Publications by authors named "Margaret Sutherland"

39 Publications

Current progress in systemic therapy for biliary tract cancers.

J Hepatobiliary Pancreat Sci 2021 Mar 18. Epub 2021 Mar 18.

Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada.

Background: Biliary tract cancers (BTCs) are heterogeneous cancers that include cancers of the bile duct and gallbladder. Although they are relatively uncommon, most patients with BTC are diagnosed at advanced-stage disease with high mortality rates. Recently, systemic therapy options for patients with BTC have evolved. This paper reviews recent advancements in systemic therapy and the results of key clinical trials in BTC.

Methods: A literature search in PubMed and Google Scholar was performed using keywords related to BTC and systemic therapy. Studies that were presented in major international cancer research conferences were also included.

Results: The evidence shows that adjuvant capecitabine has been associated with a lower relapse rate in early-stage BTC. In unselected patients with advanced BTC, combination chemotherapy is a standard treatment option. However, with a better understanding of the molecular profile of BTC, there has been a shift toward targeted agents in BTC that have shown promising responses. The evolving data also support the evolving role of immunotherapy in patients with deficient DNA mismatch repair or PD-L1-positive BTC.

Discussion: Systemic treatment options for BTC have improved. The future identification of new targets, novel compounds, and predictive markers is a key step toward the use of personalized medicine in BTC.
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http://dx.doi.org/10.1002/jhbp.939DOI Listing
March 2021

What Happens to the Worried Well? Follow-Up of Subjective Cognitive Impairment.

Can J Neurol Sci 2021 Mar 9:1-9. Epub 2021 Mar 9.

Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Background: Increasing concern around perceived neurocognitive decline is increasing the number of referrals to specialists and anxiety for patients. We aimed to explore the likelihood of the "worried well" experiencing neurocognitive decline and developing a neurological diagnosis.

Methods: A total of 166 "worried well" patients who attended the Rural and Remote Memory Clinic (RRMC) between 2004 and 2019 were included in this study. Demographic, health, social, and behavioral factors were measured at the initial visit. Mini-Mental State Examination (MMSE), Center for Epidemiologic Studies Depression Scale (CESD), and Functional Activities Questionnaire (FAQ) scores were measured and compared at initial assessment and at 1-year follow-up. MMSE scores over time were assessed with a mean follow-up of 2.95 years (SD 2.87).

Results: No statistically significant difference was seen in MMSE, CESD, or FAQ scores when comparing clinic day to 1-year follow-up, and no consistent pattern of MMSE score over time was seen. Of the 166 patients with subjective cognitive impairment (SCI) on initial assessment, 5 were diagnosed with Alzheimer's disease (AD) at 8.5, 3.5, 5, 3, and 1.75 years; 2 were diagnosed with MCI at 1 and 2 years; 1 was diagnosed with vascular cognitive impairment at 5 years; and 1 was diagnosed with frontotemporal dementia (FTD) at 0.5 years.

Conclusion: The likelihood of a patient with SCI developing a neurological diagnosis is reassuringly low (9/166), but not irrelevant. This, along with the benefits of early diagnosis and treatment for dementia, leads us to believe that patients with SCI should still be seen in follow-up at least at the 1-year mark.
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http://dx.doi.org/10.1017/cjn.2021.39DOI Listing
March 2021

Organs-on-a-Chip.

Adv Exp Med Biol 2020 ;1230:27-42

National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD, USA.

Organs-on-chips, also known as "tissue chips" or microphysiological systems (MPS), are bioengineered microsystems capable of recreating aspects of human organ physiology and function and are in vitro tools with multiple applications in drug discovery and development. The ability to recapitulate human and animal tissues in physiologically relevant three-dimensional, multi-cellular environments allows applications in the drug development field, including; (1) use in assessing the safety and toxicity testing of potential therapeutics during early-stage preclinical drug development; (2) confirmation of drug/therapeutic efficacy in vitro; and (3) disease modeling of human tissues to recapitulate pathophysiology within specific subpopulations and even individuals, thereby advancing precision medicine efforts. This chapter will discuss the development and evolution of three-dimensional organ models over the past decade, and some of the opportunities offered by MPS technology that are not available through current standard two-dimensional cell cultures, or three-dimensional organoid systems. This chapter will outline future avenues of research in the MPS field, how cutting-edge biotechnology advances are expanding the applications for these systems, and discuss the current and future potential and challenges remaining for the field to address.
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http://dx.doi.org/10.1007/978-3-030-36588-2_3DOI Listing
April 2020

Nonlinear Z-score modeling for improved detection of cognitive abnormality.

