Rebecca A Betensky
Rebecca Betensky
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Chair of the Department of Biostatistics
Professor of Biostatistics
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Professional overview
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Prior to NYU, Dr. Betensky was Professor of Biostatistics at the Harvard T.H. Chan School of Public Health. She was director of the Harvard Catalyst (Clinical and Translational Science Award) Biostatistics Program; director of the Data and Statistics Core for the Massachusetts Alzheimer’s Disease Research Center; and director of the Biostatistics Neurology Core at Massachusetts General Hospital. Previously, she was the Biostatistics Program Leader for the Dana-Farber/Harvard Cancer Center.
Dr. Betensky’s research focuses on methods for the analysis of censored and truncated outcomes and covariates, which frequently arise from the subsampling of cohort studies. She has a long-time interest in clinical trials, and has written on the evaluation of biomarkers and the use and interpretation of p-values. She has collaborated extensively in studies in neurologic diseases, and serves as statistical editor for Annals of Neurology.
Dr. Betensky was awarded, and directed for 15 years, an NIH T32 training program in neurostatistics and neuroepidemiology for pre- and post-doctoral students in biostatistics and epidemiology and for clinician-scientists. She previously directed Harvard’s Biostatistics programs to promote and support diversity at all levels in the field of quantitative public health. She was also a member of the BMRD Study Section for review of NIH statistical methodology grants; on committees for the Institute of Medicine; and a co-chair of the technical advisory committee for the scientific registry of transplant recipients.
Dr. Betensky an elected Fellow of the American Statistical Association and of the International Statistical Institute, and is a past recipient of the Spiegelman Award from the American Public Health Association. She currently serves as a member of the Board of Scientific Counselors for Clinical Science and Epidemiology at the National Cancer Institute.
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Education
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AB, Mathematics, Harvard University, Cambridge, MAPhD, Statistics, Stanford University, Stanford, CA
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Areas of research and study
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BiologyBiostatisticsNeuroepidemiologyNeurologyNeurostatisticsTranslational science
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Publications
Publications
Tau pathology does not affect experience-driven single-neuron and network-wide Arc/Arg3.1 responses
AbstractRudinskiy, N., Hawkes, J. M., Wegmann, S., Kuchibhotla, K. V., Muzikansky, A., Betensky, R. A., Spires-Jones, T. L., & Hyman, B. T. (n.d.).Publication year
2014Journal title
Acta Neuropathologica CommunicationsVolume
2Issue
1AbstractIntraneuronal neurofibrillary tangles (NFTs) - a characteristic pathological feature of Alzheimer's and several other neurodegenerative diseases - are considered a major target for drug development. Tangle load correlates well with the severity of cognitive symptoms and mouse models of tauopathy are behaviorally impaired. However, there is little evidence that NFTs directly impact physiological properties of host neurons. Here we used a transgenic mouse model of tauopathy to study how advanced tau pathology in different brain regions affects activity-driven expression of immediate-early gene Arc required for experience-dependent consolidation of long-term memories. We demonstrate in vivo that visual cortex neurons with tangles are as likely to express comparable amounts of Arc in response to structured visual stimulation as their neighbors without tangles. Probability of experience-dependent Arc response was not affected by tau tangles in both visual cortex and hippocampal pyramidal neurons as determined postmortem. Moreover, whole brain analysis showed that network-wide activity-driven Arc expression was not affected by tau pathology in any of the brain regions, including brain areas with the highest tangle load. Our findings suggest that intraneuronal NFTs do not affect signaling cascades leading to experience-dependent gene expression required for long-term synaptic plasticity.The effect of hospital care on early survival after penetrating trauma
AbstractClark, D. E., Doolittle, P. C., Winchell, R. J., & Betensky, R. A. (n.d.).Publication year
2014Journal title
Injury EpidemiologyVolume
1Issue
1Page(s)
1-9AbstractBackground: The effectiveness of emergency medical interventions can be best evaluated using time-to-event statistical methods with time-varying covariates (TVC), but this approach is complicated by uncertainty about the actual times of death. We therefore sought to evaluate the effect of hospital intervention on mortality after penetrating trauma using a method that allowed for interval censoring of the precise times of death. Methods: Data on persons with penetrating trauma due to interpersonal assault were combined from the 2008 to 2010 National Trauma Data Bank (NTDB) and the 2004 to 2010 National Violent Death Reporting System (NVDRS). Cox and Weibull proportional hazards models for survival time (tSURV) were estimated, with TVC assumed to have constant effects for specified time intervals following hospital arrival. The Weibull model was repeated with tSURV interval-censored to reflect uncertainty about the precise times of death, using an imputation method to accommodate interval censoring along with TVC. Results: All models showed that mortality was increased by older age, female sex, firearm mechanism, and