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1.  Predicting a Multi-Parametric Probability Map of Active Tumor Extent Using Random Forests* 
Glioblastoma Mulitforme is highly infiltrative, making precise delineation of tumor margin difficult. Multimodality or multi-parametric MR imaging sequences promise an advantage over anatomic sequences such as post contrast enhancement as methods for determining the spatial extent of tumor involvement. In considering multi-parametric imaging sequences however, manual image segmentation and classification is time-consuming and prone to error. As a preliminary step toward integration of multi-parametric imaging into clinical assessments of primary brain tumors, we propose a machine-learning based multi-parametric approach that uses radiologist generated labels to train a classifier that is able to classify tissue on a voxel-wise basis and automatically generate a tumor segmentation. A random forests classifier was trained using a leave-one-out experimental paradigm. A simple linear classifier was also trained for comparison. The random forests classifier accurately predicted radiologist generated segmentations and tumor extent.
doi:10.1109/EMBC.2013.6611038
PMCID: PMC4257782  PMID: 24111225
2.  Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease 
JAMA neurology  2014;71(9):1111-1122.
Importance
Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in three specific genes, in contrast to late-onset Alzheimer Disease (LOAD), which has a more polygenetic risk profile.
Design, Setting, and Participants
We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of ADAD (N=79) and LOAD (N=444) human participants using resting state functional connectivity MRI (rs-fcMRI) at multiple international academic sites.
Main Outcomes and Measures
For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity as measured by clinical dementia rating (CDR). In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within five RSNs.
Results
Functional connectivity decreases with increasing CDR were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in each type of AD accurately predicted CDR stage in the other, further demonstrating similarity of functional connectivity loss in each disease type. Among ADAD participants, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared to asymptomatic mutation non-carriers.
Conclusions and Relevance
rs-fcMRI changes with progressing AD severity are similar between ADAD and LOAD. Rs-fcMRI may be a useful endpoint for LOAD and ADAD therapy trials. ADAD disease process may be an effective model for LOAD disease process.
doi:10.1001/jamaneurol.2014.1654
PMCID: PMC4240274  PMID: 25069482
Resting-state functional connectivity; autosomal dominant Alzheimer's disease; late-onset Alzheimer's disease; default mode network; apolipoprotein E (APOE)
3.  Human Connectome Project Informatics: quality control, database services, and data visualization 
NeuroImage  2013;80:10.1016/j.neuroimage.2013.05.077.
The Human Connectome Project (HCP) has developed protocols, standard operating and quality control procedures, and a suite of informatics tools to enable high throughput data collection, data sharing, automated data processing and analysis, and data mining and visualization. Quality control procedures include methods to maintain data collection consistency over time, to measure head motion, and to establish quantitative modality-specific overall quality assessments. Database services developed as customizations of the XNAT imaging informatics platform support both internal daily operations and open access data sharing. The Connectome Workbench visualization environment enables user interaction with HCP data and is increasingly integrated with the HCP's database services. Here we describe the current state of these procedures and tools and their application in the ongoing HCP study.
doi:10.1016/j.neuroimage.2013.05.077
PMCID: PMC3845379  PMID: 23707591
4.  Targeted Ablation of Connexin26 in the Inner Ear Epithelial Gap Junction Network Causes Hearing Impairment and Cell Death 
Current biology : CB  2002;12(13):1106-1111.
Summary
Mutations in the gene encoding the gap junction protein connexin26 (Cx26) are responsible for the autosomal recessive isolated deafness, DFNB1, which accounts for half of the cases of prelingual profound hereditary deafness in Caucasian populations [1–5]. To date, in vivo approaches to decipher the role of Cx26 in the inner ear have been hampered by the embryonic lethality of the Cx26 knockout mice [6]. To overcome this difficulty, we performed targeted ablation of Cx26 specifically in one of the two cellular networks that it underlies in the inner ear, namely, the epithelial network. We show that homozygous mutant mice, Cx26OtogCre, have hearing impairment, but no vestibular dysfunction. The inner ear developed normally. However, on postnatal day 14 (P14), i.e., soon after the onset of hearing, cell death appeared and eventually extended to the cochlear epithelial network and sensory hair cells. Cell death initially affected only the supporting cells of the genuine sensory cell (inner hair cell, IHC), thus suggesting that it could be triggered by the IHC response to sound stimulation. Altogether, our results demonstrate that the Cx26-containing epithelial gap junction network is essential for cochlear function and cell survival. We conclude that prevention of cell death in the sensory epithelium is essential for any attempt to restore the auditory function in DFNB1 patients.