Alzheimers Dement (Amst) 2019 Dec 5;11:797-808. Epub 2019 Dec 5.

Mayo Clinic Rochester, Rochester, MN, USA.

Introduction: Conventional Z-scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these "adjusted" Z-scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z-scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency.

Methods: In this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance).

Results: Corrected Z-scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted-R.

Discussion: Nonlinearly corrected Z-scores with respect to age, sex, and education with age-varying residual standard deviation allow for improved detection of non-normative extreme cognitive scores.
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http://dx.doi.org/10.1016/j.dadm.2019.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911910PMC
December 2019

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies.

Lancet Neurol 2019 12;18(12):1091-1102

Department of Neurology, Baylor College of Medicine, Houston, TX, USA.

Background: Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease.

Methods: We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation.

Findings: Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10).

Interpretation: These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data.

Funding: The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).
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http://dx.doi.org/10.1016/S1474-4422(19)30320-5DOI Listing
December 2019

New directions in clinical trials for frontotemporal lobar degeneration: Methods and outcome measures.

Alzheimers Dement 2020 01 6;16(1):131-143. Epub 2020 Jan 6.

Department of Neurology, AbbVie, Chicago, IL, USA.

Introduction: Frontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed.

Methods: In March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD.

Results: Challenges exist for conducting clinical trials in FTLD. Two of the greatest challenges are (1) the heterogeneity of FTLD syndromes leading to difficulties in efficiently measuring treatment effects and (2) the rarity of FTLD disorders leading to recruitment challenges.

Discussion: New personalized endpoints that are clinically meaningful to individuals and their families should be developed. Personalized approaches to analyzing MRI data, development of new fluid biomarkers and wearable technologies will help to improve the power to detect treatment effects in FTLD clinical trials and enable new, clinical trial designs, possibly leveraged from the experience of oncology trials. A computational visualization and analysis platform that can support novel analyses of combined clinical, genetic, imaging, biomarker data with other novel modalities will be critical to the success of these endeavors.
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http://dx.doi.org/10.1016/j.jalz.2019.06.4956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949386PMC
January 2020

Motor phenotype classification in moderate to advanced PD in BioFIND study.

Parkinsonism Relat Disord 2019 08 23;65:178-183. Epub 2019 Jun 23.

Fresco Institute for Parkinson's and Movement Disorders, Department of Neurology, NYU Langone Health, New York, NY, USA. Electronic address:

Background: Three motor phenotypes have been described in PD: postural instability and gait difficulty (PIGD) dominant, tremor-dominant (TD), and indeterminate (IND) subtype. These phenotypes have been associated with different cognitive trajectories, motor outcomes, and biomarkers profiles. However, whether motor subtype classifications change with treatment and disease progression is not well established.

Methods: To evaluate motor subtype ratio changes, we used the chi-square test for the off and on state motor subtypes for 115 PD participants in the BioFIND study and used repeated-measures analyses to evaluate longitudinal changes in 162 PD participants with five-year follow-up in the PPMI study.

Results: PIGD and TD subtypes in moderate to advanced PD participants change with dopaminergic agents. For those who shifted subtypes, improvement in tremor accounted for the transition of 15 (25.4%) TD participants, while the lack of tremor improvement along with minimal changes in PIGD score resulted in changes for eight (19.0%) PIGD individuals. Analyses of PPMI data revealed that all three subgroups had a significant decrease in subtype ratio with disease progression and a significant decline in subtype ratio occurred only in the TD subgroup with dopaminergic agents. The impact of dopaminergic medication effect on subtype shift for each visit was also more notable with disease advancement.

Conclusions: Motor subtypes are not fixed but change with progression of the disease and with treatment. Improvement in tremor was the main contributor to motor phenotype transitions in the BioFIND cohort. A more stable classification system for subtypes based on underlying biological differences is desirable.
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http://dx.doi.org/10.1016/j.parkreldis.2019.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774826PMC
August 2019

Finding useful biomarkers for Parkinson's disease.

Sci Transl Med 2018 08;10(454)

Center for Advanced Parkinson's Disease Research and Precision Neurology Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

The recent advent of an "ecosystem" of shared biofluid sample biorepositories and data sets will focus biomarker efforts in Parkinson's disease, boosting the therapeutic development pipeline and enabling translation with real-world impact.
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http://dx.doi.org/10.1126/scitranslmed.aam6003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097233PMC
August 2018

Cerebrospinal fluid, plasma, and saliva in the BioFIND study: Relationships among biomarkers and Parkinson's disease Features.

