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Pierpont E.I.,University of Wisconsin - Madison | Richmond E.K.,University of Wisconsin - Madison | Abbeduto L.,University of California at Davis | Kover S.T.,University of Wisconsin - Madison | Brown W.T.,Institute for Basic Research in Developmental Disabilities
Journal of Neurodevelopmental Disorders | Year: 2011

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Although language delays are frequently observed in FXS, neither the longitudinal course of language development nor its cognitive predictors are well understood. The present study investigated whether phonological and working memory skills are predictive of growth in vocabulary and syntax in individuals with FXS during adolescence. Forty-four individuals with FXS (mean age = 12.61 years) completed assessments of phonological memory (nonword repetition and forward digit recall), verbal working memory (backward digit recall), vocabulary, syntax, and nonverbal cognition. Vocabulary and syntax skills were reassessed at a 2-year follow-up. In a series of analyses that controlled for nonverbal cognitive ability and severity of autism symptoms, the relative contributions of phonological and working memory to language change over time were investigated. These relationships were examined separately for boys and girls. In boys with FXS, phonological memory significantly predicted gains in vocabulary and syntax skills. Further, verbal working memory was uniquely associated with vocabulary gains among boys. In girls with FXS, phonological and working memory skills showed no relationship with language change across the 2-year time period. Our findings indicate that, for adolescent boys with FXS, acquisition of vocabulary and syntax may be constrained by the ability to maintain and manipulate phonological representations online. Implications for the identification and treatment of language disorders in this population are discussed. The present study is the first to identify specific cognitive mechanisms contributing to language growth over time in individuals with FXS. © 2011 Springer Science+Business Media, LLC.


Torr J.,Monash University | Strydom A.,University College London | Patti P.,Institute for Basic Research in Developmental Disabilities | Jokinen N.,University of Calgary
Journal of Policy and Practice in Intellectual Disabilities | Year: 2010

The life expectancy of adults with Down syndrome has increased dramatically over the last 30 years, leading to increasing numbers of adults with Down syndrome now living into middle and old age. Early-onset dementia of the Alzheimer type is highly prevalent in adults with Down syndrome in the sixth decade, and this has overshadowed other important conditions related to aging among adults with Down syndrome. The authors' aim was to update and summarize current knowledge on these conditions, and examine causes of morbidity and mortality in older people with Down syndrome by conducting a systematic review of the published literature for the period: 1993-2008. They reviewed English-language literature drawn from searches in the electronic databases Medline, CINAHL, and PsycINFO, as well as supplementary historical papers. The authors conclude that functional decline in older adults with Down syndrome cannot be assumed to be due only to dementia of the Alzheimer type (which is not inevitable in all adults with Down syndrome). Functional decline may be the result from a range of disorders, especially sensory and musculoskeletal impairments. Given the high rates of early-onset age-related disorders among adults with Down syndrome, programmatic screening, monitoring, and preventive interventions are required to limit secondary disabilities and premature mortality. With respect to assessment and treatment, in the absence of specialist disability physicians, geriatricians have a role to play. © 2010 International Association for the Scientific Study of Intellectual Disabilities and Wiley Periodicals, Inc.


Butler T.,New York University | Zaborszky L.,Rutgers University | Pirraglia E.,New York University | Li J.,New York University | And 14 more authors.
NeuroImage | Year: 2014

Septal nuclei, located in basal forebrain, are strongly connected with hippocampi and important in learning and memory, but have received limited research attention in human MRI studies. While probabilistic maps for estimating septal volume on MRI are now available, they have not been independently validated against manual tracing of MRI, typically considered the gold standard for delineating brain structures. We developed a protocol for manual tracing of the human septal region on MRI based on examination of neuroanatomical specimens. We applied this tracing protocol to T1 MRI scans (n. = 86) from subjects with temporal epilepsy and healthy controls to measure septal volume. To assess the inter-rater reliability of the protocol, a second tracer used the same protocol on 20 scans that were randomly selected from the 72 healthy controls. In addition to measuring septal volume, maximum septal thickness between the ventricles was measured and recorded. The same scans (n. = 86) were also analyzed using septal probabilistic maps and DARTEL toolbox in SPM. Results show that our manual tracing algorithm is reliable, and that septal volume measurements obtained via manual and automated methods correlate significantly with each other (p. <. .001). Both manual and automated methods detected significantly enlarged septal nuclei in patients with temporal lobe epilepsy in accord with a proposed compensatory neuroplastic process related to the strong connections between septal nuclei and hippocampi. Septal thickness, which was simple to measure with excellent inter-rater reliability, correlated well with both manual and automated septal volume, suggesting it could serve as an easy-to-measure surrogate for septal volume in future studies. Our results call attention to the important though understudied human septal region, confirm its enlargement in temporal lobe epilepsy, and provide a reliable new manual delineation protocol that will facilitate continued study of this critical region.© 2014 Elsevier Inc.


