A selective decrease in the number of GABAergic somata occurs in pre-seizing monkeys with alumina gel granuloma.

Previous studies have shown that a loss of GABAergic neuronal somata is associated with a loss of GABAergic terminals at chronic cortical epileptic foci in monkeys. The present study was undertaken to determine whether GABAergic neuronal loss occurs prior to the onset of clinical seizures in monkeys that were treated with alumina gel but did not display seizures. Seven adolescent (Macaca mulatta) monkeys received alumina gel implants into the left pre- and post-central gyri, specifically centered in hand-face regions of sensorimotor cortex. Three other monkeys were used as controls. Two of these were surgical controls and the third was a normal animal. Three monkeys (pre-seizing) were sacrificed 2-4 weeks after the alumina gel implant but prior to clinically active seizures. Three other monkeys with chronic seizure activity (chronically seizing) were sacrificed 3-6 months after the implant. Tissue sections were taken from an area adjacent to the alumina gel granuloma (focus), from a site distal to it (parafocus) and from the non-epileptic contralateral side. Sections from all monkeys were processed for glutamate decarboxylase (GAD) immunocytochemistry and then examined with a light microscope. In addition, adjacent sections were stained with a Nissl stain and the total number of neurons was counted in these sections. Statistical analysis showed a significant decrease in the number of GAD-positive cells in the pre-seizing and chronic animals. The pre-seizing monkeys showed a significant loss of 23-44% at the focus in contrast to the total number of neurons which did not change significantly. The loss of GAD-positive cells was greater in the chronic animals that showed significant losses at both the focus and parafocus, 42-61% and 15-26%, respectively. It is important to note that the chronic monkeys displayed an 11-61% significant loss of total neurons at the epileptic focus. The surgical control animals showed no seizure activity and no significant loss of total neurons or GAD-positive cells. The main finding of this study indicates that a selective loss of GAD-positive neuronal somata occurs in pre-seizing monkeys with alumina gel implants. This finding is consistent with the previously reported loss of GABAergic terminals in pre-seizing monkeys. Since virtually all monkeys treated with alumina gel develop seizures, the results of this study add further support to the hypothesis that GABA neuronal loss plays a causal role in focal epilepsy

Olfactory identification testing as a predictor of the development of Alzheimer's dementia: A systematic review

Objectives/Hypothesis: To evaluate the utility of olfactory identification tests as prognostic instruments for Alzheimer's dementia (AD). Study Design: Systematic review. Methods: In accordance with PRISMA guidelines, PubMed and Ovid MEDLINE, EMBASE, ISI Web of Science, PsycINFO, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched to determine the quality and quantity of longitudinal and cross‐sectional research on this topic. Results: Two prospective longitudinal cohort studies and 30 cross‐sectional studies met inclusion criteria. The prospective longitudinal studies evaluated subjects with or without mild cognitive impairment (MCI) while also using olfactory identification testing as part of a neurocognitive evaluation. The first study reported an increased risk of later onset of AD in subjects with baseline hyposmia, whereas the second study suggested a possible relationship between decreased olfaction in participants with MCI and conversion to AD but was inconclusive due to low follow‐up rates. Wide variability in the type of olfactory identification test used and the reporting of results precluded meta‐analysis. The cross‐sectional studies demonstrated a positive association between poorer performance on olfactory identification testing and AD. Conclusions: Although there is evidence suggesting an association between decreased olfaction and AD, rigorously designed longitudinal cohort studies are necessary to clarify the value of olfactory identification testing in predicting the onset of AD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92127/1/23365_ftp.pd

Transplantation of hNT neurons into the ischemic cortex: Cell survival and effect on sensorimotor behavior