PMCID: PMC4030438  PMID: 12121617
5.  Slc26a7 Chloride Channel Activity and Localization in Mouse Reissner’s Membrane Epithelium 
PLoS ONE  2014;9(5):e97191.
Several members of the SLC26 gene family have highly-restricted expression patterns in the auditory and vestibular periphery and mutations in mice of at least two of these (SLC26A4 and SLC26A5) lead to deficits in hearing and/or balance. A previous report pointed to SLC26A7 as a candidate gene important for cochlear function. In the present study, inner ears were assayed by immunostaining for Slc26a7 in neonatal and adult mice. Slc26a7 was detected in the basolateral membrane of Reissner’s membrane epithelial cells but not neighboring cells, with an onset of expression at P5; gene knockout resulted in the absence of protein expression in Reissner’s membrane. Whole-cell patch clamp recordings revealed anion currents and conductances that were elevated for NO3− over Cl− and inhibited by I− and NPPB. Elevated NO3− currents were absent in Slc26a7 knockout mice. There were, however, no major changes to hearing (auditory brainstem response) of knockout mice during early adult life under constitutive and noise exposure conditions. The lack of Slc26a7 protein expression found in the wild-type vestibular labyrinth was consistent with the observation of normal balance. We conclude that SLC26A7 participates in Cl− transport in Reissner’s membrane epithelial cells, but that either other anion pathways, such as ClC-2, possibly substitute satisfactorily under the conditions tested or that Cl− conductance in these cells is not critical to cochlear function. The involvement of SLC26A7 in cellular pH regulation in other epithelial cells leaves open the possibility that SLC26A7 is needed in Reissner’s membrane cells during local perturbations of pH.
doi:10.1371/journal.pone.0097191
PMCID: PMC4014619  PMID: 24810589
6.  Impaired default network functional connectivity in autosomal dominant Alzheimer disease 
Neurology  2013;81(8):736-744.
Objective:
To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network.
Methods:
Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO).
Results:
We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO.
Conclusion:
Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.
doi:10.1212/WNL.0b013e3182a1aafe
PMCID: PMC3776464  PMID: 23884042
7.  Obscuring Surface Anatomy in Volumetric Imaging Data 
Neuroinformatics  2013;11(1):65-75.
The identifying or sensitive anatomical features in MR and CT images used in research raise patient privacy concerns when such data are shared. In order to protect human subject privacy, we developed a method of anatomical surface modification and investigated the effects of such modification on image statistics and common neuroimaging processing tools. Common approaches to obscuring facial features typically remove large portions of the voxels. The approach described here focuses on blurring the anatomical surface instead, to avoid impinging on areas of interest and hard edges that can confuse processing tools. The algorithm proceeds by extracting a thin boundary layer containing surface anatomy from a region of interest. This layer is then “stretched” and “flattened” to fit into a thin “box” volume. After smoothing along a plane roughly parallel to anatomy surface, this volume is transformed back onto the boundary layer of the original data. The above method, named normalized anterior filtering, was coded in MATLAB and applied on a number of high resolution MR and CT scans. To test its effect on automated tools, we compared the output of selected common skull stripping and MR gain field correction methods used on unmodified and obscured data. With this paper, we hope to improve the understanding of the effect of surface deformation approaches on the quality of de-identified data and to provide a useful de-identification tool for MR and CT acquisitions.
doi:10.1007/s12021-012-9160-3
PMCID: PMC3538950  PMID: 22968671
Biomedical imaging; Facial recognition; MR imaging; CT imaging; Privacy; 3D
8.  Data dictionary services in XNAT and the Human Connectome Project 
The XNAT informatics platform is an open source data management tool used by biomedical imaging researchers around the world. An important feature of XNAT is its highly extensible architecture: users of XNAT can add new data types to the system to capture the imaging and phenotypic data generated in their studies. Until recently, XNAT has had limited capacity to broadcast the meaning of these data extensions to users, other XNAT installations, and other software. We have implemented a data dictionary service for XNAT, which is currently being used on ConnectomeDB, the Human Connectome Project (HCP) public data sharing website. The data dictionary service provides a framework to define key relationships between data elements and structures across the XNAT installation. This includes not just core data representing medical imaging data or subject or patient evaluations, but also taxonomical structures, security relationships, subject groups, and research protocols. The data dictionary allows users to define metadata for data structures and their properties, such as value types (e.g., textual, integers, floats) and valid value templates, ranges, or field lists. The service provides compatibility and integration with other research data management services by enabling easy migration of XNAT data to standards-based formats such as the Resource Description Framework (RDF), JavaScript Object Notation (JSON), and Extensible Markup Language (XML). It also facilitates the conversion of XNAT's native data schema into standard neuroimaging vocabularies and structures.
