Third Trimester Cerebellar Metabolite Concentrations are Decreased in Very Premature Infants with Structural Brain Injury

Abstract

Advanced neuroimaging techniques have improved our understanding of microstructural changes in the preterm supratentorial brain as well as the cerebellum and its association with impaired neurodevelopmental outcomes. However, the metabolic interrogation of the developing cerebellum during the early postnatal period after preterm birth remains largely unknown. Our study investigates the relationship between cerebellar neurometabolites measured by proton magnetic spectroscopy (1H-MRS) in preterm infants with advancing post-menstrual age (PMA) and brain injury during ex-utero third trimester prior to term equivalent age (TEA). We prospectively enrolled and acquired high quality 1H-MRS at median 33.0 (IQR 31.6–35.2) weeks PMA from a voxel placed in the cerebellum of 53 premature infants born at a median gestational age of 27.0 (IQR 25.0–29.0) weeks. 1H-MRS data were processed using LCModel software to calculate absolute metabolite concentrations of N-acetylaspartate (NAA), choline (Cho) and creatine (Cr). We noted positive correlations of cerebellar concentrations of NAA, Cho and Cr (Spearman correlations of 0.59, 0.64 and 0.52, respectively, p value < 0.0001) and negative correlation of Cho/Cr ratio (R −0.5, p value 0.0002) with advancing PMA. Moderate-to-severe cerebellar injury was noted on conventional magnetic resonance imaging (MRI) in 14 (26.4%) of the infants and were noted to have lower cerebellar NAA, Cho and Cr concentrations compared with those without injury (p value < 0.001). Several clinical complications of prematurity including necrotizing enterocolitis, systemic infections and bronchopulmonary dysplasia were associated with altered metabolite concentrations in the developing cerebellum. We report for the first time that ex-utero third trimester cerebellar metabolite concentrations are decreased in very preterm infants with moderate-to-severe structural cerebellar injury. We report increasing temporal trends of metabolite concentrations in the cerebellum with advancing PMA, which was impaired in infants with brain injury on MRI and may have early diagnostic and prognostic value in predicting neurodevelopmental outcomes in very preterm infants.

A unique cerebellar pattern of microglia activation in a mouse model of encephalopathy of prematurity

“…Despite the prevalence of cerebellar injury in preterm born infants (Basu et al, 2019;Bouyssi-Kobar et al, 2016;Brossard-Racine et al, 2015;Limperopoulos et al, 2007;Wu et al, 2020) and the links between these insults and poor functional outcomes (Shany et al, 2016;Tran et al, 2017) Systemic inflammation in the fetal and neonatal period plays a key role in disturbance of brain development as shown clinically (Leviton et al, 2016(Leviton et al, , 2018Patra et al, 2017) and supported by preclinical models (Du et al, 2011;Favrais et al, 2011;Gussenhoven et al, 2018) (reviewed in Fleiss et al, 2015Strunk et al, 2014). Prior studies in our validated mouse model of inflammation-associated EoP provide evidence for disruption of white matter integrity in the cerebrum, characterized by elevated fractional anisotropy as measured by DTI (Favrais et al, 2011).…”

Functional brain connectivity in ex utero premature infants compared to in utero fetuses

“…The precise impact of early exposure to the extra-uterine environment on neurodevelopmental outcomes ( Blencowe et al, 2013 ) in children born premature has yet to be fully explored. However, recent studies using advanced brain imaging techniques have shown altered metabolic profiles ( Ball et al, 2013a , 2013b ; Basu et al, 2019 ; Kwon et al, 2014 ; Vinall et al, 2013 ), cortical surface changes ( Ajayi-Obe et al, 2000 ; Boardman et al, 2007 ; Lefèvre et al, 2016 ; Orasanu et al, 2016 ), and impaired brain growth ( Padilla et al, 2015 ) in prematurely born infants. Cerebral and cerebellar growth trajectories in third trimester preterm infants without brain injury also lagged behind healthy in utero fetuses ( Bouyssi-Kobar et al, 2016 ).…”

A unique cerebellar pattern of microglia activation in a mouse model of encephalopathy of prematurity

“…Despite the prevalence of cerebellar injury in preterm born infants 5, 6, 24, 75, 76 and the links between these insults and poor outcomes in preterm born infants 77, 78 , there is not many studies focused on the cerebellum in models of preterm brain injury. We have addressed this issue and we have documented by MRI that in our model of inflammation-associated encephalopathy of prematurity that there is a global change in absolute volumes of the mouse brain, with a specific loss of cerebellar volume into adulthood.…”