Future Neurol
· 2009 Sep · PMID 20161538
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Comorbid health conditions are common among people with epilepsy. Proposed explanations for this association include the possibility that first, epilepsy (including its treatment) causes the comorbid condition; second, t...Comorbid health conditions are common among people with epilepsy. Proposed explanations for this association include the possibility that first, epilepsy (including its treatment) causes the comorbid condition; second, the comorbid condition (including its treatment) causes epilepsy; or third, a common pathogenic mechanism mediates the co-occurrence of epilepsy and the comorbid condition. It is unlikely that a single explanation will suffice for all of the epilepsy comorbid conditions. Determining the basis of the association between epilepsy and its comorbid conditions has important implications for diagnosis and management. In this paper, we discuss this issue in the context of five common epilepsy comorbid conditions: bone health and fractures, stroke, depression, migraine and attention-deficit hyperactivity disorder. Current findings, research limitations and future directions of research efforts are discussed.
Future Neurol
· 2009 May · PMID 20161214
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Hearing loss during development leads to central deficits that persist even after the restoration of peripheral function. One key class of deficits is due to changes in central inhibitory synapses, which play a fundament...Hearing loss during development leads to central deficits that persist even after the restoration of peripheral function. One key class of deficits is due to changes in central inhibitory synapses, which play a fundamental role in all aspects of auditory processing. This review focuses on the anatomical and physiological alterations of inhibitory connections at several regions within the central auditory pathway following hearing loss. Such aberrant inhibitory synaptic function may be linked to deficits in encoding binaural and spectral cues. Understanding the cellular changes that occur at inhibitory synapses following hearing loss may provide specific loci that can be targeted to improve function.
Future Neurol
· 2009 May · PMID 20161076
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As the concept of a network of injury has emerged in the treatment of epilepsy, the importance of evaluating that network noninvasively has also grown. Recently, studies utilizing magnetic resonance spectroscopic imaging...As the concept of a network of injury has emerged in the treatment of epilepsy, the importance of evaluating that network noninvasively has also grown. Recently, studies utilizing magnetic resonance spectroscopic imaging, manganese-enhanced MRI and functional (f)MRI measures of resting state connectivity have demonstrated their ability to detect injury and dysfunction in cerebral networks involved in the propagation of seizures. The ability to noninvasively detect neuronal injury and dysfunction throughout cerebral networks should improve surgical planning, provide guidance for placement of devices that target network propagation and provide insights into the mechanisms of recurrence following resective surgery.
Jeitner TM, Muma NA, Battaile KP
… +1 more, Cooper AJ
Future Neurol
· 2009 Jul · PMID 20161049
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The following review examines the role of calcium in promoting the in vitro and in vivo activation of transglutaminases in neurodegenerative disorders. Diseases such as Alzheimer's disease, Parkinson's disease and Huntin...The following review examines the role of calcium in promoting the in vitro and in vivo activation of transglutaminases in neurodegenerative disorders. Diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease exhibit increased transglutaminase activity and rises in intracellular calcium concentrations, which may be related. The aberrant activation of transglutaminase by calcium is thought to give rise to a variety of pathological moieties in these diseases, and the inhibition has been shown to have therapeutic benefit in animal and cellular models of neurodegeneration. Given the potential clinical relevance of transglutaminase inhibitors, we have also reviewed the recent development of such compounds.
Future Neurol
· 2009 Nov · PMID 20076770
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Axonal transport, the process by which membrane-bound organelles and soluble protein complexes are transported into and out of axons, ensures proper function of the neuron, including that of the synapse. As such, abnorma...Axonal transport, the process by which membrane-bound organelles and soluble protein complexes are transported into and out of axons, ensures proper function of the neuron, including that of the synapse. As such, abnormalities in axonal transport could lead to neuronal pathology and disease. Similar to many neurodegenerative diseases, axonal transport is deficient in Alzheimer's disease (AD), a neurodegenerative brain disorder that affects old-age humans and is characterized by the deterioration of cognitive function and progressive memory loss. It was proposed that the synaptic pathology and neuronal degeneration that develops in AD could be caused by an abnormal axonal transport, and that the mutated proteins that cause early-onset AD, as well as the genetic variants that confer predisposition to late-onset AD might somehow impede axonal transport. This paper analyzes the data that support or contradict this hypothesis. Together, they indicate that, although abnormalities in axonal transport are part of the disease, additional studies are required to clearly establish to what extent deficient axonal transport is the cause or the effect of the neuronal pathology in AD, and to identify mechanisms that lead to its perturbation.