injuries involving the head/neck or trunk. Uncensored models showed a paradoxical increase in mortality associated with the first hour in a hospital. The interval-censored model showed that mortality was markedly reduced after admission to a hospital, with a hazard ratio (HR) of 0.68 (95% CI 0.63, 0.73) during the first 30 min declining to a HR of 0.01 after 120 min. Admission to a verified level I trauma center (compared to other hospitals in the NTDB) was associated with a further reduction in mortality, with a HR of 0.93 (95% CI 0.82, 0.97). Conclusions: Time-to-event models with TVC and interval censoring can be used to estimate the effect of hospital care on early mortality after penetrating trauma or other acute medical conditions and could potentially be used for interhospital comparisons.Variable importance in matched case-control studies in settings of high dimensional data
AbstractBalasubramanian, R., Andres Houseman, E., Coull, B. A., Lev, M. H., Schwamm, L. H., & Betensky, R. A. (n.d.).Publication year
2014Journal title
Journal of the Royal Statistical Society. Series C: Applied StatisticsVolume
63Issue
4Page(s)
639-655AbstractSummary: We propose a method for assessing variable importance in matched case-control investigations and other highly stratified studies characterized by high dimensional data (p>>n). In simulated and real data sets, we show that the algorithm proposed performs better than a conventional univariate method (conditional logistic regression) and a popular multivariable algorithm (random forests) that does not take the matching into account. The methods are applicable to wide ranging, high impact clinical studies including metabolomic, proteomic studies and neuroimaging analyses, such as those assessing stroke and Alzheimer's disease. The methods proposed have been implemented in a freely available R library (http://cran.r-project.org/web/packages/RPCLR/index.html).Variable selection and prediction using a nested, matched case-control study: Application to hospital acquired pneumonia in stroke patients
AbstractQian, J., Payabvash, S., Kemmling, A., Lev, M. H., Schwamm, L. H., & Betensky, R. A. (n.d.).Publication year
2014Journal title
BiometricsVolume
70Issue
1Page(s)
153-163AbstractMatched case-control designs are commonly used in epidemiologic studies for increased efficiency. These designs have recently been introduced to the setting of modern imaging and genomic studies, which are characterized by high-dimensional covariates. However, appropriate statistical analyses that adjust for the matching have not been widely adopted. A matched case-control study of 430 acute ischemic stroke patients was conducted at Massachusetts General Hospital (MGH) in order to identify specific brain regions of acute infarction that are associated with hospital acquired pneumonia (HAP) in these patients. There are 138 brain regions in which infarction was measured, which introduce nearly 10,000 two-way interactions, and challenge the statistical analysis. We investigate penalized conditional and unconditional logistic regression approaches to this variable selection problem that properly differentiate between selection of main effects and of interactions, and that acknowledge the matching. This neuroimaging study was nested within a larger prospective study of HAP in 1915 stroke patients at MGH, which recorded clinical variables, but did not include neuroimaging. We demonstrate how the larger study, in conjunction with the nested, matched study, affords us the capability to derive a score for prediction of HAP in future stroke patients based on imaging and clinical features. We evaluate the proposed methods in simulation studies and we apply them to the MGH HAP study.An analysis of adaptive design variations on the sequential parallel comparison design for clinical trials
AbstractMi, M. Y., & Betensky, R. A. (n.d.).Publication year
2013Journal title
Clinical TrialsVolume
10Issue
2Page(s)
207-215AbstractBackground Currently, a growing placebo response rate has been observed in clinical trials for antidepressant drugs, a phenomenon that has made it increasingly difficult to demonstrate efficacy. The sequential parallel comparison design (SPCD) is a clinical trial design that was proposed to address this issue. The SPCD theoretically has the potential to reduce the sample-size requirement for a clinical trial and to simultaneously enrich the study population to be less responsive to the placebo. Purpose Because the basic SPCD already reduces the placebo response by removing placebo responders between the first and second phases of a trial, the purpose of this study was to examine whether we can further improve the efficiency of the basic SPCD and whether we can do so when the projected underlying drug and placebo response rates differ considerably from the actual ones. Methods Three adaptive designs that used interim analyses to readjust the length of study duration for individual patients were tested to reduce the sample-size requirement or increase the statistical power of the SPCD. Various simulations of clinical trials using the SPCD with interim analyses were conducted to test these designs through calculations of empirical power. Results From the simulations, we found that the adaptive designs can recover unnecessary resources spent in the traditional SPCD trial format with overestimated initial sample sizes and provide moderate gains in power. Under the first design, results showed up to a 25% reduction in person-days, with most power losses below 5%. In the second design, results showed up to a 8% reduction in person-days with negligible loss of power. In the third design using sample-size re-estimation, up to 25% power was recovered from underestimated sample-size scenarios. Limitations Given the numerous possible test parameters that could have been chosen for the simulations, the study's results are limited to situations described by the parameters that were used and may not generalize to all possible scenarios. Furthermore, dropout of patients is not considered in this study. Conclusions It is possible to make an already complex design such as the SPCD adaptive, and thus more efficient, potentially overcoming the problem of placebo response at lower cost. Ultimately, such a design may expedite the approval of future effective treatments.Differential relationships of reactive astrocytes and microglia to fibrillar amyloid deposits in alzheimer disease
