Josephine Asafu-Adjei

Cortical Deficits of Glutamic Acid Decarboxylase 67 Expression in Schizophrenia: Clinical, Protein, and Cell Type-Specific Features

OBJECTIVE Cognitive deficits in schizophrenia are associated with altered activity of the dorsolateral prefrontal cortex, which has been attributed to lower expression of the 67 kDa isoform of glutamic acid decarboxylase (GAD67), the major γ-aminobutyric acid (GABA)-synthesizing enzyme. However, little is known about the relationship of prefrontal GAD67 mRNA levels and illness severity, translation of the transcript into protein, and protein levels in axon terminals, the key site of GABA production and function. METHOD Quantitative polymerase chain reaction was used to measure GAD67 mRNA levels in postmortem specimens of dorsolateral prefrontal cortex from subjects with schizophrenia and matched comparison subjects with no known history of psychiatric or neurological disorders (N=42 pairs). In a subset of this cohort in which potential confounds of protein measures were controlled (N=19 pairs), Western blotting was used to quantify tissue levels of GAD67 protein in tissue. In five of these pairs, multilabel confocal immunofluorescence was used to quantify GAD67 protein levels in the axon terminals of parvalbumin-containing GABA neurons, which are known to have low levels of GAD67 mRNA in schizophrenia. RESULTS GAD67 mRNA levels were significantly lower in schizophrenia subjects (by 15%), but transcript levels were not associated with predictors or measures of illness severity or chronicity. In schizophrenia subjects, GAD67 protein levels were significantly lower in total gray matter (by 10%) and in parvalbumin axon terminals (by 49%). CONCLUSIONS The findings that lower GAD67 mRNA expression is common in schizophrenia, that it is not a consequence of having the illness, and that it leads to less translation of the protein, especially in the axon terminals of parvalbumin-containing neurons, support the hypothesis that lower GABA synthesis in parvalbumin neurons contributes to dorsolateral prefrontal cortex dysfunction and impaired cognition in schizophrenia.

Reduced Glutamate Decarboxylase 65 Protein Within Primary Auditory Cortex Inhibitory Boutons in Schizophrenia

BACKGROUND Schizophrenia is associated with perceptual and physiological auditory processing impairments that may result from primary auditory cortex excitatory and inhibitory circuit pathology. High-frequency oscillations are important for auditory function and are often reported to be disrupted in schizophrenia. These oscillations may, in part, depend on upregulation of gamma-aminobutyric acid synthesis by glutamate decarboxylase 65 (GAD65) in response to high interneuron firing rates. It is not known whether levels of GAD65 protein or GAD65-expressing boutons are altered in schizophrenia. METHODS We studied two cohorts of subjects with schizophrenia and matched control subjects, comprising 27 pairs of subjects. Relative fluorescence intensity, density, volume, and number of GAD65-immunoreactive boutons in primary auditory cortex were measured using quantitative confocal microscopy and stereologic sampling methods. Bouton fluorescence intensities were used to compare the relative expression of GAD65 protein within boutons between diagnostic groups. Additionally, we assessed the correlation between previously measured dendritic spine densities and GAD65-immunoreactive bouton fluorescence intensities. RESULTS GAD65-immunoreactive bouton fluorescence intensity was reduced by 40% in subjects with schizophrenia and was correlated with previously measured reduced spine density. The reduction was greater in subjects who were not living independently at time of death. In contrast, GAD65-immunoreactive bouton density and number were not altered in deep layer 3 of primary auditory cortex of subjects with schizophrenia. CONCLUSIONS Decreased expression of GAD65 protein within inhibitory boutons could contribute to auditory impairments in schizophrenia. The correlated reductions in dendritic spines and GAD65 protein suggest a relationship between inhibitory and excitatory synapse pathology in primary auditory cortex.

What characteristics of nutrition and physical activity interventions are key to effectively reducing weight gain in obese or overweight pregnant women? A systematic review and meta-analysis

Lifestyle interventions targeting gestational weight gain (GWG) report varying degrees of success. To better understand factors influencing efficacy, we reviewed randomized trials specifically among obese and overweight pregnant women.

