Shujuan Fan

Curcumin-conjugated magnetic nanoparticles for detecting amyloid plaques in Alzheimer's disease mice using magnetic resonance imaging (MRI).

Diagnosis of Alzheimers disease (AD) can be performed with the assistance of amyloid imaging. The current method relies on positron emission tomography (PET), which is expensive and exposes people to radiation, undesirable features for a population screening method. Magnetic resonance imaging (MRI) is cheaper and is not radioactive. Our approach uses magnetic nanoparticles (MNPs) made of superparamagnetic iron oxide (SPIO) conjugated with curcumin, a natural compound that specifically binds to amyloid plaques. Coating of curcumin-conjugated MNPs with polyethylene glycol-polylactic acid block copolymer and polyvinylpyrrolidone by antisolvent precipitation in a multi-inlet vortex mixer produces stable and biocompatible curcumin magnetic nanoparticles (Cur-MNPs) with mean diameter <100 nm. These nanoparticles were visualized by transmission electron microscopy and atomic force microscopy, and their structure and chemistry were further characterized by X-ray diffraction, thermogravimetric analysis, X-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectrometry, and Fourier transform infrared spectroscopy. Cur-MNPs exhibited no cytotoxicity in either Madin-Darby canine kidney (MDCK) or differentiated human neuroblastoma cells (SH-SY5Y). The Papp of Cur-MNPs was 1.03 × 10(-6) cm/s in an in vitro blood-brain barrier (BBB) model. Amyloid plaques could be visualized in ex vivo T2*-weighted magnetic resonance imaging (MRI) of Tg2576 mouse brains after injection of Cur-MNPs, and no plaques could be found in non-transgenic mice. Immunohistochemical examination of the mouse brains revealed that Cur-MNPs were co-localized with amyloid plaques. Thus, Cur-MNPs have the potential for non-invasive diagnosis of AD using MRI.

In vivo evaluation of retinal and callosal projections in early postnatal development and plasticity using manganese-enhanced MRI and diffusion tensor imaging

The rodents are an excellent model for understanding the development and plasticity of the visual system. In this study, we explored the feasibility of Mn-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI) at 7 T for in vivo and longitudinal assessments of the retinal and callosal pathways in normal neonatal rodent brains and after early postnatal visual impairments. Along the retinal pathways, unilateral intravitreal Mn2+ injection resulted in Mn2+ uptake and transport in normal neonatal visual brains at postnatal days (P) 1, 5 and 10 with faster Mn2+ clearance than the adult brains at P60. The reorganization of retinocollicular projections was also detected by significant Mn2+ enhancement by 2%-10% in the ipsilateral superior colliculus (SC) of normal neonatal rats, normal adult mice and adult rats after neonatal monocular enucleation (ME) but not in normal adult rats or adult rats after monocular deprivation (MD). DTI showed a significantly higher fractional anisotropy (FA) by 21% in the optic nerve projected from the remaining eye of ME rats compared to normal rats at 6 weeks old, likely as a result of the retention of axons from the ipsilaterally uncrossed retinal ganglion cells, whereas the anterior and posterior retinal pathways projected from the enucleated or deprived eyes possessed lower FA after neonatal binocular enucleation (BE), ME and MD by 22%-56%, 18%-46% and 11%-15% respectively compared to normal rats, indicative of neurodegeneration or immaturity of white matter tracts. Along the visual callosal pathways, intracortical Mn2+ injection to the visual cortex of BE rats enhanced a larger projection volume by about 74% in the V1/V2 transition zone of the contralateral hemisphere compared to normal rats, without apparent DTI parametric changes in the splenium of corpus callosum. This suggested an adaptive change in interhemispheric connections and spatial specificity in the visual cortex upon early blindness. The results of this study may help determine the mechanisms of axonal uptake and transport, microstructural reorganization and functional activities in the living visual brains during development, diseases, plasticity and early interventions in a global and longitudinal setting.

High fidelity tonotopic mapping using swept source functional magnetic resonance imaging

Tonotopy, the topographic encoding of sound frequency, is the fundamental property of the auditory system. Invasive techniques lack the spatial coverage or frequency resolution to rigorously investigate tonotopy. Conventional auditory fMRI is corrupted by significant image distortion, sporadic acoustic noise and inadequate frequency resolution. We developed an efficient and high fidelity auditory fMRI method that integrates continuous frequency sweeping stimulus, distortion free MRI sequence with stable scanner noise and Fourier analysis. We demonstrated this swept source imaging (SSI) in the rat inferior colliculus and obtained tonotopic maps with ~2 kHz resolution and 40 kHz bandwidth. The results were vastly superior to those obtained by conventional fMRI mapping approach and in excellent agreement with invasive findings. We applied SSI to examine tonotopic injury following developmental noise exposure and observed that the tonotopic organization was significantly disrupted. With SSI, we also observed the subtle effects of sound pressure level on tonotopic maps, reflecting the complex neuronal responses associated with asymmetric tuning curves. This in vivo and noninvasive technique will greatly facilitate future investigation of tonotopic plasticity and disorders and auditory information processing. SSI can also be adapted to study topographic organization in other sensory systems such as retinotopy and somatotopy.

