Commentary on review by gash et al. A clinical perspective on neural transplantation and potential applications to the aged brain

The recent advances in the transplantation of CNS tissues to mammalian brain are potentially of great clinical significance, especially as treatments for neurodegenerative diseases. A number of issues must be resolved however, before the full clinical potential of CNS transplants can be evaluated. From the clinical perspective, it will be essential for future studies to compare the relative efficacy of transplant “therapy” to more conventional treatment strategies. It will also be important to discover the neurophysiological mechanisms underlying transplant-induced restoration of function.     

Microglia activation in the brain as inflammatory biomarker of Alzheimer's disease neuropathology and clinical dementia

The role of microglia-mediated inflammation in the progression of Alzheimer's disease (AD) neuropathology remains unclear. In this study, postmortem brain sections from AD and control cases were subjected to Human Leukocyte Antigen (HLA)-DR immunohistochemistry to examine microglia activation in the progression of AD assessed by pre-mortem clinical dementia rating (CDR) and postmortem pathological manifestations of neuritic plaque (NP) and neurofibrillary tangle (NT) according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). In both gray and white matter of the entorhinal cortex (EC) and HLA-DR immunostaining increased with the progression of CDR or CERAD NP, and to a lesser degree with CERAD NT. Between CDR stages HLA-DR significance was found in moderate (CDR 2) to severe dementia (CDR 5) where as between CERAD NP stages staining increased significantly from NP 0 (no plaque) to NP 1 (sparse plaques), suggesting increased microglia activation begins with amyloid NP deposition. In the hippocampus, a significant increase in microglia immunostaining was found in the pyramidal cell layer of CA1 as early as CDR 1, and in the upper molecular layer of the dentate gyrus in CDR 0.5. This increase continues with the progression of CDR and reaches maximum in CDR 5. When assessed by CERAD NP stages however, a significant increase in microglia immunostaining was found only in mid-to-late stages (NP 3) and reduced staining was seen in NP 5. These results suggest that microglia activation increases with the progression of AD, with the increase varying depending on the involved brain region.     

p-Chloroamphetamine blocks physostigmine-induced memory enhancement in rats with unilateral nucleus basalis lesions

The present experiment examined whether p-chloroamphetamine (PCA), a serotonergic releasing/depleting agent, would block the memory-enhancing effect of physostigmine in rats with N-methyl-D-aspartic acid (NMDA)-induced unilateral lesions of the nucleus basalis of Meynert (uni-nbM). Six groups of subjects with uni-nbM lesions in addition to an isolated sham-operated control group were included. Subjects were trained and tested 72 h later on a one-trial passive avoidance task. Thirty minutes before training, rats with uni-nbM lesions were injected with either 1.0 or 5.0 mg/kg PCA or saline. Immediately after training, approximately half the subjects in each group were injected with either saline or 0.06 mg/kg physostigmine. Animals in the sham group received saline injections. Saline-injected animals with uni-nbM lesions performed poorly at test, a deficit that was reversed with physostigmine. Pretraining injections of PCA blocked physostigmine's memory-enhancing effect, although motor impairment during training may have contributed to decrements in test performance in animals injected with 5.0 mg/kg. Subjects were killed about 10 days later and their frontal cortices examined for choline acetyltransferase (ChAT). Results from the neurochemical analysis revealed that the lesion decreased ChAT levels and that the injection of 1.0 mg/kg PCA exaggerated this lesion-induced depletion. Implications for the interaction between acetylcholine and serotonin are discussed.     

Evidence for Abnormal Forward Trafficking of AMPA Receptors in Frontal Cortex of Elderly Patients with Schizophrenia

Several lines of evidence point to alterations of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor trafficking in schizophrenia. Multiple proteins, including synapse-associated protein 97 (SAP97), glutamate receptor-interacting protein 1 (GRIP1), and N-ethylmaleimide sensitive factor (NSF), facilitate the forward trafficking of AMPA receptors toward the synapse. Once localized to the synapse, AMPA receptors are trafficked in a complex endosomal system. We hypothesized that alterations in the expression of these proteins and alterations in the subcellular localization of AMPA receptors in endosomes may contribute to the pathophysiology of schizophrenia. Accordingly, we measured protein expression of SAP97, GRIP1, and NSF in the dorsolateral prefrontal cortex and found an increase in the expression of SAP97 and GRIP1 in schizophrenia. To determine the subcellular localization of AMPA receptor subunits, we developed a technique to isolate early endosomes from post-mortem tissue. We found increased GluR1 receptor subunit protein in early endosomes in subjects with schizophrenia. Together, these data suggest that there is an alteration of forward trafficking of AMPA receptors as well as changes in the subcellular localization of an AMPA receptor subunit in schizophrenia.     

