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Abstract Introduction This study assessed apolipoprotein E ( APOE ) ε4 carrier status effects on Alzheimer's disease imaging and cerebrospinal fluid (CSF) biomarkers in cognitively normal older adults with significant memory concerns (SMC). Methods Cognitively normal, SMC, and early mild cognitive impairment participants from Alzheimer's Disease Neuroimaging Initiative were divided by APOE ε4 carrier status. Diagnostic and APOE effects were evaluated with emphasis on SMC. Additional analyses in SMC evaluated the effect of the interaction between APOE and [ 18 F]Florbetapir amyloid positivity on CSF biomarkers. Results SMC ε4+ showed greater amyloid deposition than SMC ε4−, but no hypometabolism or medial temporal lobe (MTL) atrophy. SMC ε4+ showed lower amyloid beta 1–42 and higher tau/p‐tau than ε4−, which was most abnormal in APOE ε4+ and cerebral amyloid positive SMC. Discussion SMC APOE ε4+ show abnormal changes in amyloid and tau biomarkers, but no hypometabolism or MTL neurodegeneration, reflecting the at‐risk nature of the SMC group and the importance of APOE in mediating this risk.

PurposeQuantification of tissue stiffness may facilitate identification of abnormalities in orofacial muscle tone and thus contribute to differential diagnosis of dysarthria. Tissue stiffness is affected by muscle tone as well as age-related changes in muscle and connective tissue.MethodThe Myoton-3 measured tissue stiffness in 40 healthy adults, including equal numbers of men and women in each of two age groups: 18–40 years and 60+ years. Data were collected from relaxed muscles at the masseter, cheek, and lateral tongue surfaces in two positions: reclined on the side and seated with head tilted.ResultsTissue stiffness differed across age, sex, and measurement site with multiple interaction effects. Overall, older subjects exhibited higher stiffness coefficients and oscillation frequency measures than younger subjects whereas sex differences varied by tissue site. Effects of body position were inconsistent across tissue site and measurement.ConclusionsAlthough older subjects were expected to have lower muscle tone, age-related nonmuscular tissue changes may have contributed to yield a net effect of higher stiffness. These data raise several considerations for the development of accurate normative data and for future diagnostic applications of tissue stiffness assessment.

AbstractTwo recently developed fine-mapping methods, CAVIAR and PAINTOR, demonstrate better performance over other fine-mapping methods. They also have the advantage of using only the marginal test statistics and the correlation among SNPs. Both methods leverage the fact that the marginal test statistics asymptotically follow a multivariate normal distribution and are likelihood based. However, their relationship with Bayesian fine mapping, such as BIMBAM, is not clear. In this study, we first show that CAVIAR and BIMBAM are actually approximately equivalent to each other. This leads to a fine-mapping method using marginal test statistics in the Bayesian framework, which we call CAVIAR Bayes factor (CAVIARBF). Another advantage of the Bayesian framework is that it can answer both association and fine-mapping questions. We also used simulations to compare CAVIARBF with other methods under different numbers of causal variants. The results showed that both CAVIARBF and BIMBAM have better performance than PAINTOR and other methods. Compared to BIMBAM, CAVIARBF has the advantage of using only marginal test statistics and takes about one-quarter to one-fifth of the running time. We applied different methods on two independent cohorts of the same phenotype. Results showed that CAVIARBF, BIMBAM, and PAINTOR selected the same top 3 SNPs; however, CAVIARBF and BIMBAM had better consistency in selecting the top 10 ranked SNPs between the two cohorts. Software is available at https://bitbucket.org/Wenan/caviarbf.

ObjectiveTo describe the effects of percutaneously implanted valve‐in‐valve in the tricuspid position for patients with pre‐existing transvalvular device leads.MethodsIn this case series, we describe implantation of the Melody valve and SAPIEN XT valve within dysfunctional bioprosthetic tricuspid valves in three patients with transvalvular device leads.ResultsIn all cases, the valve was successfully deployed and device lead function remained unchanged. In 1/3 cases with 6‐month follow‐up, device lead parameters remain unchanged and transcatheter valve‐in‐valve function remains satisfactory.ConclusionsTranscatheter tricuspid valve‐in‐valve is feasible in patients with pre‐existing transvalvular devices leads. Further study is required to determine the long‐term clinical implications of this treatment approach. © 2015 Wiley Periodicals, Inc.

Abstract The BBB can critically limit the delivery of several molecularly-targeted agents into the brain. The discovery of focal BRAF mutations in melanoma has stimulated the development of specific BRAF inhibitors. MEK is downstream of BRAF in the MAPK pathway, and has been targeted for combination therapy with BRAF inhibition. Trametinib is a MEK1/2 inhibitor that has improved survival in combination with dabrafenib in clinical trials for metastatic melanoma. We have recently shown that BRAF inhibitors (vemurafenib and dabrafenib) have limited brain distribution due to active efflux at the blood-brain barrier (BBB). Melanoma metastasizes to the brain and effective treatments require adequate CNS exposure of all drugs used in combination therapy. The study purpose was to investigate mechanisms that influence the CNS distribution of trametinib, particularly focusing on the active efflux transport proteins P-gp and Bcrp in the BBB. Intracellular accumulation and bidirectional flux studies were conducted in polarized MDCKII cells that overexpress human P-gp (MDR1) or murine Bcrp (Bcrp1). The brain and plasma AUCs of trametinib were determined after an intravenous dose of 5 mg/kg in WT, Mdr1a/b (-/-), Bcrp1 (-/-) and Mdr1a/b (-/-) Bcrp1 (-/-) (TKO) mice. The steady-state brain distribution of trametinib was determined using osmotic pumps in WT and Mdr1a/b (-/-) (P-gp KO), Bcrp1 (-/-) (Bcrp KO), and Mdr1a/b (-/-) Bcrp1 (-/-) (TKO) mice. The steady-state brain distribution of a combination of trametinib and dabrafenib were determined in WT and TKO mice. IC50s were determined in patient-derived melanoma cell lines (WT and V600E mutant) using the MTT assay. Intracellular accumulation of trametinib was 45% lower in the MDCKII-MDR1 cells and 81% lower in the MDCKII-Bcrp1 cells as compared to WT. Trametinib permeability was ∼ 2.5 and 3.7-fold greater in the basolateral-to-apical direction as compared to apical-to-basolateral direction in the MDR1 and Bcrp1 cells, respectively. Following a single intravenous dose, the brain-to-plasma AUC ratios were approximately 5-fold greater in P-gp KO and TKO mice as compared to the WT. Interestingly, the brain distribution of trametinib in Bcrp KO mice was no different from WT mice. The steady-state brain to plasma (B/P) ratio of trametinib was 5-fold greater in the TKO mice when compared to the wild-type mice. The B/P ratio of both dabrafenib and trametinib were significantly greater in the TKO mice as compared to WT when dosed simultaneously. The IC50 for trametinib alone was > 10 μM in both the WT (M15) and V600E (M12) mutant cells, while a combination of dabrafenib and trametinib had an IC50 of 2.04 μM in the M12 cells. This study shows that P-gp and BCRP restrict the brain distribution of trametinib with P-gp playing a dominant role in the efflux of trametinib at the blood-brain barrier. These findings are clinically relevant to the efficacy of trametinib in mono or combination therapy for the treatment of melanoma brain metastases. Citation Format: Shruthi Vaidhyanathan, Rajendar K. Mittapalli, Daniel J. Ma, Mark A. Schroeder, Jann N. Sarkaria, William F. Elmquist. Trametinib (Mekinist TM) has limited brain distribution in the mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3714. doi:10.1158/1538-7445.AM2014-3714