Ultrastructural localization of high-affinity choline transporter in the rat anteroventral thalamus and ventral tegmental area: differences in axon morphology and transporter distribution.

The high‐affinity choline transporter (CHT) is a protein integral to the function of cholinergic neurons in the central nervous system (CNS). We examined the ultrastructural distribution of CHT in axonal arborizations of the mesopontine tegmental cholinergic neurons, a cell group in which CHT expression has yet to be characterized at the electron microscopic level. By using silver‐enhanced immunogold detection, we compared the morphological characteristics of CHT‐immunoreactive axon varicosities specifically within the anteroventral thalamus (AVN) and the ventral tegmental area (VTA). We found that CHT‐immunoreactive axon varicosities in the AVN displayed a smaller cross‐sectional area and a lower frequency of synapse formation and dense‐cored vesicle content than CHT‐labeled profiles in the VTA. We further examined the subcellular distribution of CHT and observed that immunoreactivity for this protein was predominantly localized to synaptic vesicles and minimally to the plasma membrane of axons in both regions. This pattern is consistent with the subcellular distribution of CHT displayed in other cholinergic systems. Axons in the AVN showed significantly higher levels of CHT immunoreactivity than those in the VTA and correspondingly displayed a higher level of membrane CHT labeling. These novel findings have important implications for elucidating regional differences in cholinergic signaling within the thalamic and brainstem targets of the mesopontine cholinergic system. J. Comp. Neurol. 518:1908–1924, 2010.

Acquisition and baseline performance of working memory tasks by adolescent rhesus monkeys

Adolescence is a transitional stage of development characterized by protracted refinements in the neural circuits required for adult level proficiency of working memory. Because impaired working memory is a hallmark feature of several psychiatric disorders that have their onset during adolescence, model systems that can be used to assess the maturation of working memory function, and of disease-related risk factors that disrupt its development, are of particular importance. However, few studies have investigated the maturation of working memory in nonhuman primates. Thus in the present study, we adapted two working memory tests that are among the most widely used in human and adult nonhuman primates, for adolescent rhesus monkeys. Using a touch-screen apparatus, monkeys were trained on a spatial delayed-response task to assess spatial working memory and a delayed match-to-sample task to assess object working memory. The results indicate that adolescent rhesus monkeys readily and efficiently acquire the ability to perform touch-screen based, complex tests of working memory. These data establish that distinct components of adult prefrontal cortex-dependent cognitive functions can be effectively modeled and evaluated in adolescent monkeys. As such, this approach should be useful for assessing the influence of environmental risk factors on the protracted maturation of working memory in adolescent macaques.

Network Structure of Perinatal Depressive Symptoms in Latinas: Relationship to Stress and Reproductive Biomarkers

Based on emerging evidence, mood disorders can be plausibly conceptualized as networks of causally interacting symptoms, rather than as latent variables of which symptoms are passive indicators. In an innovative approach in nursing research, we used network analysis to estimate the network structure of 20 perinatal depressive (PND) symptoms. Then, two proof-of-principle analyses are presented: Incorporating stress and reproductive biomarkers into the network, and comparing the network structure of PND symptoms between non-depressed and depressed women. We analyzed data from a cross-sectional sample of 515 Latina women at the second trimester of pregnancy and estimated networks using regularized partial correlation network models. The main analysis yielded five strong symptom-to-symptom associations (e.g., cry-sadness), and five symptoms of potential clinical importance (i.e., high centrality) in the network. In exploring the relationship of PND symptoms to stress and reproductive biomarkers (proof-of-principle analysis 1), a few weak relationships were found. In a comparison of non-depressed and depressed womens networks (proof-of-principle analysis 2), depressed participants had a more connected network of symptoms overall, but the networks did not differ in types of relationships (the network structures). We hope this first report of PND symptoms as a network of interacting symptoms will encourage future network studies in the realm of PND research, including investigations of symptom-to-biomarker mechanisms and interactions related to PND. Future directions and challenges are discussed.