Cell transplantation offers a potential new treatment for stroke. Animal studies using models that produce ischemic damage in both the striatum and the frontal cortex have shown beneficial effects when hNT cells (postmitotic immature neurons) were transplanted into the ischemic striatum. In this study, we investigated the effect of hNT cells in a model of stroke in which the striatum remains intact and damage is restricted to the cortex. hNT cells were transplanted into the ischemic cortex 1 week after stroke induced by distal middle cerebral artery occlusion (dMCAo). The cells exhibited robust survival at 4 weeks posttransplant even at the lesion border. hNT cells did not migrate, but they did extend long neurites into the surrounding parenchyma mainly through the white matter. Neurite extension was predominantly toward the lesion in ischemic animals but was bidirectional in uninjured animals. Extension of neurites through the cortex toward the lesion was also seen when there was some surviving cortical tissue between the graft and the infarct. Prolonged deficits were obtained in four tests of sensory-motor function. hNT-transplanted animals showed a significant improvement in functional recovery on one motor test, but there was no effect on the other three tests relative to control animals. Thus, despite clear evidence of graft survival and neurite extension, the functional benefit of hNT cells after ischemia is not guaranteed. Functional benefit could depend on other variables, such as infarct location, whether the cells mature, the behavioral tests employed, rehabilitation training, or as yet unidentified factors. © 2006 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50652/1/20800_ftp.pd

Regulation of learning and memory by meningeal immunity: a key role for IL-4

Proinflammatory cytokines have been shown to impair cognition; consequently, immune activity in the central nervous system was considered detrimental to cognitive function. Unexpectedly, however, T cells were recently shown to support learning and memory, though the underlying mechanism was unclear. We show that one of the steps in the cascade of T cell–based support of learning and memory takes place in the meningeal spaces. Performance of cognitive tasks led to accumulation of IL-4–producing T cells in the meninges. Depletion of T cells from meningeal spaces skewed meningeal myeloid cells toward a proinflammatory phenotype. T cell–derived IL-4 was critical, as IL-4−/− mice exhibited a skewed proinflammatory meningeal myeloid cell phenotype and cognitive deficits. Transplantation of IL-4−/− bone marrow into irradiated wild-type recipients also resulted in cognitive impairment and proinflammatory skew. Moreover, adoptive transfer of T cells from wild-type into IL-4−/− mice reversed cognitive impairment and attenuated the proinflammatory character of meningeal myeloid cells. Our results point to a critical role for T cell–derived IL-4 in the regulation of cognitive function through meningeal myeloid cell phenotype and brain-derived neurotrophic factor expression. These findings might lead to the development of new immune-based therapies for cognitive impairment associated with immune decline

The Neuronal Correlates of Digits Backward Are Revealed by Voxel-Based Morphometry and Resting-State Functional Connectivity Analyses

Digits backward (DB) is a widely used neuropsychological measure that is believed to be a simple and effective index of the capacity of the verbal working memory. However, its neural correlates remain elusive. The aim of this study is to investigate the neural correlates of DB in 299 healthy young adults by combining voxel-based morphometry (VBM) and resting-state functional connectivity (rsFC) analyses. The VBM analysis showed positive correlations between the DB scores and the gray matter volumes in the right anterior superior temporal gyrus (STG), the right posterior STG, the left inferior frontal gyrus and the left Rolandic operculum, which are four critical areas in the auditory phonological loop of the verbal working memory. Voxel-based correlation analysis was then performed between the positive rsFCs of these four clusters and the DB scores. We found that the DB scores were positively correlated with the rsFCs within the salience network (SN), that is, between the right anterior STG, the dorsal anterior cingulate cortex and the right fronto-insular cortex. We also found that the DB scores were negatively correlated with the rsFC within an anti-correlation network of the SN, between the right posterior STG and the left posterior insula. Our findings suggest that DB performance is related to the structural and functional organizations of the brain areas that are involved in the auditory phonological loop and the SN

Syndromics: A Bioinformatics Approach for Neurotrauma Research

Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. Translational testing of novel therapies requires standardized measures of function for comparison across different laboratories, paradigms, and species. Although numerous functional assessments have been developed in animal models, it remains unclear how to best integrate this information to describe the complete translational “syndrome” produced by neurotrauma. The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call “syndromics”, which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings