Acute Hyperglycemia and In-Hospital Mortality in Spontaneous Intracerebral Hemorrhage.

Hyperglycemia is reported to predict worse outcome in patients with stroke, including intracerebral hemorrhage (ICH). In 83 consecutive cases of ICH at a tertiary stroke center, hyperglycemia (serum glucose >7 mmol/L) compared to normoglycemia at presentation was associated with higher rates of in-hospital mortality (51.2% vs. 26.2%, OR 2.3, CI 1.2-7.6, p = 0.02). The association with in-hospital mortality withstood adjustment for age, ICH volume, intraventricular hemorrhage, and infratentorial ICH location, but not baseline Glasgow Coma Scale. Acute hyperglycemia is associated with in-hospital mortality in spontaneous ICH patients, though this may be an indirect, rather than a causal relationship.

Prevalence, Characteristics, and Outcomes of Undetermined Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis.

Background and Purpose: There are scarce data regarding the prevalence, characteristics and outcomes of intracerebral hemorrhage (ICH) of undetermined (unknown or cryptogenic) etiology. We sought to determine the prevalence, radiological characteristics, and clinical outcomes of undetermined ICH. Methods: Systematic review and meta-analysis of studies involving patients with spontaneous ICH was conducted to primarily assess the prevalence and clinical-radiological characteristics of undetermined ICH. Additionally, we assessed the rates for ICH secondary to hypertensive arteriopathy and cerebral amyloid angiopathy. Subgroup analyses were performed based on the use of (1) etiology-oriented ICH classification, (2) detailed neuroimaging, and (3) Boston criteria among patients with cerebral amyloid angiopathy related ICH. We pooled the prevalence rates using random-effects models, and assessed the heterogeneity using Cochran Q and I2 statistics. Results: We identified 24 studies comprising 15 828 spontaneous ICH patients (mean age, 64.8 years; men, 60.8%). The pooled prevalences of hypertensive arteriopathy ICH, undetermined ICH, and cerebral amyloid angiopathy ICH were 50% (95% CI, 43%­58%), 18% (95% CI, 13%­23%), and 12% (95% CI, 7%­17% [P<0.001 between subgroups]). The volume of ICH was the largest in cerebral amyloid angiopathy ICH (24.7 [95% CI, 19.7­29.8] mL), followed by hypertensive arteriopathy ICH (16.2 [95% CI, 10.9­21.5] mL) and undetermined ICH (15.4 [95% CI, 6.2­24.5] mL). Among patients with undetermined ICH, the rates of short-term mortality (within 3 months) and concomitant intraventricular hemorrhage were 33% (95% CI, 25%­42%) and 38% (95% CI, 28%­48%), respectively. Subgroup analysis demonstrated a higher rate of undetermined ICH among studies that did not use an etiology-oriented classification (22% [95% CI, 15%­29%]). No difference was observed between studies based on the completion of detailed neuroimaging to assess the rates of undetermined ICH (P=0.62). Conclusions: The etiology of spontaneous ICH remains unknown or cryptogenic among 1 in 7 patients in studies using etiology-oriented classification and among 1 in 4 patients in studies that avoid using etiology-oriented classification. The short-term mortality in undetermined ICH is high despite the relatively small ICH volume.

Development of Glutamatergic Proteins in Human Visual Cortex across the Lifespan.

Traditionally, human primary visual cortex (V1) has been thought to mature within the first few years of life, based on anatomical studies of synapse formation, and establishment of intracortical and intercortical connections. Human vision, however, develops well beyond the first few years. Previously, we found prolonged development of some GABAergic proteins in human V1 (Pinto et al., 2010). Yet as >80% of synapses in V1 are excitatory, it remains unanswered whether the majority of synapses regulating experience-dependent plasticity and receptive field properties develop late, like their inhibitory counterparts. To address this question, we used Western blotting of postmortem tissue from human V1 (12 female, 18 male) covering a range of ages. Then we quantified a set of postsynaptic glutamatergic proteins (PSD-95, GluA2, GluN1, GluN2A, GluN2B), calculated indices for functional pairs that are developmentally regulated (GluA2:GluN1; GluN2A:GluN2B), and determined interindividual variability. We found early loss of GluN1, prolonged development of PSD-95 and GluA2 into late childhood, protracted development of GluN2A until ∼40 years, and dramatic loss of GluN2A in aging. The GluA2:GluN1 index switched at ∼1 year, but the GluN2A:GluN2B index continued to shift until ∼40 year before changing back to GluN2B in aging. We also identified young childhood as a stage of heightened interindividual variability. The changes show that human V1 develops gradually through a series of five orchestrated stages, making it likely that V1 participates in visual development and plasticity across the lifespan.SIGNIFICANCE STATEMENT Anatomical structure of human V1 appears to mature early, but vision changes across the lifespan. This discrepancy has fostered two hypotheses: either other aspects of V1 continue changing, or later changes in visual perception depend on extrastriate areas. Previously, we showed that some GABAergic synaptic proteins change across the lifespan, but most synapses in V1 are excitatory leaving unanswered how they change. So we studied expression of glutamatergic proteins in human V1 to determine their development. Here we report prolonged maturation of glutamatergic proteins, with five stages that map onto life-long changes in human visual perception. Thus, the apparent discrepancy between development of structure and function may be explained by life-long synaptic changes in human V1.

