Neurodegenerative Diseases Research Papers - Academia.edu (original) (raw)

Nicotinic acetylcholine receptors (nAChRs) mediate a variety of brain functions. Findings from postmortem studies and clinical investigations have implicated them in the pathophysiology and treatment of Alzheimer's and Parkinson's diseases and other CNS disorders (e.g. Tourette's syndrome, epilepsy, nicotine dependence). Therefore, it ultimately might be useful to image nAChRs noninvasively for diagnosis, for studies on how changes in nAChRs might contribute to cerebral disorders, for development of therapies targeted at nAChRs, and to monitor the effects of such treatments. To date, only (S)-(− )-nicotine, radiolabeled with 11 C, has been used for external imaging of nAChRs in human subjects. Since this radiotracer presents drawbacks, new ligands, with more favorable properties, have been synthesized and tested. Three general classes of compounds, namely, nicotine and its analogs, epibatidine and related compounds, and 3-pyridyl ether compounds, including A-85380, have been evaluated. Analogs of A-85380 appear to be the most promising candidates because of their low toxicity and high selectivity for the a4b2 subtype of nAChRs.

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- Positron Emission Tomography, Neurodegenerative Diseases, Brain Mapping, Brain

a b s t r a c t X-linked adrenoleukodystrophy (X-ALD) is the most frequent inherited monogenic demyelinating disease (minimal incidence 1:17,000). It is often lethal and currently lacks a satisfactory therapy. The disease is caused by loss of function of the ABCD1 gene, a peroxisomal ATP-binding cassette transporter, resulting in the accumulation of VLCFA (very long-chain fatty acids) in organs and plasma. Understanding of the aetiopathogenesis is a prerequisite for the development of novel therapeutic strategies. Functional genomics analysis of an ABCD1 null mouse, a mouse model for adrenomyeloneuropathy, has revealed presymptomatic alterations in several metabolic pathways converging on redox and bioenergetic homeostasis, with failure of mitochondrial OXPHOS disruption and mitochondrial depletion. These defects could be major contributors to the neurodegenerative cascade, as has been reported in several neurodegenerative disorders. Drugs targeting the redox imbalance/mitochondria dysfunction interplay have shown efficacy at halting axonal degeneration and associated disability in the mouse, and thus offer therapeutic hope.

- by Aurora Pujol
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- Oxidative Stress, Mitochondria, Energy Metabolism, Neurodegenerative Diseases

Polyphenols are found ubiquitously in plants and their regular consumption has been associated with a reduced risk of a number of chronic diseases, including cancer, cardiovascular disease (CVD) and neurodegenerative disorders. Rather than exerting direct antioxidant effects, the mechanisms by which polyphenols express these beneficial properties appear to involve their interaction with cellular signaling pathways and related machinery that mediate cell function under both normal and pathological conditions. We illustrate that their interactions with two such pathways, the MAP kinase (ERK, JNK, p38) and PI3 kinase/Akt signaling cascades, allow them to impact upon normal and abnormal cell function, thus influencing the cellular processes involved in the initiation and progression of cancer, CVD and neurodegeneration. For example, their ability to activate ERK in neurons leads to a promotion of neuronal survival and cognitive enhancements, both of which influence the progression of Alzheimer's disease, whilst ERK activation by polyphenols in vascular endothelial cells influences nitric oxide production, blood pressure and ultimately CVD risk. The main focus of this review is to provide an overview of the role that polyphenols play in the prevention of cancer, cardiovascular disease and neurodegeneration. We present epidemiological data, human intervention study findings, as well as animal and in vitro studies in support of these actions and in each case we consider how their actions at the cellular level may underpin their physiological effects.

- by Giulia Corona
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- Nutrition and Dietetics, Cancer, Neurodegenerative Diseases, Signal Transduction

Objective:To examine whether gene expression analysis of a large-scale Parkinson disease (PD) patient cohort produces a robust blood-based PD gene signature compared to previous studies that have used relatively small cohorts (≤220 samples).Methods:Whole-blood gene expression profiles were collected from a total of 523 individuals. After preprocessing, the data contained 486 gene profiles (n = 205 PD, n = 233 controls, n = 48 other neurodegenerative diseases) that were partitioned into training, validation, and independent test cohorts to identify and validate a gene signature. Batch-effect reduction and cross-validation were performed to ensure signature reliability. Finally, functional and pathway enrichment analyses were applied to the signature to identify PD-associated gene networks.Results:A gene signature of 100 probes that mapped to 87 genes, corresponding to 64 upregulated and 23 downregulated genes differentiating between patients with idiopathic PD and controls, was ident...

