A I Faden

University of Baltimore, Baltimore, Maryland, United States

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Publications (371)1780.94 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite extensive preclinical research supporting the effectiveness of neuroprotective therapies for brain trauma, there have been no successful randomized controlled clinical trials to date. TBI results in delayed secondary tissue injury due to neurochemical, metabolic and cellular changes; modulating such effects has provided the basis for neuroprotective interventions. To establish more effective neuroprotective treatments for TBI it is essential to better understand the complex cellular and molecular events that contribute to secondary injury. Here we critically review relevant research related to causes and modulation of delayed tissue damage, with particular emphasis on cell death mechanisms and post-traumatic neuroinflammation. We discuss the concept of utilizing multipotential drugs that target multiple secondary injury pathways, rather than more specific "laser"-targeted strategies that have uniformly failed in clinical trials. Moreover, we assess data supporting use of neuroprotective drugs that are currently being evaluated in human clinical trials for TBI, as well as promising emerging experimental multipotential drug treatment strategies. Finally, we describe key challenges and provide suggestions to improve the likelihood of successful clinical translation. © 2015 Elsevier B.V. All rights reserved.
    Handbook of Clinical Neurology 01/2015; 127:343-66.
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    ABSTRACT: Autophagy is a catabolic mechanism facilitating degradation of cytoplasmic proteins and organelles in a lysosome-dependent manner. Autophagy flux is necessary for normal neuronal homeostasis and its dysfunction contributes to neuronal cell death in several neurodegenerative diseases. Elevated autophagy has been reported after spinal cord injury (SCI); however, its mechanism, cell type specificity and relationship to cell death are unknown. Using a rat model of contusive SCI, we observed accumulation of LC3-II-positive autophagosomes starting at posttrauma day 1. This was accompanied by a pronounced accumulation of autophagy substrate protein p62, indicating that early elevation of autophagy markers reflected disrupted autophagosome degradation. Levels of lysosomal protease cathepsin D and numbers of cathepsin-D-positive lysosomes were also decreased at this time, suggesting that lysosomal damage may contribute to the observed defect in autophagy flux. Normalization of p62 levels started by day 7 after SCI, and was associated with increased cathepsin D levels. At day 1 after SCI, accumulation of autophagosomes was pronounced in ventral horn motor neurons and dorsal column oligodendrocytes and microglia. In motor neurons, disruption of autophagy strongly correlated with evidence of endoplasmic reticulum (ER) stress. As autophagy is thought to protect against ER stress, its disruption after SCI could contribute to ER-stress-induced neuronal apoptosis. Consistently, motor neurons showing disrupted autophagy co-expressed ER-stress-associated initiator caspase 12 and cleaved executioner caspase 3. Together, these findings indicate that SCI causes lysosomal dysfunction that contributes to autophagy disruption and associated ER-stress-induced neuronal apoptosis.
    Cell Death & Disease 01/2015; 6:e1582. · 5.18 Impact Factor
  • Alan I Faden, David J Loane
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    ABSTRACT: It has long been suggested that prior traumatic brain injury (TBI) increases the subsequent incidence of chronic neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis. Among these, the association with Alzheimer disease has the strongest support. There is also a long-recognized association between repeated concussive insults and progressive cognitive decline or other neuropsychiatric abnormalities. The latter was first described in boxers as dementia pugilistica, and has received widespread recent attention in contact sports such as professional American football. The term chronic traumatic encephalopathy was coined to attempt to define a "specific" entity marked by neurobehavioral changes and the extensive deposition of phosphorylated tau protein. Nearly lost in the discussions of post-traumatic neurodegeneration after traumatic brain injury has been the role of sustained neuroinflammation, even though this association has been well established pathologically since the 1950s, and is strongly supported by subsequent preclinical and clinical studies. Manifested by extensive microglial and astroglial activation, such chronic traumatic brain inflammation may be the most important cause of post-traumatic neurodegeneration in terms of prevalence. Critically, emerging preclinical studies indicate that persistent neuroinflammation and associated neurodegeneration may be treatable long after the initiating insult(s).