AbstractSerrano-Pozo, A., Muzikansky, A., Gómez-Isla, T., Growdon, J. H., Betensky, R. A., Frosch, M. P., & Hyman, B. T. (n.d.).Publication year
2013Journal title
Journal of Neuropathology and Experimental NeurologyVolume
72Issue
6Page(s)
462-471AbstractAlthough it is clear that astrocytes and microglia cluster around dense-core amyloid plaques in Alzheimer disease (AD), whether they are primarily attracted to amyloid deposits or are just reacting to plaque-associated neuritic damage remains elusive. We postulate that astrocytes and microglia may differentially respond to fibrillar amyloid β. Therefore, we quantified the size distribution of dense-core thioflavin-S (ThioS)-positive plaques in the temporal neocortex of 40 AD patients and the microglial and astrocyte responses in their vicinity (≤50 μm) and performed correlations between both measures. As expected, both astrocytes and microglia were clearly spatially associated with ThioS-positive plaques (p = 0.0001, ≤50 μm vs >50 μm from their edge), but their relationship to ThioS-positive plaque size differed: larger ThioS-positive plaques were associated with more surrounding activated microglia (p = 0.0026), but this effect was not observed with reactive astrocytes. Microglial response to dense-core plaques seems to be proportional to their size, which we postulate reflects a chemotactic effect of amyloid β. By contrast, plaque-associated astrocytic response does not correlate with plaque size and seems to parallel the behavior of plaque-associated neuritic damage.Estimating the effect of emergency care on early survival after traffic crashes
AbstractClark, D. E., Winchell, R. J., & Betensky, R. A. (n.d.).Publication year
2013Journal title
Accident Analysis and PreventionVolume
60Page(s)
141-147AbstractIntroduction Traffic crash mortality is higher in rural areas, but it is unclear whether this is due to greater injury severity, time delays, or Emergency Medical Services (EMS) deficiencies. Methods Data from 2002-2003 were combined from the Fatality Analysis Reporting System (FARS) and an "expanded version" of the National Automotive Sampling System (NASS) Crashworthiness Data System (CDS). Weighted Cox and Weibull models for survival time (tSURV) were estimated, with time-varying covariates (TVC) having constant effects for specified time intervals following EMS arrival time (tEMS) and hospital arrival time (tHOS). The Weibull model was repeated with tSURV interval-censored to reflect uncertainty about the exact time of death, using an imputation method to accommodate interval censoring along with TVC. Results FARS contained records for 92,718 persons with fatal or incapacitating injuries, and NASS/CDS contained 5517 (weighted population of 642,716) with incapacitating injuries. All models associated mortality with increasing age, male sex, belt nonuse, higher speeds, and vehicle rollover. The interval-censored model associated EMS intervention with a beneficial effect until tEMS + 30 min, but not thereafter; hospital intervention was associated with a strongly beneficial effect that increased with time. Rural location was associated with a higher baseline hazard; a 50% reduction in rural prehospital time would theoretically reduce 4-h mortality by about 7%. Conclusion Rural/urban disparity in crash mortality is mostly independent of time delays and EMS effects. However, survival models with TVC support clinical intuition of a "golden hour" in EMS care, and the importance of timely transport to a hospital.Estimating Time to Disease Progression Comparing Transition Models and Survival Methods-An Analysis of Multiple Sclerosis Data
AbstractMandel, M., Mercier, F., Eckert, B., Chin, P., & Betensky, R. A. (n.d.).Publication year
2013Journal title
BiometricsVolume
69Issue
1Page(s)
225-234AbstractThis article reports an analysis that aims to quantify the effect of fingolimod, an oral treatment for relapsing remitting multiple sclerosis (MS), on disability progression. The standard approach utilizes survival analysis methods, which may be problematic for MS studies that assess disability at only a few time points and include as a cardinal feature both relapses and remissions. Instead, a Markov transition model, originally developed in the framework of longitudinal data, is fit, and its special probabilistic properties are used to estimate survival curves for time to disability progression. The transition approach models the whole disability process and uses all available transition data for inference, while survival methods concentrate on a single event of interest and use only time to event data. This article compares the transition model approach to survival analysis methods, and discusses the differences in the interpretations of the estimated parameters. It applies both models to data obtained from two phase 3 clinical trials and finds that both yield positive effects for the new treatment compared to placebo, and provide similar estimates for the probability of disability progression over time. The transition model enables calculation of covariate-specific transition matrices that describe the short-term effect of treatment and other covariates on the disability process.Examination of the clinicopathologic continuum of Alzheimer disease in the autopsy cohort of the national alzheimer coordinating center
