Citations

Abstract Background: Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism.Method: Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods.Results: Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules. Multivariate analysis with leave-one-out cross-validation allowed classification of samples as belonging to one of the two groups of mothers with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules.Conclusions: Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.

AbstractFirst‐degree relatives of patients diagnosed with schizophrenia (SZ‐FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First‐degree relatives of patients diagnosed with bipolar disorder (BD‐FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD‐FDRs are inconsistent. Here, we performed a meta‐analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ‐FDRs, 867 BD‐FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ‐FDRs showed a pattern of widespread thinner cortex, while BD‐FDRs had widespread larger cortical surface area. IQ was lower in SZ‐FDRs (d = −0.42,p = 3 × 10−5), with weak evidence of IQ reductions among BD‐FDRs (d = −0.23,p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group‐effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ‐FDRs and more pronounced effects in BD‐FDRs. To conclude, SZ‐FDRs and BD‐FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ‐FDRs and BD‐FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.

ABSTRACT Background There is only partial overlap in the genetic background of isolated rapid‐eye‐movement sleep behavior disorder (iRBD) and Parkinson's disease (PD). Objective To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD. Methods Ten genes, comprising the recessive genes PRKN , DJ‐1 (PARK7) , PINK1 , VPS13C , ATP13A2 , FBXO7 , and PLA2G6 and the dominant genes LRRK2 , GCH1 , and VPS35 , were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests. Results We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls. Conclusion Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society

Abstract This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P < 0.000001), constipation, (P < 0.000001) and age over 70 years (P = 0.0002). Combined features obtained from the generalized logistic regression achieved a hazard ratio of 5.71 (95% confidence interval 2.85–11.43). Bayesian classifier suggested that patients with higher Mini-Mental State Examination score and lower caudate SBR asymmetry were more likely to develop parkinsonism, while patients with the opposite pattern were more likely to develop dementia. This study shows that iRBD patients older than 70 with constipation and reduced nigro-putaminal dopaminergic function are at high risk of short-term phenoconversion to an overt synucleinopathy, providing an effective stratification approach for future neuroprotective trials. Moreover, we provide cut-off values for the significant predictors of phenoconversion to be used in single subjects.

Objective: Determine the radiological prevalence of popliteal artery entrapment (PAE) in subjects with anterior leg compartment chronic exertional compartment syndrome (CECS). Design: Retrospective review. Setting: Tertiary care center. Patients: Of 71 patients diagnosed with anterior leg compartment CECS using an in-scanner exercise-based magnetic resonance imaging (MRI), 64 also completed Fast Imaging Employing Steady-State Acquisition (FIESTA) imaging. Interventions: Electronic health records of patients diagnosed with anterior leg compartment CECS using an in-scanner exercise-based MRI between 2009 and 2018 were reviewed. Main Outcome Measures: Demographics, symptom laterality, and results of vascular work-up. Results: Magnetic resonance imaging was positive for PAE in 33 of 64 (51.6%). Vascular evaluation was performed in 30 of 33 (90.9%). Of these 30, ankle-brachial indices (ABIs) with PAE maneuvers were performed in 29 (96.7%) and positive in 25 (86.2%). Pre-exercise and post-exercise ABIs were performed in 29 (96.7%) and abnormal in 20 (69.0%). Thirteen arterial duplex ultrasounds were performed; 10 were consistent with PAE (76.9%). An MR angiogram was performed in 8 (26.7%) and consistent with PAE in all. One computed tomography angiogram (3.3%) was completed and was normal. Overall, one or more tests were positive for PAE in all 30 with vascular evaluation. Conclusions: The radiological prevalence of PAE and anterior leg CECS was 51.6%. All subjects with vascular studies (90.9%) had one or more tests confirming radiological PAE. These findings suggest that the coexistence of PAE and CECS is common, and the PAE protocol used has a high correlation with vascular studies.

Abstract Background: Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism.Method: Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods.Results: Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules. Multivariate analysis with leave-one-out cross-validation allowed classification of samples as belonging to one of the two groups of mothers with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules.Conclusions: Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.