In vivo visuotopic brain mapping with manganese-enhanced MRI and resting-state functional connectivity MRI

The rodents are an increasingly important model for understanding the mechanisms of development, plasticity, functional specialization and disease in the visual system. However, limited tools have been available for assessing the structural and functional connectivity of the visual brain network globally, in vivo and longitudinally. There are also ongoing debates on whether functional brain connectivity directly reflects structural brain connectivity. In this study, we explored the feasibility of manganese-enhanced MRI (MEMRI) via 3 different routes of Mn(2+) administration for visuotopic brain mapping and understanding of physiological transport in normal and visually deprived adult rats. In addition, resting-state functional connectivity MRI (RSfcMRI) was performed to evaluate the intrinsic functional network and structural-functional relationships in the corresponding anatomical visual brain connections traced by MEMRI. Upon intravitreal, subcortical, and intracortical Mn(2+) injection, different topographic and layer-specific Mn enhancement patterns could be revealed in the visual cortex and subcortical visual nuclei along retinal, callosal, cortico-subcortical, transsynaptic and intracortical horizontal connections. Loss of visual input upon monocular enucleation to adult rats appeared to reduce interhemispheric polysynaptic Mn(2+) transfer but not intra- or inter-hemispheric monosynaptic Mn(2+) transport after Mn(2+) injection into visual cortex. In normal adults, both structural and functional connectivity by MEMRI and RSfcMRI was stronger interhemispherically between bilateral primary/secondary visual cortex (V1/V2) transition zones (TZ) than between V1/V2 TZ and other cortical nuclei. Intrahemispherically, structural and functional connectivity was stronger between visual cortex and subcortical visual nuclei than between visual cortex and other subcortical nuclei. The current results demonstrated the sensitivity of MEMRI and RSfcMRI for assessing the neuroarchitecture, neurophysiology and structural-functional relationships of the visual brains in vivo. These may possess great potentials for effective monitoring and understanding of the basic anatomical and functional connections in the visual system during development, plasticity, disease, pharmacological interventions and genetic modifications in future studies.

The effect of alcohol drinking on erectile dysfunction in Chinese men

Erectile dysfunction (ED), smoking, and alcohol drinking are common in middle-aged men. Although smoking has been shown to be a risk factor of ED in Chinese and other populations, the relationship between drinking alcohol and ED is not clear. The Family Planning Association of Hong Kong conducted the Men Health Survey in 2004. In all, 1506 men aged 20–70 years were recruited by stratified random sampling of the male population. Face-to-face interviews were used to collect information on drinking and smoking and other life style factors, morbidities, and sociodemographic status during household visits. The more sensitive information on sexual activity and ED was obtained by a self-completed questionnaire at the end of the interview. A total of 816 subjects aged 31–60 years currently active in sexual activity were included in the present analysis. Compared with never drinkers, alcohol drinkers who consumed three or more standard drinks (one standard drink equals 12 g of alcohol) a week were more likely to report EDs as defined by having both sexual dissatisfaction and erectile difficulty (odds ratio (OR)=2.27, 95% confidence interval (CI)=1.28–4.03) after adjusting for age and cigarette smoking. When analyzed separately by smoking habit, the risks were higher in current smokers (OR=2.27, 95% CI=1.01–5.11) than never smokers (OR=1.91, 95% CI=0.68–5.35). Our results suggest that alcohol drinking of three or more standard drinks per week might reduce sexual satisfaction and impair erectile function in current smokers and might have less effect in never smokers.

Effect of postmenopausal hormone replacement therapy on lipoprotein and homocysteine levels in Chinese women

Epidemiological studies have revealed that postmenopausal estrogen replacement therapy results in a marked reduction in the risk for cardiovascular diseases. In the present study, we evaluated plasma lipoprotein profile as well as homocysteine levels in 145 post‐menopausal and premenopausal Chinese women living in Hong Kong. We also investigated the effect of hormone‐replacement therapy (HRT) with estrogen or estrogen combined with progestin on plasma lipoprotein profile and homocysteine concentrations in those individuals. Postmenopausal women displayed significantly higher plasma levels of total cholesterol, LDL‐cholesterol and apoB as well as higher plasma homocysteine levels than that of premenopausal women. HRT with either estrogen (17β-estradiol or conjugated equine estrogen) alone or estrogen combined with progestin for 3.5–4.5 years significantly improved the lipoprotein profile in postmenopausal women by decreasing the levels of total cholesterol (12–20% reduction), LDL-cholesterol (26–29% reduction) and apoB (21–25% reduction). In women treated with 17β‐estradiol or conjugated equine estrogens their plasma levels of apoAI were significantly elevated (18% elevation) as compared to non-users. HRT also reduced plasma concentrations of homocysteine (13–15% reduction). In conclusion, we found that long-term HRT was associated with improvement in plasma lipoprotein profile and a reduction in homocysteine concentration in postmenopausal women. These results support the notion that the improvement of lipoprotein profile and a reduction in homocysteine concentration may contribute to the beneficial effect of HRT on cardiovascular risk.