The developmental origins of disease or fetal programming model predicts that early exposures to threat or adverse conditions have lifelong consequences that result in harmful outcomes for health. The vast majority of th...The developmental origins of disease or fetal programming model predicts that early exposures to threat or adverse conditions have lifelong consequences that result in harmful outcomes for health. The vast majority of the studies in support of the programming model in human beings are retrospective and most relied on surrogate measures of early experience such as birth weight or preterm birth. Recently, a small number of prospective studies have been reported that have documented the developmental consequences of exposures to stressful intrauterine conditions. These studies of gestational stress have clearly shown that fetal exposures to psychosocial and/or biological markers of adversity have significant and largely negative consequences for fetal, infant and child neurological development. Fetal exposure to stress, especially early in gestation, results in delayed fetal maturation and impaired cognitive performance during infancy and results in decreased brain volume in areas associated with learning and memory in children. The accumulating evidence supports the conclusion that fetal exposure to stress profoundly influences the nervous system, with consequences that persist into childhood and perhaps beyond.
Future Neurol
· 2010 Jan · PMID 24348095
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Huntington disease (HD) is a devastating illness, although its autosomal dominant genetic transmission allows a unique opportunity to study apparently healthy individuals before manifest disease. Attempts to study early...Huntington disease (HD) is a devastating illness, although its autosomal dominant genetic transmission allows a unique opportunity to study apparently healthy individuals before manifest disease. Attempts to study early disease are not unique in neurology (e.g., Mild Cognitive Impairment, Vascular Cognitive Impairment), but studying otherwise-healthy appearing individuals who will go on with nearly 99% certainty to manifest the symptoms of brain disease does provide distinct but valuable information about the true natural history of the disease. The field has witnessed an explosion of research examining possible early indicators of HD during what is now referred to as the "prodrome" of HD. A NIH study in its ninth year (PREDICT-HD) has offered a glimpse into the transition from an apparently healthy state to an obviously diseased state, and can serve as a model for many other genetic diseases, both neurological and non-neurological.
Future Neurol
· 2010 Jan · PMID 23525658
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Getting gray hair is part of the natural progression of aging. People expect it and they can change their hair color, if they choose. People also expect increases in memory lapses and learning difficulties as they get ol...Getting gray hair is part of the natural progression of aging. People expect it and they can change their hair color, if they choose. People also expect increases in memory lapses and learning difficulties as they get older. However, unlike hair color, there is no magic cure or option to fix learning and memory difficulties, because the cellular mechanisms of learning and aging in all the different types of neurons throughout the brain have yet to be discovered. This review describes our efforts to identify a cellular biomarker in hippocampal pyramidal neurons that has been demonstrated to reliably change with learning and with aging - the postburst afterhyperpolarization. We propose that this biomarker, which plays a critical role in regulating neuronal excitability, can be used as a benchmark for future studies in order to understand and identify the cellular mechanisms of learning and aging in the hippocampus, as well as in other cortical regions.
Autism spectrum disorders (ASDs) are relatively infrequent but are devastating developmental conditions characterized by marked deficiencies in social, communicative and other behavioral domains. It has been known for a...Autism spectrum disorders (ASDs) are relatively infrequent but are devastating developmental conditions characterized by marked deficiencies in social, communicative and other behavioral domains. It has been known for a substantial period of time that these disorders are genetic in nature. However, elucidating the specific mechanisms of these disorders has been difficult. A major reason for such difficulty is the recognized genetic heterogeneity of ASDs. Specifically, many genetic mechanisms related to structural variations in the genome have been reported as possible genetic causes of these disorders. This review briefly exemplifies these genetic mechanisms, presents a concise overview of the evidence for the genetic basis of ASDs and provides an appraisal of the specific structural genetic variants thought to contribute to the pathogenesis of these complex disorders.