- by ROn Shamir
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- Cognitive Science, Neurology, Biomarkers, Biology
- by Florencia Tevy
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- Locomotion, Neurodegenerative Diseases, Biological Sciences, Drosophila

Alzheimer’s disease (AD) is the major cause of dementia in the elderly. The biochemical changes that precede AD may be present up to 20 years before the clinical manifestation of the disease. The translational development of AD biomarkers may be theoretically achieved via two different strategies: the first strategy can be defined as ‘knowledge-based’ (deductive method), while the second one

- by Diego Acosta-Alvear and +1
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- Protein Folding, Skeletal muscle biology, Computational Biology, Transcription Factors

Background: The pathological mechanism of the potent modifier of TDP-43 toxicity, ataxin-2, is unknown. Result: Ataxin-2 modified the subcellular distributions of truncated TDP-43 and mutant FUS. Conclusion: Increased ataxin-2 leads to a mislocation of TDP-43 and FUS, leading the RNA dysregulation. Significance: An aberrant distribution of TDP-43 and FUS mediated by ataxin-2 may be a key therapeutic target against ALS. The RNA-binding proteins TDP-43 and Fused in Sarcoma (FUS) play central roles in neurodegeneration associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Both proteins are components of messenger ribonucleoprotein (mRNP) granules and show cytoplasmic mislocalization in affected tissues. Recently, ataxin-2 was identified as a potent modifier of TDP-43 toxicity in an RNA-dependent manner. This study investigated to clarify how ataxin-2 modifies the TDP-43 and FUS pathological pathway. The expression of cytoplasmic TDP-43, the 35-kDa C-terminal fragment (TDP-p35f), and mutant FUS recruited ataxin-2 to mRNP granules, whereas increased ataxin-2 inhibited the mRNP granule formation of the 35-kDa C-terminal fragment and mutant FUS. A subcellular compartment analysis showed that the overexpressed ataxin-2 increased the cytoplasmic concentrations of both proteins, whereas it decreased their nuclear distributions. These data indicate that increased ataxin-2 impairs the assembly of TDP-43 and FUS into mRNP granules, leading to an aberrant distribution of RNA-binding proteins. Consequently, these sequences may exacerbate the impairment of the RNA-quality control system mediated by amyotrophic lateral sclerosis/frontotemporal lobar degeneration-associated RNA-binding proteins, which forms the core of the degenerative cascade.

- by Diana Gomez
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- Neurodegenerative Diseases, Stroke, Blood brain barrier, Intranasal Administration

Carnosine (b-alanyl-L-histidine) is a natural dipeptide widely and abundantly distributed in excitable tissues of several animal tissues. Although its physiological role has not been completely understood yet, many beneficial actions have been attributed to carnosine, such as being an antioxidant, antiglycating and ion-chelating agent, a wound healing promoter and a free-radical scavenger. The role of carnosine in the neuroprotection of oxidative stress-driven disorders has been reviewed. The effects of carnosine have been extensively studied both in vivo and in vitro models of cerebral damages, such as neurodegenerative disorders and hypoxia-ischemia injuries. Beside the classical sacrificial agent, carnosine has been reevaluated as a molecular chaperon and an inducer of antioxidant systems in oxidative stress conditions. Thus, beneficial effects on most of the common biochemical events that characterize neurological disorders make carnosine a very promising molecule among all the endogenous compounds in the treatment and/or prevention of oxidative driven diseases.

- by Graziella Vecchio and +1
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- Wound Healing, Oxidative Stress, Neurodegenerative Diseases, Biological Sciences

The conversion of proteins from their native state to misfolded oligomers is associated with, and thought to be the cause of, a number of human diseases, including Alzheimer's disease, Parkinson's disease, and systemic amyloidoses. The study of the structure, mechanism of formation, and biological activity of protein misfolded oligomers has been challenged by the metastability, transient formation, and structural heterogeneity of such species. In spite of these difficulties, in the past few years, many experimental approaches have emerged that enable the detection and the detailed molecular study of misfolded oligomers. In this review, we describe the basic and generic knowledge achieved on protein oligomers, describing the mechanisms of oligomer formation, the methodologies used thus far for their structural determination, and the structural elements responsible for their toxicity.

