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Biomedical subjects

Carol A Miller

Publications and source records attributed to Carol A Miller.

At least 19 recordsLinked to original sources
PubMed2006

Developmental relationships between language and theory of mind.

PURPOSE: This tutorial is intended to inform readers about the development of theory of mind (understanding of mental states) and to discuss relationships between theory of mind and language development. METHOD: A narrative review of selected literature on language and theory of mind is presented. Theory of mind is defined, and commonly used measures of theory of mind are described. Developmental relationships between language and theory of mind in typical and atypical populations are discussed. Literature-based suggestions for clinical assessment and intervention are provided, using a hypothetical case study. CONCLUSIONS: The article serves as an introduction to current research about language and theory of mind, and emphasizes their interdependence in development. Implications of the relationships between theory of mind and language development for language assessment and intervention are discussed, and an argument is made that taking theory of mind into account will help clinicians enhance children's communication and language development.

Age Factors↗
PubMed2006

Response time in 14-year-olds with language impairment.

PURPOSE: To determine whether children with language impairment were slower than typically developing peers at age 14, and whether slowing, if present, was similar across task domains; whether differences in response time (RT) across domains were the same for children with specific language impairment (SLI) and nonspecific language impairment (NLI); and whether RT performance at age 9 predicted performance at age 14. METHOD: Fourteen-year-old children with SLI (n = 20), NLI (n = 15), and typical development (NLD; n = 31) were administered several linguistic and nonlinguistic speeded tasks. The children had received the same tasks at age 9. RT performance was examined. RESULTS: Both the SLI and the NLI groups were significantly slower than the NLD group in motor, nonverbal cognitive, and language task domains, and there was no significant difference among domains. Individual analyses showed that most, but not all, children with SLI and NLI were slower than the NLD group mean. Slowing at age 9 and age 14 were moderately correlated. CONCLUSIONS: The results suggest that slow RT is a persistent characteristic of many children with language impairment; however, the nature of the relationship between RT and language performance requires further investigation.

Adolescent↗
PubMed2006

Structural priming in children with and without specific language impairment.

PRIMARY OBJECTIVE: To determine if structural priming can be demonstrated in young children with and without specific language impairment (SLI). RESEARCH DESIGN: A mixed-model design was used to compare children with SLI to two groups of typically developing (TD) children, and to compare priming conditions. METHODS AND PROCEDURES: Eighteen children with SLI and 36 TD children (18 matched on age and 18 matched on MLU) participated. Children were asked to describe drawings compatible with both a transitive or an intransitive sentence structure, after being primed with one of the structures. RESULTS: All groups of children were more likely to produce transitive sentences when they had just heard and repeated a transitive prime. Children with SLI did not differ from the other groups. CONCLUSIONS: Children with SLI show similar priming effects to TD children. Priming has promise as a method for investigating production factors in typical and atypical language development.

Case-Control Studies↗
PubMed2006

Mitogen-activated protein kinase signaling, oxygen sensors and hypoxic induction of neurogenesis.

In the adult nervous system, neuronal subpopulations sustain a hierarchical pattern of selective vulnerability to hypoxia. Hypoxia also activates quiescent neural progenitor cells (NPCs) resulting in their amplification and subsequent differentiation into neurons and glia. Use of rat organotypic hippocampal cultures facilitates examination of early signaling events in response to hypoxia and reoxygenation that result in neurogenesis. Cultures were exposed to hypoxia for up to 6 h followed by reoxygenation. CA1 neurons showed focal nuclear condensation by 2 h of hypoxia, but CA2 and CA3 neurons were spared. JNKs and c-Jun reached peak activation by 4 h, returning to basal levels by 6 h. Expression of oxygen sensors, hemoxygenase 2 and HIF1, were elevated by 30 min and 2 h, respectively. By 24 h of reoxygenation, there was proliferation of nestin-positive NPCs. With U0126, an upstream inhibitor of ERK activation, BrdU labeling was markedly reduced immunohistochemically as well as PCNA protein expression, suggesting a role for ERKs in the proliferation response. Immunohistochemically, antinestin detected NPCs and on Western blots reached peak levels by 24-48 h of reoxygenation. Proliferation and differentiation of endogenous NPCs in the area of neuronal loss further suggests that mechanisms potentially exist in vitro for replacement with functional neurons.

Animals↗
PubMed2005

Increased cholesterol in Abeta-positive nerve terminals from Alzheimer's disease cortex.

Synapse loss in Alzheimer's disease (AD) is poorly understood but evidence suggests it is a key pathological event. In order to precisely detect stable synaptic changes, we have developed methods for flow cytometry analysis of synaptosomes prepared from cryopreserved AD samples, and have previously shown that amyloid-beta (Abeta) accumulates in surviving presynaptic terminals in AD cortex. In the present experiments we have examined amyloid-containing terminals in more detail, first dual labeling synaptosomes from AD cortex for Abeta and a series of markers, and then using quadrant analysis to compare amyloid-positive and amyloid-negative terminals. Amyloid-positive synaptosomes were larger in size than amyloid-negatives (p<0.007), and significant increases were observed in mean fluorescence for the lipid raft markers cholesterol (27%; p<0.0005) and GM1 ganglioside (24%; p<0.005). SNAP-25 immunofluorescence was increased by 31% (p<0.0001) in amyloid-bearing terminals, consistent with a sprouting response to amyloid accumulation. These results suggest that Abeta accumulation in synaptic terminals may underly dysfunction prior to or independent of extracellular amyloid deposition.

Adaptation, Physiological↗
PubMed2005

JIP1 regulates neuronal apoptosis in response to stress.

We examined if the relative expression of JNK-interacting protein 1 (JIP1) and phosphorylated c-Jun N-terminal kinase (JNK) regulates cell signaling and contributes to selective neuronal vulnerability in response to environmental stress. In clonal neuroblastoma cultures, stresses such as hypoxia, ischemia, Abeta peptides, and UV irradiation rapidly reduced JIP1 expression. JIP1 mRNA expression was also down-regulated by UV stress and was accompanied by increased JNK and c-Jun activation and cell death. JIP1 protein reduction was partially reversed both by inhibitors predominantly of caspase 3 and of the JNK pathway and resulted in significantly increased cell survival. Conversely, overexpression of JIP1 decreased both nuclear translocation of activated-JNK, and c-Jun phosphorylation induced by either UV irradiation, or the JNK upstream activators, MKK7 or MEKK1. Cell death was reduced about 50% compared to GFP-transfected controls. JIP1 overexpression did not facilitate either JNK expression or activation. In the normal, non-stressed human hippocampus and rat hippocampal organotypic cultures, JIP1 and JNK3 were inversely expressed with more JIP1 in CA2 and CA3 and less in CA1 neurons. In the human hippocampus, transient hypoxia/ischemia selectively spares neurons in CA2 and CA3 and induces death of neurons in the hippocampal CA1 subregion. In the cultures, ischemia reduced JIP1 expression and activated JNK, c-Jun, and caspase 3. Inhibitors of the JNK pathway, JNK activation directly and of caspase 3 activation each partially reversed these effects. Thus, under certain stress conditions, down-regulation of JIP1 expression makes neurons more susceptible to apoptosis, suggesting JIP may serve as an anti-apoptosis factor.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Phospho-beta-catenin accumulation in Alzheimer's disease and in aggresomes attributable to proteasome dysfunction.

Accumulation of cytoplasmic inclusion bodies in many neurodegenerative diseases, including Alzheimer's disease (AD), might result from dysfunction of the ubiquitin-proteasome system. This system degrades many cellular proteins, including beta-catenin, a member of the Wnt signaling pathway, and a presenilin-1-interacting protein. Phosphorylation of beta-catenin marks it for ubiquitination and rapid proteasomal degradation. We found phospho-beta-catenin accumulated as detergent-insoluble, punctate, cytoplasmic inclusions in hippocampal pyramidal neurons more abundantly in AD than in aged controls. In AD, beta-catenin was ubiquitin conjugated, thus suggesting impaired proteasome-dependent degradation. Phospho-beta-catenin was partially sequestered within granulovacuolar degeneration bodies but not in lysosomes, indicating sequestration within autophagosomes. Exposure of neuronal cultures to proteasome inhibitors induced formation of detergent-insoluble, phospho-beta-catenin-positive cytoplasmic inclusions that coalesced into aggresomes and colocalized with gamma-tubulin and vimentin. These aggregates were associated with apoptotic cell death and with activation of caspase-3, c-Jun-N-terminal kinases, and c-Jun. These findings suggest that phospho-beta-catenin accumulation in AD might result from impaired proteasome function.

Aged↗
PubMed2004

Neurogenesis response to hypoxia-induced cell death: map kinase signal transduction mechanisms.

Hypoxic stress induces apoptosis of hippocampal CA1 neurons while selectively sparing those in CA2-3. Proliferation and differentiation of local stem cells may potentially replace lost neurons. We examined MAP kinase signaling regulation of these dual responses. Rat organotypic hippocampal cultures were exposed to hypoxia for up to 6 h followed by reoxygenation. JNKs and ERKs were maximally activated by 4 h, returning approximately to basal levels by 6 h. Apoptosis of CA1 neurons was maximal by 6-h hypoxia, although JNK activation had returned to basal levels. A neuroprotective protein, JNK-interacting protein 1 (JIP1), an inhibitor of JNK-mediated apoptosis, was reduced by 6-h hypoxia and markedly decreased by 24-h reoxygenation in CA1 neurons as was DENN/MADD, which also modulates JNK-mediated cell death. A second peak of ERK1 activation occurred at 24-h reoxygenation and declined to control levels by 48 h. Stem cells were detected by antinestin and cell proliferation confirmed with anti-PCNA immunohistochemistry and BrdU incorporation. With U0126, an inhibitor of ERK activation, BrdU labeling was strikingly reduced implicating ERKs in the proliferation response. Antidoublecortin (DCX), which detects neural progenitor cells, colabeled a subset of BrdU-positive cells that extended from the dentate granule neurons into CA1. Astrocytes were colabeled with BrdU. Thus, hypoxia concurrently triggered both JNK and ERK signaling, and with reoxygenation, ERK1 activation and stem cell proliferation followed by neuronal progenitor cell differentiation and targeted migration to the site of pyramidal neuronal loss.

Animals↗
PubMed2004

Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer's disease brain and hippocampal neurons.

Tumor necrosis factor (TNF) alpha and mitogen-activated protein kinase/c-Jun N-terminal kinase (MAPK/JNK) pathways are both implicated in Alzheimer's disease (AD) pathogenesis. Increased expression of several members of the TNF pathway and JNK activation of c-Jun ultimately result in neuronal apoptosis. DENN/MADD, a multifunctional domain protein expressed in neurons, interacts with both the p55 TNF receptor (TNFR) type 1 and JNK3, placing it at a critical juncture in regulating signaling of neurodegeneration. We examined expression and interactions of the TNFR1 binding proteins, DENN/MADD, and TNFR-associated death domain (TRADD) protein in AD-affected tissues and cell cultures. We found reduced DENN/MADD and increased TRADD expression immunohistochemically in the hippocampus in areas of AD pathology compared to normal controls but little intraneuronal colocalization. In brain homogenates, DENN/MADD protein and mRNA expression was significantly reduced in AD compared to controls. Conversely, TRADD, TNFR1, and activated JNK were increased. Murine neuroblastoma and rat hippocampal cultures stressed with Abeta1-42 and the cortices of AD transgenic mice (Tg2576Swe) each showed decreased DENN/MADD expression and TRADD up-regulation in the mice, compared to controls. DENN/MADD antisense treatment of cultured rat hippocampal neurons reduced endogenous DENN/MADD and promoted neuronal cell death. DENN/MADD and TRADD competitively bound to TNFR1 when overexpressed in N(2)A cells, with DENN/MADD abrogating TNFR1 binding to TRADD. DENN/MADD may therefore be protective by inhibiting TRADD-induced apoptotic cell death. Reduction of DENN/MADD may affect long-term neuronal viability in AD by allowing TRADD mediation of TNFR1 signaling in response to oxidative or cytokine-promoted stresses.

Alzheimer Disease↗
PubMed2004

Synaptic changes in Alzheimer's disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence.

In an effort to examine changes that precede synapse loss, we have measured amyloid-beta and a series of damage markers in the synaptic compartment of Alzheimer's disease (AD) cases. Because localization of events to the terminal region in neurons is problematic with conventional methods, we prepared synaptosomes from samples of cryopreserved human association cortex, and immunolabeled terminals with a procedure for intracellular antigens. Fluorescence was quantified using flow cytometry. The viability dye calcein AM was unchanged in AD terminals compared to controls, and the fraction of large synaptosome particles did not change, although a striking loss of large terminals was observed in some AD cases. The percent positive fraction for a series of pre- and postsynaptic markers was not affected by AD in this cohort. However, the amyloid-beta-positive fraction increased from 16 to 27% (P < 0.02) in terminals from AD cortex. The expression level on a per-terminal basis is indicated in this assay by fluorescence (relative fluorescence units). The fluorescence of presynaptic markers did not change in AD terminals, but PSD-95 fluorescence was decreased by 19% (P < 0.03). Amyloid-beta fluorescence was increased by 132% (P < 0.01), and glial fibrillary acidic protein labeling by 31% (P < 0.01). These results suggest that synapse-associated amyloid-beta is prominent in regions relatively unaffected by AD lesions, and that amyloid accumulation in surviving terminals is accompanied by gliosis and alteration in the postsynaptic structure.

