Future Neurol
· 2014 Nov · PMID 28163658
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Advances in neuroimaging have helped illuminate our understanding of how the brain works in the presence of chronic pain, which often persists with unknown etiology or after the painful stimulus has been removed and any...Advances in neuroimaging have helped illuminate our understanding of how the brain works in the presence of chronic pain, which often persists with unknown etiology or after the painful stimulus has been removed and any wounds have healed. Neuroimaging has enabled us to make great progress in identifying many of the neural mechanisms that contribute to chronic pain, and to pinpoint the specific regions of the brain that are activated in the presence of chronic pain. It has provided us with a new perception of the nature of chronic pain in general, leading researchers to move toward a whole-brain approach to the study and treatment of chronic pain, and to develop novel technologies and analysis techniques, with real potential for developing new diagnostics and more effective therapies. We review the use of neuroimaging in the study of chronic pain, with particular emphasis on magnetic resonance imaging.
Future Neurol
· 2014 Mar · PMID 25221437
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The cerebellum is an important structure for accurate control and timing of movement, and Purkinje neurons in the cerebellar cortex are key players in cerebellar motor control. Cerebellar dysfunction can result in ataxia...The cerebellum is an important structure for accurate control and timing of movement, and Purkinje neurons in the cerebellar cortex are key players in cerebellar motor control. Cerebellar dysfunction can result in ataxia, a disorder characterized by postural instability, gait disturbances and motor incoordination. Cerebellar ataxia is a symptom of a number of conditions, and the emerging evidence that Purkinje neuron dysfunction, in particular, abnormal Purkinje neuron repetitive firing, is a major driver of motor dysfunction in a subset of dominantly inherited ataxias is dicussed. Abnormalities in Purkinje neuron excitability that are observed in mouse models of each of these disorders, and where appropriate describe studies linking particular ion channels to aberrant excitability are also discussed. Common mechanisms of dysfunction and speculate about potential therapeutic targets, suggesting that Purkinje neuron firing abnormalities are a novel target for improving motor dysfunction in patients with some forms of dominantly inherited ataxia are proposed.
Future Neurol
· 2014 May · PMID 25214817
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Brain metabolism declines with age and do so in an accelerated manner in neurodegenerative disorders. Noninvasive neuroimaging techniques have played an important role to identify the metabolic biomarkers in aging brain....Brain metabolism declines with age and do so in an accelerated manner in neurodegenerative disorders. Noninvasive neuroimaging techniques have played an important role to identify the metabolic biomarkers in aging brain. Particularly, PET with fluorine-18 (F)-labeled 2-fluoro-2-deoxy-d-glucose tracer and proton magnetic resonance spectroscopy (MRS) have been widely used to monitor changes in brain metabolism over time, identify the risk for Alzheimer's disease (AD) and predict the conversion from mild cognitive impairment to AD. Novel techniques, including PET carbon-11 Pittsburgh compound B, carbon-13 and phosphorus-31 MRS, have also been introduced to determine Aβ plaques deposition, mitochondrial functions and brain bioenergetics in aging brain and neurodegenerative disorders. Here, we introduce the basic principle of the imaging techniques, review the findings from 2-fluoro-2-deoxy-d-glucose-PET, Pittsburgh compound B PET, proton, carbon-13 and phosphorus-31 MRS on changes in metabolism in normal aging brain, mild cognitive impairment and AD, and discuss the potential of neuroimaging to identify effective interventions and treatment efficacy for neurodegenerative disorders.
Besterman AD, Wilke SA, Mulligan TE
… +4 more, Allison SC, Hagerman R, Seritan AL, Bourgeois JA
Future Neurol
· 2014 Mar · PMID 25013385
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Fragile X-associated disorders (FXD) are a group of disorders caused by expansion of non-coding CGG repeat elements in the fragile X () gene. One of these disorders, fragile X syndrome (FXS), is the most common heritable...Fragile X-associated disorders (FXD) are a group of disorders caused by expansion of non-coding CGG repeat elements in the fragile X () gene. One of these disorders, fragile X syndrome (FXS), is the most common heritable cause of intellectual disability, and is caused by large CGG repeat expansions (>200) resulting in silencing of the gene. An increasingly recognized number of neuropsychiatric FXD have recently been identified that are caused by 'premutation' range expansions (55-200). These disorders are characterized by a spectrum of neuropsychiatric manifestations ranging from an increased risk of neurodevelopmental, mood and anxiety disorders to neurodegenerative phenotypes such as the fragile X-associated tremor ataxia syndrome (FXTAS). Here, we review advances in the clinical understanding of neuropsychiatric disorders in premutation carriers across the lifespan and offer guidance for the detection of such disorders by practicing psychiatrists and neurologists.
