Tan MM, Dy JB, Salcedo-Arellano MJ
… +2 more, Tassone F, Hagerman RJ
Future Neurol
· 2019 May · PMID 32089651
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Mutations in the Fragile X Mental Retardation 1 () gene create a spectrum of developmental disorders in children in addition to neurodegenerative problems in older populations. Two types of mutations are recognized in th...Mutations in the Fragile X Mental Retardation 1 () gene create a spectrum of developmental disorders in children in addition to neurodegenerative problems in older populations. Two types of mutations are recognized in the gene. The full mutation (>200 CGG repeats) in the gene leads to Fragile X Syndrome which is the most common inherited cause of intellectual disability and autism, while the premutation (55 to 200 CGG repeats) identified among carriers leads to a range of problems linked to elevated levels of the mRNA leading to mRNA toxicity and occasionally mildly deficient FMRP levels. Two disorders among premutation carriers have been recognized namely: the Fragile X-associated Primary Ovarian Insufficiency (FXPOI) and Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). Recently, in order to recognize a group of associated disorders commonly found in premutation carriers and extensively reported in co-morbidities studies, a new distinctive name was proposed: Fragile X-associated Neuropsychiatric Disorders (FXAND). This paper will present a case report of a female premutation carrier who has encountered predominantly psychiatric problems, but also chronic pain and sleep disturbances consistent with FXAND.
Future Neurol
· 2018 Aug · PMID 31396020
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Infantile-onset spinal muscular atrophy (SMA) is a prototypical disease in which to investigate selective neurodegenerative phenotypes. Caused by low levels of the ubiquitously expressed Survival Motor Neuron (SMN) prote...Infantile-onset spinal muscular atrophy (SMA) is a prototypical disease in which to investigate selective neurodegenerative phenotypes. Caused by low levels of the ubiquitously expressed Survival Motor Neuron (SMN) protein, the disease mainly targets the spinal motor neurons. This selective phenotype remains largely unexplained, but has not hindered the development of SMN repletion as a means to a treatment. Here we chronicle recent advances in the area of SMA biology. We provide a brief background to the disease, highlight major advances that have shaped our current understanding of SMA, trace efforts to treat the condition, discuss the outcome of two promising new therapies and conclude by considering contemporary as well as new challenges stemming from recent successes within the field.
Future Neurol
· 2018 May · PMID 30800004
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Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disease that affects motor, cognitive and psychiatric functions, and ultimately leads to death. The pathology of the disease is based on an e...Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disease that affects motor, cognitive and psychiatric functions, and ultimately leads to death. The pathology of the disease is based on an expansion of CAG repeats in exon 1 of the gene on chromosome 4, which produces a mutant huntingtin protein (mHtt). This protein is involved in neurotoxicity and brain atrophy, and can form β-sheets and abnormal mHtt aggregates. Currently, there are no approved effective treatments for HD, although tetrabenazine (Xenazine™) and deutetrabenazine (AUSTEDO™) have been approved for treatment of the motor symptom chorea in HD. This literature review aims to address the latest research on promising therapeutics based on influencing the hypothesized pathological mechanisms.
Future Neurol
· 2018 May · PMID 30505235
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Nearly a third of patients with epilepsy have seizures refractory to current medical therapies. In the search for novel drug targets, the mTOR pathway has emerged as key in the regulation of neuronal function, growth and...Nearly a third of patients with epilepsy have seizures refractory to current medical therapies. In the search for novel drug targets, the mTOR pathway has emerged as key in the regulation of neuronal function, growth and survival, and other cellular processes related to epileptogenesis. Hyperactivation of the mTOR pathway has been implicated in tuberous sclerosis complex and other 'mTORopathies', clinical syndromes associated with cortical developmental malformations and drug-resistant epilepsy. Recently published clinical trials of mTOR inhibitors in tuberous sclerosis complex have shown that these drugs are effective at decreasing seizure frequency. Future studies may establish whether mTOR inhibitors can provide effective treatment for patients with diverse genetic and acquired epilepsies, including preventative, disease-modifying therapies.