In vivo chromium-enhanced MRI of the retina

Chromium (Cr) has been used histologically to stabilize lipid fractions in the retina and is suggested to enhance oxidizable lipids in brain MRI. This study explored the feasibility, sensitivity, and specificity of in vivo chromium‐enhanced MRI of retinal lipids by determining its spatiotemporal profiles and toxic effect after intravitreal Cr(VI) injection to normal adult rats. One day after 3 μL Cr(VI) administration at 1–100 mM, the retina exhibited a dose‐dependent increase in T1‐weighted hyperintensity until 50 mM. Time‐dependently, significant T1‐weighted hyperintensity persisted up to 2 weeks after 10 mM Cr(VI) administration. Three‐dimensional chromium‐enhanced MRI of ex vivo normal eyes at isotropic 50‐μm resolution showed at least five alternating bands across retinal layers, with the outermost layer being the brightest. This agreed with histology indicating alternating lipid contents with the highest level in the photoreceptor layer of the outer retina. Although Cr(VI) reduction may induce oxidative stress and depolymerize microtubules, manganese‐enhanced MRI after chromium‐enhanced MRI showed a dose‐dependent effect of Cr toxicity on manganese uptake and axonal transport along the visual pathway. These results potentiated future longitudinal chromium‐enhanced MRI studies on retinal lipid metabolism upon further optimization of Cr doses with visual cell viability. Magn Reson Med, 2012.

In vivo diffusion tensor imaging of chronic spinal cord compression in rat model

Chronic spinal cord compression induced cervical myelopathy is a comon cause of spinal cord dysfunction. The exact mechanisms of underlying progressive cell death remain to be elucidated. In this study, in vivo diffusion tensor imaging (DTI) has been applied to investigate the microstructural changes of white matter (WM) in this neurodegenerative disease. Compared with conventional MRI techniques, DTI is believed to be more specific to pathological changes. Radial diffusivity (λ┴) is higher in the ipilesional region, suggesting demyelination or axonal degradation may occur after prolonged compression. Near the epicenter of lesion, axial diffusivity (λ//) is lower. Also, caudal-rostral asymmetry has been observed in λ//. Feasibility of using DTI to detect microstructural changes in chronic disease has been demonstrated.

Bilateral substantia nigra and pyramidal tract changes following experimental intracerebral hemorrhage: an MR diffusion tensor imaging study

The amelioration of secondary neurological damage is among the most important therapeutic goals for patients with intracerebral hemorrhage (ICH). Secondary injury of the ipsilateral substantia nigra (SN) and pyramidal tract (PY) is common after cerebral stroke. Such injury has been characterized previously by anatomical or diffusion MRI, but not in a comprehensive manner, and the knowledge regarding the contralateral changes is relatively poor. This study examined longitudinally both contralateral and ipsilateral SN and PY changes following experimental ICH with diffusion tensor imaging (DTI) and histology. ICH was induced in 14 Sprague‐Dawley rats by the infusion of collagenase into the right striatum. Four‐shot, spin‐echo, echo‐planar DTI was performed at 7 T with a b value of 1000 s/mm2 and 30 diffusion gradient directions at 3.5 h and days 1, 3, 7, 14, 42 and 120 after ICH. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ//) and radial diffusivity (λ┴) were measured in SN and PY accordingly. Two to three rats were sacrificed at days 3, 7, 42 and 120 for histology. The contralateral SN showed an increase in λ// with perivascular enlargement during the first 3 days after ICH. The ipsilateral SN showed increases in FA, λ//, λ┴ and MD at day 1, dramatic decreases at day 3 with neuronal degeneration and neuropil vacuolation, and subsequent gradual normalization. The contralateral PY showed diffusivity decreases at day 1. The ipsilateral PY showed early decreases and then late increases in MD and λ┴, and continuously decreasing FA and λ// with progressive axonal loss and demyelination. In summary, DTI revealed early bilateral changes in SN and PY following ICH. The evolution of the ipsilateral parameters correlated with the histological findings. In the ipsilateral PY, λ// and λ┴ changes indicated evolving and complex pathological processes underlying the monotonic FA decrease. These results support the use of quantitative multiparametric DTI for the evaluation of SN and PY injuries in clinical and preclinical investigations of ICH. Copyright

Diffusion magnetic resonance monitors intramyocellular lipid droplet size in vivo

Intramyocellular lipid (IMCL) droplets are dynamic organelles whose morphology reflects their vital roles in lipid synthesis, usage, and storage in muscle energy metabolism. To develop noninvasive means to measure droplet microstructure in vivo, we investigated the molecular diffusion behavior of IMCL with diffusion magnetic resonance spectroscopy.