Mov Disord 2018 02 4;33(2):282-288. Epub 2017 Dec 4.

Division of Movement Disorders, Department of Neurology, Columbia University Medical Center, New York, New York, USA.

Objective: Examine relationships among neurodegenerative biomarkers and PD motor and nonmotor symptoms.

Background: CSF alpha-synuclein is decreased in PD versus healthy controls, but whether plasma and saliva alpha-synuclein differentiate these groups is controversial. Correlations of alpha-synuclein among biofluids (CSF, plasma, saliva) or biomarkers (eg, beta-amyloid, tau [total, phosphorylated]) are not fully understood. The relationships of these biomarkers with PD clinical features remain unclear.

Methods: BioFIND, a cross-sectional, observational study, examines clinical and biomarker characteristics in moderate-advanced PD and matched healthy controls. We compared alpha-synuclein concentrations across diagnosis, biofluids, and CSF biomarkers. Correlations of CSF biomarkers and MDS-UPDRS, motor phenotype, MoCA, and rapid eye movement sleep behavior disorder questionnaire scores in PD were examined.

Results: CSF alpha-synuclein was lower in PD versus controls (P = .01), controlling for age, gender, and education. Plasma and saliva alpha-synuclein did not differ between PD and controls, and alpha-synuclein did not significantly correlate among biofluids. CSF beta-amyloid was lower in PD versus controls (P < .01), and correlated weakly with MoCA recall scores (r = 0.23, P = .02). CSF alpha-synuclein was lower in the postural instability/gait difficulty phenotype than other motor phenotypes (P < .01). No CSF biomarkers predicted or correlated with total motor or rapid eye movement sleep behavior disorder scores. CSF alpha-synuclein correlated with beta-amyloid , total-tau, and phosphorylated-tau (r = 0.41, 0.81, 0.43, respectively; Ps < .001).

Conclusion: Lower CSF alpha-synuclein is associated with diagnosis and motor phenotype in moderate-advanced PD. Plasma and saliva alpha-synuclein neither correlate with CSF alpha-synuclein, nor distinguish PD from controls. CSF beta-amyloid remains a potential biomarker for cognitive impairment in PD. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836918PMC
February 2018

Alzheimer's Disease-Related Dementias Summit 2016: National research priorities.

Neurology 2017 Dec 8;89(23):2381-2391. Epub 2017 Nov 8.

From the National Institute of Neurological Disorders and Stroke (R.A.C., W.J.K., J.T.G., S.J., D.B., M.E., C.S.M., P.A.S., B.-A.S., M.L.S., C.L.T., A.K.G.), Bethesda, MD; Rush Alzheimer's Disease Center (D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (S.T.C.), David Geffen School of Medicine, University of California, Los Angeles; The Association for Frontotemporal Degeneration (S.L.-J.D.), Radnor, PA; Department of Neuroscience (D.W.D.), Mayo Clinic, Jacksonville, FL; The Alzheimer's Drug Discovery Foundation (H.F.); Icahn School of Medicine at Mount Sinai (H.F.), New York, NY; Department of Neurology (S.M.G.), Massachusetts General Hospital, Harvard Medical School, Boston; Eli Lilly and Company (M.L.H.), Lilly Research Centre, Erl Wood Manor, Windlesham, UK; Department of Neurology (D.S.K.), Mayo Clinic Rochester, MN; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (J.J.M., K.S.M.) and College of Physicians and Surgeons (K.S.M.), Columbia University, New York, NY; National Institute on Aging (C.H.P., N.B.S.), Bethesda, MD; Memory and Aging Center, Department of Neurology (W.W.S.), and Department of Pathology (W.W.S.), University of California San Francisco; Lewy Body Dementia Association (A.T.), Lilburn, GA; National Institute of Diabetes and Digestive and Kidney Diseases (S.P.W.), Bethesda, MD; and Knight Alzheimer's Disease Research Center (D.M.H.), Hope Center for Neurological Disorders (D.M.H.), and Department of Neurology (D.M.H.), Washington University in St. Louis, MO.

Goal 1 of the National Plan to Address Alzheimer's Disease is to prevent and effectively treat Alzheimer disease and Alzheimer disease-related dementias by 2025. To help inform the research agenda toward achieving this goal, the NIH hosts periodic summits that set and refine relevant research priorities for the subsequent 5 to 10 years. This proceedings article summarizes the 2016 Alzheimer's Disease-Related Dementias Summit, including discussion of scientific progress, challenges, and opportunities in major areas of dementia research, including mixed-etiology dementias, Lewy body dementia, frontotemporal degeneration, vascular contributions to cognitive impairment and dementia, dementia disparities, and dementia nomenclature.
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http://dx.doi.org/10.1212/WNL.0000000000004717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719928PMC
December 2017

Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program.

