Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits.

An improved understanding of sterol and lipid abnormalities in individuals with autism spectrum disorder (ASD) could lead to personalized treatment approaches. Toward this end, in blood, we identified reduced synthesis of cholesterol in families with ≥2 children with ASD participating with the Autism Genetic Resource Exchange (AGRE), as well as reduced amounts of high-density lipoprotein cholesterol (HDL), apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB), with 19.9% of the subjects presenting with apolipoprotein patterns similar to hypolipidemic clinical syndromes and 30% with either or both ApoA1 and ApoB less than the fifth centile. Subjects with levels less than the fifth centile of HDL or ApoA1 or ApoA1 + ApoB had lower adaptive functioning than other individuals with ASD, and hypocholesterolemic subjects had apolipoprotein deficits significantly divergent from either typically developing individuals participating in National Institutes of Health or the National Health and Nutrition Examination Survey III.

Role of Diffusion Tensor Imaging in Prognostication and Treatment Monitoring in Niemann-Pick Disease Type C1.

Niemann-Pick Disease, type C1 (NPC1) is a rapidly progressive neurodegenerative disorder characterized by cholesterol sequestration within late endosomes and lysosomes, for which no reliable imaging marker exists for prognostication and management. Cerebellar volume deficits are found to correlate with disease severity and diffusion tensor imaging (DTI) of the corpus callosum and brainstem, which has shown that microstructural disorganization is associated with NPC1 severity. This study investigates the utility of cerebellar DTI in clinical severity assessment. We hypothesize that cerebellar volume, fractional anisotropy (FA) and mean diffusivity (MD) negatively correlate with NIH NPC neurological severity score (NNSS) and motor severity subscores. Magnetic resonance imaging (MRI) was obtained for thirty-nine NPC1 subjects, ages 1-21.9 years (mean = 11.1, SD = 6.1). Using an atlas-based automated approach, the cerebellum of each patient was measured for FA, MD and volume. Additionally, each patient was given an NNSS. Decreased cerebellar FA and volume, and elevated MD correlate with higher NNSS. The cognition subscore and motor subscores for eye movement, ambulation, speech, swallowing, and fine motor skills were also statistically significant. Microstructural disorganization negatively correlated with motor severity in subjects. Additionally, Miglustat therapy correlated with lower severity scores across ranges of FA, MD and volume in all regions except the inferior peduncle, where a paradoxical effect was observed at high FA values. These findings suggest that DTI is a promising prognostication tool.

Corpus callosum diffusion tensor imaging and volume measures are associated with disease severity in pediatric Niemann-Pick disease type C1.

BACKGROUND: Niemann-Pick disease type C1 is a neurodegenerative lysosomal storage disorder. Without a highly effective treatment, biomarkers of severity would be beneficial for prognostication and testing new interventions. Diffusion tensor imaging has shown microstructural abnormalities in adults with Niemann-Pick disease type C1. This is the first study to apply diffusion tensor imaging and volume analysis to evaluate the corpus callosum in a pediatric and adolescent population of patients with Niemann-Pick disease type C1. We hypothesized that the callosal fractional anisotropy, volume, and cross-sectional area will negatively correlate with NPC severity score. METHODS: Thirty-nine individuals with Niemann-Pick disease type C1 aged 1-21.9 years (mean = 11.1; S.D. = 6.1), and each received one magnetic resonance imaging examination. Severity score were obtained by examination and clinical observation. An atlas-based automated approach was used to measure fractional anisotropy, cross-sectional area, and volume. For comparative analysis and validation of this atlas-based approach, one midsagittal image was chosen and the corpus callosum manually traced to obtain cross-sectional area. Statistical analyses were applied to study the relationships between imaging and clinical severity. RESULTS: For patients with Niemann-Pick disease type C1, lower corpus callosum fractional anisotropy, volume, and cross-sectional area significantly correlate with higher severity score. Severity subdomain analysis revealed ambulation, speech, seizures, and incontinence have the strongest relationships with callosal measures. Comparison of atlas-based processing and manual tracing techniques demonstrated validity for the automated method. CONCLUSIONS: For individuals with Niemann-Pick disease type C1, the corpus callosum measures correlate with clinical severity. These findings reveal promise for the discovery of new imaging biomarkers for this disorder.

Cocaine-induced behavioral sensitization in mice: effects of microinjection of dopamine d2 receptor antagonist into the nucleus accumbens.

To determine the role of dopamine D2 receptor (D2R) in the nucleus accumbens (NAc) core in cocaine-induced behavioral sensitization, D2R antagonist, raclopride was bilaterally microinjected (2.5 or 5 nmol) into the NAc core of WT and D2R(-/-) mice and the initiation and expression phase of cocaine-mediated locomotor sensitization were analyzed. WT and D2R knockout (D2R(-/-)) mice received bilateral injections of either saline, or raclopride at the NAc core 30 min before each of five daily repeated injections of saline or cocaine (15 mg/kg i.p.). Following 2 weeks of withdrawal after repeated exposure to cocaine, the animals were pre-treated with an intra-accumbal injection of vehicle or raclopride before receiving a systemic cocaine challenge for the expression of sensitization. Animals which had been microinjected raclopride into NAc core displayed the enhancement of cocaine-induced behavioral response for the initiation but also for the expression of sensitization in WT as well as in D2R(-/-) mice, which was thus unaltered as compared to vehicle-injected control group. These results suggest that D2R in NAc core is not involved in cocaine-induced behavioral sensitization.

Corpus callosum measurements correlate with developmental delay in Smith-Lemli-Opitz syndrome.

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation, neurodevelopmental disorder of cholesterol metabolism caused by mutations in 7-dehydrocholesterol reductase. Corpus callosum (CC) malformations and developmental delay are common, but the relation between the two has not been evaluated. This study hypothesizes shorter callosal length and smaller area correlate with higher serum 7-dehydrocholesterol and increased severity of neurodevelopmental delay in SLOS. METHODS: Thirty-six individuals with SLOS (18M/18F) between 0.20 and 12.5 years (mean = 3.9, SD = 3.6) and 36 typically developing controls (18 boys and 18 girls) between 0.12 and 12.8 years (mean = 4.0, SD = 3.6) were each imaged once on a 1.5T scanner. One midsagittal image per study was selected for manual CC measurement. Gross motor, fine motor, and language developmental quotients; anatomical severity score; and serum sterol levels were assessed. RESULTS: Shorter CC length and smaller area correlated with a lower developmental quotient in gross motor and language domains. Furthermore, length and area negatively correlated with a serum sterol precursors and severity score, and positively correlated with total cholesterol. Degree of developmental delay ranged from mild to severe, involving all domains. CONCLUSIONS: For individuals with SLOS, smaller callosal area and length are associated with higher 7-dehydrocholesterol, severity scores, and developmental delay. The relationship between callosal development and biochemical abnormalities in this cohort may lead to further studies supporting imaging biomarkers.