Cerebellar Metabolite Levels and Social-Communication Impairments in Twins with Autism Spectrum Disorder

Background:  

Cerebellar circuits are important for providing regulatory feedback to other regions of the brain. Traditionally the cerebellum was thought to be exclusively involved with motor control, but imaging and lesion studies have implicated higher-order cognitive domains as well. The cerebellum is of particular interest in ASD because neuronal circuits in the cerebellar hemispheres have consistently been implicated in the disorder with multiple studies also reporting either hypo- or hyper- plasia in the vermis. 

Objectives:  

The goal of this study was to examine neurochemical profiles of the cerebellum to determine whether individuals with ASD exhibit differences in neuronal density, neurotransmitter signaling capability, or metabolic activity that are related to social-communication impairments.  

Methods:  

Data were acquired from a neuroimaging study of same-sex twin pairs that included monozygotic (MZ) and dizygotic (DZ) twin pairs with ASD and MZ and DZ control twin pairs. Cognitive/behavioral assessment included measures of intelligence (SB-5) and social-communication impairments (SRS). An oblique MR spectroscopy chemical shift imaging slab that covered portions of the cerebellar hemispheres and vermis was acquired. A subset of individuals with ASD and controls with valid spectra from the cerebellum was included in the present preliminary study and consisted of 25 individuals with ASD and 25 controls. Voxels (4.5 mL) included primarily grey matter (GM) or white matter (WM) in the right cerebellar hemisphere (R Cere Hemi) and a combination of GM and WM in the vermis. Metabolites were assessed in relation to internal creatine levels and adjusted for tissue composition. Compounds containing n-acetyl aspartate (NAA), glutamate (Gln), choline (Cho), and myo-inositol (mI) were examined. 

Results:  

Individuals with ASD exhibited the anticipated cognitive/behavioral profile including social-communication impairments (M_ASD=69.88,SD=19.73; M_CTRL=44.58,SD=10.89) and lower IQ (M_ASD=84.88,SD=31.13; M_CTRL=109.88,SD=16.49); but groups did not significantly differ in age (M_ASD=11.44,SD=2.76; M_CTRL=10.40,SD=2.38) or gender (M/F_ASD=19/6, M/F_CTRL=16/9), indicating sufficient control matching. Metabolites in the R Cere Hemi did not significantly differ between groups; however, there was a trend towards a difference in choline-containing compounds such that individuals with ASD exhibited higher concentrations in GM (M_ASD=0.29,SD=0.06; M_CTRL=0.26,SD=0.04), F(1,47)=3.509, p=0.067, η²=0.069, and WM (M_ASD=0.31,SD=0.05; M_CTRL=0.28,SD=0.07), F(1,47)=3.197, p=0.080, η²=0.064. R Cere Hemi GM and WM concentrations of NAA, Gln and mI did not differ between groups, and there were also no differences across metabolites in the vermis. Within individuals with ASD, there was a strong positive association between social-communication impairments and GM Cho (r=0.58) and a moderate association with WM Cho (r=0.39). 

Conclusions:  

Preliminary data from this investigation show that individuals with ASD may be more likely to present elevated choline-containing compounds in the right cerebellar hemisphere. Choline is a precursor of acetylcholine and marker of cellular membrane turnover. Elevated choline may indicate membrane degradation or increased cellular proliferation and is also present in less mature neuronal circuits. Therefore, our findings may suggest greater perturbation or less maturation of cerebellar circuits in some individuals with ASD that are related to social-communication impairments. The examination of additional participants and the assessment of heritability will allow further elucidation of potential differences in cerebellar choline in individuals with ASD.