Lipidomic Evaluation of Feline Neurologic Disease after AAV Gene Therapy

GM1 gangliosidosis is a fatal lysosomal disorder, for which there is no effective treatment. Adeno-associated virus (AAV) gene therapy in GM1 cats has resulted in a greater than 6-fold increase in lifespan, with many cats remaining alive at \u3e 5.7 years of age, with minimal clinical signs. Glycolipids are the principal storage product in GM1 gangliosidosis whose pathogenic mechanism is not completely understood. Targeted lipidomics analysis was performed to better define disease mechanisms and identify markers of disease progression for upcoming clinical trials in humans. 36 sphingolipids and subspecies associated with ganglioside biosynthesis were tested in the cerebrospinal fluid of untreated GM1 cats at a humane endpoint ( approximately 8 months), AAV-treated GM1 cats ( approximately 5 years old), and normal adult controls. In untreated GM1 cats, significant alterations were noted in 16 sphingolipid species, including gangliosides (GM1 and GM3), lactosylceramides, ceramides, sphingomyelins, monohexosylceramides, and sulfatides. Variable degrees of correction in many lipid metabolites reflected the efficacy of AAV gene therapy. Sphingolipid levels were highly predictive of neurologic disease progression, with 11 metabolites having a coefficient of determination (R(2)) \u3e 0.75. Also, a specific detergent additive significantly increased the recovery of certain lipid species in cerebrospinal fluid samples. This report demonstrates the methodology and utility of targeted lipidomics to examine the pathophysiology of lipid storage disorders

The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels

Mutations in the human progranulin gene resulting in protein haploinsufficiency cause frontotemporal lobar degeneration with TDP-43 inclusions. Although progress has been made in understanding the normal functions of progranulin and TDP-43, the molecular interactions between these proteins remain unclear. Progranulin is proteolytically processed into granulins, but the role of granulins in the pathogenesis of neurodegenerative disease is unknown. We used a Caenorhabditis elegans model of neuronal TDP-43 proteinopathy to specifically interrogate the contribution of granulins to the neurodegenerative process. Complete loss of the progranulin gene did not worsen TDP-43 toxicity, whereas progranulin heterozygosity did. Interestingly, expression of individual granulins alone had little effect on behavior. In contrast, when granulins were coexpressed with TDP-43, they exacerbated its toxicity in a variety of behaviors including motor coordination. These same granulins increased TDP-43 levels via a post-translational mechanism. We further found that in human neurodegenerative disease subjects, granulin fragments accumulated specifically in diseased regions of brain. To our knowledge, this is the first demonstration of a toxic role for granulin fragments in a neurodegenerative disease model. These studies suggest that presence of cleaved granulins, rather than or in addition to loss of full-length progranulin, may contribute to disease in TDP-43 proteinopathies

Gadolinium Chelate Contrast Material in Pregnancy: Fetal Biodistribution in the Nonhuman Primate

PURPOSE: To determine the extent to which gadolinium chelate is found in nonhuman primate fetal tissues and amniotic fluid at 19–45 hours after intravenous injection of a weight-appropriate maternal dose of the contrast agent gadoteridol. MATERIALS AND METHODS: Gravid Japanese macaques (n = 14) were maintained as approved by the institutional animal care and utilization committee. In the 3rd trimester of pregnancy, the macaques were injected with gadoteridol (0.1 mmol per kilogram of maternal weight). Fetuses were delivered by means of cesarean section within 24 hours of maternal injection (range, 19–21 hours; n = 11) or 45 hours after injection (n = 3). Gadolinium chelate levels in the placenta, fetal tissues, and amniotic fluid were obtained by using inductively coupled plasma mass spectrometry. The Wilcoxon rank sum test was used for quantitative comparisons. RESULTS: Gadoteridol was present in the fetoplacental circulation at much lower quantities than in the mother. At both time points, the distribution of gadolinium chelate in the fetus was comparable to that expected in an adult. The highest concentration of the injected dose (ID) was found in the fetal kidney (0.0161% ID per gram in the 19–21-hour group). The majority of the in utero gadolinium chelate was found in the amniotic fluid and the placenta (mean, 0.1361% ID per organ ± 0.076 [standard deviation] and 0.0939% ID per organ ± 0.0494, respectively). Data acquired 45 hours after injection showed a significant decrease in the gadolinium chelate concentration in amniotic fluid compared with that in the 19–21-hour group (from 0.0017% to 0.0007% ID per gram; P = .01). CONCLUSION: Amounts of gadolinium chelate in the fetal tissues and amniotic fluid were minimal compared with the maternal ID. This may impact future clinical studies on the safety of gadolinium contrast agent use in pregnancy. (©) RSNA, 201

Impact of prenatal exercise on both prenatal and postnatal anxiety and depressive symptoms: a systematic review and meta-analysis

Objective To examine the influence of prenatal exercise on depression and anxiety during pregnancy and the postpartum period. Design Systematic review with random effects meta-analysis and meta-regression. Data sources Online databases were searched up to 6 January 2017. Study eligibility criteria Studies of all designs were included (except case studies) if they were published in English, Spanish or French and contained information on the Population (pregnant women without contraindication to exercise), Intervention (subjective or objective measures of frequency, intensity, duration, volume or type of exercise), Comparator (no exercise or different frequency, intensity, duration, volume and type of exercise) and Outcome (prenatal or postnatal depression or anxiety). Results A total of 52 studies (n=131406) were included. Moderate\u27 quality evidence from randomised controlled trials (RCTs) revealed that exercise-only interventions, but not exercise+cointerventions, reduced the severity of prenatal depressive symptoms (13 RCTs, n=1076; standardised mean difference: -0.38, 95%CI -0.51 to -0.25, I-2=10%) and the odds of prenatal depression by 67% (5 RCTs, n=683; OR: 0.33, 95%CI 0.21 to 0.53, I-2=0%) compared with no exercise. Prenatal exercise did not alter the odds of postpartum depression or the severity of depressive symptoms, nor anxiety or anxiety symptoms during or following pregnancy. To achieve at least a moderate effect size in the reduction of the severity of prenatal depressive symptoms, pregnant women needed to accumulate at least 644 MET-min/week of exercise (eg, 150min of moderate intensity exercise, such as brisk walking, water aerobics, stationary cycling, resistance training). Summary/Conclusions Prenatal exercise reduced the odds and severity of prenatal depression