Biomark Med 2017 May 23;11(6):451-473. Epub 2017 Jun 23.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset.
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http://dx.doi.org/10.2217/bmm-2016-0370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619098PMC
May 2017

Using a logic model to evaluate the Kids Together early education inclusion program for children with disabilities and additional needs.

Eval Program Plann 2017 04 9;61:96-105. Epub 2016 Dec 9.

Noah's Shoalhaven, Nowra, 2541, Australia.

Despite clear evidence that learning and social opportunities for children with disabilities and special needs are more effective in inclusive not segregated settings, there are few known effective inclusion programs available to children with disabilities, their families or teachers in the early years within Australia. The Kids Together program was developed to support children with disabilities/additional needs aged 0-8 years attending mainstream early learning environments. Using a key worker transdisciplinary team model, the program aligns with the individualised package approach of the National Disability Insurance Scheme (NDIS).

Aim: This paper reports on the use of a logic model to underpin the process, outcomes and impact evaluation of the Kids Together program.

Methods: The research team worked across 15 Early Childhood Education and Care (ECEC) centres and in home and community settings. A realist evaluation using mixed methods was undertaken to understand what works, for whom and in what contexts. The development of a logic model provided a structured way to explore how the program was implemented and achieved short, medium and long term outcomes within a complex community setting.

Discussion And Conclusion: Kids Together was shown to be a highly effective and innovative model for supporting the inclusion of children with disabilities/additional needs in a range of environments central for early childhood learning and development. The use of a logic model provided a visual representation of the Kids Together model and its component parts and enabled a theory of change to be inferred, showing how a coordinated and collaborative approached can work across multiple environments.
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http://dx.doi.org/10.1016/j.evalprogplan.2016.12.004DOI Listing
April 2017

The BioFIND study: Characteristics of a clinically typical Parkinson's disease biomarker cohort.

Mov Disord 2016 06 26;31(6):924-32. Epub 2016 Apr 26.

The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA.

Background: Identifying PD-specific biomarkers in biofluids will greatly aid in diagnosis, monitoring progression, and therapeutic interventions. PD biomarkers have been limited by poor discriminatory power, partly driven by heterogeneity of the disease, variability of collection protocols, and focus on de novo, unmedicated patients. Thus, a platform for biomarker discovery and validation in well-characterized, clinically typical, moderate to advanced PD cohorts is critically needed.

Methods: BioFIND (Fox Investigation for New Discovery of Biomarkers in Parkinson's Disease) is a cross-sectional, multicenter biomarker study that established a repository of clinical data, blood, DNA, RNA, CSF, saliva, and urine samples from 118 moderate to advanced PD and 88 healthy control subjects. Inclusion criteria were designed to maximize diagnostic specificity by selecting participants with clinically typical PD symptoms, and clinical data and biospecimen collection utilized standardized procedures to minimize variability across sites.

Results: We present the study methodology and data on the cohort's clinical characteristics. Motor scores and biospecimen samples including plasma are available for practically defined off and on states and thus enable testing the effects of PD medications on biomarkers. Other biospecimens are available from off state PD assessments and from controls.

Conclusion: Our cohort provides a valuable resource for biomarker discovery and validation in PD. Clinical data and biospecimens, available through The Michael J. Fox Foundation for Parkinson's Research and the National Institute of Neurological Disorders and Stroke, can serve as a platform for discovering biomarkers in clinically typical PD and comparisons across PD's broad and heterogeneous spectrum. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021110PMC
http://dx.doi.org/10.1002/mds.26613DOI Listing
June 2016

The NINDS Parkinson's disease biomarkers program.

Mov Disord 2016 06 7;31(6):915-23. Epub 2015 Oct 7.

National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

Background: Neuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinson's Disease Biomarkers Program to promote discovery of PD biomarkers for use in phase II and III clinical trials.

Methods: Using a novel consortium design, the Parkinson's Disease Biomarker Program is focused on the development of clinical and laboratory-based biomarkers for PD diagnosis, progression, and prognosis. Standardized operating procedures and pooled reference samples were created to allow cross-project comparisons and assessment of batch effects. A web-based Data Management Resource facilitates rapid sharing of data and biosamples across the research community for additional biomarker projects.