Oh E.S.,Johns Hopkins University | Mielke M.M.,Johns Hopkins University | Rosenberg P.B.,Johns Hopkins University | Jain A.,Johns Hopkins University | And 3 more authors.
Journal of Alzheimer's Disease | Year: 2010

Plasma amyloid-β (Aβ) level could be useful as a non-invasive biomarker in Alzheimer's disease research. We compared a multiplex electrochemiluminescence detection method with a well established ELISA method for plasma Aβ quantification. Compared to the ELISA method, the electrochemiluminescence detection method demonstrates a statistically significant, but modest correlation. The reasons for th s may include the differences in the affinities of antibodies, and purity and source of Aβ peptides used as standards. However, the advantages of electrochemiluminescence detection technology include short processing time and small sample volume. This comparison demonstrates the need for a further study in optimizing this system. © 2010 - IOS Press and the authors. All rights reserved.


Brown W.T.,Institute for Basic Research in Developmental Disabilities
Results and Problems in Cell Differentiation | Year: 2012

Fragile X syndrome patients express a wide array of cognitive and other gender-specific phenotypic features. These manifestations result not only from molecular mechanisms that are altered as a result of the expansion of a CGG-repeat region in the FMR1 promoter, but also genetic factors such as founder effects and mosaicism. In this chapter, I will summarize the many and varied features of fragile X syndrome as they present themselves in a clinical setting and describe the procedures that are used to diagnose patients. Finally, I will briefly touch on recent developments that will affect patient screening in the future. © 2012 Springer-Verlag Berlin Heidelberg.


Isaacs C.E.,Institute for Basic Research in Developmental Disabilities | Xu W.,Institute for Basic Research in Developmental Disabilities | Merz G.,Institute for Basic Research in Developmental Disabilities | Hillier S.,University of Pittsburgh | And 2 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2011

Topical microbicides are potentially an alternative method to vaccines for reducing the spread of herpes simplex virus (HSV). We have previously shown (S. Liu et al., Biochim. Biophys. Acta 1723:270-281, 2005) that the catechin (-)-epigallocatechin gallate (EGCG) inactivates HSV at neutral pH; however, to function in the female genital tract EGCG must also be effective at acidic pH. EGCG inactivated HSV-1 and HSV-2 at pH 8.0 by 3 log 10 to 4 log 10 but was ineffective at pH 5.7. The EGCG digallate dimers theasinensin A, P2, and theaflavin-3,3′-digallate (TF-3) inactivated both viruses by 3 log 10 to 4 log 10 at pH 5.7 and as much as 5 log 10at pH 8.0. TF-3 inactivated HSV-1 and HSV-2 by 4 to 5 log 10 in the pH range of 4.0 to 5.7. Dimers with one gallate moiety had antiviral activity intermediate between the activities of EGCG and digallate dimers. Confocal and electron microscopy showed that theasinensin A did not damage Vero cells. All EGCG dimers inactivated enveloped viruses with class I, class II, and class III (HSV-1, HSV-2) fusion proteins more effectively than did monomeric EGCG. EGCG had no activity against the nonenveloped viruses tested, but TF-3 reduced the titer of 4 of 5 nonenveloped viruses by ≅2 to 3.5 log 10. Results also showed that HSV-1 glycoprotein B (gB) was aggregated more rapidly by theasinensin A than EGCG, which, when taken together with the nonenveloped virus data, suggests that dimers may inhibit the function of viral proteins required for infectivity. Digallate dimers of EGCG appear to have excellent potential as microbicidal agents against HSV at acidic and neutral pHs. Copyright © 2011, American Society for Microbiology. All Rights Reserved.


Baker L.D.,University of Washington | Baker L.D.,Geriatric Research | Frank L.L.,University of Washington | Frank L.L.,Washington State University | And 21 more authors.
Archives of Neurology | Year: 2010