    Journal of the American Society for Experimental NeuroTherapeutics 11/2014; 12(1). · 3.88 Impact Factor
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    ABSTRACT: Physical activity can attenuate neuronal loss, reduce neuroinflammation and facilitate recovery after brain injury. However, little is known about the mechanisms of exercise-induced neuroprotection after traumatic brain injury (TBI), or its modulation of posttraumatic neuronal cell death. Voluntary exercise using a running wheel was conducted for 4 weeks immediately preceding (preconditioning) moderate level controlled cortical impact (CCI), a well-established experimental TBI model in mice. Compared to non-exercised controls, exercise preconditioning (pre-exercise) improved recovery of sensorimotor performance in the beam walk task, and cognitive/affective functions in the Morris water maze, novel object recognition, and tail-suspension tests. Furthermore, pre-exercise reduced the lesion size; attenuated neuronal loss in the hippocampus, cortex and thalamus; and decreased microglial activation in the cortex. In addition, exercise preconditioning activated the BDNF pathway before trauma and amplified the injury-dependent increased in HSP70 expression, thus attenuating key apoptotic pathways. The latter include reduction in CCI-induced up-regulation of pro-apoptotic BH3-only Bcl-2 family molecules (Bid, Puma); decreased mitochondria permeabilization with attenuated release of cytochrome c and AIF; reduced AIF translocation to the nucleus and attenuated caspase activation. Given these neuroprotective actions, voluntary physical exercise may serve to limit the consequences of TBI.
    Journal of Neurotrauma 11/2014; · 3.97 Impact Factor
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    ABSTRACT: Dysregulation of autophagy contributes to neuronal cell death in several neurodegenerative and lysosomal storage diseases. Markers of autophagy are also increased after traumatic brain injury (TBI), but its mechanisms and function are not known. Following controlled cortical impact (CCI) brain injury in GFP-Lc3 (green fluorescent protein-LC3) transgenic mice, we observed accumulation of autophagosomes in ipsilateral cortex and hippocampus between 1 and 7 d. This accumulation was not due to increased initiation of autophagy but rather to a decrease in clearance of autophagosomes, as reflected by accumulation of the autophagic substrate SQSTM1/p62 (sequestosome 1). This was confirmed by ex vivo studies, which demonstrated impaired autophagic flux in brain slices from injured as compared to control animals. Increased SQSTM1 peaked at d 1-3 but resolved by d 7, suggesting that the defect in autophagy flux is temporary. The early impairment of autophagy is at least in part caused by lysosomal dysfunction, as evidenced by lower protein levels and enzymatic activity of CTSD (cathepsin D). Furthermore, immediately after injury both autophagosomes and SQSTM1 accumulated predominantly in neurons. This was accompanied by appearance of SQSTM1 and ubiquitin-positive puncta in the affected cells, suggesting that, similar to the situation observed in neurodegenerative diseases, impaired autophagy may contribute to neuronal injury. Consistently, GFP-LC3 and SQSTM1 colocalized with markers of both caspase-dependent and caspase-independent cell death in neuronal cells proximal to the injury site. Taken together, our data indicated for the first time that autophagic clearance is impaired early after TBI due to lysosomal dysfunction, and correlates with neuronal cell death.
    Autophagy 11/2014; · 11.42 Impact Factor
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    ABSTRACT: Traumatic brain injury (TBI) can cause sleep-wake disturbances and excessive daytime sleepiness. However, the pathobiology of sleep disorders in TBI is not well understood and animal models have been underutilized in studying such changes and potential underlying mechanisms. Here we used the rat lateral fluid percussion (LFP) model to analyze sleep-wake patterns as a function of time after injury. Rapid-eye movement sleep (REM), non-REM sleep (NREM), and wake bouts during light and dark phases were measured with electroencephalography (EEG) and electromyography (EMG) at an early as well as chronic time points following LFP. Moderate TBI caused disturbances in ability to maintain consolidated wake bouts during the active phase and chronic loss of wakefulness. Furthermore, TBI resulted in cognitive impairments and depressive-like symptoms, and reduced the number of Orexin-A (ORX-A)-positive neurons in the lateral hypothalamus.
    Journal of Neurotrauma 09/2014; · 3.97 Impact Factor
  • ChemInform 09/2014; 45(35).