Effect of physostigmine on memory consolidation and retrieval processes in intact and nucleus basalis-lesioned rats

The efficacy of physostigmine on memory enhancement in rats trained on a passive avoidance task was investigated. In experiment 1, the effect of posttraining injections of physostigmine (0.03 mg/kg) in subjects tested at either short (1.25 h or 72 h) or long (3 weeks or 5 weeks) retention intervals was explored. Results indicated druginduced enhancement of memory at only the two short intervals. Experiment 2 examined the mnemonic consequences of pretest administration of physostigmine. Administration of physostigmine (0.015 mg/kg and 0.03 mg/kg) shortly prior to testing led to a significant potentiation of memory retrieval. The aim of experiment 3 was to determine whether or not an intact cholinergic system is necessary for pretest physostigmine to enhance memory retrieval. Results from this experiment indicated that physostigmine (0.03 mg/kg) was effective in enhancing memory in rats prepared with ibotenic acid-induced lesions of the nucleus basalis of Meynert. Together, these data provide further empirical support for the importance of the cholinergic system in memory processes.A preliminary report of these data was presented at the annual meeting of the Midwestern Psychological Association, Chicago, IL, May 1988     

The relationship between asthma,asthma control and economic outcomes in the United States

Objective: Asthma, a serious chronic lung disease affecting approximately 26 million Americans, remains clinical and economic burdens on the healthcare system. Although associations between uncontrolled asthma and poor health outcomes is known, the extent of this impact of uncontrolled asthma on economic outcomes in the United States (US) is unknown. We sought to determine the relationship between asthma, asthma control and economic outcomes in the US. Methods: The 2008–2010 Medical Expenditure Panel Surveys were used to estimate the impact of uncontrolled asthma (asthma-related emergency department [ED] visit, use of >3 canisters of quick-relief inhaler in past 3 months or asthma attack in past 12 months) on medical expenditures, utilization and productivity. Estimates were generated using multivariate regression controlling for sociodemographics and comorbidity. Results: Medical expenditures attributable to asthma were up to $4423 greater for those with markers of uncontrolled asthma compared with those who did not have asthma. Frequency of hospital discharges were up to 4.6-fold greater for those with uncontrolled asthma than those without asthma (p?<?0.01), while all others with asthma did not have significantly more discharges. ED visits were up to 1.8-fold greater for those with uncontrolled asthma compared with those without asthma (p?<?0.01). Productivity was significantly (p?<?0.01) decreased (more likely to be unemployed, more days absent from work and more activity limitations) for those with uncontrolled asthma. Conclusions: In recent national data, individuals with asthma and markers of uncontrolled asthma had higher medical expenditures, greater utilization and decreased productivity.     

Measuring the cost of poor asthma control and exacerbations

Background: Previous studies have shown an association between cost and poor asthma control. However, longitudinal studies of general populations are lacking. Objective: To examine the cost of poor asthma control and exacerbations across a broad spectrum of asthma patients. Methods: The Observational Study of Asthma Control and Outcomes (OSACO) was a prospective survey of persistent asthma patients in Kaiser Colorado in 2011–2012. Patients received a survey 3 times in one year, which included the Asthma Control Questionnaire (ACQ) and questions on exacerbations. Self-reported exacerbations were compared to actual oral corticosteroid (OCS) use. Regression analyses examined the association of control (ACQ-5 scores) and exacerbations with healthcare expenditures, controlling for sociodemographics and smoking. Analyses of expenditures used Generalized Linear Models (GLM) with log-link. Results: 2681 individuals completed at least one survey; 1799 completed all three. ACQ-5 scores were associated with higher all-cause and asthma-specific expenditures across all categories of costs (medical, outpatient, ER, pharmacy) except for inpatient expenditures. Each 1-point increase in the ACQ-5 score (i.e., worse control) was associated with a corresponding increase in all-cause annual healthcare and asthma-specific expenditures of $1443 and $927 ($US 2013). Asthma exacerbations with documented OCS use were associated with an increase of $3014 and $1626 over 4 months, while self-reported exacerbations were $713 and $506. Conclusion: Results demonstrate that poor asthma control and exacerbations are strongly associated with higher healthcare expenditures. Results also confirm that collection of validated measures of control such as the ACQ-5 may provide valuable information toward improving clinical and economic outcomes.     

Economic grand rounds: psychological distress and depression associated with job loss and gain: the social costs of job instability

The authors used Medical Expenditure Panel Survey data for 81,097 respondents in 2004-2007, a period of economic expansion, to examine psychological distress among depressed and nondepressed persons in four categories: employed (73%), unemployed (23%), recent job loss (4%), and recent job gain (<1%). Depressed persons who experienced job loss or unemployment were significantly more distressed than depressed persons who were employed. Among depressed persons, on all measures of distress except one (worthlessness), unadjusted distress levels for those who gained a job were higher than for those who had lost a job. Measurements of the social costs of job instability need to account for costs related to unemployment and underemployment.