AbstractSerrano-Pozo, A., Qian, J., Monsell, S. E., Frosch, M. P., Betensky, R. A., & Hyman, B. T. (n.d.).Publication year
2013Journal title
Journal of Neuropathology and Experimental NeurologyVolume
72Issue
12Page(s)
1182-1192AbstractTo test the hypothesis that Alzheimer disease (AD) is a clinical and pathologic continuum between normal aging and end-stage dementia, we selected a convenience sample of subjects from the National Alzheimer Coordinating Center 2005 to 2012 autopsy cohort (n = 2,083) with the last clinical evaluation within 2 years before autopsy and no other primary neuropathologic diagnosis. Demographic and neuropathologic characteristics were correlated with the Clinical Dementia Rating-Sum of Boxes in the 835 subjects meeting these criteria. Both neuritic plaques and neurofibrillary tangles independently predicted Clinical Dementia Rating-Sum of Boxes. Severe small-vessel disease, severe amyloid angiopathy, and hippocampal sclerosis were also independently associated with the degree of cognitive impairment. By contrast, education was a strong independent protective factor against cognitive deficits. The cause of mild to moderate dementia remained uncertain in 14% of the patients. Inverse probability weighting suggests the generalizability of these results to nonautopsied cohorts. These data indicate that plaques and tangles independently contribute to cognitive impairment, that concurrent vascular disease strongly correlates with cognitive dysfunction even in a sample selected to represent the AD pathologic continuum, and that education further modifies clinical expression. Thus, multiple concomitant etiologies of brain damage and premorbid characteristics contribute to the uncertainty of AD clinicopathologic correlations based only on tangles and plaques.Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain
AbstractHudry, E., Dashkoff, J., Roe, A. D., Takeda, S., Koffie, R. M., Hashimoto, T., Scheel, M., Spires-Jones, T., Arbel-Ornath, M., Betensky, R., Davidson, B. L., & Hyman, B. T. (n.d.).Publication year
2013Journal title
Science Translational MedicineVolume
5Issue
212AbstractInheritance of the ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor associated with the sporadic form of Alzheimer's disease (AD), whereas the rare APOE ε2 allele has the opposite effect. However, the mechanisms whereby APOE confers risk and protection remain uncertain. We used a gene transfer approach to bathe the cortex of amyloid plaque-bearing transgenic mice with virally expressed human APOE. We monitored amyloid-β (Aβ) with multiphoton imaging, in vivo microdialysis, and postmortem array tomography to study the kinetics of human APOE mediated changes in Aβ-related neurotoxicity in a mouse model of AD. We observed that human APOE4 increased the concentrations of oligomeric Aβ within the interstitial fluid and exacerbated plaque deposition; the converse occurred after exposure to human APOE2. Peri-plaque synapse loss and dystrophic neurites were also worsened by APOE4 or attenuated by APOE2. Egress of Aβ from the central nervous system (CNS) into the plasma was diminished by APOE3 and APOE4 compared to APOE2, in accord with isoform-specific retention of Aβ in the CNS. Overall, our data show a differential effect of human APOE isoforms on amyloid deposition and clearance in transgenic mice and, more importantly, on Aβ-mediated synaptotoxicity. These results suggest that the APOE genetic risk is mediated by Aβ, and that therapeutic approaches aimed at decreasing APOE4, or increasing APOE2, may be beneficial in AD.Hospital Acquired Pneumonia Is Linked to Right Hemispheric Peri-Insular Stroke
AbstractKemmling, A., Lev, M. H., Payabvash, S., Betensky, R. A., Qian, J., Masrur, S., & Schwamm, L. H. (n.d.).Publication year
2013Journal title
PloS oneVolume
8Issue
8AbstractPurpose:Hospital acquired pneumonia (HAP) is a major complication of stroke. We sought to determine associations between infarction of specific brain regions and HAP.Methods:215 consecutive acute stroke patients with HAP (2003-2009) were carefully matched with 215 non-pneumonia controls by gender, then NIHSS, then age. Admission imaging and binary masks of infarction were registered to MNI-152 space. Regional atlas and voxel-based log-odds were calculated to assess the relationship between infarct location and the likelihood of HAP. An independently validated penalized conditional logistic regression model was used to identify HAP associated imaging regions.Results:The HAP and control patients were well matched by gender (100%), age (95% within 5-years), NIHSS (98% within 1-point), infarct size, dysphagia, and six other clinical variables. Right hemispheric infarcts were more frequent in patients with HAP versus controls (43.3% vs. 34.0%, p = 0.054), whereas left hemispheric infarcts were more frequent in controls (56.7% vs. 44.7%, p = 0.012); there was no significant difference between groups in the rate of brainstem strokes (p = 1.0). Of the 10 most infarcted regions, only right insular cortex volume was different in HAP versus controls (20 vs. 12 ml, p = 0.02). In univariate analyses, the highest log-odds regions for pneumonia were right hemisphere, cerebellum, and brainstem. The best performing multivariate model selected 7 brain regions of infarction and 2 infarct volume-based variables independently associated with HAP.Conclusions:HAP is associated with right hemispheric peri-insular stroke. These associations may be related to autonomic modulation of immune mechanisms, supporting recent hypotheses of stroke mediated immune suppression.Human miRNome profiling identifies microRNAs differentially present in the urine after kidney injury