Increased Prognostic Yield by Combined Assessment of Non-Contrast Computed Tomography Markers of Antithrombotic-Related Spontaneous Intracerebral Hemorrhage Expansion.

Background and aims: The utility of proposed non-contrast computed tomography (NCCT) markers for the prediction of hematoma expansion in patients with antithrombotic-related spontaneous intracerebral hemorrhage (ICH) is limited. Additionally, there is significant overlap between different suggested ICH shape and density markers. Methods: We assessed the prognostic yield for hematoma expansion of a combined score incorporating features of ICH shape irregularity (satellite sign and/or Barras score ≥ 3), heterogeneous ICH density (swirl sign and/or Barras score ≥ 3) on baseline NCCT and timing from ICH onset to NCCT. Results: We evaluated data from 79 patients with antithrombotic-related spontaneous ICH (32% with hematoma expansion). Swirl (84% vs. 39%) and satellite signs (20% vs. 7%) on baseline NCCT were significantly more prevalent (p < 0.001) in patients with hematoma expansion. Patients with hematoma expansion had more irregular and heterogeneous bleeds on baseline NCCT scans, as quantified by higher (p < 0.001) Barras shape (4 (4−5) vs. 3 (2−4)) and density scores (4 (3−5) vs. 2 (1−3)), respectively. The overall diagnostic yield of the combined score (area under the curve: 0.86, 95%CI: 0.78−0.94) significantly outperformed (p < 0.001) the diagnostic yield of each individual marker. Scores of 4 or 5 in the combined score were associated with a sensitivity of 60.0%, specificity of 90.7%, overall diagnostic accuracy of 81.0%, positive likelihood ratio (LR) of 6.48, negative LR of 0.44, positive predictive value (PV) of 0.76 and negative PV of 0.83. Conclusion: Combined NCCT marker assessment seems to increase the prognostic accuracy for hematoma expansion in antithrombotic-related spontaneous ICH patients.

Experience-Dependent Changes in Myelin Basic Protein Expression in Adult Visual and Somatosensory Cortex.

An experience-driven increase in oligodendrocytes and myelin in the somatosensory cortex (S1) has emerged as a new marker of adult cortical plasticity. That finding contrasts with the view that myelin is a structural brake on plasticity, and that contributes to ending the critical period (CP) in the visual cortex (V1). Despite the evidence that myelin-derived signaling acts to end CP in V1, there is no information about myelin changes during adult plasticity in V1. To address this, we quantified the effect of three manipulations that drive adult plasticity (monocular deprivation (MD), fluoxetine treatment or the combination of MD and fluoxetine) on the expression of myelin basic protein (MBP) in adult rat V1. In tandem, we validated that environmental enrichment (EE) increased cortical myelin by measuring MBP in adult S1. For comparison with the MBP measurements, three plasticity markers were also quantified, the spine markers drebrin E and drebrin A, and a plasticity maintenance marker Ube3A. First, we confirmed that EE increased MBP in S1. Next, that expression of the plasticity markers was affected in S1 by EE and in V1 by the visual manipulations. Finally, we found that after adult MD, MBP increased in the non-deprived V1 hemisphere, but it decreased in the deprived hemisphere, and those changes were not influenced by fluoxetine. Together, the findings suggest that modulation of myelin expression in adult V1 may reflect the levels of visually driven activity rather than synaptic plasticity caused by adult plasticity.

Effects of Fluoxetine and Visual Experience on Glutamatergic and GABAergic Synaptic Proteins in Adult Rat Visual Cortex.