- by Fabrizio Chiti
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- Organic Chemistry, Protein Folding, Biology, Medicine
- by Nadja Schreier
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- Multiple sclerosis, Neuroepidemiology, Magnetic field, Neurodegenerative Diseases

The disease classification neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of progressive neurodegenerative disorders characterized by brain iron deposits in the basal ganglia. For about half of the cases, the molecular basis is currently unknown. We used homozygosity mapping followed by candidate gene sequencing to identify a homozygous 11 bp deletion in the orphan gene C19orf12. Mutation screening of 23 ideopathic NBIA index cases revealed two mutated alleles in 18 of them, and one loss-of-function mutation is the most prevalent. We also identified compound heterozygous missense mutations in a case initially diagnosed with Parkinson disease at age 49. Psychiatric signs, optic atrophy, and motor axonal neuropathy were common findings. Compared to the most prevalent NBIA subtype, pantothenate kinase associated neurodegeneration (PKAN), individuals with two C19orf12 mutations were older at age of onset and the disease progressed more slowly. A polyclonal antibody against the predicted membrane spanning protein showed a mitochondrial localization. A histopathological examination in a single autopsy case detected Lewy bodies, tangles, spheroids, and tau pathology. The mitochondrial localization together with the immunohistopathological findings suggests a pathomechanistic overlap with common forms of neurodegenerative disorders.

- by Holger Prokisch
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- Mitochondria, Adolescent, Neurodegenerative Diseases, Biological Sciences
- by Grace Sun
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- Cognitive Science, Oxidative Stress, Neurodegenerative Diseases, Molecular Neurobiology

Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hingebinding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike molecules, we came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. Our lead inhibitor GNE-3511 (26) displayed concentration-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacological inhibition of DLK may have therapeutic potential in multiple indications. | J. Med. Chem. XXXX, XXX, XXX−XXX C a All assay results represent the geometric mean of a minimum of two determinations, and these assays generally produced results within 3-fold of the reported mean. b MDCK−MDR1 human P-gp transfected cell line. Basolateral-to-apical/apical-to-basolateral. Units = ×10 −6 cm s −1 . c Liver microsome-predicted hepatic clearance. d H/R/M = human/rat/mouse. e LipE = −log K i − ClogP.

- by Kimberly Stark and +1
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- Organic Chemistry, Medicinal Chemistry, Biology, Drug Discovery

Clinical studies have shown that the antioxidant vitamin E can slow the progression of Alzheimer's disease (AD). Other antioxidants reported to affect cognitive function include ginkgo biloba, vitamin C, and lipoic acid. To examine the effects of combination antioxidant therapy (CAT) on longevity and neuropathology in mice, we supplemented the diet of ApoE-deficient mice with vitamin E, ginkgo biloba, pycnogenol, and ascorbyl palmitate. ApoEdeficient mice normally exhibit increased numbers of PAS-positive inclusion bodies with aging. However, supplementation with CAT resulted in a significant increase in life span and a marked reduction of inclusion body histopathology in the hippocampus. In addition, while untreated apoE-deficient mice exhibited increased levels of TUNEL staining, a marker of DNA fragmentation, supplementation with CAT resulted in a significant reduction in the levels of TUNEL staining. These findings suggest that oxidative mechanisms, perhaps related to neuronal apoptosis, are integral to inclusion body formation in aging mice. The association between the reduced number of apoptotic cells and the reduction in inclusion bodies may explain in part the increased longevity of mice fed CAT, and supports the contention that the combined actions of selected antioxidants may be therapeutically effective against neurodegenerative diseases.

- by Kevin Taddei
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- Free Radicals, Immunohistochemistry, Apoptosis, Neurodegenerative Diseases
- by Steve Iliffe
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- Psychology, Cognitive Science, Primary Care, Psychotherapy
- by Don Gash
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- Electrochemistry, Neurochemistry, Oxidative Stress, Mitochondria

