Michael H. Lanier

Bio: Michael H. Lanier is an academic researcher from Washington University in St. Louis. The author has contributed to research in topics: Oxysterol & Cholesterol. The author has an hindex of 5, co-authored 5 publications receiving 459 citations.

Cholesterol Oxidation Products Are Sensitive and Specific Blood-Based Biomarkers for Niemann-Pick C1 Disease

Abstract: Niemann-Pick type C1 (NPC1) disease is a rare progressive neurodegenerative disorder characterized by accumulation of cholesterol in the endolysosomes. Previous studies implicating oxidative stress in NPC1 disease pathogenesis raised the possibility that nonenzymatic formation of cholesterol oxidation products could serve as disease biomarkers. We measured these metabolites in the plasma and tissues of the Npc1 −/− mouse model and found several cholesterol oxidation products that were elevated in Npc1 −/− mice, were detectable before the onset of symptoms, and were associated with disease progression. Nonenzymatically formed cholesterol oxidation products were similarly increased in the plasma of all human NPC1 subjects studied and delineated an oxysterol profile specific for NPC1 disease. This oxysterol profile also correlated with the age of disease onset and disease severity. We further show that the plasma oxysterol markers decreased in response to an established therapeutic intervention in the NPC1 feline model. These cholesterol oxidation products are robust blood-based biochemical markers for NPC1 disease that may prove transformative for diagnosis and treatment of this disorder, and as outcome measures to monitor response to therapy.

Evaluation of noncontrast MR enterography for pediatric inflammatory bowel disease assessment.

Abstract: BACKGROUND Gadolinium deposition in normal tissues is being increasingly recognized. Children with inflammatory bowel disease (IBD) undergo frequent imaging with contrast-enhanced MR enterography (MRE). PURPOSE To determine the impact of intravenous (IV) gadolinium in assessment of pediatric IBD by MRE. STUDY TYPE Retrospective, case series. POPULATION Radiology information system was searched to identify all children who underwent MRE and endoscopy within 30 days in 2016. FIELD STRENGTH/SEQUENCE 1.5T and 3T. ASSESSMENT Imaging studies were evaluated for bowel inflammation interpreted by two blinded radiologists in two sessions 6 weeks apart (session 1 pre-MRE; session 2 pre/postcontrast-MRE). Endoscopic histology was the reference standard. STATISTICAL TESTS A logistic regression model was evaluated using receiver operating characteristics curves and expressed by c-statistics. Agreement between readers was evaluated using Cohen's or weighted kappa statistic, as appropriate. Two-sided P < 0.05 was considered statistically significant. Descriptive statistics were used for assessment of IBD complications. RESULTS In all, 52 children (46% female), mean age 13.2 (SD 3.42) years formed the study cohort. 77% (40/52) had inflammation on endoscopic biopsy. Pre/post-MRE showed no significant increase in the c-statistic compared to pre-MRE for assessment of small bowel (Reader 1 P = 0.56, Reader 2 P = 1.00) or large bowel inflammation (Reader 1 P = 0.42, Reader 2 P = 1.00)). Intravenous contrast showed no improvement in interobserver agreement for assessment of inflammation in small (kappa 0.92 pre-MRE, 0.88 pre/post-MRE) or large bowel (kappa 0.83 pre-MRE, 0.73 pre/post-MRE). IV contrast had no meaningful impact on interobserver agreement for length of small bowel inflamed (intraclass correlation coefficient 0.90 pre-MRE, 0.95 pre/post-MRE). Assessment of IBD complications was improved with IV contrast, with 3/5 cases with perianal penetrating disease not recognized on pre-MRE. DATA CONCLUSION Routine administration of IV gadolinium has no impact on the assessment of bowel inflammation. However, there is potential for missing perianal complications using a noncontrast MRE protocol without dedicated pelvic imaging. LEVEL OF EVIDENCE 3 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2018;48:341-348.

Niemann-Pick disease type C

Abstract: Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations.