Publications by authors named "Karen T Chang"

37 Publications

DSCR1 upregulation enhances dural meningeal lymphatic drainage to attenuate amyloid pathology of Alzheimer's disease.

J Pathol 2021 Jul 26. Epub 2021 Jul 26.

Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.

Highly developed meningeal lymphatics remove waste products from the brain. Disruption of meningeal lymphatic vessels in a mouse model of amyloid pathology (5XFAD) accelerates the accumulation of amyloid plaques in the meninges and brain, and causes learning and memory deficits, suggesting that clearance of toxic wastes by lymphatic vessels plays a key role in neurodegenerative diseases. Here, we discovered that DSCR1 (Down syndrome critical region 1, known also as RCAN1, regulator of calcineurin 1) facilitates the drainage of waste products by increasing the coverage of dorsal meningeal lymphatic vessels. Furthermore, upregulation of DSCR1 in 5XFAD mice diminishes Aβ pathology in the brain and improves memory defects. Surgical ligation of cervical lymphatic vessels afferent to dcLN blocks the beneficial effects of DSCR1 on Aβ accumulation and cognitive function. Interestingly, intracerebroventricular delivery of AAV1-DSCR1 to 5XFAD mice is sufficient to rebuild the meningeal lymphatic system and re-establish cognitive performance. Collectively, our data indicate that DSCR1 facilitates the growth of dorsal meningeal lymphatics to improve drainage efficiency and protect against Alzheimer's disease (AD) pathologies, further highlighting that improving meningeal lymphatic function is a feasible treatment strategy for AD. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5767DOI Listing
July 2021

Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons.

N Engl J Med 2021 06 21;384(24):2273-2282. Epub 2021 Apr 21.

From the Immunization Safety Office, Division of Healthcare Quality Promotion (T.T.S., T.R.M., P.L. Moro, L.P., P.L. Marquez, C.K.O., C.L., B.C.Z., J.M.G.), and the Arboviral Diseases Branch, Division of Vector-Borne Diseases (S.W.M.), National Center for Emerging and Zoonotic Infectious Diseases, the Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities (S.Y.K., V.K.B., C.J.G., D.M.M.-D.), the Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion (T.O., K.T.C., S.R.E., A.N.S.), the World Trade Center Health Program, National Institute for Occupational Safety and Health (R.L.), and the Epidemic Intelligence Service (K.T.C.) - all at the Centers for Disease Control and Prevention, Atlanta; and the Division of Epidemiology, Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD (M.A., A.M.-J.).

Background: Many pregnant persons in the United States are receiving messenger RNA (mRNA) coronavirus disease 2019 (Covid-19) vaccines, but data are limited on their safety in pregnancy.

Methods: From December 14, 2020, to February 28, 2021, we used data from the "v-safe after vaccination health checker" surveillance system, the v-safe pregnancy registry, and the Vaccine Adverse Event Reporting System (VAERS) to characterize the initial safety of mRNA Covid-19 vaccines in pregnant persons.

Results: A total of 35,691 v-safe participants 16 to 54 years of age identified as pregnant. Injection-site pain was reported more frequently among pregnant persons than among nonpregnant women, whereas headache, myalgia, chills, and fever were reported less frequently. Among 3958 participants enrolled in the v-safe pregnancy registry, 827 had a completed pregnancy, of which 115 (13.9%) resulted in a pregnancy loss and 712 (86.1%) resulted in a live birth (mostly among participants with vaccination in the third trimester). Adverse neonatal outcomes included preterm birth (in 9.4%) and small size for gestational age (in 3.2%); no neonatal deaths were reported. Although not directly comparable, calculated proportions of adverse pregnancy and neonatal outcomes in persons vaccinated against Covid-19 who had a completed pregnancy were similar to incidences reported in studies involving pregnant women that were conducted before the Covid-19 pandemic. Among 221 pregnancy-related adverse events reported to the VAERS, the most frequently reported event was spontaneous abortion (46 cases).

Conclusions: Preliminary findings did not show obvious safety signals among pregnant persons who received mRNA Covid-19 vaccines. However, more longitudinal follow-up, including follow-up of large numbers of women vaccinated earlier in pregnancy, is necessary to inform maternal, pregnancy, and infant outcomes.
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http://dx.doi.org/10.1056/NEJMoa2104983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117969PMC
June 2021

SARS-CoV-2 Transmission Dynamics in a Sleep-Away Camp.

Pediatrics 2021 04 27;147(4). Epub 2021 Jan 27.

Coronavirus Disease 2019 Response Team and.

Objectives: In late June 2020, a large outbreak of coronavirus disease 2019 (COVID-19) occurred at a sleep-away youth camp in Georgia, affecting primarily persons ≤21 years. We conducted a retrospective cohort study among campers and staff (attendees) to determine the extent of the outbreak and assess factors contributing to transmission.

Methods: Attendees were interviewed to ascertain demographic characteristics, known exposures to COVID-19 and community exposures, and mitigation measures before, during, and after attending camp. COVID-19 case status was determined for all camp attendees on the basis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test results and reported symptoms. We calculated attack rates and instantaneous reproduction numbers and sequenced SARS-CoV-2 viral genomes from the outbreak.

Results: Among 627 attendees, the median age was 15 years (interquartile range: 12-16 years); 56% (351 of 627) of attendees were female. The attack rate was 56% (351 of 627) among all attendees. On the basis of date of illness onset or first positive test result on a specimen collected, 12 case patients were infected before arriving at camp and 339 case patients were camp associated. Among 288 case patients with available symptom information, 45 (16%) were asymptomatic. Despite cohorting, 50% of attendees reported direct contact with people outside their cabin cohort. On the first day of camp session, the instantaneous reproduction number was 10. Viral genomic diversity was low.

Conclusions: Few introductions of SARS-CoV-2 into a youth congregate setting resulted in a large outbreak. Testing strategies should be combined with prearrival quarantine, routine symptom monitoring with appropriate isolation and quarantine, cohorting, social distancing, mask wearing, and enhanced disinfection and hand hygiene. Promotion of mitigation measures among younger populations is needed.
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http://dx.doi.org/10.1542/peds.2020-046524DOI Listing
April 2021

Reliability of maternal recall of delivery and immediate newborn care indicators in Sarlahi, Nepal.

BMC Pregnancy Childbirth 2021 Jan 25;21(1):82. Epub 2021 Jan 25.

Department of International Health, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD, USA.

Background: The intrapartum period is a time of high mortality risk for newborns and mothers. Numerous interventions exist to minimize risk during this period. Data on intervention coverage are needed for health system improvement. Maternal report of intrapartum interventions through surveys is the primary source of coverage data, but they may be invalid or unreliable.

Methods: We assessed the reliability of maternal report of delivery and immediate newborn care for a sample of home and health facility births in Sarlahi, Nepal. Mothers were visited as soon as possible following delivery (< 72 h) and asked to report circumstances of labor and delivery. A subset was revisited 1-24 months after delivery and asked to recall interventions received using standard household survey questions. We assessed the reliability of each indicator by comparing what mothers reported immediately after delivery against what they reported at the follow-up survey. We assessed potential variation in reliability of maternal report by characteristics of the mother, birth event, or intervention prevalence.

Results: One thousand five hundred two mother/child pairs were included in the reliability study, with approximately half of births occurring at home. A higher proportion of women who delivered in facilities reported "don't know" when asked to recall specific interventions both initially and at follow-up. Most indicators had high observed percent agreement, but kappa values were below 0.4, indicating agreement was primarily due to chance. Only "received any injection during delivery" demonstrated high reliability among all births (kappa: 0.737). The reliability of maternal report was typically lower among women who delivered at a facility. There was no difference in reliability based on time since birth of the follow-up interview. We observed over-reporting of interventions at follow-up that were more common in the population and under-reporting of less common interventions.

Conclusions: This study reinforces previous findings that mothers are unable to report reliably on many interventions within the peripartum period. Household surveys which rely on maternal report, therefore, may not be an appropriate method for collecting data on coverage of many interventions during the peripartum period. This is particularly true among facility births, where many interventions may occur without the mother's full knowledge.
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http://dx.doi.org/10.1186/s12884-021-03547-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831166PMC
January 2021

Adolescent with COVID-19 as the Source of an Outbreak at a 3-Week Family Gathering - Four States, June-July 2020.

MMWR Morb Mortal Wkly Rep 2020 Oct 9;69(40):1457-1459. Epub 2020 Oct 9.

There is increasing evidence that children and adolescents can efficiently transmit SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) (1-3). During July-August 2020, four state health departments and CDC investigated a COVID-19 outbreak that occurred during a 3-week family gathering of five households in which an adolescent aged 13 years was the index and suspected primary patient; 11 subsequent cases occurred.
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http://dx.doi.org/10.15585/mmwr.mm6940e2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561219PMC
October 2020

Measuring Service Quality and Assessing Its Relationship to Contraceptive Discontinuation: A Prospective Cohort Study in Pakistan and Uganda.

Glob Health Sci Pract 2020 09 30;8(3):442-454. Epub 2020 Sep 30.

Metrics for Management, Baltimore, MD, USA.

Background: The quality of contraceptive counseling that women receive from their provider can influence their future contraceptive continuation. We examined (1) whether the quality of contraceptive service provision could be measured in a consistent way by using existing tools from 2 large-scale social franchises, and (2) whether facility quality measures based on these tools were consistently associated with contraceptive discontinuation.

Methods: We linked existing, routinely collected facility audit data from social franchise clinics in Pakistan and Uganda with client data. Clients were women aged 15-49 who initiated a modern, reversible contraceptive method from a sampled clinic. Consented participants completed an exit interview and were contacted 3, 6, and 12 months later. We collapsed indicators into quality domains using theory-based categorization, created summative quality domain scores, and used Cox proportional hazards models to estimate the relationship between these quality domains and discontinuation while in need of contraception.

Results: The 12-month all-modern method discontinuation rate was 12.5% among the 813 enrolled women in Pakistan and 5.1% among the 1,185 women in Uganda. We did not observe similar associations between facility-level quality measures and discontinuation across these 2 settings. In Pakistan, an increase in the structural privacy domain was associated with a 60% lower risk of discontinuation, adjusting for age and baseline method (<.001). In Uganda, an increase in the management support domain was associated with a 33% reduction in discontinuation risk, controlling for age and baseline method (=.005).

Conclusions: We were not able to leverage existing, widely used quality measurement tools to create quality domains that were consistently associated with discontinuation in 2 study settings. Given the importance of contraceptive service quality and recent advances in indicator standardization in other areas, we recommend further effort to harmonize and simplify measurement tools to measure and improve contraceptive quality of care for all.
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http://dx.doi.org/10.9745/GHSP-D-20-00105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541109PMC
September 2020

SARS-CoV-2 Transmission and Infection Among Attendees of an Overnight Camp - Georgia, June 2020.

MMWR Morb Mortal Wkly Rep 2020 Aug 7;69(31):1023-1025. Epub 2020 Aug 7.

Limited data are available about transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), among youths. During June 17-20, an overnight camp in Georgia (camp A) held orientation for 138 trainees and 120 staff members; staff members remained for the first camp session, scheduled during June 21-27, and were joined by 363 campers and three senior staff members on June 21. Camp A adhered to the measures in Georgia's Executive Order* that allowed overnight camps to operate beginning on May 31, including requiring all trainees, staff members, and campers to provide documentation of a negative viral SARS-CoV-2 test ≤12 days before arriving. Camp A adopted most components of CDC's Suggestions for Youth and Summer Camps to minimize the risk for SARS-CoV-2 introduction and transmission. Measures not implemented were cloth masks for campers and opening windows and doors for increased ventilation in buildings. Cloth masks were required for staff members. Camp attendees were cohorted by cabin and engaged in a variety of indoor and outdoor activities, including daily vigorous singing and cheering. On June 23, a teenage staff member left camp A after developing chills the previous evening. The staff member was tested and reported a positive test result for SARS-CoV-2 the following day (June 24). Camp A officials began sending campers home on June 24 and closed the camp on June 27. On June 25, the Georgia Department of Public Health (DPH) was notified and initiated an investigation. DPH recommended that all attendees be tested and self-quarantine, and isolate if they had a positive test result.
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http://dx.doi.org/10.15585/mmwr.mm6931e1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454898PMC
August 2020

Translating international guidelines for use in routine maternal and neonatal healthcare quality measurement.

Glob Health Action 2020 12;13(1):1783956

Metrics for Management , Oakland, CA, USA.

Background: Improving facility-based quality for maternal and neonatal care is the key to reducing morbidity and mortality rates in low- and middle-income countries. Recent guidance from WHO and others has produced a large number of indicators to choose from to track quality.

Objective: To explore how to translate complex global maternal and neonatal health standards into actionable application at the facility level.

Methods: We applied a two-step process as an example of how the 352 indicators in WHO's 2016 Standards for Improving Quality of Maternal and Newborn Care in Health Facilities might be reduced to only those with the strongest evidence base, associated with outcomes, and actionable by facility managers. We applied Hill criteria and assessed whether indicators were within the control of facility managers. We next conducted a rapid review of supporting literature and applied GRADE analysis, retaining those with scores of 'moderate' or 'high'. To understand the utility and barriers to measuring this limited set of indicators in practice, we undertook a case study of hypothetical measurement application in two districts in Bangladesh, interviewing 25 clinicians, managers, and other stakeholders.

Results: From the initial 352 indicators, 56 were retained. The 56 indicators were used as a base for interviews. Respondents emphasized the practical challenges to the use of complex guides and the need for parsimonious and actionable sets of quality indicators.

Conclusions: This work offers one way to move towards a reduced quality indicator set, beginning from current WHO guidance. Despite study limitations, this work provides evidence of the need for reduced and evidence-based sets of quality indicators if guides are to be used to improve quality in practice. We hope that future research will build on and refine our efforts. Measuring quality effectively so that evidence guides and improves practice is the first step to assuring safe maternal and neonatal care.
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http://dx.doi.org/10.1080/16549716.2020.1783956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480423PMC
December 2020

DSCR1-mediated TET1 splicing regulates miR-124 expression to control adult hippocampal neurogenesis.

EMBO J 2019 07 11;38(14):e101293. Epub 2019 Jun 11.

Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.

Whether epigenetic factors such as DNA methylation and microRNAs interact to control adult hippocampal neurogenesis is not fully understood. Here, we show that Down syndrome critical region 1 (DSCR1) protein plays a key role in adult hippocampal neurogenesis by modulating two epigenetic factors: TET1 and miR-124. We find that DSCR1 mutant mice have impaired adult hippocampal neurogenesis. DSCR1 binds to TET1 introns to regulate splicing of TET1, thereby modulating TET1 level. Furthermore, TET1 controls the demethylation of the miRNA-124 promoter to modulate miR-124 expression. Correcting the level of TET1 in DSCR1 knockout mice is sufficient to prevent defective adult neurogenesis. Importantly, restoring DSCR1 level in a Down syndrome mouse model effectively rescued adult neurogenesis and learning and memory deficits. Our study reveals that DSCR1 plays a critical upstream role in epigenetic regulation of adult neurogenesis and provides insights into potential therapeutic strategy for treating cognitive defects in Down syndrome.
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http://dx.doi.org/10.15252/embj.2018101293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627232PMC
July 2019

Evaluating Quality of Contraceptive Counseling: An Analysis of the Method Information Index.

Stud Fam Plann 2019 03 21;50(1):25-42. Epub 2019 Jan 21.

The Method Information Index (MII) is calculated from contraceptive users' responses to questions regarding counseling content-whether they were informed about methods other than the one they received, told about method-specific side effects, and advised what to do if they experienced side effects. The MII is increasingly reported in national surveys and used to track program performance, but little is known about its properties. Using additional questions, we assessed the consistency between responses and the method received in a prospective, multicountry study. We employed two definitions of consistency: (1) presence of any concordant response, and (2) absence of discordant responses. Consistency was high when asking whether users were informed about other methods and what to do about side effects. Responses were least consistent when asking whether side effects were mentioned. Adjusting for inconsistency, scores were up to 50 percent and 30 percent lower in Pakistan and Uganda, respectively, compared to unadjusted MII scores. Additional questions facilitated better understanding of counseling quality.
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http://dx.doi.org/10.1111/sifp.12081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590213PMC
March 2019

Why some mothers overestimate birth size and length of pregnancy in rural Nepal.

J Glob Health 2018 Dec;8(2):020801

Johns Hopkins University Bloomberg School of Public Health, Department of International Health, Baltimore, Maryland, USA.

Background: Quantitative validation studies alone may not be able to distinguish between instances when participants did not accurately report an event vs when participants did not understand a question. We used an explanatory qualitative study design to acquire an in-depth understanding of why some mothers in rural Nepal overestimate birth size of their newborn and their length of pregnancy.