Future Neurol
· 2014 Jan · PMID 24678267
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We are studying the projections from the entorhinal cortex to the hippocampal formation in the mouse. The dentate gyrus is innervated by the lateral entorhinal cortex (lateral perforant path) and medial entorhinal cortex...We are studying the projections from the entorhinal cortex to the hippocampal formation in the mouse. The dentate gyrus is innervated by the lateral entorhinal cortex (lateral perforant path) and medial entorhinal cortex (medial perforant path). The entorhinal cortex also projects to hippocampal areas CA3 and CA1, and to the subiculum. In young transgenic Alzheimer's disease mouse models (before amyloid-β pathology), the connections are not different from normal mice. In Alzheimer's disease mice with pathology, two changes occur: first, dystrophic axon endings appear near amyloid-β plaques, and second, there are sparse aberrant axon terminations not in the appropriate area or lamina of the hippocampus. Furthermore, MRI-diffusion tensor imaging analysis indicates a decrease in the quality of the white matter tracts connecting the hippocampus to the brain; in other words, the fimbria/fornix and perforant path. Similar changes in white matter integrity have been found in Alzheimer's disease patients and could potentially be used as early indicators of disease onset.
Future Neurol
· 2014 Jan · PMID 24648831
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Of the numerous inherited diseases known to afflict the pediatric population, spinal muscular atrophy (SMA) is among the most common. It has an incidence of approximately one in 10,000 newborns and a carrier frequency of...Of the numerous inherited diseases known to afflict the pediatric population, spinal muscular atrophy (SMA) is among the most common. It has an incidence of approximately one in 10,000 newborns and a carrier frequency of one in 50. Despite its relatively high incidence, SMA remains somewhat obscure among the many neurodegenerative diseases that affect humans. Nevertheless, the last two decades have witnessed remarkable progress in our understanding of the pathology, underlying biology and especially the molecular genetics of SMA. This has led to a genuine expectation within the scientific community that a robust treatment will be available to patients before the end of the decade. The progress made in our understanding of SMA and, therefore, towards a viable therapy for affected individuals is in large measure a consequence of the simple yet fascinating genetics of the disease. Nevertheless, important questions remain. Addressing these questions promises not only to accelerate the march towards a cure for SMA, but also to uncover novel therapies for related neurodegenerative disorders. This review discusses our current understanding of SMA, considers the challenges ahead, describes existing treatment options and highlights state-of-the-art research being conducted as a means to a better, safer and more effective treatment for the disease.
Future Neurol
· 2013 Nov · PMID 24489483
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The revised 'expanded' neurovascular unit (eNVU) is a physiological and functional unit encompassing endothelial cells, pericytes, smooth muscle cells, astrocytes and neurons. Ischemic stroke and traumatic brain injury a...The revised 'expanded' neurovascular unit (eNVU) is a physiological and functional unit encompassing endothelial cells, pericytes, smooth muscle cells, astrocytes and neurons. Ischemic stroke and traumatic brain injury are acute brain injuries directly affecting the eNVU with secondary damage, such as blood-brain barrier (BBB) disruption, edema formation and hypoperfusion. BBB dysfunctions are observed at an early postinjury time point, and are associated with eNVU activation of proteases, such as tissue plasminogen activator and matrix metalloproteinases. BBB opening is accompanied by edema formation using astrocytic AQP4 as a key protein regulating water movement. Finally, nitric oxide dysfunction plays a dual role in association with BBB injury and dysregulation of cerebral blood flow. These mechanisms are discussed including all targets of eNVU encompassing endothelium, glial cells and neurons, as well as larger blood vessels with smooth muscle. In fact, the feeding blood vessels should also be considered to treat stroke and traumatic brain injury. This review underlines the importance of the eNVU in drug development aimed at improving clinical outcome after stroke and traumatic brain injury.
Peters JM, Taquet M, Prohl AK
… +5 more, Scherrer B, van Eeghen AM, Prabhu SP, Sahin M, Warfield SK
Future Neurol
· 2013 Sep · PMID 24489482
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In this article, the authors aim to introduce the nonradiologist to diffusion tensor imaging (DTI) and its applications to both clinical and research aspects of tuberous sclerosis complex. Tuberous sclerosis complex is a...In this article, the authors aim to introduce the nonradiologist to diffusion tensor imaging (DTI) and its applications to both clinical and research aspects of tuberous sclerosis complex. Tuberous sclerosis complex is a genetic neurocutaneous syndrome with variable and unpredictable neurological comorbidity that includes refractory epilepsy, intellectual disability, behavioral abnormalities and autism spectrum disorder. DTI is a method for modeling water diffusion in tissue and can noninvasively characterize microstructural properties of the brain. In tuberous sclerosis complex, DTI measures reflect well-known pathological changes. Clinically, DTI can assist with detecting the epileptogenic tuber. For research, DTI has a putative role in identifying potential disease biomarkers, as DTI abnormalities of the white matter are associated with neurocognitive morbidity including autism. If indeed DTI changes parallel phenotypical changes related to the investigational treatment of epilepsy, cognition and behavior with mTOR inhibitors, it will facilitate future clinical trials.