doi:10.3389/fninf.2014.00065
PMCID: PMC4080781  PMID: 25071542
XNAT; ontologies; translations; publishing; human connectome; human computer interaction
10.  XCEDE: An Extensible Schema For Biomedical Data 
Neuroinformatics  2012;10(1):10.1007/s12021-011-9119-9.
The XCEDE (XML-based Clinical and Experimental Data Exchange) XML schema, developed by members of the BIRN (Biomedical Informatics Research Network), provides an extensive metadata hierarchy for storing, describing and documenting the data generated by scientific studies. Currently at version 2.0, the XCEDE schema serves as a specification for the exchange of scientific data between databases, analysis tools, and web services. It provides a structured metadata hierarchy, storing information relevant to various aspects of an experiment (project, subject, protocol, etc.). Each hierarchy level also provides for the storage of data provenance information allowing for a traceable record of processing and/or changes to the underlying data. The schema is extensible to support the needs of various data modalities and to express types of data not originally envisioned by the developers. The latest version of the XCEDE schema and manual are available from http://www.xcede.org/
doi:10.1007/s12021-011-9119-9
PMCID: PMC3836560  PMID: 21479735
XML; Schema; Database; Biomedical Technology
11.  Quantitative Analysis of PiB-PET with FreeSurfer ROIs 
PLoS ONE  2013;8(11):e73377.
In vivo quantification of β-amyloid deposition using positron emission tomography is emerging as an important procedure for the early diagnosis of the Alzheimer's disease and is likely to play an important role in upcoming clinical trials of disease modifying agents. However, many groups use manually defined regions, which are non-standard across imaging centers. Analyses often are limited to a handful of regions because of the labor-intensive nature of manual region drawing. In this study, we developed an automatic image quantification protocol based on FreeSurfer, an automated whole brain segmentation tool, for quantitative analysis of amyloid images. Standard manual tracing and FreeSurfer-based analyses were performed in 77 participants including 67 cognitively normal individuals and 10 individuals with early Alzheimer's disease. The manual and FreeSurfer approaches yielded nearly identical estimates of amyloid burden (intraclass correlation = 0.98) as assessed by the mean cortical binding potential. An MRI test-retest study demonstrated excellent reliability of FreeSurfer based regional amyloid burden measurements. The FreeSurfer-based analysis also revealed that the majority of cerebral cortical regions accumulate amyloid in parallel, with slope of accumulation being the primary difference between regions.
doi:10.1371/journal.pone.0073377
PMCID: PMC3819320  PMID: 24223109
12.  The pattern of atrophy in familial Alzheimer disease 
Neurology  2013;81(16):1425-1433.
Objective:
To assess regional patterns of gray and white matter atrophy in familial Alzheimer disease (FAD) mutation carriers.
Methods:
A total of 192 participants with volumetric T1-weighted MRI, genotyping, and clinical diagnosis were available from the Dominantly Inherited Alzheimer Network. Of these, 69 were presymptomatic mutation carriers, 50 were symptomatic carriers (31 with Clinical Dementia Rating [CDR] = 0.5, 19 with CDR > 0.5), and 73 were noncarriers from the same families. Voxel-based morphometry was used to identify cross-sectional group differences in gray matter and white matter volume.