Methods: We conducted two focus group discussions (FGDs) with study staff who administered a quantitative questionnaire and 12 in-depth interviews (IDIs) with mothers who had participated in a quantitative validation study. Transcripts were coded and analyzed for themes in patterns of meaning within and across FGDs and IDIs. Using this thematic map, we synthesized our data into common and divergent responses from participants to facilitate our interpretation of the quantitative findings.

Results: We identified five themes specific to this analysis: difficulties with the length of pregnancy question, challenges in administering the birth size question, the perceived effect of time since birth on mothers' ability to remember information, the language and style differences specific to this setting, and the study context shaping the relationship between study staff and mothers who participated and how this may have influenced mothers' responses. Visual aids may help to scale the question about birth size within a cultural frame of reference for maternal reports to be more interpretable. Among both study staff and mothers, a longer period of time since the birth of a child was thought to be associated with diminished accuracy of maternal reports, a perception not supported by our previously published quantitative findings.

Conclusions: Poor validity of low birth weight (LBW) and preterm birth indicators based on maternal reports may be partly attributed to challenges in maternal understanding of questions assessing birth size and length of pregnancy. Additional research is needed to confirm these findings regarding maternal comprehension and to further evaluate the utility of visual aids developed for this study.
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http://dx.doi.org/10.7189/jogh.08.020801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122007PMC
December 2018

Validation of maternal reports for low birthweight and preterm birth indicators in rural Nepal.

J Glob Health 2018 Jun;8(1):010604

Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.

Background: Tracking progress towards global newborn health targets depends largely on maternal reported data collected through large, nationally representative surveys. We evaluated the validity, across a range of recall period lengths (1 to 24 months post-delivery), of maternal report of birthweight, birth size and length of pregnancy.

Methods: We compared maternal reports to reference standards of birthweights measured within 72 hours of delivery and gestational age generated from reported first day of the last menstrual period (LMP) prospectively collected as part of a population-based study (n = 1502). We calculated sensitivity, specificity, area the under the receiver operating curve (AUC) as a measure of individual-level accuracy, and the inflation factor (IF) to quantify population-level bias for each indicator. We assessed if length of recall period modified accuracy by stratifying measurements across time bins and using a modified Poisson regression with robust error variance to estimate the relative risk (RR) of correctly classifying newborns as low birthweight (LBW) or preterm, adjusting for child sex, place of delivery, maternal age, maternal education, parity, and ethnicity.

Results: The LBW indicator using maternally reported birthweight in grams had low individual-level accuracy (AUC = 0.69) and high population-level bias (inflation factor IF = 0.62). LBW using maternally reported birth size and the preterm birth indicator had lower individual-level accuracy (AUC = 0.58 and 0.56, respectively) and higher population-level bias (IF = 0.28 and 0.35, respectively) up to 24 months following birth. Length of recall time did not affect accuracy of LBW indicators. For the preterm birth indicator, accuracy did not change with length of recall up to 20 months after birth and improved slightly beyond 20 months.

Conclusions: The use of maternal reports may underestimate and bias indicators for LBW and preterm birth. In settings with high prevalence of LBW and preterm births, these indicators generated from maternal reports may be more vulnerable to misclassification. In populations where an important proportion of births occur at home or where weight is not routinely measured, mothers perhaps place less importance on remembering size at birth. Further work is needed to explore whether these conclusions on the validity of maternal reports hold in similar rural and low-income settings.
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http://dx.doi.org/10.7189/jogh.08.010604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997365PMC
June 2018

Activity-Induced Synaptic Structural Modifications by an Activator of Integrin Signaling at the Neuromuscular Junction.

J Neurosci 2017 03 20;37(12):3246-3263. Epub 2017 Feb 20.

Zilkha Neurogenetic Institute and

Activity-induced synaptic structural modification is crucial for neural development and synaptic plasticity, but the molecular players involved in this process are not well defined. Here, we report that a protein named Shriveled (Shv) regulates synaptic growth and activity-dependent synaptic remodeling at the neuromuscular junction. Depletion of Shv causes synaptic overgrowth and an accumulation of immature boutons. We find that Shv physically and genetically interacts with βPS integrin. Furthermore, Shv is secreted during intense, but not mild, neuronal activity to acutely activate integrin signaling, induce synaptic bouton enlargement, and increase postsynaptic glutamate receptor abundance. Consequently, loss of Shv prevents activity-induced synapse maturation and abolishes post-tetanic potentiation, a form of synaptic plasticity. Our data identify Shv as a novel trans-synaptic signal secreted upon intense neuronal activity to promote synapse remodeling through integrin receptor signaling. The ability of neurons to rapidly modify synaptic structure in response to neuronal activity, a process called activity-induced structural remodeling, is crucial for neuronal development and complex brain functions. The molecular players that are important for this fundamental biological process are not well understood. Here we show that the Shriveled (Shv) protein is required during development to maintain normal synaptic growth. We further demonstrate that Shv is selectively released during intense neuronal activity, but not mild neuronal activity, to acutely activate integrin signaling and trigger structural modifications at the neuromuscular junction. This work identifies Shv as a key modulator of activity-induced structural remodeling and suggests that neurons use distinct molecular cues to differentially modulate synaptic growth and remodeling to meet synaptic demand.
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http://dx.doi.org/10.1523/JNEUROSCI.3128-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373117PMC
March 2017

Phosphorylation of Synaptojanin Differentially Regulates Endocytosis of Functionally Distinct Synaptic Vesicle Pools.