Future Neurol
· 2013 Sep · PMID 24489481
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Few specific therapeutic targets exist to manage brain injury, despite the prevalence of stroke or traumatic brain injury. With traumatic brain injury, characteristic neuronal changes include axonal swelling and degenera...Few specific therapeutic targets exist to manage brain injury, despite the prevalence of stroke or traumatic brain injury. With traumatic brain injury, characteristic neuronal changes include axonal swelling and degeneration, and the loss of synapses, the sites of communication between neurons. This is followed by axonal sprouting and alterations in synaptic markers in recovery. The resulting changes in neuronal connectivity are likely to contribute to the effects of traumatic brain injury on cognitive functions and the underlying mechanisms may represent points of therapeutic intervention. In agreement, animal studies implicate adhesion and signaling molecules that organize synapses as molecular players in neuronal recovery. In this article, the authors focus on the role of cell surface interactions in the recovery after brain injury in humans and animals. The authors review cellular and synaptic alterations that occur with injury and how changes in cell adhesion, protein expression and modification may be involved in recovery. The changes in neuronal surface interactions as potential targets and their possible value for the development of therapeutics are also discussed.
Considerable evidence, particularly from genetics, points to the aggregation-prone amyloid β-peptide as a pathogenic entity in Alzheimer's disease. Hence, the proteases that produce this peptide from its precursor protei...Considerable evidence, particularly from genetics, points to the aggregation-prone amyloid β-peptide as a pathogenic entity in Alzheimer's disease. Hence, the proteases that produce this peptide from its precursor protein have been prime targets for the development of potential therapeutics. One of these proteases, γ-secretase, has been a particular focus. Many inhibitors and modulators of this membrane-embedded protease complex have been identified, with some brought into late-stage clinical trials, where they have spectacularly failed. The reasons for these failures will be discussed, along with recent findings on the mechanism of γ-secretase and of Alzheimer-causing mutations that may suggest new strategies for targeting this enzyme.
Future Neurol
· 2013 Nov · PMID 24376373
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The formation of cerebral aneurysms and their rupture propensity is of immediate clinical importance. Current management includes observation with expectant management, microsurgical clipping and/or endovascular coiling....The formation of cerebral aneurysms and their rupture propensity is of immediate clinical importance. Current management includes observation with expectant management, microsurgical clipping and/or endovascular coiling. The surgical options are invasive and are not without increased risk despite the technological advances. Recent human and animal studies have shown that inflammation plays a critical role in aneurysm formation and progression to rupture. Modulating this inflammatory process may prove to be clinically significant. This review will discuss cerebral aneurysm pathogenesis with a focus on current and future research of potential use of pharmaceutical agents that attenuate inflammation in the aneurysm wall leading to decreased risk of aneurysm rupture.
Future Neurol
· 2013 Sep · PMID 24376372
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Astrocytes are the predominant glial cell type in the CNS. Although astrocytes are electrically nonexcitable, their excitability is manifested by their Ca signaling, which serves as a mediator of neuron-glia bidirectiona...Astrocytes are the predominant glial cell type in the CNS. Although astrocytes are electrically nonexcitable, their excitability is manifested by their Ca signaling, which serves as a mediator of neuron-glia bidirectional interactions via tripartite synapses. Studies from two-photon imaging indicate that in healthy animals, the properties of spontaneous astrocytic Ca signaling are affected by animal species, age, wakefulness and the location of astrocytes in the brain. Intercellular Ca waves in astrocytes can be evoked by a variety of stimulations. In animal models of some brain disorders, astrocytes can exhibit enhanced Ca excitability featured as regenerative intercellular Ca waves. This review first briefly summarizes the astrocytic Ca signaling pathway and the procedure of two-photon Ca imaging of astrocytes. It subsequently summarizes astrocytic Ca signaling in health and brain disorders from experimental studies of animal models, and discusses the possible mechanisms and therapeutic implications underlying the enhanced Ca excitability in astrocytes in brain disorders. Finally, this review summarizes molecular genetic approaches used to selectively manipulate astrocyte function and their applications to study the role of astrocytes in synaptic plasticity and brain disorders.