Fluoxetine has emerged as a novel treatment for persistent amblyopia because in adult animals it reinstates critical period-like ocular dominance plasticity and promotes recovery of visual acuity. Translation of these results from animal models to the clinic, however, has been challenging because of the lack of understanding of how this selective serotonin reuptake inhibitor affects glutamatergic and GABAergic synaptic mechanisms that are essential for experience-dependent plasticity. An appealing hypothesis is that fluoxetine recreates a critical period (CP)-like state by shifting synaptic mechanisms to be more juvenile. To test this we studied the effect of fluoxetine treatment in adult rats, alone or in combination with visual deprivation [monocular deprivation (MD)], on a set of highly conserved presynaptic and postsynaptic proteins (synapsin, synaptophysin, VGLUT1, VGAT, PSD-95, gephyrin, GluN1, GluA2, GluN2B, GluN2A, GABAAα1, GABAAα3). We did not find evidence that fluoxetine shifted the protein amounts or balances to a CP-like state. Instead, it drove the balances in favor of the more mature subunits (GluN2A, GABAAα1). In addition, when fluoxetine was paired with MD it created a neuroprotective-like environment by normalizing the glutamatergic gain found in adult MDs. Together, our results suggest that fluoxetine treatment creates a novel synaptic environment dominated by GluN2A- and GABAAα1-dependent plasticity.

Experience-dependent central vision deficits: Neurobiology and visual acuity.

Abnormal visual experience during childhood often leads to amblyopia, with strong links to binocular dysfunction that can include poor acuity in both eyes, especially in central vision. In animal models of amblyopia, the non-deprived eye is often considered normal and what limits binocular acuity. This leaves open the question whether monocular deprivation (MD) induces binocular dysfunction similar to what is found in amblyopia. In previous studies of MD cats, we found a loss of excitatory receptors restricted to the central visual field representation in visual cortex (V1), including both eyes' columns. This led us to ask two questions about the effects of MD: how quickly are receptors lost in V1? and is there an impact on binocular acuity? We found that just a few hours of MD caused a rapid loss of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor proteins across all of V1. But after a few days of MD, there was recovery in the visual periphery, leaving a loss of AMPA receptors only in the central region of V1. We reared animals with early MD followed by a long period of binocular vision and found binocular acuity deficits that were greatest in the central visual field. Our results suggest that the greater binocular acuity deficits in the central visual field are driven in part by the long-term loss of AMPA receptors in the central region of V1.

A high-throughput semi-automated preparation for filtered synaptoneurosomes.

BACKGROUND: Synaptoneurosomes have become an important tool for studying synaptic proteins. The filtered synaptoneurosomes preparation originally developed by Hollingsworth et al. (1985) is widely used and is an easy method to prepare synaptoneurosomes. The hand processing steps in that preparation, however, are labor intensive and have become a bottleneck for current proteomic studies using synaptoneurosomes. For this reason, we developed new steps for tissue homogenization and filtration that transform the preparation of synaptoneurosomes to a high-throughput, semi-automated process. NEW METHOD: We implemented a standardized protocol with easy to follow steps for homogenizing multiple samples simultaneously using a FastPrep tissue homogenizer (MP Biomedicals, LLC) and then filtering all of the samples in centrifugal filter units (EMD Millipore, Corp). RESULTS AND COMPARISON WITH EXISTING METHODS: The new steps dramatically reduce the time to prepare synaptoneurosomes from hours to minutes, increase sample recovery, and nearly double enrichment for synaptic proteins. These steps are also compatible with biosafety requirements for working with pathogen infected brain tissue. CONCLUSIONS: The new high-throughput semi-automated steps to prepare synaptoneurosomes are timely technical advances for studies of low abundance synaptic proteins in valuable tissue samples.

Cortical development of AMPA receptor trafficking proteins.

AMPA-receptor trafficking plays a central role in excitatory plasticity, especially during development. Changes in the number of AMPA receptors and time spent at the synaptic surface are important factors of plasticity that directly affect long-term potentiation (LTP), long-term depression (LTD), synaptic scaling, and the excitatory-inhibitory (E/I) balance in the developing cortex. Experience-dependent changes in synaptic strength in visual cortex (V1) use a molecularly distinct AMPA trafficking pathway that includes the GluA2 subunit. We studied developmental changes in AMPA receptor trafficking proteins by quantifying expression of GluA2, pGluA2 (GluA2serine880), GRIP1, and PICK1 in rat visual and frontal cortex. We used Western Blot analysis of synaptoneurosome preparations of rat visual and frontal cortex from animals ranging in age from P0 to P105. GluA2 and pGluA2 followed different developmental trajectories in visual and frontal cortex, with a brief period of over expression in frontal cortex. The over expression of GluA2 and pGluA2 in immature frontal cortex raises the possibility that there may be a period of GluA2-dependent vulnerability in frontal cortex that is not found in V1. In contrast, GRIP1 and PICK1 had the same developmental trajectories and were expressed very early in development of both cortical areas. This suggests that the AMPA-interacting proteins are available to begin trafficking receptors as soon as GluA2-containing receptors are expressed. Finally, we used all four proteins to analyze the surface-to-internalization balance and found that this balance was roughly equal across both cortical regions, and throughout development. Our finding of an exquisite surface-to-internalization balance highlights that these AMPA receptor trafficking proteins function as a tightly controlled system in the developing cortex.