Results: Eleven consortium projects are ongoing, seven of which recruit participants and obtain biosamples. As of October 2014, 1,082 participants have enrolled (620 PD, 101 with other causes of parkinsonism, 23 essential tremor, and 338 controls), 1,040 of whom have at least one biosample. Six thousand eight hundred ninety-eight total biosamples are available from baseline, 6-, 12-, and 18-month visits: 1,006 DNA, 1,661 RNA, 1,419 whole blood, 1,382 plasma, 1,200 serum, and 230 cerebrospinal fluid (CSF). Quality control analysis of plasma, serum, and CSF samples indicates that almost all samples are high quality (24 of 2,812 samples exceed acceptable hemoglobin levels).

Conclusions: By making samples and data widely available, using stringent operating procedures based on existing standards, hypothesis testing for biomarker discovery, and providing a resource that complements existing programs, the Parkinson's Disease Biomarker Program will accelerate the pace of PD biomarker research. © 2015 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824671PMC
June 2016

Precompetitive Data Sharing as a Catalyst to Address Unmet Needs in Parkinson's Disease.

J Parkinsons Dis 2015 ;5(3):581-94

Parkinson's UK, London, UK.

Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson's UK and co-organized by Critical Path Institute's (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contribute to disease progression heterogeneity. Novel therapeutic targets and trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination are required. The integration of robust clinical data sets is viewed as a powerful approach to hasten medical discovery and therapies, as is being realized across diverse disease conditions employing big data analytics for healthcare. The application of lessons learned from parallel efforts is critical to identify barriers and enable a viable path forward. A roadmap is presented for a regulatory, academic, industry and advocacy driven integrated initiative that aims to facilitate and streamline new drug trials and registrations in Parkinson's disease.
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http://dx.doi.org/10.3233/JPD-150570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887129PMC
July 2016

The NIH Extracellular RNA Communication Consortium.

J Extracell Vesicles 2015 28;4:27493. Epub 2015 Aug 28.

Integrative Biology and Infectious Diseases Branch, National Institute of Dental and Craniofacial Research (NIDCR), Bethesda, MD, USA.

The Extracellular RNA (exRNA) Communication Consortium, funded as an initiative of the NIH Common Fund, represents a consortium of investigators assembled to address the critical issues in the exRNA research arena. The overarching goal is to generate a multi-component community resource for sharing fundamental scientific discoveries, protocols, and innovative tools and technologies. The key initiatives include (a) generating a reference catalogue of exRNAs present in body fluids of normal healthy individuals that would facilitate disease diagnosis and therapies, (b) defining the fundamental principles of exRNA biogenesis, distribution, uptake, and function, as well as development of molecular tools, technologies, and imaging modalities to enable these studies,
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553264PMC
http://dx.doi.org/10.3402/jev.v4.27493DOI Listing
August 2015

Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study.

Lancet Neurol 2015 Oct 10;14(10):1002-9. Epub 2015 Aug 10.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.

Background: Accurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts.

Methods: We developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD).

Findings: In the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0·923 (95% CI 0·900-0·946) with high sensitivity (0·834, 95% CI 0·711-0·883) and specificity (0·903, 95% CI 0·824-0·946) at its optimum AUC threshold (0·655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0·894 (95% CI 0·867-0·921) in the PDBP cohort, 0·998 (0·992-1·000) in PARS, 0·955 (no 95% CI available) in 23andMe, 0·929 (0·896-0·962) in LABS-PD, and 0·939 (0·891-0·986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0·003).

Interpretation: Our model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions.

Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation.
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http://dx.doi.org/10.1016/S1474-4422(15)00178-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575273PMC
October 2015

NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases.

Neurobiol Aging 2015 Mar 4;36(3):1605.e7-12. Epub 2014 Aug 4.

Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and accessible technology. Central to this project, we wanted to make the content of the platform open to any investigator without restriction. In designing this array we prioritized a number of types of genetic variability for inclusion, such as known risk alleles, disease-causing mutations, putative risk alleles, and other functionally important variants. The array was primarily designed to allow rapid screening of samples for disease-causing mutations and large population studies of risk factors. Notably, an explicit aim was to make this array widely available to facilitate data sharing across and within diseases. The resulting array, NeuroX, is a remarkably cost and time effective solution for high-quality genotyping. NeuroX comprises a backbone of standard Illumina exome content of approximately 240,000 variants, and over 24,000 custom content variants focusing on neurologic diseases. Data are generated at approximately $50-$60 per sample using a 12-sample format chip and regular Infinium infrastructure; thus, genotyping is rapid and accessible to many investigators. Here, we describe the design of NeuroX, discuss the utility of NeuroX in the analyses of rare and common risk variants, and present quality control metrics and a brief primer for the analysis of NeuroX derived data.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317375PMC
March 2015

Recommendations of the Alzheimer's disease-related dementias conference.