  • Shruti V. Kabadi, Alan I. Faden
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    ABSTRACT: Traumatic brain injury induces secondary injury that contributes to neuroinflammation, neuronal loss, and neurological dysfunction. One important injury mechanism is cell cycle activation which causes neuronal apoptosis and glial activation. The neuroprotective effects of both non-selective (Flavopiridol) and selective (Roscovitine and CR-8) cyclin-dependent kinase inhibitors have been shown across multiple experimental traumatic brain injury models and species. Cyclin-dependent kinaseinhibitors, administered as a single systemic dose up to 24 hours after traumatic brain injury, provide strong neuroprotection-reducing neuronal cell death, neuroinflammation and neurological dysfunction. Given their effectiveness and long therapeutic window, cyclin-dependent kinase inhibitors appear to be promising candidates for clinical traumatic brain injury trials.
    Neural Regeneration Research 09/2014; 9(17):1578-1580. · 0.23 Impact Factor
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    ABSTRACT: Experimental spinal cord injury (SCI) causes chronic neuropathic pain associated with inflammatory changes in thalamic pain regulatory sites. Our recent studies examining chronic pain mechanisms after rodent SCI showed chronic inflammatory changes not only in thalamus, but also in other regions including hippocampus and cerebral cortex. Because changes appeared similar to those in our rodent TBI models that are associated with neurodegeneration and neurobehavioral dysfunction, we examined effects of mouse SCI on cognition, depressive-like behavior, and brain inflammation. SCI caused spatial and retention memory impairment and depressive-like behavior, as evidenced by poor performance in the Morris water maze, Y-maze, novel objective recognition, step-down passive avoidance, tail suspension, and sucrose preference tests. SCI caused chronic microglial activation in the hippocampus and cerebral cortex, where microglia with hypertrophic morphologies and M1 phenotype predominated. Stereological analyses showed significant neuronal loss in the hippocampus at 12 weeks but not 8 d after injury. Increased cell-cycle-related gene (cyclins A1, A2, D1, E2F1, and PCNA) and protein (cyclin D1 and CDK4) expression were found chronically in hippocampus and cerebral cortex. Systemic administration of the selective cyclin-dependent kinase inhibitor CR8 after SCI significantly reduced cell cycle gene and protein expression, microglial activation and neurodegeneration in the brain, cognitive decline, and depression. These studies indicate that SCI can initiate a chronic brain neurodegenerative response, likely related to delayed, sustained induction of M1-type microglia and related cell cycle activation, which result in cognitive deficits and physiological depression.
    Journal of Neuroscience 08/2014; 34(33):10989-11006. · 6.75 Impact Factor
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    ABSTRACT: MicroRNAs (miRs) are small noncoding RNAs that negatively regulate gene expression at the post-transcriptional level. To identify miRs that may regulate neuronal cell death after experimental traumatic brain injury (TBI), we profiled miR expression changes during the first several days after controlled cortical impact (CCI) in mice. miR-23a and miR-27a were rapidly downregulated in the injured cortex in the first hour after TBI. These changes coincided with increased expression of the proapoptotic Bcl-2 family members Noxa, Puma, and Bax. In an etoposide-induced in vitro model of apoptosis in primary cortical neurons, miR-23a and miR-27a were markedly downregulated as early as 1 h after exposure, before the upregulation of proapoptotic Bcl-2 family molecules. Administration of miR-23a and miR-27a mimics attenuated etoposide-induced changes in Noxa, Puma, and Bax, reduced downstream markers of caspase-dependent (cyto-chrome c release and caspase activation) and caspase-independent (apoptosis-inducing factor release) pathways, and limited neuronal cell death. In contrast, miRs hairpin inhibitors enhanced etoposide-induced neuronal apoptosis and caspase activation. Importantly, administration of miR-23a and miR-27a mimics significantly reduced activation of Puma, Noxa, and Bax as well as attenuated markers of caspase-dependent and -independent apoptosis after TBI. Furthermore, miR-23a and miR-27a mimics significantly attenuated cortical lesion volume and neuronal cell loss in the hippocampus after TBI. These findings indicate that post-traumatic decreases in miR-23a and miR-27a contribute to neuronal cell death after TBI by upregulating proapoptotic Bcl-2 family members, thus providing a novel thera-peutic target.