Future Neurol
· 2009 Jan · PMID 19946620
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A declining cell-mediated immunity to varicella zoster virus (VZV) with advancing age or immunosuppression results in virus reactivation from latently infected human ganglia anywhere along the neuraxis. Virus reactivatio...A declining cell-mediated immunity to varicella zoster virus (VZV) with advancing age or immunosuppression results in virus reactivation from latently infected human ganglia anywhere along the neuraxis. Virus reactivation produces zoster, often followed by chronic pain (postherpetic neuralgia or PHN) as well as vasculopathy, myelopathy, retinal necrosis and cerebellitis. VZV reactivation also produces pain without rash (zoster sine herpete). Vaccination after age 60 reduces the incidence of shingles by 51%, PHN by 66% and the burden of illness by 61%. However, even if every healthy adult over age 60 years is vaccinated, there would still be about 500,000 zoster cases annually in the United States alone, about 200,000 of whom will experience PHN. Analyses of viral nucleic acid and gene expression in latently infected human ganglia and in an animal model of varicella latency in primates are serving to determine the mechanism(s) of VZV reactivation with the aim of preventing reactivation and the clinical sequelae.
Since its original discovery as a negative regulator of neuronal differentiation, the repressor element (RE)-1 silencing transcription factor (REST), also known as the neuron-restrictive silencer factor, has been implica...Since its original discovery as a negative regulator of neuronal differentiation, the repressor element (RE)-1 silencing transcription factor (REST), also known as the neuron-restrictive silencer factor, has been implicated in novel processes such as maintenance of embryonic stem cell pluripotency and self-renewal and regulation of mitotic fidelity in non-neural cells. REST expression and activity is tightly controlled by transcriptional and post-transcriptional mechanisms in a cell and developmental stage-specific manner and perturbations in its levels or function are associated with various pathological states. REST differentially influences target-gene expression through interaction with a wide variety of cellular cofactors in a context-dependent manner. However, the influence of the microenvironment on REST-mediated regulation of gene expression is poorly understood. This review will present our current understanding of REST signaling with a greater focus on its emerging ties with noncoding RNAs and novel interacting partners, as well as its roles in embryonic stem cell self-renewal, cellular plasticity and oncogenesis/tumor suppression.
The receptor for advanced glycation end products (RAGE) has been demonstrated to play a central role in the pathogenic mechanisms of a growing number of important neurological diseases, including Alzheimer's disease (AD)...The receptor for advanced glycation end products (RAGE) has been demonstrated to play a central role in the pathogenic mechanisms of a growing number of important neurological diseases, including Alzheimer's disease (AD) and stroke. Two functional types of RAGE have been associated with neurological diseases: cell membrane-bound (full length) and soluble. In general, ligand binding to full-length RAGE initiates sustained cellular activation and receptor-dependent signaling resulting in inflammation and cellular stress, and is ultimately associated with increased RAGE expression. By comparison, soluble forms of RAGE, generated either by alternative splicing or by proteolysis, can reduce the severity of the consequence of ligand-membrane RAGE interactions by preventing ligands from binding to the full-length RAGE. This can inhibit the neurotoxic or proinflammatory responses involved in disease states. This article reviews the pathobiology of RAGE, with emphasis on soluble forms of RAGE, and discusses its relevance to AD and to other neurological diseases, as well as how manipulation of the different forms of RAGE is becoming a powerful therapeutic strategy.
Ischemic tolerance is a biological process that can be utilized to unlock the brain's own endogenous protection mechanisms and, as such, holds true promise for patients at risk of ischemic injury. Experimentally, precond...Ischemic tolerance is a biological process that can be utilized to unlock the brain's own endogenous protection mechanisms and, as such, holds true promise for patients at risk of ischemic injury. Experimentally, preconditioning with various Toll-like receptor (TLR) agonists has now been demonstrated to successfully attenuate ischemic damage, partly through genomic reprogramming of the body's response to stroke. This treatment diminishes the inflammatory response to stroke and at the same time enhances the production of anti-inflammatory cytokines and neuroprotective mediators. This review discusses recent discoveries about the role of TLRs in preconditioning and ischemic tolerance.
Future Neurol
· 2009 Jan · PMID 19884978
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Several factors have amplified concern about the possibility that antidepressant medication may contribute to induction of pediatric mania. These include the high rate of antidepressant medication prescription, the recen...Several factors have amplified concern about the possibility that antidepressant medication may contribute to induction of pediatric mania. These include the high rate of antidepressant medication prescription, the recent surge in the rate of diagnosis of pediatric bipolar disorder in the USA, and a growing number of case reports and clinical studies showing coincidence of manic symptoms with antidepressant pharmacotherapy in both youths and adults. However, the question of how medications and manic symptoms might be related is complicated, and decisive research studies with rigorous designs for evaluating the issues have not been published. The situation makes it difficult for practitioners to make good, evidence-based decisions. The scientific literature is ambiguous, and the stakes are high. We review the extant literature, offer seven different conceptual models of how medication and mania might be related, and comment on the evidence and clinical implications of each.