Results:
Significant differences in gray matter (p < 0.05, family-wise error–corrected) were observed between noncarriers and mildly symptomatic (CDR = 0.5) carriers in the thalamus and putamen, as well as in the temporal lobe, precuneus, and cingulate gyrus; the same pattern, but with more extensive changes, was seen in those with CDR > 0.5. Significant white matter differences between noncarriers and symptomatic carriers were observed in the cingulum and fornix; these form input and output connections to the medial temporal lobe, cingulate, and precuneus. No differences between noncarriers and presymptomatic carriers survived correction for multiple comparisons, but there was a trend for decreased gray matter in the thalamus for carriers closer to their estimated age at onset. There were no significant increases of gray or white matter in asymptomatic or symptomatic carriers compared to noncarriers.
Conclusions:
Atrophy in FAD is observed early, both in areas commonly associated with sporadic Alzheimer disease and also in the putamen and thalamus, 2 regions associated with early amyloid deposition in FAD mutation carriers.
doi:10.1212/WNL.0b013e3182a841c6
PMCID: PMC3806583  PMID: 24049139
13.  DicomBrowser: Software for Viewing and Modifying DICOM Metadata 
Journal of Digital Imaging  2012;25(5):635-645.
Digital Imaging and Communications in Medicine (DICOM) is the dominant standard for medical imaging data. DICOM-compliant devices and the data they produce are generally designed for clinical use and often do not match the needs of users in research or clinical trial settings. DicomBrowser is software designed to ease the transition between clinically oriented DICOM tools and the specialized workflows of research imaging. It supports interactive loading and viewing of DICOM images and metadata across multiple studies and provides a rich and flexible system for modifying DICOM metadata. Users can make ad hoc changes in a graphical user interface, write metadata modification scripts for batch operations, use partly automated methods that guide users to modify specific attributes, or combine any of these approaches. DicomBrowser can save modified objects as local files or send them to a DICOM storage service using the C-STORE network protocol. DicomBrowser is open-source software, available for download at http://nrg.wustl.edu/software/dicom-browser.
doi:10.1007/s10278-012-9462-x
PMCID: PMC3447088  PMID: 22349992
Digital imaging and communications in medicine (DICOM); Workflow; Image viewer; Imaging informatics
14.  Imaging Infrastructure for Research. Part 2. Data Management Practices 
Journal of Digital Imaging  2012;25(5):566-569.
In part one of this series, best practices were described for acquiring and handling data at study sites and importing them into an image repository or database. Here, we present a similar treatment on data management practices for imaging-based studies.
doi:10.1007/s10278-012-9502-6
PMCID: PMC3447091  PMID: 22710986
Clinical trials; Research image database
15.  Developing an international network for Alzheimer research: The Dominantly Inherited Alzheimer Network 
Clinical investigation  2012;2(10):975-984.
The Dominantly Inherited Alzheimer Network (DIAN) is a collaborative effort of international Alzheimer disease (AD) centers that are conducting a multifaceted prospective biomarker study in individuals at-risk for autosomal dominant AD (ADAD). DIAN collects comprehensive information and tissue in accordance with standard protocols from asymptomatic and symptomatic ADAD mutation carriers and their non-carrier family members to determine the pathochronology of clinical, cognitive, neuroimaging, and fluid biomarkers of AD. This article describes the structure, implementation, and underlying principles of DIAN, as well as the demographic features of the initial DIAN cohort.
doi:10.4155/cli.12.93
PMCID: PMC3489185  PMID: 23139856
Alzheimer disease; autosomal dominant; biomarkers of Alzheimer disease; PSEN1; PSEN2; APP; amyloid-beta; preclinical Alzheimer disease
16.  Whitepapers on Imaging Infrastructure for Research 
Journal of Digital Imaging  2012;25(4):449-453.
doi:10.1007/s10278-012-9490-6
PMCID: PMC3389084  PMID: 22644338
17.  SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice 
PLoS Genetics  2013;9(7):e1003641.
Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the vestibular labyrinth and the endolymphatic sac. Slc26a4Δ/Δ mice are devoid of pendrin and develop a severe enlargement of the membranous labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4Δ/Δ line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the vestibular labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy will restore normal hearing in human patients carrying a variety of mutations of SLC26A4.