Aged↗
PubMed2004

Detecting bioactive amyloid beta peptide species in Alzheimer's disease.

Amyloid beta peptide (A beta) is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the form of A beta that induces neurodegeneration in AD, defined here as bioactive A beta, is not clear. Preventing the formation of bioactive A beta or inactivating previously formed bioactive A beta should be a promising approach to treat AD. We have previously developed a cell-based assay for the detection of bioactive A beta species. The assay is based upon the correlation between the ability of an A beta sample to induce a unique form of cellular MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] formazan exocytosis, and its ability to activate glia and induce neurotoxicity. Here, we show that this cell-based assay is not only useful for a cellular model of A beta amyloidogenesis but is also able to detect bioactive A beta species in a transgenic mouse model of AD, as well as in post-mortem cortex samples from AD patients. There is a good correlation between the extent of glia activation and the level of bioactive A beta species in the mouse brain. A promising deuteroporphyrin that can inactivate bioactive A beta species was also identified using this assay. These novel insights and findings should have important implications for the treatment of AD.

Age Factors↗
PubMed2003

The use of grammatical morphemes reflecting aspect and modality by children with specific language impairment.

Children with specific language impairment (SLI) have well-documented problems in the use of tense-related grammatical morphemes. However, in English, tense often overlaps with aspect and modality. In this study, 15 children with SLI (mean age 5;2) and two groups of 15 typically developing children (mean ages 3;6 and 5;3) were compared in terms of their use of previously studied morphemes in contexts that more clearly assessed the role of aspect. The children's use of less frequently studied morphemes tied to modality or tense was also examined. The children with SLI were found to use -ing to mark progressive aspect in past as well as present contexts, even though they were relatively poor in using the tense morphemes (auxiliary was, were) that should accompany the progressive inflection. These children were inconsistent in their use of third person singular -s to describe habitual actions that were not occurring during the time of their utterance. However, the pattern of the children's use suggested that the source of the problem was the formal tense feature of the inflection, not the habitual action context. The children's use of modal can was comparable to that of the typically developing children, raising the possibility that the modality function of possibility had been learned without necessarily acquiring the tense feature of this morpheme. These children's proficiency with can suggests that their bare verb stem productions should probably not be re-interpreted as cases of missing modals. Together these findings suggest that the more serious tense-related problems seen in English-speaking children with SLI co-occur with a less impaired ability to express temporal relations through aspect and modality.

Child↗
PubMed2003

Surface forms and grammatical functions: past tense and passive participle use by children with specific language impairment.

Children with specific language impairment (SLI) use past tense -ed in fewer obligatory contexts than younger normally developing children matched for mean length of utterance (MLU). In this study, the use of passive participle -ed (e.g., kissed in The frog got kissed by the kitty) as well as past tense -ed was examined in children with SLI, normally developing children matched for age (ND-A), and normally developing children matched for MLU (ND-MLU). The children with SLI used both past tense -ed and passive participle -ed in fewer obligatory contexts than bath the ND-A and the ND-MLU children. Only the children with SLI had greater difficulty with past tense -ed than with passive participle -ed. The pattern of findings indicates that the surface properties of -ed cannot adequately account for the past tense -ed difficulty shown by the children with SLI. However, the fact that the children with SLI were less consistant than the ND-MLU children in using passive participle -ed suggests that either the surface properties of -ed are responsible for a portion of the difficulty or these children have a separate, non-tense-related deficit in the area of verb morphology.

Child↗
PubMed2003

A method for examining productivity of grammatical morphology in children with and without specific language impairment.

Children with specific language impairment (SLI) show inconsistent use of grammatical morphology. Children who are developing language typically also show a period during which they produce grammatical morphemes inconsistently. Various theories claim that both young typically developing children and children with SLI achieve correct production through memorization of some inflected forms (M. Gopnik, 1997; M. Tomasello, 2000a, 2000b). Adapting a method introduced by C. Miller and L. Leonard (1998), the authors investigated the use of present tense third singular -s by 24 typically developing preschoolers and 36 preschoolers with SLI. Each group was divided into 2 mean length of utterance (MLU) levels. Group and individual data provided little evidence that memorization could explain the correct productions of the third singular morpheme for either children with SLI or typically developing children, and there was no difference between children with higher and lower MLUs.