Abstract Patients diagnosed with germline mutations in MMR genes (Lynch Syndrome, LS) have up to 70-80% lifetime risk of colorectal cancer. Therefore, this high-risk population has the potential to benefit from effective chemopreventive strategies. Naproxen is an NSAID widely used for pain treatment with an excellent safety profile that has demonstrated to be more efficacious preventing colorectal cancer compared to aspirin in vivo using an intestinal tissue-specific mouse model of LS (VC-Msh2-LoxP). The ‘Naproxen trial' was designed to evaluate the modulation of PGE2 levels in colorectal mucosa, evaluate safety and tolerability, and discover novel molecular pathways involved in the chemopreventive activity of naproxen in LS patients. Methods: Participants were randomized to naproxen 440 mg (HD), 220 mg (LD) and placebo by mouth daily for 6 months. Modulation of prostaglandin levels, number of adverse events (AEs) observed in each treatment arm and gene expression profiles by next-generation sequencing (mRNAseq) in normal colorectal mucosa of LS patients after 6 months of intervention were examined. Results: Eighty participants diagnosed with LS were randomized, 25 participants to HD, 27 to LD, and 28 to placebo. From these patients, 54 were considered evaluable per-protocol analysis: 16 in the HD group, 15 in the LD and 23 in placebo. The level of prostaglandin E2 in the colorectal mucosa decreased significantly after treatment with both LD and HD naproxen when compared to placebo (-91.2%±14.1, -93.6%±7.9, and 23.8%±108.4, P-value<0.001, respectively). Moreover, levels of PGE2 urinary metabolite (PGE-M) were significantly changed in both treatment groups when compared to placebo (-47.7%±56.9, -41.1%±40.5, 7.6%±94.3, P-Value<0.018). The intervention was well tolerated, no severe AEs related to treatment were reported, and the total number of AEs was not different across treatment arms. LD and HD naproxen promoted the activity of the immune system by activating different immune cell types without any effect on lymphoid cellularity and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Conclusions: Naproxen is a promising strategy for immune interception in LS that induces immune-modulation coupled with changes in the dynamics of the intestinal crypt. We have also discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. Citation Format: Laura Reyes Uribe, Wenhui Wu, Ozkan Gelincik, Prashant V. Bommi, Alejandro Francisco-Cruz, Luisa M. Solis, Patrick M. Lynch, Ramona Lim, Elena Stoffel, Priyanka Kanth, N. Jewel Samadder, Maureen E. Mork, Melissa W. Taggart, Ginger L. Milne, Lawrence J. Marnett, Lana Vornik, Diane D. Liu, Maria Revuelta, Kyle Chang, Y. Nancy You, Levy Kopelovich, Ignacio I. Wistuba, J. Jack Lee, Shizuko Sei, Robert H. Shoemaker, Eva Szabo, Ellen Richmond, Asad Umar, Marjorie Perloff, Powell H. Brown, Steven M. Lipkin, Eduardo Vilar. Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT111.

Abstract More Americans die every year of lung cancer than any other cancer. While the environmental risks for lung cancer are well understood, the genetic risk factors for this disease are not, even though it has been shown that lung cancer risk aggregates in families. Segregation analyses have confirmed the likelihood of rare, highly penetrant variants affecting lung cancer. Family studies offer a unique opportunity to identify such rare risk variants. We have previously identified a genome-wide significant risk locus for lung cancer using multipoint linkage analysis in highly aggregated lung cancer families. In this study, we performed targeted sequencing on this 6q23-6q27 region on 75 individuals from the 9 most strongly linked families. Parametric two-point linkage analysis using an autosomal dominant model with 10% penetrance for carriers and a 1% phenocopy rate and disease allele frequency of 1% was performed for each family. While we did not find any genome-wide significant results in any of the individual families, we did observe several interesting potential rare risk variants. First, we observed that the significant signal previously observed on 6q is recapitulated in these data but the location of the peak LOD is highly heterogeneous across families and it is likely that each family has a different risk gene. While most of the highest LOD scores were in noncoding variants, we did observe exonic variants with the highest LOD scores in two families (44 and 42). Both variants were rare, with a minor allele frequency (MAF) of approximately 1% and were in LPA and GPR126 respectively. Both these genes have been implicated somatically in lung cancer, however this is the first time that they have been implicated in the germline. While the other families have their highest LOD scores in noncoding variants, some of these genes are also good potential candidate genes including PARK2 (family 30), GRM1 (family 47), and PDE10A (family 102). All three genes have been implicated in lung cancer in some capacity, and this is the first time that GRM1 and PDE10A have been implicated as germline mutations. Again, all these variants are rare (MAF ⇐ 0.01) in the general population, which makes sense for a potential highly penetrant risk variant. In this study, we have elucidated that a previously identified risk locus on 6q25 is heterogeneous in the nine most strongly linked families, with different families appearing to be carrying different risk variants. Many of the top variants in each family are rare variants that are in good potential causal genes that have been identified for the first time here as germline risk variants for lung cancer. Further functional annotation is underway for these variants and some additional linkage analyses using other penetrance matrices may also be performed. Citation Format: Anthony M. Musolf, Claire L. Simpson, Bilal A. Moiz, Mariza de Andrade, Diptasri Mandal, Colette Gaba, Ping Yang, Ming You, Elena Y. Kupert, Marshall W. Anderson, Ann G. Schwartz, Susan M. Pinney, Christopher I. Amos, Joan E. Bailey-Wilson. Highly aggregated lung cancer families reveal a heterogeneous cause for a previous linkage signal on 6q [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 37.