    Journal of Neuroscience 07/2014; 34(30):10055-71. · 6.75 Impact Factor
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    ABSTRACT: 1-(3-Oxocyclobutyl) carboxylic acid (4a) was converted into N-Boc-protected 1-(3-oxocyclobutyl) urea (5a), a key intermediate for the preparation of agonists of metabotropic glutamate receptor 5, in one-step when treated with diphenyl phosphoryl azide and triethylamine in tert-butanol. The mechanism of the reaction involves a nucleophilic addition of the in situ generated tert-butyl carbamate to the isocyanate intermediate. This reaction is applicable to other 1-(3-oxocycloalkyl) carboxylic acids but not to linear γ-keto carboxylic acids.
    Tetrahedron Letters 07/2014; 55(4):842–844. · 2.39 Impact Factor
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    ABSTRACT: Cognitive dysfunction has been reported in patients with spinal cord injury (SCI), but it has been questioned whether such changes may reflect concurrent head injury, and the issue has not been addressed mechanistically or in a well-controlled experimental model. Our recent rodent studies examining SCI-induced hyperesthesia revealed neuroinflammatory changes not only in supratentorial pain-regulatory sites, but also in other brain regions, suggesting that additional brain functions may be impacted following SCI. Here we examined effects of isolated thoracic SCI in rats on cognition, brain inflammation, and neurodegeneration. We show for the first time that SCI causes widespread microglial activation in the brain, with increased expression of markers for activated microglia/macrophages, including translocator protein and chemokine ligand 21 (C-C motif). Stereological analysis demonstrated significant neuronal loss in the cortex, thalamus, and hippocampus. SCI caused chronic impairment in spatial, retention, contextual, and fear-related emotional memory-evidenced by poor performance in the Morris water maze, novel objective recognition, and passive avoidance tests. Based on our prior work implicating cell cycle activation (CCA) in chronic neuroinflammation after SCI or traumatic brain injury, we evaluated whether CCA contributed to the observed changes. Increased expression of cell cycle-related genes and proteins was found in hippocampus and cortex after SCI. Posttraumatic brain inflammation, neuronal loss, and cognitive changes were attenuated by systemic post-injury administration of a selective cyclin-dependent kinase inhibitor. These studies demonstrate that chronic brain neurodegeneration occurs after isolated SCI, likely related to sustained microglial activation mediated by cell cycle activation.
    Cell cycle (Georgetown, Tex.) 06/2014; 13(15). · 5.24 Impact Factor
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    ABSTRACT: Traumatic brain injury (TBI) causes microglial activation and related neurotoxicity that contributes to chronic neurodegeneration and loss of neurological function. Selective activation of metabotropic glutamate receptor 5 (mGluR5) by the orthosteric agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), is neuroprotective in experimental models of TBI, and has potent anti-inflammatory effects in vitro. However, the therapeutic potential of CHPG is limited due to its relatively weak potency and brain permeability. Highly potent, selective and brain penetrant mGluR5 positive allosteric modulators (PAMs) have been developed and show promise as therapeutic agents. We evaluated the therapeutic potential of a novel mGluR5 PAM, VU0360172, after controlled cortical impact (CCI) in mice. Vehicle, VU0360172, or VU0360172 plus mGluR5 antagonist (MTEP), were administered systemically to CCI mice at 3 h post-injury; lesion volume, hippocampal neurodegeneration, microglial activation, and functional recovery were assessed through 28 days post-injury. Anti-inflammatory effects of VU0360172 were also examined in vitro using BV2 and primary microglia. VU0360172 treatment significantly reduced the lesion, attenuated hippocampal neurodegeneration, and improved motor function recovery after CCI. Effects were mediated by mGluR5 as co-administration of MTEP blocked the protective effects of VU0360172. VU0360172 significantly reduced CD68 and NOX2 expression in activated microglia in the cortex at 28 days post-injury, and also suppressed pro-inflammatory signaling pathways in BV2 and primary microglia. In addition, VU0360172 treatment shifted the balance between M1/M2 microglial activation states towards an M2 pro-repair phenotype. This study demonstrates that VU0360172 confers neuroprotection after experimental TBI, and suggests that mGluR5 PAMs may be promising therapeutic agents for head injury. © 2014 The American Society for Experimental NeuroTherapeutics, Inc.