Future Neurol
· 2018 Feb · PMID 29379397
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Appearing in 40% of the cases of autism spectrum disorder (ASD), comorbid anxiety presents unique challenges for practitioners by amplifying problem behaviors such as social skills deficits, resistance to change and repe...Appearing in 40% of the cases of autism spectrum disorder (ASD), comorbid anxiety presents unique challenges for practitioners by amplifying problem behaviors such as social skills deficits, resistance to change and repetitive behaviors. Furthermore, comorbid ASD/anxiety strains familial relationships and increases parental stress. Research indicates that the neurobiological interactions between anxiety and ASD require comprehensive assessment approaches, modified cognitive behavioral therapy and carefully managed pharmacological interventions. Meta-analyses indicate that cognitive behavioral therapy with exposure is an effective treatment option when adequately accounting for social, familial and cognitive variables. The purpose of this focused review is to update readers on the latest research advances in comorbid ASD and anxiety, including prevalence, assessment, psychosocial and pharmacological treatment.
Future Neurol
· 2018 Feb · PMID 29379396
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Brain activity levels are tightly regulated to minimize imbalances in activity state. Deviations from the normal range of activity are deleterious and often associated with neurological disorders. To maintain optimal lev...Brain activity levels are tightly regulated to minimize imbalances in activity state. Deviations from the normal range of activity are deleterious and often associated with neurological disorders. To maintain optimal levels of activity, regulatory mechanisms termed homeostatic synaptic plasticity establish desired 'set points' for neural activity, monitor the network for deviations from the set point and initiate compensatory responses to return activity to the appropriate level that permits physiological function [1,2]. We speculate that impaired homeostatic control may contribute to the etiology of various neurological disorders including epilepsy and Alzheimer's disease, two disorders that exhibit hyperexcitability as a key feature during pathogenesis. Here, we will focus on recent progress in developing homeostatic regulation of neural activity as a therapeutic tool.
Future Neurol
· 2016 Nov · PMID 28757807
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AIM: Report a case of cortical subarachnoid hemorrhage (cSAH) and discuss its management. PATIENT & METHODS: A 66-year-old woman presents with acute onset left arm numbness and weakness. Initial head CT shows small hyper...AIM: Report a case of cortical subarachnoid hemorrhage (cSAH) and discuss its management. PATIENT & METHODS: A 66-year-old woman presents with acute onset left arm numbness and weakness. Initial head CT shows small hyperdensity in sulci typical for cSAH. Extensive workup with MRI, lumbar puncture and blood tests is performed. No signs of infection, vascular malformations, thrombosis or cancer are found. At outpatient follow-up, she is diagnosed with cSAH secondary to amyloid angiopathy. She is treated with gabapentin. RESULTS & CONCLUSION: Diagnosis of cSAH is challenging given its subtle findings, and management is empiric as there are only a few case series in literature.
Future Neurol
· 2016 May · PMID 29339929
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Valproic acid and lithium are widely used to treat bipolar disorder, a severe illness characterized by cycles of mania and depression. However, their efficacy is limited, and treatment is often accompanied by serious sid...Valproic acid and lithium are widely used to treat bipolar disorder, a severe illness characterized by cycles of mania and depression. However, their efficacy is limited, and treatment is often accompanied by serious side effects. The therapeutic mechanisms of these drugs are not understood, hampering the development of more effective treatments. Among the plethora of biochemical effects of the drugs, those that are common to both may be more related to therapeutic efficacy. Two common outcomes include inositol depletion and GSK3 inhibition, which have been proposed to explain the efficacy of both valproic acid and lithium. Here, we discuss the inositol depletion and GSK3 inhibition hypotheses, and introduce a unified model suggesting that inositol depletion and GSK3 inhibition are inter-related.