Neurology 2014 Aug 30;83(9):851-60. Epub 2014 Jul 30.

From the Department of Pathology (T.J.M.), University of Washington, Seattle; National Institute of Neurological Disorders and Stroke (W.J.K., D.B., W.R.G., A.N.K., B.-A.S., M.S., C.L.T., S.P.W., R.A.C.), Bethesda, MD; Neuropathology Lab (D.W.D.), Mayo Clinic, Jacksonville, FL; Department of Epidemiology & Biostatistics (M.M.G.), University of California San Francisco; Hemorrhagic Stroke Research Program (S.M.G.), Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Neurodegenerative Diseases DHT at Eli Lilly and Company (M.L.H.), Lilly Research Center, Windlesham, UK; Department of Neurology (D.S.K.), Mayo Clinic Rochester, MN; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (J.J.M., K.S.M.), Columbia University Medical Center, New York; Columbia University (J.J.M., K.S.M.), College of Physicians and Surgeons, New York, NY; University of California San Francisco Memory and Aging Center (B.L.M., W.W.S.); National Institute on Aging (C.H.P., N.B.S.), Bethesda, MD; and Zilhka Neurogenetic Institute (B.V.Z.), Center for Neurodegeneration and Regeneration and Department of Physiology and Biophysics, University of Southern California, Keck School of Medicine, Los Angeles, CA.

The National Alzheimer's Project Act, signed into law in 2011, mandates a National Plan to Address Alzheimer's Disease that is updated annually. In the Plan, the term Alzheimer disease includes not only Alzheimer disease (AD) proper, but also several specified related dementias, namely, frontotemporal, Lewy body, vascular, and mixed dementia. In response to a specific action item in the 2012 National Plan, the National Institute of Neurological Disorders and Stroke, in collaboration with the National Institute on Aging, convened panels of experts and conducted a 2-day public conference to develop research priorities and timelines for addressing Alzheimer disease-related dementias (ADRD) in 5 topic areas: multiple etiology dementias, health disparities, Lewy body dementias including dementia with Lewy bodies and Parkinson disease dementia, frontotemporal dementia and related tauopathies, and vascular contributions to ADRD. By design, the product was up to 8 prioritized research recommendations in each topic area including estimated timelines from when work on a recommendation is started to completion or to full implementation of an ongoing activity, and recognition of shared research themes across recommendations. These included increased education and training of both researchers and health care professionals, addressing health disparities, fundamental neurobiology research, advanced diagnostics, collaborative biosample repositories, and a focus on developing effective interventions to prevent or treat ADRD by the year 2025 as targeted by the National Plan.
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http://dx.doi.org/10.1212/WNL.0000000000000733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155046PMC
August 2014

Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.

Nat Genet 2014 Sep 27;46(9):989-93. Epub 2014 Jul 27.

The Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, USA.

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.
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http://dx.doi.org/10.1038/ng.3043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146673PMC
September 2014

The National Institutes of Health Microphysiological Systems Program focuses on a critical challenge in the drug discovery pipeline.

Stem Cell Res Ther 2013 20;4 Suppl 1:I1. Epub 2013 Dec 20.

The National Institutes of Health has partnered with the US Food and Drug Administration and the Defense Advanced Research Projects Agency to accelerate the development of human microphysiological systems (MPS) that address challenges faced in predictive toxicity assessment and efficacy analysis of new molecular entities during the preclinical phase of drug development. Use of human MPS could provide better models for predicting the efficacy of new molecular entities in clinical trials. It is also anticipated that improvements in predicting drug toxicities early in the drug development process through the use of MPS or human organs-on-a-chip will decrease the need to withdraw new therapies from the market and minimize or eliminate deaths due to unidentified drug toxicities.
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http://dx.doi.org/10.1186/scrt361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4029183PMC
October 2014

Deletion of galectin-3 exacerbates microglial activation and accelerates disease progression and demise in a SOD1(G93A) mouse model of amyotrophic lateral sclerosis.

Brain Behav 2012 Sep 23;2(5):563-75. Epub 2012 Jul 23.

Department of Pharmacology, George Washington University School of Medicine and Health Sciences Washington, DC.

Galectins are pleiotropic carbohydrate-binding lectins involved in inflammation, growth/differentiation, and tissue remodeling. The functional role of galectins in amyotrophic lateral sclerosis (ALS) is unknown. Expression studies revealed increases in galectin-1 mRNA and protein in spinal cords from SOD1(G93A) mice, and in galectin-3 and -9 mRNAs and proteins in spinal cords of both SOD1(G93A) mice and sporadic ALS patients. As the increase in galectin-3 appeared in early presymptomatic stages and increased progressively through to end stage of disease in the mouse, it was selected for additional study, where it was found to be mainly expressed by microglia. Galectin-3 antagonists are not selective and do not readily cross the blood-brain barrier; therefore, we generated SOD1(G93A)/Gal-3(-/-) transgenic mice to evaluate galectin-3 deletion in a widely used mouse model of ALS. Disease progression, neurological symptoms, survival, and inflammation were assessed to determine the effect of galectin-3 deletion on the SOD1(G93A) disease phenotype. Galectin-3 deletion did not change disease onset, but resulted in more rapid progression through functionally defined disease stages, more severely impaired neurological symptoms at all stages of disease, and expiration, on average, 25 days earlier than SOD1(G93A)/Gal-3(+/+) cohorts. In addition, microglial staining, as well as TNF-α, and oxidative injury were increased in SOD1(G93A)/Gal-3(-/-) mice compared with SOD1(G93A)/Gal-3(+/+) cohorts. These data support an important functional role for microglial galectin-3 in neuroinflammation during chronic neurodegenerative disease. We suggest that elevations in galectin-3 by microglia as disease progresses may represent a protective, anti-inflammatory innate immune response to chronic motor neuron degeneration.
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http://dx.doi.org/10.1002/brb3.75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3489809PMC
September 2012

The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier).

Alzheimers Dement 2013 Mar 10;9(2):189-98. Epub 2012 Oct 10.

Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.

Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.
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http://dx.doi.org/10.1016/j.jalz.2012.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562382PMC
March 2013

Frontotemporal degeneration, the next therapeutic frontier: molecules and animal models for frontotemporal degeneration drug development.

Alzheimers Dement 2013 Mar 5;9(2):176-88. Epub 2012 Oct 5.

Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.

Frontotemporal degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade, there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug's success in treating FTD may predict efficacy in more common diseases such as Alzheimer's disease. A variety of regulatory incentives, clinical features of FTD such as rapid disease progression, and relatively pure molecular pathology suggest that there are advantages to developing drugs for FTD as compared with other more common neurodegenerative diseases such as Alzheimer's disease. In March 2011, the Frontotemporal Degeneration Treatment Study Group sponsored a conference entitled "FTD, the Next Therapeutic Frontier," which focused on preclinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development; epidemiological, genetic, and neuropathological features of FTD; FTD animal models and how best to use them; and examples of successful drug development collaborations in other neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.jalz.2012.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542408PMC
March 2013

Creation of an open-access, mutation-defined fibroblast resource for neurological disease research.

PLoS One 2012 27;7(8):e43099. Epub 2012 Aug 27.

Department of Molecular Neuroscience, University College London Institute of Neurology, London, United Kingdom.

Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0043099PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428297PMC
February 2013

Alteration of ganglioside synthesis by GM3 synthase knockout in murine embryonic fibroblasts.

Biochim Biophys Acta 2007 Sep 7;1771(9):1226-34. Epub 2007 Jun 7.

Center for Cancer and Immunology Research, Children's Research Institute, 111 Michigan Avenue, NW, Washington, DC 20010, USA.

To probe the functions of membrane gangliosides, the availability of ganglioside-depleted cells would be a valuable resource. To attempt to identify a useful genetic model of ganglioside depletion, we assessed ganglioside metabolism in murine GM3 synthase (GM3S)-/- knockout primary embryonic fibroblasts (MEF), because normal fibroblast gangliosides (GM3, GM2, GM1, and GD1a), all downstream products of GM3S, should be absent. We found that heterozygote MEF (GM3S+/-) did have a 36% reduced content of qualitatively normal gangliosides (7.0+/-0.8 nmol LBSA/mg cell protein; control: 11+/-1.6 nmol). However, two unexpected findings characterized the homozygous (GM3-/-) MEF. Despite complete knockout of GM3S, (i) GM3-/- MEF retained substantial ganglioside content (21% of normal or 2.3+/-1.1 nmol) and (ii) these gangliosides were entirely different from those of wild type MEF by HPTLC. Mass spectrometry identified them as GM1b, GalNAc-GM1b, and GD1alpha, containing both N-acetyl and N-glycolylneuraminic acid and diverse ceramide structures. All are products of the 0 pathway of ganglioside synthesis, not normally expressed in fibroblasts. The results suggest that complete, but not partial, inhibition of GM3 synthesis results in robust activation of an alternate pathway that may compensate for the complete absence of the products of GM3S.
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http://dx.doi.org/10.1016/j.bbalip.2007.05.008DOI Listing
September 2007

Executive functions in the heterozygous reeler mouse model of schizophrenia.