    Neurotherapeutics 06/2014; · 3.88 Impact Factor
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    ABSTRACT: Repeated mild traumatic brain injury (mTBI) can cause sustained cognitive and psychiatric changes, as well as neurodegeneration, but the underlying mechanisms remain unclear. We examined histologic, neurophysiological, and cognitive changes after single or repeated (three injuries) mTBI using the rat lateral fluid percussion (LFP) model. Repeated mTBI caused substantial neuronal cell loss and significantly increased numbers of activated microglia in both ipsilateral and contralateral hippocampus on post-injury day (PID) 28. Long-term potentiation (LTP) could not be induced on PID 28 after repeated mTBI in ex vivo hippocampal slices from either hemisphere. N-Methyl-D-aspartate (NMDA) receptor-mediated responses were significantly attenuated after repeated mTBI, with no significant changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated responses. Long-term potentiation was elicited in slices after single mTBI, with potentiation significantly increased in ipsilateral versus contralateral hippocampus. After repeated mTBI, rats displayed cognitive impairments in the Morris water maze (MWM) and novel object recognition (NOR) tests. Thus, repeated mTBI causes deficits in the hippocampal function and changes in excitatory synaptic neurotransmission, which are associated with chronic neuroinflammation and neurodegeneration.Journal of Cerebral Blood Flow & Metabolism advance online publication, 23 April 2014; doi:10.1038/jcbfm.2014.75.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 04/2014; · 5.46 Impact Factor
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    ABSTRACT: Amyloid-β (Aβ) is produced through the enzymatic cleavage of amyloid precursor protein (APP) by β (Bace1) and γ -secretases. The accumulation and aggregation of Aβ as amyloid plaques is the hallmark pathology of Alzheimer’s disease and has been found in other neurological disorders, such as traumatic brain injury and multiple sclerosis. Although the role of Aβ after injury is not well understood, several studies have reported a negative correlation between Aβ formation and functional outcome. In this study we show that levels of APP, the enzymes cleaving APP (Bace1 and γ-secretase), and Aβ are significantly increased from 1 to 3 days after impact spinal cord injury (SCI) in mice. To determine the role of Aβ after SCI, we reduced or inhibited Aβ in vivo through pharmacological (using DAPT) or genetic (Bace1 knockout mice) approaches. We found that these interventions significantly impaired functional recovery as evaluated by white matter sparing and behavioral testing. These data are consistent with a beneficial role for Aβ after SCI.
    Brain research 04/2014; · 2.83 Impact Factor
  • Tetrahedron Letters 03/2014; · 2.39 Impact Factor
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    ABSTRACT: Abstract Traumatic brain injury (TBI) causes neuronal cell death as well as microglial activation and related neurotoxicity that contribute to subsequent neurological dysfunction. Poly (ADP-ribose) polymerase (PARP-1) induces neuronal cell death through activation of caspase-independent mechanisms, including release of apoptosis inducing factor (AIF), and microglial activation. Administration of PJ34, a selective PARP-1 inhibitor, reduced cell death of primary cortical neurons exposed to N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG), a potent inducer of AIF-dependent cell death. PJ34 also attenuated lipopolysaccharide and interferon-γ-induced activation of BV2 or primary microglia, limiting NF-κB activity and iNOS expression as well as decreasing generation of reactive oxygen species and TNFα. Systemic administration of PJ34 starting as late as 24 h after controlled cortical impact resulted in improved motor function recovery in mice with TBI. Stereological analysis demonstrated that PJ34 treatment reduced the lesion volume, attenuated neuronal cell loss in the cortex and thalamus, and reduced microglial activation in the TBI cortex. PJ34 treatment did not improve cognitive performance in a Morris water maze test or reduce neuronal cell loss in the hippocampus. Overall, our data indicate that PJ34 has a significant, albeit selective, neuroprotective effect after experimental TBI, and its therapeutic effect may be from multipotential actions on neuronal cell death and neuroinflammatory pathways.