Objectives: To examine the effects of aerobic exercise on cognition and other biomarkers associated with Alzheimer disease pathology for older adults with mild cognitive impairment, and assess the role of sex as a predictor of response. Design: Six-month, randomized, controlled, clinical trial. Setting: Veterans Affairs Puget Sound Health Care System clinical research unit. Participants: Thirty-three adults (17 women) with amnestic mild cognitive impairment ranging in age from 55 to 85 years (mean age,70 years). Intervention: Participants were randomized either to a high-intensity aerobic exercise or stretching control group. The aerobic group exercised under the supervision of a fitness trainer at 75% to 85% of heart rate reserve for 45 to 60 min/d, 4 d/wk for 6 months. The control group carried out supervised stretching activities according to the same schedule but maintained their heart rate at or below 50% of their heart rate reserve. Before and after the study, glucometabolic and treadmill tests were performed and fat distribution was assessed using dual-energy x-ray absorptiometry. At baseline, month 3, and month 6, blood was collected for assay and cognitive tests were administered. Main Outcome Measures: Performance measures on Symbol-Digit Modalities, Verbal Fluency, Stroop, Trails B, Task Switching, Story Recall, and List Learning. Fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulinlike growth factor-I, and β-amyloids 40 and 42. Results: Six months of high-intensity aerobic exercise had sex-specific effects on cognition, glucose metabolism, and hypothalamic-pituitary-adrenal axis and trophic activity despite comparable gains in cardiorespiratory fitness and body fat reduction. For women, aerobic exercise improved performance on multiple tests of executive function, increased glucose disposal during the metabolic clamp, and reduced fasting plasma levels of insulin, cortisol, and brain-derived neurotrophic factor. For men, aerobic exercise increased plasma levels of insulinlike growth factor I and had a favorable effect only on Trails B performance. Conclusions: This study provides support, using rigorous controlled methodology, for a potent nonpharmacologic intervention that improves executive control processes for older women at high risk of cognitive decline. Moreover, our results suggest that a sex bias in cognitive response may relate to sex-based differences in glucometabolic and hypothalamic-pituitary-adrenal axis responses to aerobic exercise. ©2010 American Medical Association. All rights reserved.


McDuffie A.,University of Wisconsin - Madison | Abbeduto L.,University of Wisconsin - Madison | Lewis P.,University of Wisconsin - Madison | Kover S.,University of Wisconsin - Madison | And 3 more authors.
American Journal on Intellectual and Developmental Disabilities | Year: 2010

The Autism Diagnostic Interview-Revised (ADI-R) was used to examine diagnostic profiles and age-related changes in autism symptoms for a group of verbal children and adolescents who had fragile X syndrome, with and without autism. After controlling for nonverbal IQ, we found statistically significant between-group differences for lifetime and current autism symptoms for the Communication and Restricted Interests/Repetitive Behaviors domains, but not the Reciprocal Social Interaction domain. Effect sizes for differences in Reciprocal Social Interaction also were smaller than effect sizes for the other domains, with one exception. Overall, severity of autism symptoms improved with age for all participants, with the least improvement noted for Restricted Interests and Repetitive Behaviors. FMRP did not account for unique variance in autism symptoms over and above nonverbal IQ. © American Association on Intellectual and Developmental Disabilities.


PubMed | Institute for Basic Research in Developmental Disabilities
Type: Journal Article | Journal: Lipids | Year: 2016

Anesthetic molecules can form hydrogen bonds or organize hydrogen-bond networks. It is argued that they affect the neuronal cell membrane not by an amorphous fluidization of the hyprophobic core of the lipid bilayer but by a restructuring of its hydrogen belts, i.e., the regions occupied by the CO and OH groups of the membrane lipids. The structured disturbance of the hydrogen-bond network is translated latitudinally to hydrogen-bonding sites of the proteins of the membrane, causing allosteric changes of ion channels that result in neuronal blocking.


Reitz C.,Columbia University | Cheng R.,Columbia University | Schupf N.,Columbia University | Lee J.H.,Columbia University | And 5 more authors.
Neurobiology of Aging | Year: 2012

Genetic linkage and association studies in late-onset Alzheimer's disease (LOAD) or its endophenotypes have pointed to several regions on chromosome 10q, among these the ~ 250 kb linkage disequilibrium (LD) block harboring the genes IDE, KIF1, and HHEX. We explored the association between variants in the genomic region harboring the IDE-KIF11-HHEX complex with plasma Aβ40 and Aβ42 levels in a case-control cohort of Caribbean Hispanics. First, we performed single marker linear regression analysis relating the individual single nucleotide polymorphisms (SNPs) with plasma Aβ40 and Aβ42 levels. Then we performed 3-SNP sliding window haplotype analyses, correcting all analyses for multiple testing. Out of 32 SNPs in this region, 3 SNPs in IDE (rs2421943, rs12264682, rs11187060) were associated with plasma Aβ40 or Aβ42 levels in single marker and haplotype analyses after correction for multiple testing. All these SNPs lie within the same LD block, and are in LD with the previously reported haplotypes. Our findings provide support for an association in the IDE region on chromosome 10q with Aβ40 and 42 levels. © 2012 Elsevier Inc.

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