Author Summary
Mutations of SLC26A4 are the most common cause for hearing loss associated with a swelling of the inner ear. This human disease is largely recapitulated in a mutant mouse model. Mutant mice lack Slc26a4 expression and their inner ears swell during embryonic development, which leads to failure of the cochlea and the vestibular organs resulting in deafness and loss of balance. SLC26A4 is normally found in the cochlea and vestibular organs of the inner ear as well as in the endolymphatic sac, which is a non-sensory part of the inner ear. The multitude of sites where SLC26A4 is located made the goal to restore function through restoration look futile, unless some sites were more important than others. Here, we generated a new mutant mouse that expresses SLC26A4 in the endolymphatic sac but not in the cochlea or the vestibular organs of the inner ear. Fantastically, this mouse did not develop the detrimental swelling of the inner ear and even more exciting, the mouse developed normal hearing and balance. Our study provides the proof-of-concept that a therapy aimed at repairing the endolymphatic sac during embryonic development is sufficient to restore a life-time of normal hearing and balance.
doi:10.1371/journal.pgen.1003641
PMCID: PMC3708829  PMID: 23874234
18.  Endolymphatic Na+ and K+ Concentrations during Cochlear Growth and Enlargement in Mice Lacking Slc26a4/pendrin 
PLoS ONE  2013;8(5):e65977.
Slc26a4Δ/Δ mice are deaf, develop an enlarged membranous labyrinth, and thereby largely resemble the human phenotype where mutations of SLC26A4 cause an enlarged vestibular aqueduct and sensorineural hearing loss. The enlargement is likely caused by abnormal ion and fluid transport during the time of embryonic development, however, neither the mechanisms of ion transport nor the ionic composition of the luminal fluid during this time of development are known. Here we determine the ionic composition of inner ear fluids at the time at which the enlargement develops and the onset of expression of selected ion transporters. Concentrations of Na+ and K+ were measured with double-barreled ion-selective electrodes in the cochlea and the endolymphatic sac of Slc26a4Δ/+, which develop normal hearing, and of Slc26a4Δ/Δ mice, which fail to develop hearing. The expression of specific ion transporters was examined by quantitative RT-PCR and immunohistochemistry. High Na+ (∼141 mM) and low K+ concentrations (∼11 mM) were found at embryonic day (E) 16.5 in cochlear endolymph of Slc26a4Δ/+ and Slc26a4Δ/Δ mice. Shortly before birth the K+ concentration began to rise. Immediately after birth (postnatal day 0), the Na+ and K+ concentrations in cochlear endolymph were each ∼80 mM. In Slc26a4Δ/Δ mice, the rise in the K+ concentration occurred with a ∼3 day delay. K+ concentrations were also found to be low (∼15 mM) in the embryonic endolymphatic sac. The onset of expression of the K+ channel KCNQ1 and the Na+/2Cl−/K+ cotransporter SLC12A2 occurred in the cochlea at E19.5 in Slc26a4Δ/+ and Slc26a4Δ/Δ mice. These data demonstrate that endolymph, at the time at which the enlargement develops, is a Na+-rich fluid, which transitions into a K+-rich fluid before birth. The data suggest that the endolymphatic enlargement caused by a loss of Slc26a4 is a consequence of disrupted Na+ transport.
doi:10.1371/journal.pone.0065977
PMCID: PMC3669272  PMID: 23741519
19.  cAMP-stimulated Cl- secretion is increased by glucocorticoids and inhibited by bumetanide in semicircular canal duct epithelium 
BMC Physiology  2013;13:6.
Background
The vestibular system controls the ion composition of its luminal fluid through several epithelial cell transport mechanisms under hormonal regulation. The semicircular canal duct (SCCD) epithelium has been shown to secrete Cl- under β2-adrenergic stimulation. In the current study, we sought to determine the ion transporters involved in Cl- secretion and whether secretion is regulated by PKA and glucocorticoids.