    Journal of neurotrauma 01/2014; · 4.25 Impact Factor
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    ABSTRACT: Central nervous system injury causes a marked increase in the expression of cell cycle-related proteins. In this study, we show that cell cycle activation (CCA) is detected in mature neurons at 24 hours after rat lateral fluid percussion (LFP)-induced traumatic brain injury (TBI), as reflected by increased expression of cyclin G1, phosphorylated retinoblastoma (phospho-Rb), E2F1 and proliferating cell nuclear antigen (PCNA). These changes were associated with progressive cortical, hippocampal, and thalamic neuronal loss and microglial and astrocyte activation. Notably, we detected 5-bromo-2'-deoxyuridine (BrdU)-positive neurons, microglia, and astrocytes at 7 days, but not at 24 hours, suggesting that cell cycle reaches the S phase in these cell types at the latter time point. A delayed systemic post-LFP administration at 3 hours of CR8-a potent second-generation cyclin-dependent kinase (CDK) inhibitor-reduced CCA; cortical, hippocampal, and thalamic neuronal loss; and cortical microglial and astrocyte activation. Furthermore, CR8 treatment attenuated sensorimotor and cognitive deficits, alleviated depressive-like symptoms, and decreased lesion volume. These findings underscore the contribution of CCA to progressive neurodegeneration and chronic neuroinflammation following TBI, and demonstrate the neuroprotective potential of cell cycle inhibition in a clinically relevant experimental TBI model.Journal of Cerebral Blood Flow & Metabolism advance online publication, 8 January 2014; doi:10.1038/jcbfm.2013.228.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 01/2014; · 5.46 Impact Factor
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    Shruti V Kabadi, Alan I Faden
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    ABSTRACT: Traumatic brain injury (TBI) induces secondary biochemical changes that contribute to delayed neuroinflammation, neuronal cell death, and neurological dysfunction. Attenuating such secondary injury has provided the conceptual basis for neuroprotective treatments. Despite strong experimental data, more than 30 clinical trials of neuroprotection in TBI patients have failed. In part, these failures likely reflect methodological differences between the clinical and animal studies, as well as inadequate pre-clinical evaluation and/or trial design problems. However, recent changes in experimental approach and advances in clinical trial methodology have raised the potential for successful clinical translation. Here we critically analyze the current limitations and translational opportunities for developing successful neuroprotective therapies for TBI.
    International Journal of Molecular Sciences 01/2014; 15(1):1216-1236. · 2.34 Impact Factor
  • Alan I Faden
    Journal of the American Society for Experimental NeuroTherapeutics 12/2013; · 3.88 Impact Factor

Publication Stats

14k Citations
1,780.94 Total Impact Points

Institutions

  • 2014
    • University of Baltimore
      Baltimore, Maryland, United States
  • 2010–2014
    • Loyola University Maryland
      Baltimore, Maryland, United States
    • University of Maryland, Baltimore
      • Department of Anesthesiology
      Baltimore, Maryland, United States
  • 2012–2013
    • University of Maryland Medical Center
      Baltimore, Maryland, United States
  • 1992–2012
    • Georgetown University
      • • Department of Neuroscience
      • • Institute for Cognitive and Computational Sciences
      • • Department of Neurology
      Washington, Washington, D.C., United States
  • 2007
    • Washington DC VA Medical Center
      Washington, Washington, D.C., United States
  • 2006
    • Hertie-Institute for Clinical Brain Research
      Tübingen, Baden-Württemberg, Germany
  • 1981–2006
    • Uniformed Services University of the Health Sciences
      • Department of Neurology
      Maryland, United States
  • 2003–2005
    • Children's National Medical Center
      • Center for Genetic Medicine Research
      Washington, D. C., DC, United States
  • 1995
    • Chiba University
      Tiba, Chiba, Japan
  • 1990–1995
    • James Cook University
      • School of Pharmacy and Molecular Sciences
      Townsville, Queensland, Australia
    • University of California, Berkeley
      • Division of Neurobiology
      Berkeley, MO, United States
  • 1985–1995
    • University of California, San Francisco
      • • Division of Hospital Medicine
      • • Department of Neurology
      San Francisco, California, United States
  • 1994
    • University of Pennsylvania
      • Department of Surgery
      Philadelphia, PA, United States
  • 1989
    • CSU Mentor
      Long Beach, California, United States
  • 1985–1988
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 1983
    • University of Massachusetts Medical School
      • Department of Neurology
      Worcester, Massachusetts, United States
  • 1978–1983
    • Walter Reed Army Institute of Research
      Silver Spring, Maryland, United States