Behav Neurosci 2006 Aug;120(4):984-8

Department of Psychology, George Washington University, Washington, DC 20052, USA.

Deficits in working memory and executive functions are now considered among the most reliable endophenotypes for schizophrenia. To determine whether cognitive deficits exist in mouse models of the disease, the authors trained heterozygous reeler (+/rl) mice on a series of visual discriminations similar to those used to test executive abilities in primates. These mice resemble schizophrenia patients in that both have reduced levels of reelin protein and altered gamma aminobutyric acid neurotransmission in the prefrontal cortex. The +/rl mice showed a selective deficit in reversal learning, with a pattern of errors that suggested impaired visual attention rather than a deficiency in perseveration and inhibitory control. These results show that cognitive dysfunction may serve as a useful biomarker in mouse models of neuropsychiatric disease.
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http://dx.doi.org/10.1037/0735-7044.120.4.984DOI Listing
August 2006

Glutamate transporter cluster formation in astrocytic processes regulates glutamate uptake activity.

J Neurosci 2004 Jul;24(28):6301-6

Department of Pharmacology, The George Washington University, Washington, DC 20037, USA.

Glutamate is the predominant excitatory neurotransmitter in the CNS, and it is removed from the synaptic cleft by sodium-dependent glutamate transport activity. Glutamate transporter-1 (GLT-1) is expressed predominantly in astroglial cells and is responsible for the largest proportion of glutamate transport in the adult forebrain. In the present study, we demonstrate the ability of endogenous and recombinant GLT-1 to form clusters in astrocytic processes and characterize the mobility and physiological importance of these clusters in the regulation of GLT-1 activity in the presence or absence of neurons. At the distal end of C6 glioma cell processes, GLT-1 clusters undergo rapid morphological changes in both shape and size, and these changes are inhibited by cytochalasin D treatment, suggesting that the morphogenesis of GLT-1 clusters is highly dependent on the actin network. Treatment of astrocytes with phorbol 12-myristate 13-acetate (PMA) quickly and preferentially decreases GLT-1 localization on the process membrane, leading to de novo generation of GLT-1 clusters along the process shaft. Pretreatment with the PKC inhibitor bisindolylmaleimide II (Bis II), with sucrose (0.4 m), or through the expression of a dominant-negative form of dynamin prevents PMA-induced GLT-1 internalization and cluster formation. In terms of glutamate transporter function, PMA treatment elicits a significant decrease in GLT-1 activity that is prevented by preexposure to either Bis II or hypertonic treatment. Together, these data indicate that GLT-1 trafficking and cluster formation in glial cell processes are dynamic events that play important roles in regulating glutamate uptake in astrocytes and glioma cells.
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http://dx.doi.org/10.1523/JNEUROSCI.1404-04.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729534PMC
July 2004

Abbreviated action potential kinetics in a mouse model of potassium channel overexpression during hippocampal development.

Cell Mol Neurobiol 2004 Jun;24(3):423-41

Department of Pharmacology, George Washington University, Washington, District of Columbia 20037, USA.

Loss or "gain" of function mutations in voltage-gated ion channels often results in an adverse neurological phenotype. We have examined the electrical characteristics of hippocampal pyramidal cells in a transgenic mouse model to determine how overexpression of a Shaker-type potassium channel subunit during early postnatal development might alter excitability properties of developing neurons. We found that in CA3 neurons potassium channel overexpression led to a transient shortening in duration of single action potentials during the first two postnatal weeks. There was an increase in maximal repolarization rate, without significant effect on the rate of rise. Transgenic CA3 neurons also showed a decrease of firing frequency in response to sustained depolarizing current injection. In contrast, repolarization of action potentials in CA1 neurons was not significantly altered by trangene expression. Western Blot Analysis of membrane-associated transgene protein indicated that transgene protein levels decreased during development, in agreement with functional measures of spike width. Our data indicate that the functional consequences of potassium channel transgene expression are dependent on cellular environment and developmental stage. A transient period of hypoexcitability during a critical period of development for CA3 neurons may contribute to the hyperexcitable phenotype observed in adult animals.
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http://dx.doi.org/10.1023/b:cemn.0000022772.82534.39DOI Listing
June 2004