Cutforth T, DeMille MM, Agalliu I
… +1 more, Agalliu D
Future Neurol
· 2016 Dec · PMID 27110222
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infections have been associated with two autoimmune diseases of the CNS: Sydenham's chorea (SC) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with infections (PANDAS). Despite the high frequency of phar...infections have been associated with two autoimmune diseases of the CNS: Sydenham's chorea (SC) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with infections (PANDAS). Despite the high frequency of pharyngeal streptococcus infections among children, only a small fraction develops SC or PANDAS. This suggests that several factors in combination are necessary to trigger autoimmune complications: specific strains that induce a strong immune response toward the host nervous system; genetic susceptibility that predispose children toward an autoimmune response involving movement or tic symptoms; and multiple infections of the throat or tonsils that lead to a robust T17 cellular and humoral immune response when untreated. In this review, we summarize the evidence for each factor and propose that all must be met for the requisite neurovascular pathology and behavioral deficits found in SC/PANDAS.
Future Neurol
· 2015 Dec · PMID 27057151
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Late-onset Alzheimer's disease (AD), a highly prevalent neurodegenerative disorder characterized by progressive deterioration in cognition, function and behavior terminating in incapacity and death, is a clinically and p...Late-onset Alzheimer's disease (AD), a highly prevalent neurodegenerative disorder characterized by progressive deterioration in cognition, function and behavior terminating in incapacity and death, is a clinically and pathologically heterogeneous disease with a substantial heritable component. During the past 5 years, the technological developments in next-generation high-throughput genome technologies have led to the identification of more than 20 novel susceptibility loci for AD, and have implicated specific pathways in the disease, in particular intracellular trafficking/endocytosis, inflammation and immune response and lipid metabolism. These observations have significantly advanced our understanding of underlying pathogenic mechanisms and potential therapeutic targets. This review article summarizes these recent advances in AD genomics and discusses the value of identified susceptibility loci for diagnosis and prognosis of AD.
The hippocampo-prefrontal (H-PFC) pathway has been linked to cognitive and emotional disturbances in several psychiatric disorders including schizophrenia. Preclinical evidence from the NMDA receptor antagonism rodent mo...The hippocampo-prefrontal (H-PFC) pathway has been linked to cognitive and emotional disturbances in several psychiatric disorders including schizophrenia. Preclinical evidence from the NMDA receptor antagonism rodent model of schizophrenia shows severe pathology selective to the H-PFC pathway. It is speculated that there is an increased excitatory drive from the hippocampus to the prefrontal cortex due to dysfunctions in the H-PFC plasticity, which may serve as the basis for the behavioral consequences observed in this rodent model. Thus, the H-PFC pathway is currently emerging as a promising therapeutic target for the negative and cognitive symptom clusters of schizophrenia. Here, we have reviewed the physiological, pharmacological and functional characteristics of the H-PFC pathway and we propose that allosteric activation of glutamatergic and cholinergic neurotransmission can serve as a plausible therapeutic approach.
Future Neurol
· 2015 Jan · PMID 25774094
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MRI and magnetic resonance spectroscopy (MRS) along with computed tomography and PET are the most common imaging modalities used in the clinics to detect structural abnormalities and pathological conditions in the brain....MRI and magnetic resonance spectroscopy (MRS) along with computed tomography and PET are the most common imaging modalities used in the clinics to detect structural abnormalities and pathological conditions in the brain. MRI generates superb image resolution/contrast without radiation exposure that is associated with computed tomography and PET; MRS and spectroscopic imaging technologies allow us to measure changes in brain biochemistry. Increasingly, neurobiologists and MRI scientists are collaborating to solve neuroscience problems across sub-cellular through anatomical levels. To achieve successful cross-disciplinary collaborations, neurobiologists must have sufficient knowledge of magnetic resonance principles and applications in order to effectively communicate with their MRI colleagues. This review provides an overview of magnetic resonance techniques and how they can be used to gain insight into the active brain at the anatomical, functional and molecular levels with the goal of encouraging neurobiologists to include MRI/MRS as a research tool in their endeavors.