AbstractRamachandran, K., Saikumar, J., Bijol, V., Koyner, J. L., Qian, J., Betensky, R. A., Waikar, S. S., & Vaidya, V. S. (n.d.).Publication year
2013Journal title
Clinical ChemistryVolume
59Issue
12Page(s)
1742-1752AbstractBACKGROUND: Extracellular microRNAs (miRNAs) have been proposed as potentially robust and stable biomarkers of various disease conditions. The primary objective of this study was to identify miRNAs differentially occurring in the urine that could serve as potential biomarkers of acute kidney injury (AKI), because traditional AKI markers have limitations with respect to sensitivity, specificity, and timeliness of diagnosis. METHODS: We profiled 1809 miRNAs in pooled urine samples from 6 patients with AKI and from 6 healthy controls. We measured the 378 stably detectable miRNAs in the 12 samples individually and selected the top 7 miRNAs that were most different in the urine of patients with AKI compared with the non-AKI control individuals. These miRNAs were assessed in a larger cohort of patients with AKI (n = 98: 71 AKI patients in the intensive care unit (ICU) and 27 kidney transplantation patients with biopsy-proven tubular injury) and patients without AKI (n = 97: 74 healthy volunteers and 23 ICU patients without AKI). RESULTS: We identified 4 miRNAs capable of significantly differentiating patients with AKI from individuals without AKI: miR-21 (P = 0.0005), miR-200c (P < 0.0001), miR-423 (P = 0.001), and miR-4640 (P = 0.0355). The combined cross-validated area under the ROC curve for these 4 miRNAs was 0.91. The imprecision with respect to miRNA isolation and reverse transcription efficiency was <9% across 224 samples. CONCLUSIONS: In this study we determined the entire miRNome of human urine and identified a panel of miRNAs that are both detectable noninvasively and diagnostically sensitive indicators of kidney damage.Imperfect gold standards for biomarker evaluation
AbstractWaikar, S. S., Betensky, R. A., Emerson, S. C., & Bonventre, J. V. (n.d.).Publication year
2013Journal title
Clinical TrialsVolume
10Issue
5Page(s)
696-700AbstractBackground Serum creatinine has been used as the diagnostic test for acute kidney injury (AKI) for decades despite having imperfect sensitivity and specificity. Novel tubular injury biomarkers may revolutionize the diagnosis of KI; however, even if a novel tubular injury biomarker is 100% sensitive and 100% specific, it may appear inaccurate when using serum creatinine as the gold standard. Conclusions In general, the apparent diagnostic performance of a biomarker depends not only on its ability to detect injury but also on disease prevalence and the sensitivity and specificity of the imperfect gold standard. Apparent errors in diagnosis using a new biomarker may be a reflection of errors in the imperfect gold standard itself rather than poor performance of the biomarker. Clinical Trials 2013; 10: 696700. http://ctj.sagepub.com.Improved design of prodromal Alzheimer's disease trials through cohort enrichment and surrogate endpoints
AbstractMacklin, E. A., Blacker, D., Hyman, B. T., & Betensky, R. A. (n.d.).Publication year
2013Journal title
Journal of Alzheimer's DiseaseVolume
36Issue
3Page(s)
475-486AbstractAlzheimer's disease (AD) trials initiated during or before the prodrome are costly and lengthy because patients are enrolled long before clinical symptoms are apparent, when disease progression is slow. We hypothesized that design of such trials could be improved by: 1) selecting individuals at moderate near-term risk of progression to AD dementia (the current clinical standard) and 2) by using short-term surrogate endpoints that predict progression to AD dementia. We used a longitudinal cohort of older, initially non-demented, community-dwelling participants (n = 358) to derive selection criteria and surrogate endpoints and tested them in an independent national data set (n = 6,243). To identify a 'mid-risk' subgroup, we applied conditional tree-based survival models to Clinical Dementia Rating (CDR) scale scores and common neuropsychological tests. In the validation cohort, a time-to-AD dementia trial applying these mid-risk selection criteria to a pool of all non-demented individuals could achieve equivalent power with 47% fewer participants than enrolling at random from that pool. We evaluated surrogate endpoints measureable over two years of follow-up based on cross-validated concordance between predictions from Cox models and observed time to AD dementia. The best performing surrogate, rate of change in CDR sum-of-boxes, did not reduce the trial duration required for equivalent power using estimates from the validation cohort, but alternative surrogates with better ability to predict time to AD dementia should be able to do so. The approach tested here might improve efficiency of prodromal AD trials using other potential measures and could be generalized to other diseases with long prodromal phases.Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer's disease mouse models
AbstractArbel-Ornath, M., Hudry, E., Eikermann-Haerter, K., Hou, S., Gregory, J. L., Zhao, L., Betensky, R. A., Frosch, M. P., Greenberg, S. M., & Bacskai, B. J. (n.d.).Publication year
2013Journal title
Acta NeuropathologicaVolume
126Issue
3Page(s)