J Neurosci 2016 08;36(34):8882-94

Zilkha Neurogenetic Institute, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, and Neuroscience Graduate Program, University of Southern California, Los Angeles, California 90089

Unlabelled: The rapid replenishment of synaptic vesicles through endocytosis is crucial for sustaining synaptic transmission during intense neuronal activity. Synaptojanin (Synj), a phosphoinositide phosphatase, is known to play an important role in vesicle recycling by promoting the uncoating of clathrin following synaptic vesicle uptake. Synj has been shown to be a substrate of the minibrain (Mnb) kinase, a fly homolog of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); however, the functional impacts of Synj phosphorylation by Mnb are not well understood. Here we identify that Mnb phosphorylates Synj at S1029 in Drosophila We find that phosphorylation of Synj at S1029 enhances Synj phosphatase activity, alters interaction between Synj and endophilin, and promotes efficient endocytosis of the active cycling vesicle pool (also referred to as exo-endo cycling pool) at the expense of reserve pool vesicle endocytosis. Dephosphorylated Synj, on the other hand, is deficient in the endocytosis of the active recycling pool vesicles but maintains reserve pool vesicle endocytosis to restore total vesicle pool size and sustain synaptic transmission. Together, our findings reveal a novel role for Synj in modulating reserve pool vesicle endocytosis and further indicate that dynamic phosphorylation and dephosphorylation of Synj differentially maintain endocytosis of distinct functional synaptic vesicle pools.

Significance Statement: Synaptic vesicle endocytosis sustains communication between neurons during a wide range of neuronal activities by recycling used vesicle membrane and protein components. Here we identify that Synaptojanin, a protein with a known role in synaptic vesicle endocytosis, is phosphorylated at S1029 in vivo by the Minibrain kinase. We further demonstrate that the phosphorylation status of Synaptojanin at S1029 differentially regulates its participation in the recycling of distinct synaptic vesicle pools. Our results reveal a new role for Synaptojanin in maintaining synaptic vesicle pool size and in reserve vesicle endocytosis. As Synaptojanin and Minibrain perturbations are associated with various neurological disorders, such as Parkinson's, autism, and Down syndrome, understanding mechanisms modulating Synaptojanin function provides valuable insights into processes affecting neuronal communication.
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http://dx.doi.org/10.1523/JNEUROSCI.1470-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995302PMC
August 2016

Dynamics of Mitochondrial Transport in Axons.

Front Cell Neurosci 2016 13;10:123. Epub 2016 May 13.

Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology Ulsan, South Korea.

The polarized structure and long neurites of neurons pose a unique challenge for proper mitochondrial distribution. It is widely accepted that mitochondria move from the cell body to axon ends and vice versa; however, we have found that mitochondria originating from the axon ends moving in the retrograde direction never reach to the cell body, and only a limited number of mitochondria moving in the anterograde direction from the cell body arrive at the axon ends of mouse hippocampal neurons. Furthermore, we have derived a mathematical formula using the Fokker-Planck equation to characterize features of mitochondrial transport, and the equation could determine altered mitochondrial transport in axons overexpressing parkin. Our analysis will provide new insights into the dynamics of mitochondrial transport in axons of normal and unhealthy neurons.
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http://dx.doi.org/10.3389/fncel.2016.00123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865487PMC
May 2016

Maintenance of Stem Cell Niche Integrity by a Novel Activator of Integrin Signaling.

PLoS Genet 2016 05 18;12(5):e1006043. Epub 2016 May 18.

Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.

Stem cells depend critically on the surrounding microenvironment, or niche, for their maintenance and self-renewal. While much is known about how the niche regulates stem cell self-renewal and differentiation, mechanisms for how the niche is maintained over time are not well understood. At the apical tip of the Drosophila testes, germline stem cells (GSCs) and somatic stem cells share a common niche formed by hub cells. Here we demonstrate that a novel protein named Shriveled (Shv) is necessary for the maintenance of hub/niche integrity. Depletion of Shv protein results in age-dependent deterioration of the hub structure and loss of GSCs, whereas upregulation of Shv preserves the niche during aging. We find Shv is a secreted protein that modulates DE-cadherin levels through extracellular activation of integrin signaling. Our work identifies Shv as a novel activator of integrin signaling and suggests a new integration model in which crosstalk between integrin and DE-cadherin in niche cells promote their own preservation by maintaining the niche architecture.
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http://dx.doi.org/10.1371/journal.pgen.1006043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871447PMC
May 2016

DSCR1 is required for both axonal growth cone extension and steering.

J Cell Biol 2016 05 16;213(4):451-62. Epub 2016 May 16.

Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Korea

Local information processing in the growth cone is essential for correct wiring of the nervous system. As an axon navigates through the developing nervous system, the growth cone responds to extrinsic guidance cues by coordinating axon outgrowth with growth cone steering. It has become increasingly clear that axon extension requires proper actin polymerization dynamics, whereas growth cone steering involves local protein synthesis. However, molecular components integrating these two processes have not been identified. Here, we show that Down syndrome critical region 1 protein (DSCR1) controls axon outgrowth by modulating growth cone actin dynamics through regulation of cofilin activity (phospho/dephospho-cofilin). Additionally, DSCR1 mediates brain-derived neurotrophic factor-induced local protein synthesis and growth cone turning. Our study identifies DSCR1 as a key protein that couples axon growth and pathfinding by dually regulating actin dynamics and local protein synthesis.
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http://dx.doi.org/10.1083/jcb.201510107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878092PMC
May 2016

Bidirectional Regulation of Amyloid Precursor Protein-Induced Memory Defects by Nebula/DSCR1: A Protein Upregulated in Alzheimer's Disease and Down Syndrome.

