Magnetic resonance spectroscopy outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders

Abstract

Magnetic resonance (MR) technology offers noninvasive methods for in vivo assessment of neuroabnormalities. A comprehensive neuropsychological/behavioral, MR imaging (MRI), MR spectroscopy (MRS) and functional MRI (fMRI) assessment was administered to children with fetal alcohol spectrum disorders (FASD) to determine whether global and/or focal abnormalities could be identified and to distinguish diagnostic subclassifications across the spectrum. The four study groups included (1) FAS/partial FAS; (2) static encephalopathy/alcohol exposed (SE/AE); (3) neurobehavioral disorder/alcohol exposed (ND/AE) as diagnosed with the FASD 4-Digit Code; and (4) healthy peers with no prenatal alcohol exposure. Results are presented in four separate reports: MRS (reported here) and neuropsychological/behavioral, MRI and fMRI outcomes (reported separately). MRS was used to compare neurometabolite concentrations [choline (Cho), n-acetyl-aspartate (NAA) and creatine (Cre)] in a white matter region and a hippocampal region between the four study groups. Choline concentration in the frontal/parietal white matter region, lateral to the midsection of the corpus callosum, was significantly lower in FAS/PFAS relative to all other study groups. Choline decreased significantly with decreasing frontal white matter volume and corpus callosum length. These outcomes suggest low choline concentrations may reflect white matter deficits among FAS/PFAS. Choline also decreased significantly with increasing severity of the 4-Digit FAS facial phenotype, increasing impairment in psychological performance and increasing alcohol exposure. NAA and Cre concentrations did not vary significantly. This study provides further evidence of the vulnerability of the cholinergic system in FASD.

Fig. 1

Nonhuman primate FASD MRS study [16]. (A) The 34×34×34-mm³ voxel included the thalamus, parts of the internal capsule and basal ganglia, and adjacent white matter. Current MRS Study. (B) Five equiangular subregions of the corpus callosum [(1) genu, (2) anterior body, (3) posterior body, (4) isthmus, (5) splenium] were constructed using the mammilary body as a point of reference. Coronal, sagittal and horizontal views of (C) 15×15×15-mm³ hippocampus/basal nuclear voxel in the left hemisphere, (D) 15×15×15-mm³ white matter voxel in the right frontal/parietal region (to replicate the voxel position in the previous nonhuman primate study) and (E) 20-mm-thick axial multivoxel slice (data to be presented in a separate report).

Fig. 2

(A) FASD 4-Digit Diagnostic Code. FASD is defined by growth deficiency, specific FAS facial features, evidence of CNS damage, and prenatal alcohol exposure. The 4-Digit Code ranks each of these areas on 4-point, case-defined, Likert scales. The 4-Digit Code (3444) inserted in the grid is 1 of 12 codes that meet the diagnostic criteria for FAS [25]. (B) The Rank 4 FAS facial phenotype, as defined by the FASD 4-Digit Diagnostic Code, requires the presence of all 3 of the following anomalies: (1) palpebral fissure length 2 or more standard deviations below the mean (2) smooth philtrum (Rank 4 or 5 on the Lip-Philtrum Guide); (3) thin upper lip (Rank 4 or 5 on the Lip-Philtrum Guide). Examples of the full Rank 4 FAS facial phenotype for Caucasian, Native American, African American, and Asian American children are shown (copyright Susan Astley Ph.D., University of Washington).

Fig. 2

(A) FASD 4-Digit Diagnostic Code. FASD is defined by growth deficiency, specific FAS facial features, evidence of CNS damage, and prenatal alcohol exposure. The 4-Digit Code ranks each of these areas on 4-point, case-defined, Likert scales. The 4-Digit Code (3444) inserted in the grid is 1 of 12 codes that meet the diagnostic criteria for FAS [25]. (B) The Rank 4 FAS facial phenotype, as defined by the FASD 4-Digit Diagnostic Code, requires the presence of all 3 of the following anomalies: (1) palpebral fissure length 2 or more standard deviations below the mean (2) smooth philtrum (Rank 4 or 5 on the Lip-Philtrum Guide); (3) thin upper lip (Rank 4 or 5 on the Lip-Philtrum Guide). Examples of the full Rank 4 FAS facial phenotype for Caucasian, Native American, African American, and Asian American children are shown (copyright Susan Astley Ph.D., University of Washington).

Fig. 3

Choline concentration (millimolar) across all the four study groups in the (A) frontal/parietal white matter and (B) hippocampus voxels.

Fig. 4

The mean Cho concentration (millimolar) in the frontal/parietal white matter voxel was significantly lower among the 46 subjects with alcohol exposure through the second and third trimesters than the 26 subjects with no exposure or exposure only through the first trimester.

Fig. 5

Spectral frequency showing key metabolites: Cho, Cre and NAA.

Fig. 6

The FAS/PFAS group had (A) significantly lower wCho concentration in the white matter voxel, (B) shorter corpus callosum lengths and (C) smaller frontal lobe volumes than controls. (D) The smaller the frontal lobe, the shorter the corpus callosum (Pearson correlation coefficient 0.64; P<.001). (E) The shorter the corpus callosum, the lower the wCho concentration (Pearson correlation coefficient 0.45; P<.001). (F) The smaller the frontal lobe, the lower the wCho concentration (Pearson correlation coefficient 0.24; P=.04). Four study groups: FAS/Partial FAS, SE/AE; ND/AE; healthy control with no alcohol exposure.

Fig. 7

Correlation between frontal lobe volume (cubic centimeter) and choline concentration (millimolar) in the hippocampus voxel containing the nucleus basilis of Meynert. The frontal lobe is innervated by cholinergic projections from the nucleus basilis of Meynert. (A) Frontal lobe volume was significantly smaller in FAS/PFAS relative to all other groups. (B) hCho in the hippocampus voxel was significantly lower in the FAS/PFAS group relative to all other groups. (C) Frontal lobe volume decreased significantly with decreasing hCho concentration in the hippocampus voxel.

Fig. 8

Intercorrelations between hCho, hippocampus volume and cognition. (A) Hippocampus volume increased significantly as one advances across the four study groups from FAS/PFAS to controls. (B) hCho in the hippocampus voxel was lower in the FAS/PFAS group. (C) hCho decreased significantly with decreasing size of the hippocampus (Pearson correlation coefficient 0.22, P=.049.). (D) Performance on the California Verbal Learning Test decreased significantly with decreasing hippocampus volume (Pearson correlation coefficient 0.30, P=.007).