Regional brain volume reductions relate to facial dysmorphology and neurocognitive function in fetal alcohol spectrum disorders

Individuals with heavy prenatal alcohol exposure can experience significant deficits in cognitive and psychosocial functioning and alterations in brain structure that persist into adulthood. In this report, data from 99 participants collected across three sites (Los Angeles and San Diego, California, and Cape Town, South Africa) were analyzed to examine relationships between brain structure, neurocognitive function, facial morphology, and maternal reports of quantities of alcohol consumption during the first trimester. Across study sites, we found highly significant volume reductions in the FASD group for all of the brain regions evaluated. After correcting for scan location, age, and total brain volume, these differences remained significant in some regions of the basal ganglia and diencephalon. In alcohol-exposed subjects, we found that smaller palpebral fissures were significantly associated with reduced volumes in the diencephalon bilaterally, that greater dysmorphology of the philtrum predicted smaller volumes in basal ganglia and diencephalic structures, and that lower IQ scores were associated with both smaller basal ganglia volumes and greater facial dysmorphology. In subjects from South Africa, we found a significant negative correlation between intracranial volume and total number of drinks per week in the first trimester. These results corroborate previous reports that prenatal alcohol exposure is particularly toxic to basal ganglia and diencephalic structures. We extend previous findings by illustrating relationships between specific measures of facial dysmorphology and the volumes of particular subcortical structures, and for the first time show that continuous measures of maternal alcohol consumption during the first trimester relates to overall brain volume reduction

Abnormal Cortical Thickness Alterations in Fetal Alcohol Spectrum Disorders and Their Relationships with Facial Dysmorphology

Accumulating evidence from structural brain imaging studies on individuals with fetal alcohol spectrum disorder (FASD) has supported links between prenatal alcohol exposure and brain morphological deficits. Although global and regional volumetric reductions appear relatively robust, the effects of alcohol exposure on cortical thickness and relationships with facial dysmorphology are not yet known. The structural magnetic resonance imaging data from 69 children and adolescents with FASD and 58 nonexposed controls collected from 3 sites were examined using FreeSurfer to detect cortical thickness changes across the entire brain in FASD and their associations with facial dysmorphology. Controlling for brain size, subjects with FASD showed significantly thicker cortices than controls in several frontal, temporal, and parietal regions. Analyses conducted within site further revealed prominent group differences in left inferior frontal cortex within all 3 sites. In addition, increased inferior frontal thickness was significantly correlated with reduced palpebral fissure length. Consistent with previous reports, findings of this study are supportive of regional increases in cortical thickness serving as a biomarker for disrupted brain development in FASD. Furthermore, the significant associations between thickness and dysmorphic measures suggest that the severity of brain anomalies may be reflected by that of the face

Imaging the Impact of Prenatal Alcohol Exposure on the Structure of the Developing Human Brain

Prenatal alcohol exposure has numerous effects on the developing brain, including damage to selective brain structure. We review structural magnetic resonance imaging (MRI) studies of brain abnormalities in subjects prenatally exposed to alcohol. The most common findings include reduced brain volume and malformations of the corpus callosum. Advanced methods have been able to detect shape, thickness and displacement changes throughout multiple brain regions. The teratogenic effects of alcohol appear to be widespread, affecting almost the entire brain. The only region that appears to be relatively spared is the occipital lobe. More recent studies have linked cognition to the underlying brain structure in alcohol-exposed subjects, and several report patterns in the severity of brain damage as it relates to facial dysmorphology or to extent of alcohol exposure. Future studies exploring relationships between brain structure, cognitive measures, dysmorphology, age, and other variables will be valuable for further comprehending the vast effects of prenatal alcohol exposure and for evaluating possible interventions

Structural, Metabolic, and Functional Brain Abnormalities as a Result of Prenatal Exposure to Drugs of Abuse: Evidence from Neuroimaging