J Neurosci 2015 Aug;35(32):11374-83

Zilkha Neurogenetic Institute, Neuroscience Graduate Program, and Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089

Unlabelled: Aging individuals with Down syndrome (DS) have an increased risk of developing Alzheimer's disease (AD), a neurodegenerative disorder characterized by impaired memory. Memory problems in both DS and AD individuals usually develop slowly and progressively get worse with age, but the cause of this age-dependent memory impairment is not well understood. This study examines the functional interactions between Down syndrome critical region 1 (DSCR1) and amyloid-precursor protein (APP), proteins upregulated in both DS and AD, in regulating memory. Using Drosophila as a model, we find that overexpression of nebula (fly homolog of DSCR1) initially protects against APP-induced memory defects by correcting calcineurin and cAMP signaling pathways but accelerates the rate of memory loss and exacerbates mitochondrial dysfunction in older animals. We report that transient upregulation of Nebula/DSCR1 or acute pharmacological inhibition of calcineurin in aged flies protected against APP-induced memory loss. Our data suggest that calcineurin dyshomeostasis underlies age-dependent memory impairments and further imply that chronic Nebula/DSCR1 upregulation may contribute to age-dependent memory impairments in AD in DS.

Significance Statement: Most Down syndrome (DS) individuals eventually develop Alzheimer's disease (AD)-like dementia, but mechanisms underlying this age-dependent memory impairment remain poorly understood. This study examines Nebula/Down syndrome critical region 1 (DSCR1) and amyloid-precursor protein (APP), proteins upregulated in both DS and AD, in regulating memory. We uncover a previously unidentified role for Nebula/DSCR1 in modulating APP-induced memory defects during aging. We show that upregulation of Nebula/DSCR1, an inhibitor of calcineurin, rescues APP-induced memory defects in young flies but enhances memory loss of older flies. Excitingly, transient Nebula/DSCR1 overexpression or calcineurin inhibition in aged flies ameliorates APP-mediated memory problems. These results suggest that chronic Nebula/DSCR1 upregulation may contribute to age-dependent memory loss in DS and AD and points to correcting calcineurin signaling as a means to improve memory during aging.
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http://dx.doi.org/10.1523/JNEUROSCI.1163-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532765PMC
August 2015

Activity-dependent facilitation of Synaptojanin and synaptic vesicle recycling by the Minibrain kinase.

Nat Commun 2014 Jun 30;5:4246. Epub 2014 Jun 30.

1] Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA [2] Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.

Phosphorylation has emerged as a crucial regulatory mechanism in the nervous system to integrate the dynamic signalling required for proper synaptic development, function and plasticity, particularly during changes in neuronal activity. Here we present evidence that Minibrain (Mnb; also known as Dyrk1A), a serine/threonine kinase implicated in autism spectrum disorder and Down syndrome, is required presynaptically for normal synaptic growth and rapid synaptic vesicle endocytosis at the Drosophila neuromuscular junction (NMJ). We find that Mnb-dependent phosphorylation of Synaptojanin (Synj) is required, in vivo, for complex endocytic protein interactions and to enhance Synj activity. Neuronal stimulation drives Mnb mobilization to endocytic zones and triggers Mnb-dependent phosphorylation of Synj. Our data identify Mnb as a synaptic kinase that promotes efficient synaptic vesicle recycling by dynamically calibrating Synj function at the Drosophila NMJ, and in turn endocytic capacity, to adapt to conditions of high synaptic activity.
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http://dx.doi.org/10.1038/ncomms5246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183159PMC
June 2014

Nebula/DSCR1 upregulation delays neurodegeneration and protects against APP-induced axonal transport defects by restoring calcineurin and GSK-3β signaling.

PLoS Genet 2013 26;9(9):e1003792. Epub 2013 Sep 26.

Zilkha Neurogenetic Institute and Department of Cell & Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America ; Neuroscience Graduate Program, University of Southern California, Los Angeles, California, United States of America.

Post-mortem brains from Down syndrome (DS) and Alzheimer's disease (AD) patients show an upregulation of the Down syndrome critical region 1 protein (DSCR1), but its contribution to AD is not known. To gain insights into the role of DSCR1 in AD, we explored the functional interaction between DSCR1 and the amyloid precursor protein (APP), which is known to cause AD when duplicated or upregulated in DS. We find that the Drosophila homolog of DSCR1, Nebula, delays neurodegeneration and ameliorates axonal transport defects caused by APP overexpression. Live-imaging reveals that Nebula facilitates the transport of synaptic proteins and mitochondria affected by APP upregulation. Furthermore, we show that Nebula upregulation protects against axonal transport defects by restoring calcineurin and GSK-3β signaling altered by APP overexpression, thereby preserving cargo-motor interactions. As impaired transport of essential organelles caused by APP perturbation is thought to be an underlying cause of synaptic failure and neurodegeneration in AD, our findings imply that correcting calcineurin and GSK-3β signaling can prevent APP-induced pathologies. Our data further suggest that upregulation of Nebula/DSCR1 is neuroprotective in the presence of APP upregulation and provides evidence for calcineurin inhibition as a novel target for therapeutic intervention in preventing axonal transport impairments associated with AD.
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http://dx.doi.org/10.1371/journal.pgen.1003792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784514PMC
March 2014

Meeting at the crossroads: common mechanisms in Fragile X and Down syndrome.

Trends Neurosci 2013 Dec 25;36(12):685-94. Epub 2013 Sep 25.

Zilkha Neurogenetic Institute and Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA 90033, USA.

Intellectual disability is characterized by significantly impaired cognitive abilities and is due to various etiological factors, including both genetic and non-genetic causes. Two of the most common genetic forms of intellectual disability are Fragile X syndrome (FXS) and Down syndrome (DS). Recent studies have shown that proteins altered in FXS and DS can physically interact and participate in common signaling pathways regulating dendritic spine development and local protein synthesis, thus supporting the notion that spine dysmorphogenesis and abnormal local protein synthesis may be molecular underpinnings of intellectual disability. Here we review the molecular constituents regulating local protein synthesis and spine morphology and their alterations in FXS and DS. We argue that these changes might ultimately affect synaptic homeostasis and alter cognitive performance.
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http://dx.doi.org/10.1016/j.tins.2013.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090020PMC
December 2013

Miro, MCU, and calcium: bridging our understanding of mitochondrial movement in axons.