353-364AbstractThe interstitial fluid (ISF) drainage pathway has been hypothesized to underlie the clearance of solutes and metabolites from the brain. Previous work has implicated the perivascular spaces along arteries as the likely route for ISF clearance; however, it has never been demonstrated directly. The accumulation of amyloid β (Aβ) peptides in brain parenchyma is one of the pathological hallmarks of Alzheimer disease (AD), and it is likely related to an imbalance between production and clearance of the peptide. Aβ drainage along perivascular spaces has been postulated to be one of the mechanisms that mediate the peptide clearance from the brain. We therefore devised a novel method to visualize solute clearance in real time in the living mouse brain using laser guided bolus dye injections and multiphoton imaging. This methodology allows high spatial and temporal resolution and revealed the kinetics of ISF clearance. We found that the ISF drains along perivascular spaces of arteries and capillaries but not veins, and its clearance exhibits a bi-exponential profile. ISF drainage requires a functional vasculature, as solute clearance decreased when perfusion was impaired. In addition, reduced solute clearance was observed in transgenic mice with significant vascular amyloid deposition; we suggest the existence of a feed-forward mechanism, by which amyloid deposition promotes further amyloid deposition. This important finding provides a mechanistic link between cerebrovascular disease and Alzheimer disease and suggests that facilitation of Aβ clearance along the perivascular pathway should be considered as a new target for therapeutic approaches to Alzheimer disease and cerebral amyloid angiopathy.Molecular evolution of human adenoviruses
AbstractRobinson, C. M., Singh, G., Lee, J. Y., Dehghan, S., Rajaiya, J., Liu, E. B., Yousuf, M. A., Betensky, R. A., Jones, M. S., Dyer, D. W., Seto, D., & Chodosh, J. (n.d.).Publication year
2013Journal title
Scientific reportsVolume
3AbstractThe recent emergence of highly virulent human adenoviruses (HAdVs) with new tissue tropisms underscores the need to determine their ontogeny. Here we report complete high quality genome sequences and analyses for all the previously unsequenced HAdV serotypes (n = 20) within HAdV species D. Analysis of nucleotide sequence variability for these in conjunction with another 40 HAdV prototypes, comprising all seven HAdV species, confirmed the uniquely hypervariable regions within species. The mutation rate among HAdV-Ds was low when compared to other HAdV species. Homologous recombination was identified in at least two of five examined hypervariable regions for every virus, suggesting the evolution of HAdV-Ds has been highly dependent on homologous recombination. Patterns of alternating GC and AT rich motifs correlated well with hypervariable region recombination sites across the HAdV-D genomes, suggesting foci of DNA instability lead to formulaic patterns of homologous recombination and confer agility to adenovirus evolution.Patients with celiac disease have a lower prevalence of non-insulin-dependent diabetes mellitus and metabolic syndrome
AbstractKabbani, T. A., Kelly, C. P., Betensky, R. A., Hansen, J., Pallav, K., Villafuerte-Gálvez, J. A., Vanga, R., Mukherjee, R., Novero, A., Dennis, M., & Leffler, D. A. (n.d.).Publication year
2013Journal title
GastroenterologyVolume
144Issue
5Page(s)
912-917.e1AbstractBackground & Aims: We investigated whether risk for non-insulin-dependent diabetes mellitus (NIDDM) and metabolic syndrome are affected by celiac disease. We examined the prevalence of NIDDM and metabolic syndrome among adults with celiac disease, compared with matched controls. Methods: We assessed medical records of 840 patients with biopsy-proven celiac disease for diagnoses of NIDDM, hypertension, or hyperlipidemia; body mass index (BMI); lipid profile; and levels of glucose or glycosylated hemoglobin, to identify those with metabolic syndrome. Patients without celiac disease were matched for age, sex, and ethnicity (n = 840 controls). The prevalence of NIDDM and metabolic syndrome in the celiac disease cohort was compared with that of the controls and subjects included in the National Health and Nutrition Examination Survey. Results: Twenty-six patients with celiac disease (3.1%) had NIDDM compared with 81 controls (9.6%) (P <.0001). Similarly, the prevalence of metabolic syndrome was significantly lower among patients with celiac disease than controls (3.5% vs 12.7%; P <.0001). The mean BMI of patients with celiac disease was significantly lower than that of controls (24.7 vs 27.5; P <.0001). However, celiac disease was still associated with a lower risk of NIDDM, after controlling for BMI. Conclusions: The prevalence of NIDDM and metabolic syndrome are lower among patients with celiac disease than in matched controls and the general population. These differences are not explained by differences in BMI. Studies are needed to determine the mechanisms by which celiac disease affects the risk for NIDDM and metabolic syndrome.Primary leptomeningeal lymphoma: International Primary CNS lymphoma collaborative group report
AbstractTaylor, J. W., Flanagan, E. P., O’Neill, B. P., Siegal, T., Omuro, A., DeAngelis, L., Baehring, J., Nishikawa, R., Pinto, F., Chamberlain, M., Hoang-Xuan, K., Gonzalez-Aguilar, A., Batchelor, T., Blay, J. Y., Korfel, A., Betensky, R. A., Lopes, M. B. S., & Schiff, D. (n.d.).Publication year
2013Journal title
NeurologyVolume
81Issue
19Page(s)
