The major pathway of brain cholesterol turnover relies on its hydroxylation into 24S-hydroxycholesterol (24S-HC) using brain-specific cytochrome P450 46A1 (CYP46A1). 24S-HC produced exclusively in the brain normally traverses the blood-brain barrier to enter the circulation to the liver for excretion; therefore, the serum 24S-HC level is an indication of cholesterol metabolism in the brain. We recently reported an upregulation of CYP46A1 following hypoxia-ischemia (HI) in the neonatal mouse brain and a correlation between serum 24S-HC levels and acute brain damage. Here, we performed a longitudinal study to investigate whether the serum 24S-HC concentrations predict long-term brain structural and functional outcomes. In postnatal day 9 mice subjected to HI, the serum 24S-HC levels increased at 6 h and 24 h after HI and correlated with the infarct volumes measured histologically or by T2-weighted MRI. The 24 h levels were associated with white matter volume loss quantified by MBP immunostaining and luxol fast blue staining. The animals with higher serum 24S-HC at 6 h and 24 h corresponded to those with more severe motor and cognitive deficits at 35-40 days after HI. These data suggest that 24S-HC could be a novel and early blood biomarker for severity of neonatal HI brain damage and associated functional impairments.

The major pathway of brain cholesterol turnover relies on its hydroxylation into 24S-hydroxycholesterol (24S-HC) using brain-specific cytochrome P450 46A1 (CYP46A1). 24S-HC produced exclusively in the brain normally traverses the blood-brain barrier to enter the circulation to the liver for excretion; therefore, the serum 24S-HC level is an indication of cholesterol metabolism in the brain. We recently reported an upregulation of CYP46A1 following hypoxia-ischemia (HI) in the neonatal mouse brain and a correlation between serum 24S-HC levels and acute brain damage. Here, we performed a longitudinal study to investigate whether the serum 24S-HC concentrations predict long-term brain structural and functional outcomes. In postnatal day 9 mice subjected to HI, the serum 24S-HC levels increased at 6 h and 24 h after HI and correlated with the infarct volumes measured histologically or by T2-weighted MRI. The 24 h levels were associated with white matter volume loss quantified by MBP immunostaining and luxol fast blue staining. The animals with higher serum 24S-HC at 6 h and 24 h corresponded to those with more severe motor and cognitive deficits at 35-40 days after HI. These data suggest that 24S-HC could be a novel and early blood biomarker for severity of neonatal HI brain damage and associated functional impairments.

Purpose

To investigate two-dimensional (2D) and three-dimensional (3D) ultrashort echo time (UTE) and 3D magnetization-prepared rapid gradient-echo (MP-RAGE) sequences for the imaging of iron-oxide nanoparticles (IONP).

Methods

The phantoms were composed of tubes filled with different IONP concentrations ranging from 2 to 45 mM. The tubes were fixed in an agarose gel phantom (0.9% by weight). Morphological imaging was performed with 3D MP-RAGE, 2D UTE, 2D adiabatic inversion recovery-prepared UTE (2D IR-UTE), 3D UTE with Cones trajectory (3D Cones), and 3D IR-Cones sequences. Quantitative assessment of IONP concentration was performed using R2*(1/T2*) and R₁ (1/T₁ ) measurements using a 3 Tesla (T) scanner.

Results

The 3D MP-RAGE sequence provides high-contrast images of IONP with concentration up to 7.5 mM. Higher IONP concentration up to 37.5 mM can be detected with the UTE sequences, with the highest IONP contrast provided by the 3D IR-Cones sequence. A linear relationship was observed between R2* and IONP concentration up to ∼45 mM, and between R₁ and IONP concentration up to ∼30 mM.

Conclusion

The clinical 3D MP-RAGE sequence can be used to assess lower IONP concentration up to 7.5 mM. The UTE sequences can be used to assess higher IONP concentration up to 45 mM. Magn Reson Med 78:226-232, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Multiple sclerosis (MS) causes demyelinating lesions in the white matter and increased iron deposition in the subcortical gray matter. Myelin protons have an extremely short T2* (<1ms) and are not directly detected with conventional clinical magnetic resonance (MR) imaging sequences. Iron deposition also reduces T2*, leading to reduced signal on clinical sequences. In this study we tested the hypothesis that the inversion recovery ultrashort echo time (IR-UTE) pulse sequence can directly and simultaneously image myelin and iron deposition using a clinical 3T scanner. The technique was first validated on a synthetic myelin phantom (myelin powder in D₂O) and a Feridex iron phantom. This was followed by studies of cadaveric MS specimens, healthy volunteers and MS patients. UTE imaging of the synthetic myelin phantom showed an excellent bi-component signal decay with two populations of protons, one with a T2* of 1.2ms (residual water protons) and the other with a T2* of 290μs (myelin protons). IR-UTE imaging shows sensitivity to a wide range of iron concentrations from 0.5 to ~30mM. The IR-UTE signal from white matter of the brain of healthy volunteers shows a rapid signal decay with a short T2* of ~300μs, consistent with the T2* values of myelin protons in the synthetic myelin phantom. IR-UTE imaging in MS brain specimens and patients showed multiple white matter lesions as well as areas of high signal in subcortical gray matter. This in specimens corresponded in position to Perl's diaminobenzide staining results, consistent with increased iron deposition. IR-UTE imaging simultaneously detects lesions with myelin loss in the white matter and iron deposition in the gray matter.