Prenatal exposure to alcohol and stimulants negatively affects the developing trajectory of the central nervous system in many ways. Recent advances in neuroimaging methods have allowed researchers to study the structural, metabolic, and functional abnormalities resulting from prenatal exposure to drugs of abuse in living human subjects. Here we review the neuroimaging literature of prenatal exposure to alcohol, cocaine, and methamphetamine. Neuroimaging studies of prenatal alcohol exposure have reported differences in the structure and metabolism of many brain systems, including in frontal, parietal, and temporal regions, in the cerebellum and basal ganglia, as well as in the white matter tracts that connect these brain regions. Functional imaging studies have identified significant differences in brain activation related to various cognitive domains as a result of prenatal alcohol exposure. The published literature of prenatal exposure to cocaine and methamphetamine is much smaller, but evidence is beginning to emerge suggesting that exposure to stimulant drugs in utero may be particularly toxic to dopamine-rich basal ganglia regions. Although the interpretation of such findings is somewhat limited by the problem of polysubstance abuse and by the difficulty of obtaining precise exposure histories in retrospective studies, such investigations provide important insights into the effects of drugs of abuse on the structure, function, and metabolism of the developing human brain. These insights may ultimately help clinicians develop better diagnostic tools and devise appropriate therapeutic interventions to improve the condition of children with prenatal exposure to drugs of abuse

The C677T variant in MTHFR modulates associations between blood-based and cerebrospinal fluid biomarkers of neurodegeneration.

The C677T functional variant in the methylene-tetrahydrofolate reductase (MTHFR) gene results in reduced enzymatic activity and elevated blood levels of homocysteine. Plasma levels of apolipoprotein E (ApoE) are negatively correlated with cerebral amyloid burden, but plasma homocysteine concentrations are associated with increased amyloid-β (Aβ) deposition in the brain. Here, we sought to determine whether associations between low plasma ApoE levels and elevated in-vivo amyloid burden were modulated by carrying the C677T variant. We tested this hypothesis in a large sample of elderly participants from the Alzheimer's Disease Neuroimaging Initiative. We used general linear models to examine associations between plasma homocysteine concentrations, circulating ApoE levels, cerebrospinal fluid concentrations of Aβ, and their modulation by MTHFR and ApoE genotype. Age, sex, and dementia status were included as covariates in all analyses. Higher circulating levels of ApoE predicted increased cerebrospinal fluid concentrations of Aβ, indicating lower in-vivo burden, in C-allele carriers, but not in homozygotes at the C677T variant, who showed significant elevations in plasma homocysteine levels. This modulation by the MTHFR genotype did not remain significant after controlling for ApoE genotype. In T-homozygotes who do not carry the ApoE-ε4 allele, the relationship between low plasma ApoE levels and an increased risk of dementia is likely obscured by the presence of elevated plasma homocysteine. This report suggests the value of genotyping patients at the C677T functional variant when using plasma ApoE levels as a preclinical biomarker for Alzheimer's disease

The C677T variant in MTHFR modulates associations between brain integrity, mood, and cognitive functioning in old age.

IntroductionThe C677T functional variant in the methylene-tetrahydrofolate reductase (MTHFR) gene leads to reduced enzymatic activity and elevated blood levels of homocysteine. Hyperhomocysteinemia has been linked with higher rates of cardiovascular diseases, cognitive decline, and late-life depression.Methods and materialsHere, 3D magnetic resonance imaging data was analyzed from 738 individuals (age: 75.5 ± 6.8 years; 438 men/300 women) including 173 Alzheimer's patients, 359 subjects with mild cognitive impairment, and 206 healthy older adults, scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI).ResultsWe found that this variant associates with localized brain atrophy, after controlling for age, sex, and dementia status, in brain regions implicated in both intellectual and emotional functioning, notably the medial orbitofrontal cortices. The medial orbitofrontal cortex is involved in the cognitive modulation of emotional processes, and localized atrophy in this region was previously linked with both cognitive impairment and depressive symptoms. Here, we report that increased plasma homocysteine mediates the association between MTHFR genotype and lower medial orbitofrontal volumes, and that these volumes mediate the association between cognitive decline and depressed mood in this elderly cohort. We additionally show that vitamin B12 deficiency interacts with the C677T variant in the etiology of hyperhomocysteinemia.ConclusionThis study sheds light on important relationships between vascular risk factors, age-related cognitive decline, and late-life depression, and represents a significant advance in our understanding of clinically relevant associations relating to MTHFR genotype