Chapleau CA, Lane J, Larimore J
… +3 more, Li W, Pozzo-Miller L, Percy AK
Future Neurol
· 2013 Jan · PMID 24348096
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Synaptic communication is highly regulated process of contact between cells allowing information to be stored and modified. Synaptic formation and maturation is the result of interactions between intrinsic genetic/molecu...Synaptic communication is highly regulated process of contact between cells allowing information to be stored and modified. Synaptic formation and maturation is the result of interactions between intrinsic genetic/molecular factors and the external environment to establish the communication in the brain. One disorder associated with faulty synapse communication is Rett Syndrome (RTT). RTT is the leading form of severe MR in females, affecting approximately 1:10,000 females worldwide, without predisposition to any particular racial or ethnic group. Mutations in , the gene encoding methyl-CpG-binding protein-2, have been identified in more than 95% of individuals with RTT. Birth and the milestones of early development appear to be normal in individuals with RTT until approximately 6-18 months when in the subsequent months and years that follows, physical, motor, and social-cognitive development enter a period of regression. The clinical management of these individuals is extremely multifaceted, relying on collaborations of specialists and researchers from many different fields. In this critical literature review, we provide an overview of Rett Syndrome, from patient to pathophysiology with a therapeutic summary of clinical trials in RTT and preclinical studies using mouse and cell models of RTT.
Future Neurol
· 2013 Jul · PMID 24273459
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The Second Muscular Dystrophy Association Scientific Meeting was held on 21-24 April 2013 in Washington (DC, USA). The meeting provided an opportunity for research scientists, clinicians, government agencies and industry...The Second Muscular Dystrophy Association Scientific Meeting was held on 21-24 April 2013 in Washington (DC, USA). The meeting provided an opportunity for research scientists, clinicians, government agencies and industry experts to highlight and discuss different aspects of therapy development for neuromuscular diseases, including novel targets, biomarkers, therapeutic approaches, animal models and clinical trials. With 500 participants, 66 presentations and 200 abstracts, the 3-day conference has become a central focus for scientists interested in translational research and moving potential therapies forward from the bench to the bedside. Key issues covered by the meeting included the need to identify new drugs to treat patients with neuromuscular diseases and the importance of establishing collaborations between government, academic and industry sectors toward an efficient and rigorous translational path for neuromuscular diseases.
Future Neurol
· 2013 May · PMID 24198718
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CD200 and its receptor, CD200 receptor (CD200R), have uniaue roles in controlling damaging inflammatory processes. At present, the only identified function for CD200 is as a ligand for CD200R. These proteins interact res...CD200 and its receptor, CD200 receptor (CD200R), have uniaue roles in controlling damaging inflammatory processes. At present, the only identified function for CD200 is as a ligand for CD200R. These proteins interact resulting in the activation of anti-inflammatory signaling by CD200R-expressing cells. When this interaction becomes deficient with aging or disease, chronic inflammation occurs, Experimental animal studies have demonstrated the consequences of disrupting CD200-CD200R interactions in the brain, but there have been few studies in human brains. Deficiency in neuronal CD200 may explain the chronic inflammation in human neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis; however, deficits in the microglial expression of CD200R may also be of functional significance. The purpose of this review is to assess the data regarding the role of CD200-CD200R interactions in relation to the brain in order to determine if this could be a therapeutic target for human brain diseases with inflammatory components, and what additional studies are needed.
Future Neurol
· 2013 Jul · PMID 23882162
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Treatment of visual hallucinations in neurodegenerative disorders is not well advanced. The complexity of underlying mechanisms presents a number of potential avenues for developing treatments, but also suggests that any...Treatment of visual hallucinations in neurodegenerative disorders is not well advanced. The complexity of underlying mechanisms presents a number of potential avenues for developing treatments, but also suggests that any single one may be of limited efficacy. Reducing medication, with the careful introduction of antidementia medication if needed, is the mainstay of current management. Antipsychotic medication leads to excessive morbidity and mortality and should only be used in cases of high distress that do not otherwise respond. Education, reduction of risk factors and psychological treatments have limited evidence of efficacy, but are unlikely to cause harm.
Future Neurol
· 2013 Mar · PMID 23658503
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Astroglia encompass a subset of versatile glial cells that fulfill a major homeostatic role in the mammalian brain. Since any brain disease results from failure in brain homeostasis, astroglial cells are involved in many...Astroglia encompass a subset of versatile glial cells that fulfill a major homeostatic role in the mammalian brain. Since any brain disease results from failure in brain homeostasis, astroglial cells are involved in many, if not all, aspects of neurological and/or psychiatric disorders. In this article, the roles of astrocytes as homeostatic cells in healthy and diseased brains are surveyed. These cells can mount the defence response to the insult of the brain, astrogliosis, when and where they display hypertrophy. Interestingly, astrocytes can alternatively display atrophy in some pathological conditions. Various pathologies, including Alexander and Alzheimer's diseases, amyotrophic lateral sclerosis, stroke and epilepsy, to mention a few, are discussed. Astrocytes could represent a novel target for medical intervention in the treatment of brain disorders.