neuro-HIV small animal models. We wanted to validate the HIV-1 Transgenic rat (Tg) as an appropriate neuro-HIV model and then establish in vivo imaging biomarkers of neuropathology, within this model, using MR structural and diffusion tensor imaging (DTI).Young and middle-aged Tg and control rats were imaged using MRI. A subset of middle-aged animals underwent longitudinal repeat imaging six months later. Total brain volume (TBV), ventricular volume (VV) and parenchymal volume (PV = TBV-VV) were measured. Fractional anisotropy (FA) and mean diffusivity (MD) values of the corpus callosum (CC) were calculated from DTI data.TBV and PV were smaller in Tg compared to control rats in young and middle-aged cohorts (p0.05).We detected brain volume loss in the Tg rat, probably due to astrocytic dysfunction/loss, loss of structural/axonal matrix and striatal neuronal loss as suggested by immunofluorescence. Increased MD and decreased FA in the CC probably reflect microstructural differences between the Tg and Control rats which could include increased extracellular space between white matter tracts, demyelination and axonal degeneration, among other pathologies. We believe that the Tg rat is an adequate model of neuropathology in HIV and that volumetric MR and DTI measures can be potentially used as biomarkers of disease progression

Imaging Dopaminergic Dysfunction as a Surrogate Marker of Neuropathology in a Small-Animal Model of HIV

The dopaminergic system is especially vulnerable to the effects of human immunodeficiency virus (HIV) infection, rendering dopaminergic deficits early surrogate markers of HIV-associated neuropathology. We quantified dopamine D 2/3 receptors in young HIV-1 transgenic (Tg) ( n = 6) and age-matched control rats ( n = 7) and adult Tg ( n = 5) and age-matched control rats ( n = 5) using [ 18 F]fallypride positron emission tomography (PET). Regional uptake was quantified as binding potential ( BP ND ) using the two-tissue reference model with the cerebellum as the reference. Time-activity curves were generated for the ventral striatum, dorsal striatum, thalamus, and cerebellum. Whereas BP ND values were significantly lower in the ventral striatum ( p < .001) and dorsal striatum ( p = .001) in the adult Tg rats compared to controls rats, they were significantly lower only in the dorsal striatum ( p < .05) in the young rats. Tg rats had smaller striatal volumes on magnetic resonance imaging. We also found lower expression levels of tyrosine hydroxylase on immunohistochemistry in the Tg animals. Our findings suggest that progressive striatal D 2/3 receptor deficits occur in Tg rats as they age and can be detected using small-animal PET imaging. The effectiveness of various approaches in preventing or halting this dopaminergic loss in the Tg rat can thus be measured preclinically using [ 18 F]fallypride PET as a molecular imaging biomarker of HIV-associated neuropathology

Neurobehavioral Abnormalities in the HIV-1 Transgenic Rat Do Not Correspond to Neuronal Hypometabolism on 18F-FDG-PET.

Motor and behavioral abnormalities are common presentations among individuals with HIV-1 associated neurocognitive disorders (HAND). We investigated whether longitudinal motor and behavioral performance in the HIV-1 transgenic rat (Tg), a commonly used neuro-HIV model, corresponded to in vivo neuronal death/dysfunction, by using rotarod and open field testing in parallel to [18F] 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). We demonstrated that age-matched non-Tg wild type (WT) rats outperformed the HIV-1 Tg rats at most time points on rotarod testing. Habituation to rotarod occurred at 8 weeks of age (fifth weekly testing session) in the WT rats but it never occurred in the Tg rats, suggesting deficits in motor learning. Similarly, in open field testing, WT rats outperformed the Tg rats at most time points, suggesting defective exploratory/motor behavior and increased emotionality in the Tg rat. Despite the neurobehavioral abnormalities, there were no concomitant deficits in 18F-FDG uptake in Tg rats on PET compared to age-matched WT rats and no significant longitudinal loss of FDG uptake in either group. The negative PET findings were confirmed using 14C- Deoxy-D-glucose autoradiography in 32 week-old Tg and WT rats. We believe that the neuropathology in the HIV-1 Tg rat is more likely a consequence of neuronal dysfunction rather than overt neurodegeneration/neuronal cell death, similar to what is seen in HIV-positive patients in the post-ART era

Additional file 1: Figure S1. of Lack of neuroinflammation in the HIV-1 transgenic rat: an [18F]-DPA714 PET imaging study

[18F]DPA-714 PET time-activity curves over 60 min derived from the caudate and hippocampus of 3-, 6-, and 9-month-old Tg and WT rats. Error bars represent standard deviation values at each time point. (TIFF 2460 kb

Changes in (A) parenchymal volume and (B) ventricular volume, between the Tg rats and their age-matched controls at both young and middle-age.

<p>Changes in (A) parenchymal volume and (B) ventricular volume, between the Tg rats and their age-matched controls at both young and middle-age.</p

Coronal T1-weighted, directionally-encoded color FA map and T2-weighted MR images obtained from middle-aged transgenic rat (A) and age-matched control rat (B).

<p>White arrows point to enlarged ventricular size in the Tg rat. The red contour delineates the ROI selected for measurement of DTI parameters in the CC.</p

Quantitative measurements of Neu-N counts and GFAP and NFH staining intensities in the young and middle-aged animals, in various locations.

<p>The numerical values represent the mean and standard deviations of staining count ratios (for Neu-N) and staining intensity ratios (for GFAP and NFH) of Tg/Control animals. Only animals stained in the same session were compared and used to obtain the ratios. Data was obtained from 8 young animals (5 Tg and 3 controls; 5 ratios) and 5 middle-aged animals (3 Tg and 2 controls; 3 ratios) except for NFH (*) where we had only two ratio values for the 7-month old group.</p