Front Cell Neurosci 2013 Sep 10;7:148. Epub 2013 Sep 10.

School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology Ulsan, South Korea.

Neurons are extremely polarized structures with long axons and dendrites, which require proper distribution of mitochondria and maintenance of mitochondrial dynamics for neuronal functions and survival. Indeed, recent studies show that various neurological disorders are linked to mitochondrial transport in neurons. Mitochondrial anterograde transport is believed to deliver metabolic energy to synaptic terminals where energy demands are high, while mitochondrial retrograde transport is required to repair or remove damaged mitochondria in axons. It has been suggested that Ca(2) (+) plays a key role in regulating mitochondrial transport by altering the configuration of mitochondrial protein, miro. However, molecular mechanisms that regulate mitochondrial transport in neurons still are not well characterized. In this review, we will discuss the roles of miro in mitochondrial transport and how the recently identified components of the mitochondrial calcium uniporter add to our current model of mitochondrial mobility regulation.
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http://dx.doi.org/10.3389/fncel.2013.00148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767916PMC
September 2013

Establishment of a Shigella sonnei human challenge model in Thailand.

Vaccine 2012 Nov 12;30(49):7040-5. Epub 2012 Oct 12.

Department of Enteric Diseases, Armed Forces Research Institute of Medical Sciences, Thailand.

In order to establish a human challenge model of Shigella related disease for vaccine testing, a dose-escalating inpatient trial was performed. Three groups of 12 healthy adult volunteers were orally challenged with 93,440 and 1680 CFU of Shigella sonnei strain 53G. Subjects were admitted to the Vaccine Trial Centre (VTC) at Mahidol University in Bangkok, Thailand. The primary purpose of this study was to identify the dose of S. sonnei 53G required to elicit clinical disease in at least 70% of Thai adult subjects. At the highest dose of 1680 CFU, the attack rate was 75%, while at the two lower doses, the attack rate was approximately 50%. This human challenge model, which is the first of its kind in an endemic region, will provide an opportunity for S. sonnei vaccine evaluation in endemic populations.
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http://dx.doi.org/10.1016/j.vaccine.2012.09.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732056PMC
November 2012

DSCR1 interacts with FMRP and is required for spine morphogenesis and local protein synthesis.

EMBO J 2012 Sep 3;31(18):3655-66. Epub 2012 Aug 3.

Department of Biology, Indiana University, Bloomington, USA.

Most common genetic factors known to cause intellectual disability are Down syndrome and Fragile X syndrome. However, the underlying cellular and molecular mechanisms of intellectual disability remain unclear. Recently, dendritic spine dysmorphogenesis and impaired local protein synthesis are posited to contribute to the cellular mechanisms of intellectual disability. Here, we show that Down syndrome critical region1 (DSCR1) interacts with Fragile X mental retardation protein (FMRP) and regulates both dendritic spine morphogenesis and local protein synthesis. Interestingly, decreasing the level of FMRP restores the DSCR1-induced changes in dendritic spine morphology. Our results imply that DSCR1 is a novel regulator of FMRP and that Fragile X syndrome and Down syndrome may share disturbances in common pathways that regulate dendritic spine morphology and local protein synthesis.
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http://dx.doi.org/10.1038/emboj.2012.190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442268PMC
September 2012

Mitochondrial matrix Ca2+ as an intrinsic signal regulating mitochondrial motility in axons.

Proc Natl Acad Sci U S A 2011 Sep 29;108(37):15456-61. Epub 2011 Aug 29.

Zilkha Neurogenetic Institute and Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA 90033, USA.

The proper distribution of mitochondria is particularly vital for neurons because of their polarized structure and high energy demand. Mitochondria in axons constantly move in response to physiological needs, but signals that regulate mitochondrial movement are not well understood. Aside from producing ATP, Ca(2+) buffering is another main function of mitochondria. Activities of many enzymes in mitochondria are also Ca(2+)-dependent, suggesting that intramitochondrial Ca(2+) concentration is important for mitochondrial functions. Here, we report that mitochondrial motility in axons is actively regulated by mitochondrial matrix Ca(2+). Ca(2+) entry through the mitochondrial Ca(2+) uniporter modulates mitochondrial transport, and mitochondrial Ca(2+) content correlates inversely with the speed of mitochondrial movement. Furthermore, the miro1 protein plays a role in Ca(2+) uptake into the mitochondria, which subsequently affects mitochondrial movement.
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http://dx.doi.org/10.1073/pnas.1106862108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174631PMC
September 2011

Upregulation of three Drosophila homologs of human chromosome 21 genes alters synaptic function: implications for Down syndrome.

Proc Natl Acad Sci U S A 2009 Oct 21;106(40):17117-22. Epub 2009 Sep 21.

Department of Biology, Indiana University, Bloomington, IN 47405, USA.

