Quantitative assessment of cerebral metabolism and hemodynamics in small-for-gestational-age (SGA) newborns

Abstract

Background: Small-for-gestational-age (SGA) newborns represent approximately 10% of births worldwide and 45% of births in some countries. It has been suggested that SGA might cause learning difficulties and behavioral abnormalities in childhood, yet the neurobiological basis for this is poorly understood. In this study, we employed several advanced imaging techniques-including T2-relaxation-under-spin-tagging (TRUST) magnetic resonance imaging (MRI), and phase-contrast (PC) MRI-to quantify oxygen extraction fraction (OEF), global cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO₂) to elucidate pathophysiological vulnerabilities of SGA neonates.

Methods: A total of 41 newborns were enrolled in this study, consisting of 29 SGA and 12 appropriate-for-gestational-age (AGA) neonates. The SGA group was further divided into subgroups with and without abnormalities on structural MRI, denoted as SGA-a (N=17) and SGA-n (N=12). TRUST and PC MRI were performed to determine OEF, CBF, and CMRO₂. Linear regression analyses were performed to examine physiological parameters' dependence on scan age, gender, and group. Similar analyses were conducted for birth weight and brain volume. Receiver operating characteristic (ROC) curves were used to test physiological parameters' ability to different diagnostic groups.

Results: Regression analysis revealed that CMRO₂ was significantly lower (P=0.04) in the SGA group relative to the AGA group. When further stratifying the SGA participants into SGA-a and SGA-n subgroups, the SGA-a subgroup was found to have the most pronounced physiological deficits, with a lower CMRO₂ (P=0.004) and lower CBF (P=0.007) than those in the AGA group. Conversely, CMRO₂ (P=0.40) and CBF (P=0.90) in the SGA-n subgroup were not different from those of the AGA group. Accordingly, CBF in the SGA-a group was significantly lower (P=0.01) than that of the SGA-n group and CMRO2 also showed a difference (P=0.09). Additionally, CMRO₂ (P=0.002) and CBF (P=0.04) showed an age-related increase during this early developmental period. In analyzing the SGA-a subgroup relative to the remaining neonates, the area under curve (AUC) values were 0.6, 0.6, 0.7, 0.8, and 0.5 for birth weight, OEF, CMRO₂, CBF, and brain volume, respectively. In analyzing the SGA-a subgroup relative to the SGA-n subgroup, AUC values were 0.5, 0.6, 0.7, 0.8, and 0.5 for birth weight, OEF, CMRO₂, CBF, and brain volume.

Conclusions: Structural damage in SGA-a neonates is associated with cerebral hemodynamic and metabolic deficits. SGA neonates with normal CBF and CMRO₂reveal minimal structural abnormalities. Physiological imaging may help identify SGA patients at high risk of developing irreversible brain damage.

Keywords: Small-for-gestational-age (SGA); T2-relaxation-under-spin-tagging (TRUST); cerebral blood flow (CBF); cerebral metabolic rate of oxygen (CMRO2); magnetic resonance imaging (MRI); oxygen extraction fraction (OEF); oxygen saturation fraction in venous blood (Yv); phase-contrast (PC).

Figure 1

Measurement of Yv and CBF using T2-relaxation-under-spin-tagging (TRUST) and phase-contrast (PC) MRI. (A,D) Axial T1-weighted imaging (T₁WI); (B,E) sagittal T₁WI for positioning of TRUSTMRI study; views at effective TEs (eTEs) of 0, 40, 80, and 160 ms; mono-exponential fitting of signal intensity in targeted venous sinus (as function of eTE) yielding venous blood, T₂ then converted to Yv via calibration plot; (C,F) positioning for PCMRI of internal carotid arteries (left, LICA; right, RICA) and vertebral arteries (left, LVA; right, RVA), using maximal-intensity-projection (MIP) angiogram images; velocity maps of LICA, RICA, LVA, and RVA. (A,B,C) show 35.7-old newborn (birth weight, 1,780 g) in SGA-n group. There was normal signal intensity on T₁WI; (D,E,F) as above of 35.1 week-old newborn (birth weight, 1,200 g) in SGA-a group. There were multiple areas of 35.7-week white matter damage enclosed in the periventricular areas. LICA, left internal carotid artery; RICA, right internal carotid artery; SGA, small-for-gestational-age.

Figure 2

T₁WI, T₂WI and DWI for SGA-a neonates. (A,B,C) A 34.4-week-old newborn (birth weight, 1,840 g; male) with white matter damage and increased signal intensity on T₁WI and DWI; (D,E,F) a 36.1-week-old newborn (birth weight, 1,125 g; male) with periventricular leukomalacia with multiple cystic lesions enclosed in bilateral centrum semiovale. (G,H,I) A 36.1-week-old newborn (birth weight, 1,140 g; male) with cerebral infarction with mixed signal intensity in the right basal ganglia on T₁WI, and increased signal intensity on T₂WI and DWI. T₁WI, T1-weighted imaging; DWI, diffusion-weighted imaging; SGA, small-for-gestational-age.

Figure 3

Comparison of ROC curves for five models (birth weight, OEF, CMRO₂, CBF, brain volume) to identify SGA newborns with abnormal structural MRI (denoted SGA-a). (A) ROC curves used to distinguish SGA-a neonates from AGA and SGA newborns with normal structural MRI (denoted SGA-n). (B) ROC curves used to distinguish SGA-a neonates from SGA-n neonates. CBF and CMRO₂all showed fair utility in diagnosing SGA-a. The physiological parameters had higher AUC than the morphological index of brain volume. ROC, receiver operating characteristic; SGA, small-for-gestational-age; OEF, oxygen extraction fraction; CMRO₂, cerebral metabolic rate of oxygen; CBF, cerebral blood flow.