1690-1696AbstractObjective: To evaluate clinical presentation, optimal diagnostic evaluation and treatment, and outcome in primary leptomeningeal lymphoma, a rare form of primary CNS lymphoma without parenchymal or systemic involvement. Methods: The International Primary CNS Lymphoma Collaborative Group, a multidisciplinary group of physicians with a particular interest in primary CNS lymphoma, retrospectively identified cases of lymphoma isolated to the leptomeninges as diagnosed by CSF cytology, flow cytometry, or biopsy, without systemic or parenchymal brain/spinal cord lymphoma or immunodeficiency. Results: Forty-eight patients were identified, with median age at diagnosis of 51 years and median Eastern Cooperative Oncology Group performance status of 2. Presenting symptoms were multifocal in 68%. Leptomeningeal enhancement was seen in 74% and CSF profile was abnormal in all cases. CSF cytology detected malignant lymphocytes in 67%. Flow cytometry identified monoclonal population in 80%, as did receptor gene rearrangement studies in 71%. Sixty-two percent had B-cell lymphoma, 19% T-cell, and 19% unclassified. Treatment varied and included fractionated radiotherapy (36%), systemic chemotherapy (78%), and intra-CSF chemotherapy (66%), with 66% receiving ≥2 modalities. Seventy-one percent had a favorable clinical response; ultimately, 44% received salvage treatment. Median overall survival was 24 months, with 11 patients still alive at 50 months follow-up. Conclusion: Primary leptomeningeal lymphoma is a rare form of primary CNS lymphoma. Patients usually present with multifocal symptoms, with evidence of leptomeningeal enhancement and diagnostic CSF analysis. Although treatment is highly variable, patients have a better prognosis than previously reported and a subset may be cured.Reply to Sabanés Bové and Held's "Comment on Cai and Betensky (2003), On the Poisson Approximation for Hazard Regression"
Cai, T., & Betensky, R. (n.d.).Publication year
2013Journal title
BiometricsVolume
69Issue
3Page(s)
796Tau causes synapse loss without disrupting calcium homeostasis in the rTg4510 model of tauopathy
AbstractKopeikina, K. J., Wegmann, S., Pitstick, R., Carlson, G. A., Bacskai, B. J., Betensky, R. A., Hyman, B. T., & Spires-Jones, T. L. (n.d.).Publication year
2013Journal title
PloS oneVolume
8Issue
11AbstractNeurofibrillary tangles (NFTs) of tau are one of the defining hallmarks of Alzheimer's disease (AD), and are closely associated with neuronal degeneration. Although it has been suggested that calcium dysregulation is important to AD pathogenesis, few studies have probed the link between calcium homeostasis, synapse loss and pathological changes in tau. Here we test the hypothesis that pathological changes in tau are associated with changes in calcium by utilizing in vivo calcium imaging in adult rTg4510 mice that exhibit severe tau pathology due to over-expression of human mutant P301L tau. We observe prominent dendritic spine loss without disruptions in calcium homeostasis, indicating that tangles do not disrupt this fundamental feature of neuronal health, and that tau likely induces spine loss in a calcium-independent manner.Application of futility analysis to refine jitter recordings in myasthenia gravis
AbstractNarayanaswami, P., Pantoja-Galicia, N., Betensky, R. A., & Rutkove, S. B. (n.d.).Publication year
2012Journal title
Muscle and NerveVolume
45Issue
4Page(s)
486-491AbstractIntroduction: The current practice of single-fiber electromyography (SFEMG) requires that 20 fiber pairs with normal jitter be collected to exclude myasthenia gravis (MG). We applied principles of futility analysis from clinical trials in an attempt to reduce that requirement. Methods: We utilized conditional power futility analysis to assess the probability of an abnormal 20-pair SFEMG based on ongoing analysis of jitter as each pair is collected. Rules for early test termination in the presence of 0, 1, or 2 abnormal pairs were identified. These rules were then applied to previously collected SFEMG data. Results: SFEMG could be stopped at just 12 pairs if all are normal and at 17 pairs if 1 is abnormal. The rules successfully determined when SFEMG could be stopped in 104 of 106 (98%) studies originally reported to be normal. Conclusions: If the first 12 SFEMG pairs have normal jitter, the study can be terminated and interpreted as normal.Calcineurin activation causes retinal ganglion cell degeneration
AbstractQu, J., Matsouaka, R., Betensky, R. A., Hyman, B. T., & Grosskreutz, C. L. (n.d.).Publication year
2012Journal title
Molecular VisionVolume
18Page(s)
2828-2838AbstractPurpose: We previously reported that calcineurin, a Ca2+/calmodulin-dependent serine/threonine phosphatase, is activated and proposed that it participates in retinal ganglion cell (RGC) apoptosis in two rodent ocular hypertension models. In this study, we tested whether calcineurin activation by itself, even in the absence of ocular hypertension, is sufficient to cause RGC degeneration. Methods: We compared RGC and optic nerve morphology after adeno-associated virus serotype 2 (AAV2)-mediated transduction of RGCs with constitutively active calcineurin (CaNCA) or unactivated, wild-type calcineurin (CaNwt). Retinas and optic nerves were harvested 7-16 weeks after injection of the AAV into mouse vitreous. In flatmounted retinas, the transduced RGCs were identified with immunohistochemistry. The morphology of the RGCs was revealed by immunostaining for neurofilament SMI32 or by using GFP-M transgenic mice. A modified Sholl analysis was applied to analyze the RGC dendritic morphology. Optic nerve damage was assessed with optic nerve grading according to the Morrison standard. Results: CaNwt and CaNCA were highly expressed in the injected eyes. Compared to the CaNwt-expressing RGCs, the CaNCA-expressing RGCs had smaller somas, smaller dendritic field areas, shorter total dendrite lengths, and simpler dendritic branching patterns. At 16 weeks, the CaNCA-expressing eyes had greater optic nerve damage than the CaNwt-expressing eyes. Conclusions: Calcineurin activation is sufficient to cause RGC dendritic degeneration and optic nerve damage. These data support the hypothesis that calcineurin activation is an important mediator of RGC degeneration, and are consistent with the hypothesis that calcineurin activation may contribute to RGC neurodegeneration in glaucoma.Corelease of dopamine and GABA by a retinal dopaminergic neuron