At the neuronal level of Down syndrome (DS) brains, there are evidences of altered shape, number, and density of synapses, as well as aberrant endocytosis associated with accumulation of enlarged endosomes, suggesting that proteins involved in synaptic vesicle recycling may play key roles in DS neurons. However, the exact mechanism underlying those anomalies is not well understood. We hypothesize that overexpression of three genes, dap160/itsn1, synj/synj1, and nla/dscr1, located on human chromosome 21 play important roles in DS neurons. Here, we systematically investigate the effects of multiple gene overexpression on synaptic morphology and endocytosis to identify possible dominant gene or genes. We found that overexpression of individual genes lead to abnormal synaptic morphology, but all three genes are necessary to cause impaired vesicle recycling and affect locomotor vigor. Furthermore, we report that dap160 overexpression alters the subcellular distribution of synaptojanin, and overexpression of nla regulates the phosphoinositol 5' phosphatase activity of synaptojanin. These findings imply that restoring the level of any one of these genes may reduce endocytic defects seen in DS.
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http://dx.doi.org/10.1073/pnas.0904397106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761307PMC
October 2009

Relationship between angiographic and optical coherence tomographic (OCT) parameters for quantifying choroidal neovascular lesions.

Graefes Arch Clin Exp Ophthalmol 2010 Feb 17;248(2):175-84. Epub 2009 Sep 17.

Doheny Image Reading Center, Doheny Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.

Background: To correlate the volume of various spaces on optical coherence tomography (OCT) with fluorescein angiographic (FA) parameters in neovascular age-related macular degeneration (AMD).

Methods: Sixty-five consecutive cases of active subfoveal choroidal neovascularization (CNV) associated with AMD were retrospectively collected. Area and greatest linear dimension of CNV lesion components were calculated on FA. Corresponding StratusOCT image sets were analyzed using custom software (termed OCTOR), which allows manual measurement of the volume of the neurosensory retina, subretinal fluid, subretinal tissue, and pigment epithelial detachment (PED).

Results: Area of occult CNV on FA correlated with PED (R = 0.62) and subretinal fluid (R = 0.28) volume and negatively with subretinal tissue volume (R = -0.26) on OCT. Area of classic CNV on FA correlated with subretinal tissue (R = 0.60) and retinal (R = 0.38) volume on OCT. Automated StratusOCT output values showed poorer correlations than manually calculated OCTOR values.

Conclusions: OCT features of CNV lesions as measured by manual quantitative subanalysis correlate better with angiographic parameters than values provided by the automated StratusOCT analysis. These measures may improve our understanding of the morphologic effects of CNV lesions and may facilitate the development of a hybrid FA and OCT-based classification system for future clinical trials, which more fully characterizes CNV lesions.
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http://dx.doi.org/10.1007/s00417-009-1193-4DOI Listing
February 2010

Effect of ranibizumab retreatment frequency on neurosensory retinal volume in neovascular amd.

Retina 2009 May;29(5):592-600

Doheny Image Reading Center, Doheny Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, California 90033, USA.

Purpose: To determine the characteristics of patients with neovascular age-related macular degeneration who show initial anatomic improvements on optical coherence tomography in response to treatment with ranibizumab, but who subsequently regress toward their anatomic baseline.

Methods: Data from 50 consecutive patients, receiving ranibizumab therapy for neovascular age-related macular degeneration, were collected. Raw StratusOCT images were analyzed using custom software ("OCTOR"). Changes in volume of neurosensory retina at months 1, 3, and 6 were calculated. Baseline demographic and morphologic characteristics were compared.

Results: Forty-two patients (84%) showed a reduction in total retinal volume 1 month after initial treatment with ranibizumab. Of the patients that initially showed a reduction, 16 (38%) maintained this reduction through month 6, whereas 26 patients (62%) demonstrated a subsequent increase in retinal volume. Patients who maintained a reduction in edema received 3.75 +/- 1.18 injections of ranibizumab versus 2.96 +/- 1.34 injections for patients who did not (P = 0.049). Regression of initial anatomic improvements was associated with worsening of visual acuity (r = 0.599, P = 0.002).

Conclusion: Patients receiving fewer injections of ranibizumab appeared less likely to maintain anatomic improvements achieved following commencement of ranibizumab therapy; regression of these improvements was associated with deterioration in visual acuity.
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http://dx.doi.org/10.1097/IAE.0b013e31819b17a5DOI Listing
May 2009

Evaluation of optical coherence tomography retinal thickness parameters for use in clinical trials for neovascular age-related macular degeneration.

Invest Ophthalmol Vis Sci 2009 Jul 5;50(7):3378-85. Epub 2009 Mar 5.

Doheny Image Reading Center, Doheny Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.

Purpose: To investigate the relationship between automated and manually derived measurements of central retinal thickness from optical coherence tomography (OCT) and to determine the relationship between the foveal center point (FCP) and the foveal central subfield (FCS) in neovascular age-related macular degeneration (AMD).

Methods: Data were collected from 216 patients with newly diagnosed neovascular AMD, who underwent StratusOCT imaging at diagnosis. Raw StratusOCT images for each patient were analyzed with the publicly available custom software OCTOR, which allows accurate manual grading of OCT B-scans. Manually derived central retinal thickness measurements were compared with measurements obtained from automated StratusOCT analysis. Manually obtained measurements of FCP and FCS were also compared.

Results: The mean (+/-SD) difference in thickness between automated and manually derived FCP thickness was 7.9 microm (+/-90.8), but the maximum difference was 455 microm. The limits of agreement (95% confidence interval), between automated and manually obtained FCP thicknesses, were -173.7 microm (lower limit) and 189.6 microm (upper limit), with a coefficient of determination (R(2)) of 0.49 (P < 0.001). In contrast, the R(2) for manually derived FCP and manually derived FCS thickness was 0.94 (P < 0.001), with a smaller mean (+/-SD) difference in thickness of 13.8 microm (+/-29.8).

Conclusions: Manual correction of errors in automated OCT segmentation may be necessary for accurate interpretation of anatomic outcomes for clinical trials of neovascular AMD. In addition, although measurement of FCS remains preferable for assessment of central retinal thickness, accurate measurement of FCP may represent an adequate alternative when FCS is unavailable.
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http://dx.doi.org/10.1167/iovs.08-2728DOI Listing
July 2009
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