Future Neurol
· 2009 Mar · PMID 19779591
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Soluble epoxide hydrolase (sEH) is a key enzyme in the metabolic conversion and degradation of P450 eicosanoids called epoxyeicosatrienoic acids (EETs). Genetic variations in the sEH gene, designated EPHX2, are associate...Soluble epoxide hydrolase (sEH) is a key enzyme in the metabolic conversion and degradation of P450 eicosanoids called epoxyeicosatrienoic acids (EETs). Genetic variations in the sEH gene, designated EPHX2, are associated with ischemic stroke risk. In experimental studies, sEH inhibition and gene deletion reduce infarct size after focal cerebral ischemia in mice. Although the precise mechanism of protection afforded by sEH inhibition remains under investigation, EETs exhibit a wide array of potentially beneficial actions in stroke, including vasodilation, neuroprotection, promotion of angiogenesis and suppression of platelet aggregation, oxidative stress and post-ischemic inflammation. Herein we argue that by capitalizing on this broad protective profile, sEH inhibition represents a prototype "combination therapy" targeting multiple mechanisms of stroke injury with a single agent.
Future Neurol
· 2008 Nov · PMID 19727426
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The selective RNA-binding protein QKI play a key role in advancing oligodendrocyte-dependent myelination, which is essential for the function and development of the CNS. The emerging evidence that QKI abnormalities are a...The selective RNA-binding protein QKI play a key role in advancing oligodendrocyte-dependent myelination, which is essential for the function and development of the CNS. The emerging evidence that QKI abnormalities are associated with schizophrenia and may underlie myelin impairment in this devastating disease has greatly increased interest in understanding the function of QKI. Despite the discovery of the biochemical basis for QKI-RNA interaction, a comprehensive model is currently missing regarding how QKI regulates its mRNA ligands to promote normal myelinogenesis and how deficiency of the QKI pathway is involved in the pathogenesis of human diseases that affect CNS myelin. In this review, we will focus on the role of QKI in regulating distinct mRNA targets at critical developmental steps to promote oligodendrocyte differentiation and myelin formation. In addition, we will discuss molecular mechanisms that control QKI expression and activity during normal myelinogenesis as well as the pathological impact of QKI deficiency in dysmyelination mutant animals and in human myelin disorders.
The etiology of Parkinson's disease (PD) was long thought to be due to environmental factors. Following the discovery of autosomal-dominant mutations in the α-synuclein gene, and later recessive mutations in the DJ-1, Pa...The etiology of Parkinson's disease (PD) was long thought to be due to environmental factors. Following the discovery of autosomal-dominant mutations in the α-synuclein gene, and later recessive mutations in the DJ-1, Parkin and PINK-1 genes, the field of PD genetics exploded. In 2004, it was discovered that mutations in the PARK8 locus - leucine-rich repeat kinase 2 (LRRK2, Lrrk2) - are the most important genetic cause of autosomal-dominant PD. Lrrk2 substitutions also account for sporadic PD in certain ethnic populations and have been shown to increase the risk of PD in Asian populations. Drug therapies targeting Lrrk2 activity may therefore be beneficial to both familial and sporadic PD patients, hence understanding the role of Lrrk2 in health and disease is critical. This review aims to highlight the research effort concentrated on elucidating the functional biological role of Lrrk2, and to provide some future therapeutic perspectives.
Future Neurol
· 2007 Nov · PMID 19079759
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Remyelination facilitates recovery of saltatory conduction along demyelinated axons and may help prevent axon damage in patients with demyelinating diseases, such as multiple sclerosis. The extent of remyelination in mul...Remyelination facilitates recovery of saltatory conduction along demyelinated axons and may help prevent axon damage in patients with demyelinating diseases, such as multiple sclerosis. The extent of remyelination in multiple sclerosis lesions varies dramatically, indicating a capacity for repair that is not fulfilled in lesions with poor remyelination. In experimental models of demyelinating disease, remyelination is limited by chronic disease that depletes the oligodendrocyte progenitor (OP) population, inhibits OP differentiation into remyelinating oligodendrocytes and/or perturbs cell survival in the lesion environment. Manipulating the activity of growth factor signaling pathways significantly improves the ability of endogenous OP cells to accomplish extensive remyelination. Specifically, growth factors have been identified that can regulate OP proliferation, differentiation and survival in demyelinated lesions. Therefore, growth factors may be key signals for strategies to improve conditions with poor remyelination.