AbstractHirasawa, H., Betensky, R. A., & Raviola, E. (n.d.).Publication year
2012Journal title
Journal of NeuroscienceVolume
32Issue
38Page(s)
13281-13291AbstractNumerous neurons release two transmitters of low molecular mass, but it is controversial whether they are localized within the same synaptic vesicle, with the single exception of GABA and glycine because they are ferried into the vesicle by the same transporter. Retinal dopaminergic (DAergic) amacrine cells synthesize both dopamine (DA) and GABA. Both transmitters are released over the entire cell surface and act on neighboring and distant neurons by volume transmission, but, in addition, DAergic cells establish GABAergic synapses onto AII amacrine cells, the neurons that transfer rod signals to cone bipolars. By combining recordings of DA and GABA release from isolated, genetically identified perikarya of DAergic cells from the mouse retina, we observed that a proportion of the events of DA and GABA exocytosis were simultaneous, suggesting corelease. Furthermore, a proportion of the secretory organelles in the perikaryon and synaptic endings of DAergic cells contained both vesicular transporters for DA [vesicular monoamine transporter 2 (VMAT2)] and GABA [vesicular GABA transporter (VGAT)]. Because the majority of the DA release events concerned a single transmitter and organelles were present that contained a single transporter, either VMAT2 or VGAT, we conclude that the secretory organelles of DAergic cells contain variable concentrations of the two transmitters, which are in turn determined by a variable mixture of the two transporter molecules in their limiting membrane. This variability can be explained if the relative numbers of transporter molecules is determined stochastically during the budding of the somatic organelles from the trans-Golgi network or the retrieval of the vesicular membrane from the plasmalemma after exocytosis.Digital quantification of precursor frequency in the fallopian tube and its significance
AbstractBijron, J. G., Ning, G., Laury, A. R., Quick, C. M., Betensky, R. A., Monte, N. M., King, E., McKeon, F. D., Xian, W., & Crum, C. P. (n.d.).Publication year
2012Journal title
Modern PathologyVolume
25Issue
12Page(s)
1654-1661AbstractA high frequency of precursor lesions is a risk factor for cancer in many organ systems but must be precisely quantified. Pelvic serous neoplasia is associated with an estimated increase in frequency of secretory cell outgrowths (SCOUTs) with loss of PAX2 protein (PAX2p) expression (PAX2p-null SCOUTs) in the fallopian tube. However, to confirm this, PAX2p-null SCOUTs must be precisely quantified relative to the epithelial surface. We developed a method by which fallopian tube sections were digitized using an iScan brightfield scanner (BioImagene) and uploaded in Adobe Photoshop CS3 Extended. Pixel length was translated into microns and epithelial length measured with the Magic Wand tool. SCOUTs were expressed as a function of total epithelial perimeter. Frequency, required perimeter length, topographic clustering tendency and effects of age were ascertained. SCOUT frequency per 10 cm was 0-4.60 for cases and 0-1.66 for controls, averaging 0.84 and 0.27, respectively, (P0.007). Required perimeter length for SCOUT detection was less in serous cancer cases and topographic distribution followed a random pattern without aberrant clustering. Age was also associated with SCOUT frequency (P0.025) and differences between cancers and controls were still significant after adjusting for age (P0.001). We describe an efficient method for quantifying epithelial perimeter in the fallopian tube and verify its relevance to precursor frequency. This has important implications for assessing precursor frequency both in the fallopian tube and in other organs - such as prostate, pancreas and colon - where epithelial precursors are integral to carcinogenesis.Gain of chromosome arm 1q in atypical meningioma correlates with shorter progression-free survival
AbstractJansen, M., Mohapatra, G., Betensky, R. A., Keohane, C., & Louis, D. N. (n.d.).Publication year
2012Journal title
Neuropathology and Applied NeurobiologyVolume
38Issue
2Page(s)
213-219AbstractAims: Atypical (World Health Organization grade II) meningiomas have moderately high recurrence rates; even for completely resected tumours, approximately one-third will recur. Post-operative radiotherapy may aid local control and improve survival, but carries the risk of side effects. More accurate prediction of recurrence risk is therefore needed for patients with atypical meningioma. Previously, we used high-resolution array comparative genomic hybridization to identify genetic variations in 47 primary atypical meningiomas and found that approximately 60% of tumours show gain of 1q at 1q25.1 and 1q25.3 to 1q32.1 and that 1q gain appeared to correlate with shorter progression-free survival. This study aimed to validate and extend these findings in an independent sample. Methods: Eighty-six completely resected atypical meningiomas (with 25 recurrences) from two neurosurgical centres in Ireland were identified and clinical follow-up was obtained. Utilizing a dual-colour interphase fluorescence in situ hybridization assay, 1q gain was assessed using Bacterial Artificial Chromosome probes directed against 1q25.1 and 1q32.1. Results: The results confirm the high prevalence of 1q gain at these loci in atypical meningiomas. We further show that gain at 1q32.1 and age each correlate with progression-free survival in patients who have undergone complete surgical resection of atypical meningiomas. Conclusions: These independent findings suggest that assessment of 1q copy number status can add clinically useful information for the management of patients with atypical meningiomas.