Intracortical excitatory and thalamocortical boutons are intact in primary auditory cortex in schizophrenia

Schizophrenia is associated with auditory processing impairments that could arise as a result of primary auditory cortex excitatory circuit pathology. We have previously reported a deficit in dendritic spine density in deep layer 3 of primary auditory cortex in subjects with schizophrenia. As boutons and spines can be structurally and functionally co-regulated, we asked whether the densities of intracortical excitatory or thalamocortical presynaptic boutons are also reduced. We studied 2 cohorts of subjects with schizophrenia and matched controls, comprising 27 subject pairs, and assessed the density, number, and within-bouton vesicular glutamate transporter (VGluT) protein level of intracortical excitatory (VGluT1-immunoreactive) and thalamocortical (VGluT2-immunoreactive) boutons in deep layer 3 of primary auditory cortex using quantitative confocal microscopy and stereologic sampling methods. We found that VGluT1- and VGluT2-immunoreactive puncta densities and numbers were not altered in deep layer 3 of primary auditory cortex of subjects with schizophrenia. Our results indicate that reduced dendritic spine density in primary auditory cortex of subjects with schizophrenia is not matched by a corresponding reduction in excitatory bouton density. This suggests excitatory boutons in primary auditory cortex in schizophrenia may synapse with structures other than spines, such as dendritic shafts, with greater frequency. The discrepancy between dendritic spine reduction and excitatory bouton preservation may contribute to functional impairments of the primary auditory cortex in subjects with schizophrenia.

Episodic Memory of Odors Stratifies Alzheimer Biomarkers in Normal Elderly

The objective of this study was to relate a novel test of identifying and recalling odor percepts to biomarkers of Alzheimers disease (AD) in well‐characterized elderly individuals, ranging from cognitively normal to demented.

Transitional care of older adults in skilled nursing facilities: A systematic review

Transitional care may be an effective strategy for preparing older adults for transitions from skilled nursing facilities (SNF) to home. In this systematic review, studies of patients discharged from SNFs to home were reviewed. Study findings were assessed (1) to identify whether transitional care interventions, as compared to usual care, improved clinical outcomes such as mortality, readmission rates, quality of life or functional status; and (2) to describe intervention characteristics, resources needed for implementation, and methodologic challenges. Of 1082 unique studies identified in a systematic search, the full texts of six studies meeting criteria for inclusion were reviewed. Although the risk for bias was high across studies, the findings suggest that there is promising but limited evidence that transitional care improves clinical outcomes for SNF patients. Evidence in the review identifies needs for further study, such as the need for randomized studies of transitional care in SNFs, and methodological challenges to studying transitional care for SNF patients.

Comparison of Urine Output among Patients Treated with More Intensive Versus Less Intensive RRT: Results from the Acute Renal Failure Trial Network Study

BACKGROUND AND OBJECTIVES Intensive RRT may have adverse effects that account for the absence of benefit observed in randomized trials of more intensive versus less intensive RRT. We wished to determine the association of more intensive RRT with changes in urine output as a marker of worsening residual renal function in critically ill patients with severe AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Acute Renal Failure Trial Network Study (n=1124) was a multicenter trial that randomized critically ill patients requiring initiation of RRT to more intensive (hemodialysis or sustained low-efficiency dialysis six times per week or continuous venovenous hemodiafiltration at 35 ml/kg per hour) versus less intensive (hemodialysis or sustained low-efficiency dialysis three times per week or continuous venovenous hemodiafiltration at 20 ml/kg per hour) RRT. Mixed linear regression models were fit to estimate the association of RRT intensity with change in daily urine output in survivors through day 7 (n=871); Cox regression models were fit to determine the association of RRT intensity with time to ≥50% decline in urine output in all patients through day 28. RESULTS Mean age of participants was 60±15 years old, 72% were men, and 30% were diabetic. In unadjusted models, among patients who survived ≥7 days, mean urine output was, on average, 31.7 ml/d higher (95% confidence interval, 8.2 to 55.2 ml/d) for the less intensive group compared with the more intensive group (P=0.01). More intensive RRT was associated with 29% greater unadjusted risk of decline in urine output of ≥50% (hazard ratio, 1.29; 95% confidence interval, 1.10 to 1.51). CONCLUSIONS More intensive versus less intensive RRT is associated with a greater reduction in urine output during the first 7 days of therapy and a greater risk of developing a decline in urine output of ≥50% in critically ill patients with severe AKI.