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

Abstract

The dopaminergic system is especially vulnerable to the effects of HIV infection rendering dopaminergic deficits early surrogate markers of HIV-associated neuropathology. We quantified dopamine D2/3 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 [18F]fallypride PET. Regional uptake was quantified as binding potential (BPND) using the two-tissue reference model with cerebellum as reference. Time activity curves were generated for the ventral striatum (VS), dorsal striatum (DS), thalamus (Th), and cerebellum. While BPND values were significantly lower in the VS (p<0.001) and DS (p=0.001) in the adult Tg rats compared to controls rats, they were significantly lower only in the DS (p<0.05) in the young rats. Tg rats had smaller striatal volumes on MRI. We also found lower expression levels of tyrosine hydroxylase on immunohistochemistry in the Tg animals. Our findings suggest that progressive striatal D2/3 receptor deficits occur in Tg rats as they age and can be detected using small animal PET imaging. Effectiveness of various approaches in preventing/halting this dopaminergic loss in the Tg rat can thus be measured preclinically using [18F]fallypride PET as a molecular imaging biomarker of HIV-associated neuropathology.

Cross-sectional and longitudinal small animal PET shows pre and post-synaptic striatal dopaminergic deficits in an animal model of HIV

“…2A, 3A). This was discordant with our previous findings of significantly decreased [18F]-Fallypride binding in the Tg rats compared to WT rats at a similar age (5–9 months) [26]. Since we know D2/D3 receptors are expressed in many cell types other than dopaminergic neurons [19–23, 38] we believe this discrepancy could be related to loss/dysfunction of those cell types, such as astrocytes and GABAergic neurons.…”

“…[26] To derive estimates for binding potential ( BP ND ) of [18F]-fallypride, TACs were fit to Watabe’s reference tissue model with two compartments [27], an extension of the simplified reference model [28]. For [18F]-FP-CMT PET images, a simplified reference tissue reference model (SRTM) was used to fit the time activity curve for a region of interest based on only three parameters, k 2 , R 1 and BP ND as shown below [24]: $${\mathrm{normalC}}_{\mathrm{normalt}}(\mathrm{t})={\mathrm{normalR}}_1{\mathrm{normalC}}_{\mathrm{normalr}}(\mathrm{t})+\{{\mathrm{normalk}}_2-{\mathrm{normalR}}_1{\mathrm{normalk}}_2/(1+{\text{BP}}_{\text{ND}})\}{\mathrm{normalC}}_{\mathrm{normalr}}(\mathrm{t})exp\{-{\mathrm{normalk}}_2/\mathrm{t}(1+{\text{BP}}_{\text{ND}})\}$$ where, ${\mathrm{normalR}}_1=\frac{{\mathrm{K}}_{1}false(\text{rate}\text{constant}\text{from}\text{plasma}\text{to}\text{free}\text{compartment}false)}{{{\mathrm{normalK}}^{\prime }}_{1}false(\text{rate}\text{constant}\text{from}\text{plasma}\text{to}\text{reference}\text{compartment}false)}$…”

Selective developmental alterations in The HIV-1 transgenic rat: Opportunities for diagnosis of pediatric HIV-1

“…Preclinical studies in the HIV-1 Tg rat have previously implicated DA system impairments as an underlying factor in chronic neurological impairment in HIV-1 infected children (Lee et al 2014; Moran et al 2012; Moran et al 2014b; Webb et al 2010). Specifically, pharmacological assessments were used to examine alterations in the midbrain dopaminergic system in the HIV-1 Tg rat (Moran et al 2012; Webb et al 2010).…”

“…Dopaminergic system dysfunction, assessed using Western blotting, was evidenced by alterations in phosphorylated tyrosine hydroxylase (pTH), dopamine transporter (DAT) mRNA, and/or monoamine oxidase A (MAO-A; Moran et al 2012; Webb et al 2010). In addition, young HIV-1 Tg rats exhibit deficits in D 2 / 3 receptors in the dorsal striatum, assessed using [ 18 F]fallypride positron emission tomography (PET) (Lee et al 2014). …”

Dose‐dependent neurocognitive deficits following postnatal day 10 HIV‐1 viral protein exposure: Relationship to hippocampal anatomy parameters

“…Dopamine (DA) system dysfunction, observed in both clinical (e.g., Wang et al, 2004;Chang et al, 2008;Kumar et al, 2009;Lee et al, 2014) and preclinical studies (e.g., Webb et al, 2010;Moran et al, 2012;Reid et al, 2016a), may also underlie alterations in spatial learning. Specifically, alterations in the striatal DA system have been reported in pediatric HIV-1 research (Webb et al, 2009;Fitting et al, 2015).…”