Results
Short circuit current (Isc) from rat SCCD epithelia demonstrated stimulation by forskolin (EC50: 0.8 μM), 8-Br-cAMP (EC50: 180 μM), 8-pCPT-cAMP (100 μM), IBMX (250 μM), and RO-20-1724 (100 μM). The PKA activator N6-BNZ-cAMP (0.1, 0.3 & 1 mM) also stimulated Isc. Partial inhibition of stimulated Isc individually by bumetanide (10 & 50 μM), and [(dihydroindenyl)oxy]alkanoic acid (DIOA, 100 μM) were additive and complete. Stimulated Isc was also partially inhibited by CFTRinh-172 (5 & 30 μM), flufenamic acid (5 μM) and diphenylamine-2,2′-dicarboxylic acid (DPC; 1 mM). Native canals of CFTR+/− mice showed a stimulation of Isc from isoproterenol and forskolin+IBMX but not in the presence of both bumetanide and DIOA, while canals from CFTR−/− mice had no responses. Nonetheless, CFTR−/− mice showed no difference from CFTR+/− mice in their ability to balance (rota-rod). Stimulated Isc was greater after chronic incubation (24 hr) with the glucocorticoids dexamethasone (0.1 & 0.3 μM), prednisolone (0.3, 1 & 3 μM), hydrocortisone (0.01, 0.1 & 1 μM), and corticosterone (0.1 & 1 μM) and mineralocorticoid aldosterone (1 μM). Steroid action was blocked by mifepristone but not by spironolactone, indicating all the steroids activated the glucocorticoid, but not mineralocorticoid, receptor. Expression of transcripts for CFTR; for KCC1, KCC3a, KCC3b and KCC4, but not KCC2; for NKCC1 but not NKCC2 and for WNK1 but only very low WNK4 was determined.
Conclusions
These results are consistent with a model of Cl- secretion whereby Cl- is taken up across the basolateral membrane by a Na+-K+-2Cl- cotransporter (NKCC) and potentially another transporter, is secreted across the apical membrane via a Cl- channel, likely CFTR, and demonstrate the regulation of Cl- secretion by protein kinase A and glucocorticoids.
doi:10.1186/1472-6793-13-6
PMCID: PMC3622586  PMID: 23537040
Chloride secretion; Rat; Knockout mouse; Primary culture; Epithelium; Inner ear; Bumetanide; DIOA; Glucocorticoid; NKCC; KCC
20.  Clinical and Biomarker Changes in Dominantly Inherited Alzheimer’s Disease 
The New England journal of medicine  2012;367(9):795-804.
BACKGROUND
The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.
METHODS
In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes.
RESULTS
Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.
CONCLUSIONS
We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)
doi:10.1056/NEJMoa1202753
PMCID: PMC3474597  PMID: 22784036
21.  Northwestern University Schizophrenia Data and Software Tool (NUSDAST) 
The schizophrenia research community has invested substantial resources on collecting, managing and sharing large neuroimaging datasets. As part of this effort, our group has collected high resolution magnetic resonance (MR) datasets from individuals with schizophrenia, their non-psychotic siblings, healthy controls and their siblings. This effort has resulted in a growing resource, the Northwestern University Schizophrenia Data and Software Tool (NUSDAST), an NIH-funded data sharing project to stimulate new research. This resource resides on XNAT Central, and it contains neuroimaging (MR scans, landmarks and surface maps for deep subcortical structures, and FreeSurfer cortical parcellation and measurement data), cognitive (cognitive domain scores for crystallized intelligence, working memory, episodic memory, and executive function), clinical (demographic, sibling relationship, SAPS and SANS psychopathology), and genetic (20 polymorphisms) data, collected from more than 450 subjects, most with 2-year longitudinal follow-up. A neuroimaging mapping, analysis and visualization software tool, CAWorks, is also part of this resource. Moreover, in making our existing neuroimaging data along with the associated meta-data and computational tools publically accessible, we have established a web-based information retrieval portal that allows the user to efficiently search the collection. This research-ready dataset meaningfully combines neuroimaging data with other relevant information, and it can be used to help facilitate advancing neuroimaging research. It is our hope that this effort will help to overcome some of the commonly recognized technical barriers in advancing neuroimaging research such as lack of local organization and standard descriptions.
doi:10.3389/fninf.2013.00025
PMCID: PMC3819522  PMID: 24223551
data sharing; neuroimaging; schizophrenia; computational anatomy; cognitive data; meta data
22.  Regulation of Sodium Transport in the Inner Ear 
Hearing research  2011;280(1-2):21-29.