Future Neurol
· 2015 Mar · PMID 30774557
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Child-bearing years are often the most precarious management period in the life of a woman with epilepsy. This article reviews the results of many different studies with findings that enable the healthcare team to make c...Child-bearing years are often the most precarious management period in the life of a woman with epilepsy. This article reviews the results of many different studies with findings that enable the healthcare team to make confident decisions and recommendations during these critical periods. Preconceptional planning, effective contraception and folic acid supplementation are important fundamentals in preparation for pregnancy. There is growing evidence to avoid valproic acid use during the child-bearing years. Emerging data on congenital malformations and neurocognitive outcomes are available for some of the second-generation antiepileptic drugs and appear reassuring for lamotrigine and levetiracetam. Also reviewed are the benefits of postpartum drug tapers and favorable breastfeeding facts. Counseling the mother and her family on medication choices enables the healthcare team to implement informed decisions that are beneficial for the mother and child.
The immune system generates antibodies and antigen-specific T-cells as basic elements of the immune networks that differentiate self from non-self in a finely tuned manner. The antigen-specific nature of immune responses...The immune system generates antibodies and antigen-specific T-cells as basic elements of the immune networks that differentiate self from non-self in a finely tuned manner. The antigen-specific nature of immune responses ensures that normal immune activation contains non-self when tolerating self. Here we review the B-1 subset of lymphocytes which produce self-reactive antibodies. By analyzing the IgM class of natural antibodies that recognize antigens from the nervous system, we emphasize that natural antibodies are biomarkers of how the immune system monitors the host. The immune response activated against self can be detrimental when triggered in an autoimmune genetic background. In contrast, tuning immune activity with natural antibodies is a potential therapeutic strategy.
Future Neurol
· 2014 Nov · PMID 25574155
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A young women developed unilateral facial neuropathy 2 weeks after a motor vehicle collision involving fractures of the skull and mandible. MRI showed contrast enhancement of the facial nerve. We review the literature de...A young women developed unilateral facial neuropathy 2 weeks after a motor vehicle collision involving fractures of the skull and mandible. MRI showed contrast enhancement of the facial nerve. We review the literature describing facial neuropathy after trauma and facial nerve enhancement patterns with different causes of facial neuropathy.
Future Neurol
· 2014 Sep · PMID 25530721
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Translation from basic science bench research in ischemic stroke to bedside treatment of patients suffering ischemic stroke remains a difficult challenge. Despite literally hundreds of compounds and interventions that pr...Translation from basic science bench research in ischemic stroke to bedside treatment of patients suffering ischemic stroke remains a difficult challenge. Despite literally hundreds of compounds and interventions that provide benefit in experimental models of cerebral ischemia, efficacy in humans remains to be demonstrated. The reasons for failure to translate the extensive positive basic science findings to successful clinical trials have been the focus of discussion for years. Some attribute the failure to flaws in clinical trial design, others question the predictive value of current animal models and some question the quality of preclinical data. It is likely that a combination of all these shortcomings have ultimately led to the failure. The purpose of this review is to analyze the commonly used animal models used in the field today, provide a framework for understanding the current state of basic science research in the ischemic stroke field and discuss a path forward.
Future Neurol
· 2014 Mar · PMID 25530720
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The article by Lambert reports the identification of 11 novel susceptibility loci for late-onset Alzheimer's disease. The observations of this study significantly enhance the field since they further disentangle the gen...The article by Lambert reports the identification of 11 novel susceptibility loci for late-onset Alzheimer's disease. The observations of this study significantly enhance the field since they further disentangle the genetic causes and pathways underlying Alzheimer's disease by identifying novel disease-associated variants clustering in specific pathways. These pathways include APP processing, lipid metabolism, inflammation/immune response, intracellular trafficking/endocytosis, tau metabolism, synaptic function. All of the newly identified disease-associated variants have small effect sizes with increases in risk of 10-20%. The cumulative population attributable fraction associated with known genetic variants amounts now to approximately 80%. This article also underlines the ongoing value of genome-wide association studies for identification of causative common variants in the era of whole-exome and whole-genome sequencing studies.