Case-Control Studies↗
PubMed2003

Beta-amyloid racemized at the Ser26 residue in the brains of patients with Alzheimer disease: implications in the pathogenesis of Alzheimer disease.

Oligomeric and fibrillar beta-amyloid (Abeta) may be toxic in Alzheimer disease (AD), especially after post-translation modification cumulative over time. Racemization of Ser and Asp residues of Abeta in senile plaques (SPs) occurs as an age-dependent process in AD. We previously reported that Abeta1-40 racemized at Ser26 is soluble and susceptible to proteolysis yielding toxic [D-Ser26]Abeta25-35/40 fragments in vitro and in vivo. Here, we focus on the localization of racemized Ser26 residues in AD brains within the limbic system, the earliest site of AD histopathology. We developed antisera (20.1 and 22.7). each with epitopes within [D-Ser26]Abeta25-40. Two forms of truncated [D-Ser26]Abeta were detected either in SPs or within neurons in all 11 AD-affected brains, but not in age-matched controls. [D-Ser26]Abeta25/26-35 (detected by 20.1) was localized to plaque cores, extracellular neurofibrillary "ghost" tangles and vascular amyloid deposits. In contrast, [D-Ser26]Abeta25-40 (detected by 22.7) was observed in most neurons containing intracellular neurofibrillary tangles, but not in SPs. These results suggest [D-Ser26]Abeta]1-40, formed during aging, becomes soluble and diffuses from SPs. It is then proteolyzed to [D-Ser26]Abeta25-35/40, which is toxic and may contribute to the neurodegeneration. This hypothesis may explain the long lag between SP formation and neurofibrillary degeneration in AD brains.

Aged↗
PubMed2002

Production operations and the use of nonfinite verbs by children with specific language impairment.

Recent evidence from structural priming studies suggests that children with specific language impairment (SLI) are more likely to produce verb morphemes such as auxiliary is when their previous sentence contained an auxiliary than when it did not. The same paradigm was employed in the present study to determine whether failures to include auxiliary is might be due to prior use of nonfinite sentences (e.g., The mouse eating the cheese). Preschoolers with SLI and a group of younger normally developing children were more likely to produce auxiliary is to describe target pictures when the preceding sentence contained auxiliary are than when it contained past tense. Use of is in the target sentence was least likely when the preceding sentence was nonfinite. The implications of these findings for current accounts of SLI and current models of sentence production are discussed.

Child↗
PubMed2002

Effect of endothelial cell polarity on beta-amyloid-induced migration of monocytes across normal and AD endothelium.

During normal aging and amyloid beta-peptide (Abeta) disorders such as Alzheimer's disease (AD), one finds increased deposition of Abeta and activated monocytes/microglial cells in the brain. Our previous studies show that Abeta interaction with a monolayer of normal human brain microvascular endothelial cells results in increased adherence and transmigration of monocytes. Relatively little is known of the role of Abeta accumulated in the AD brain in mediating trafficking of peripheral blood monocytes (PBM) across the blood-brain barrier (BBB) and concomitant accumulation of monocytes/microglia in the AD brain. In this study, we showed that interaction of Abeta(1--40) with apical surface of monolayer of brain endothelial cells (BEC), derived either from normal or AD individuals, resulted in increased transendothelial migration of monocytic cells (HL-60 and THP-1) and PBM. However, transmigration of monocytes across the BEC monolayer cultivated in a Transwell chamber was increased 2.5-fold when Abeta was added to the basolateral side of AD compared with normal individual BEC. The Abeta-induced transmigration of monocytes was inhibited in both normal and AD-BEC by antibodies to the putative Abeta receptor, receptor for advanced glycation end products (RAGE), and to the endothelial cell junction molecule, platelet-endothelial cell adhesion molecule-1 (PECAM-1). We conclude that interaction of Abeta with the basolateral surface of AD-BEC induces cellular signaling, promoting transmigration of monocytes from the apical to basolateral direction. We suggest that Abeta in the AD brain parenchyma or cerebrovasculature initiates cellular signaling that induces PBM to transmigrate across the BBB and accumulate in the brain.

Aged↗