Na+ concentrations in endolymph must be controlled to maintain hair cell function since the transduction channels of hair cells are cation-permeable, but not K+-selective. Flooding or fluctuations of the hair cell cytosol with Na+ would be expected to lead to cellular dysfunction, hearing loss and vertigo. This review briefly describes cellular mechanisms known to be responsible for Na+homeostasis in each compartment of the inner ear, including the cochlea, saccule, semicircular canals and endolymphatic sac. The influx of Na+into endolymph of each of the organs is likely via passive diffusion, but these pathways have not yet been identified or characterized. Na+ absorption is controlled by gate -keeper channels in the apical (endolymphatic) membrane of the transporting cells. Highly Na+-selective epithelial sodium channels (ENaC) control absorption by Reissner’s membrane, saccular extramacular epithelium, semicircular canal duct epithelium and endolymphatic sac. ENaC activity is controlled by a number of signal pathways, but most notably by genomic regulation of channel numbers in the membrane via glucocorticoid signaling. Nonselective cation channels in the apical membrane of outer sulcus epithelial cells and vestibular transitional cells mediate Na+ and parasensory K+ absorption. The K+-mediated transduction current in hair cells is also accompanied by a Na+ flux since the transduction channels are nonselective cation channels. Cation absorption by all of these cells is regulated by extracellular ATP via apical nonselective cation channels (P2X receptors). The heterogeneous population of epithelial cells in the endolymphatic sac is thought to have multiple absorptive pathways for Na+ with regulatory pathways that include glucocorticoids and purinergic agonists.
doi:10.1016/j.heares.2011.05.003
PMCID: PMC3176991  PMID: 21620939
inner ear; sodium homeostasis; epithelial sodium channel; Meniere’s disease
23.  Cerebrospinal Fluid Biomarkers, Education, Brain Volume and Future Cognition 
Archives of neurology  2011;68(9):1145-1151.
Objective
To evaluate the combination of cerebrospinal fluid biomarkers of Aβ42, tau, and phosphorylated tau (ptau181) with education and normalized whole brain volume (nWBV) to predict incident cognitive impairment and test the cognitive/brain reserve hypothesis.
Design
Longitudinal cohort study.
Setting
Charles F. and Joanne Knight Alzheimer’s Disease Research Center of Washington University, St. Louis, Missouri.
Participants
Convenience sample of 197 participants aged 50 years and above, with normal cognition (Clinical Dementia Rating [CDR] of 0) at baseline, followed for a mean of 3.3 years.
Main outcome measure
Time to cognitive impairment (CDR ≥ 0.5).
Results
Three-factor interactions between the baseline biomarker values, education, and nWBV were found for Cox proportional hazards models testing tau (p=.03) and ptau (p=.008). Among those with lower tau values, nWBV (hazard ratio [HR]=.54, 95% confidence interval [CI]=.31–.91; p=.02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (p=.01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment among those with higher ptau values (p=.02). In models testing Aβ42, larger nWBV was associated with a slower time to cognitive impairment (HR=.84, 95%CI=.71–.99, p=.0348), but there was no effect of Aβ42 or education.
Conclusions
Among individuals with higher levels of CSF tau and ptau, but normal cognition at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.
doi:10.1001/archneurol.2011.192
PMCID: PMC3203689  PMID: 21911695
24.  Evidence for Purinergic Receptors in Vestibular Dark Cell and Strial Marginal Cell Epithelia of Gerbil 
Auditory neuroscience  1995;1(4):331-340.
Purinergic receptors have been found to modulate ion transport in several types of epithelial cells as well as excitable cells. It was of interest to determine whether vestibular dark cells and strial marginal cells contain purinergic receptors in either the apicalor basolateral membrane which modulate transepithelial ion transport. Vestibular dark cell and strial marginal cell epithelia were mounted in a micro-Ussing chamber for the measurement of the transepithelial voltage and resistance from which the equivalent short circuit current (Isc) was obtained. The apical and basolateral sides were independently perfused with adenosine and adenosine 5′-triphosphate (ATP). Adenosine (10−5 M) had no effect on Isc at either the apical or basolateral side of vestibular dark cells and strial marginal cells, suggesting either the absence of P1 receptors or the absence of coupling of P1 receptors to vectorial ion transport by these epithelia. Apical perfusion of ATP (10−8 to 10−4 M) caused a decrease in Isc of both vestibular dark cells and strial marginal cells. Apical perfusion of the nucleotides uridine 5′-triphosphate (UTP), 2-methylthioadenosine triphosphate (2-meS-ATP), adenosine 5′-O-(3-thiotriphosphate) (ATPγS) and α,β-methylene adenosine 5′-triphosphate (α,β-meth-ATP) caused qualitatively similar responses with different magnitudes of response. The sequence of the magnitude of response of each compound at 10−6 or 10−5 M was assessed from the fractional change of Isc. The sequence for vestibular dark cells was UTP = ATP = ATPγS ≫ 2-meS-ATP > α,β-meth-ATP, and for strial marginal cells it was UTP = ATP ≫ 2-meS-ATP, corresponding to the sequence for the P2U receptor. The effect of agonist on the apical membrane was reduced by the antagonist 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) but not cibacron blue or suramin. DIDS in the absence of exogenous purinergic agonist caused a sustained increase in Isc. The effect of ATP on the apical membrane was greater in the absence of divalent cations. Basolateral perfusion of ATP led to a biphasic response of Isc in vestibular dark cell and strial marginal cell epithelia, consisting of an initial rapid increase followed by a slower decrease. Perfusion of the perilymphatic surface of the stria vascularis (basal cell layer) with ATP had no acute effect on Isc. The initial increase of Isc in vestibular dark cell epithelium during basolateral perfusion had a sequence of 2-meS-ATP > ATP ≫ UTP = α,β-meth-ATP = ATPγS, corresponding to the sequence for the P2Y receptor. Subsequently, the agonists caused a sustained decrease in Isc with a sequence of ATPγS > 2-meS-ATP > ATP > UTP >α,β-meth-ATP. This sequence is most simply interpreted as the result of the coexistence of P2U and P2Y receptors in the basolateral membrane. Both the increase and decrease of Isc by ATP at the basolateral membrane were reduced by the antagonist suramin. These findings provide evidence for the regulation of transepithelial ion transport by P2U receptors in the apical membrane and by coexisting P2U and P2Y receptors in the basolateral membrane of K+-secretory epithelial cells in the inner ear and are consistent with the hypothesis that the apical receptors are part of an autocrine negative feedback system in these cells.
PMCID: PMC3348583  PMID: 22582019
P2U receptor; P2 agonists; adenosine; DIDS; cibacron blue; suramin; reactive blue 2
25.  IsK Channel in Strial Marginal Cells. Voltage-Dependence, Ion-Selectivity, Inhibition by 293B and Sensitivity to Clofilium 
Auditory neuroscience  1997;3(3):215-230.
Strial marginal cells (SMC) and vestibular dark cells (VDC) are known to secrete K+ into endolymph. Slowly-activating, voltage-dependent K+ channels (KCNQ1/KCNE1; IsK; min K) have been identified in the apical membrane of these cells. Several experimental maneuvers known to increase or decrease transepithelial K+ secretion have been found in VDC to change the current through these channels in the same ways. In both SMC and VDC the kinetics of activation and deactivation resemble those of the IsK channel exogenously expressed in Xenopus oocytes and endogenous to heart myocytes. The present study sought evidence that this current is indeed carried by IsK channels and that this current is the basis for transepithelial K+ secretion. Both on-cell macro-patch recordings of the apical membrane and perforated-patch whole-cell recordings were made on SMC from gerbil in order to measure macroscopic cell currents. The on-cell current was found to 1) be K+-selective, 2) have a cation permeability sequence of K+ ~ Rb+ > Cs+ >> Li+ = Na+, 3) be activated with a time constant of 1764 ± 413 ms by voltage steps from 0 to +40 mV, 4) be deactivated with a time constant of 324 ± 57 ms by voltage steps from 0 to -40 mV and 5) be reduced 84 ± 5% by bumetanide (10-5 M), an inhibitor of K+ secretion. The single-channel conductance of the apical currents in the homologous VDC was estimated by fluctuation analysis to be 1.6 pS. The potent inhibitor of IsK channels, chromanol 293B (10-5 M), reduced the whole-cell current in SMC by 72 ± 10 %. Clofilium (10-4 M), a putative IsK channel inhibitor known to have additional non-specific effects, led to a stimulation of both on-cell (by 598 ± 177%) and whole-cell (by 162 ± 18%) currents in gerbil SMC but to a decrease of whole-cell currents (by 39 ± 12%) in rat SMC. Taken together with other findings reviewed here, these results strongly argue that the slowly-activating, voltage-dependent conductance in the apical membrane of SMC is the IsK channel and provide additional evidence for the poor specificity of clofilium.
PMCID: PMC3348584  PMID: 22582020
K+ channel; perforated-patch whole-cell voltage clamp; fluctuation analysis; KCNQ1/KCNE1 K channel; gerbil; rat

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