Background: A subset of patients with schizophrenia, defined on the basis of longitudinal deficits in self-care, may show a classic (“Kraepelinian”) degenerative course. An independent validator of the phenomenologically defined Kraepelinian subtype might be provided by a structural indicator of possible brain degeneration: ventricular size as measured by computed tomography (CT).Methods: To examine whether Kraepelinian patients would show a differential increase in ventricular size over time, two CT scans were conducted at intervals separated by >4 years, an average of 5 years. Fifty-three male patients with DSM-III-R diagnoses of chronic schizophrenia were subdivided into Kraepelinian (n = 22; mean age = 42 ± 8.6 years) and non-Kraepelinian (n = 31; mean age = 38 ± 12.2 years) subgroups. Kraepelinian patients were defined on the basis of longitudinal criteria: >5 years of complete dependence on others for life necessities and care, lack of employment, and sustained symptomatology. Thirteen normal elderly volunteers (mean age = 60 ± 17.8) were also scanned at 4-year intervals. CT measurements were made by raters without knowledge of subgroup membership. A semiautomated computer program was used to trace the anterior horn, lateral ventricles, and temporal horns for each slice level on which they were clearly seen.Results: The ventricles showed a bilateral increase in size over the 4-year interval in the Kraepelinian subgroup, more marked in the left hemisphere than the right. By contrast, neither the non-Kraepelinian subgroup nor the normal volunteers showed significant CT changes from scan 1 to scan 2.Conclusions: Thus, the longitudinal dysfunctions in self-care that characterize the Kraepelinian patients were associated with an independent indicator of brain abnormality.

- by Monte Buchsbaum
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- Computed Tomography, Schizophrenia, Evolution, Neurodegenerative Diseases

Many lines of independent research have provided convergent evidence regarding oxidative stress, cerebrovascular disease, dementia, and Alzheimer's disease (AD). Clinical studies spurred by these findings engage basic and clinical communities with tangible results regarding molecular targets and patient outcomes. Focusing on recent progress in characterizing age-related diseases specifically highlights oxidative stress and mechanisms for therapeutic action in AD. Oxidative stress has been investigated independently for its relationship with aging and cardiovascular and neurodegenerative diseases and provides evidence of shared pathophysiology across these conditions. The mechanisms by which oxidative stress impacts the cerebrovasculature and bloodbrain barrier are of critical importance for evaluating antioxidant therapies. Clinical research has identified homocysteine as a relevant risk factor for AD and dementia; basic research into molecular mechanisms associated with homocysteine metabolism has revealed important findings. Oxidative stress has direct implications in the pathogenesis of age-related neurodegenerative diseases and careful scrutiny of oxidative stress in the CNS has therapeutic implications for future clinical trials. These mechanisms of dysfunction, acting independently or in concert, through oxidative stress may provide the research community with concise working concepts and promising new directions to yield new methods for evaluation and treatment of dementia and AD.

- by George Perry
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- Cognitive Science, Dementia, Clinical Trial, Oxidative Stress

This study was aimed to investigate the potential neuroprotective effect of neuropeptide Y (NPY) on the survival of dopaminergic cells in both in vitro and in animal models of Parkinson's disease (PD). NPY protected human SH-SY5Y dopaminergic neuroblastoma cells from 6-hydroxydopamine-induced toxicity. In rat and mice models of PD, striatal injection of NPY preserved the nigrostriatal dopamine pathway from degeneration as evidenced by quantification of (1) tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta, levels of (2) striatal tyrosine hydroxylase and dopamine transporter, (3) dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) as well as (4) rotational behavior. NPY had no neuroprotective effects in mice treated with Y 2 receptor antagonist or in transgenic mice deficient for Y 2 receptor suggesting that NPY effects are mediated through this receptor. Stimulation of Y 2 receptor by NPY triggered the activation of both the ERK1/2 and Akt pathways but did not modify levels of brain derived neurotrophic factor (BDNF) or glial cell line-derived neurotrophic factor. These results open new perspectives in neuroprotective therapies using NPY and suggest potential beneficial effects in PD.

- by Laura Frangeul
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- Enzyme Inhibitors, Neurobiology, Neurodegenerative Diseases, Transgenic Mice

Background/Aims: Neurodegenerative disorders (ND) have a major impact on quality of life (QoL) and place a substantial burden on patients, their families and carers; they are the second leading cause of disability. The objective of this... more

- by Ramona Lucas
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- Cognitive Science, Psychometrics, Multiple sclerosis, Depression

The development of new molecular and neurobiological methods, computer-assisted quantification techniques and neurobiological investigation methods which can be applied to the human brain, all have evoked an increased demand for post-mortem tissue in research. Psychiatric disorders are considered to be of neurobiological origin. Thus far, however, the etiology and pathophysiology of schizophrenia, depression and dementias are not well understood at the cellular and molecular level. The following will outline the consensus of the working group for neuropsychiatric brain banking organized in the Brainnet Europe II, on ethical guidelines for brain banking, clinical diagnostic criteria, the minimal clinical data set of retrospectively analyzed cases as well as neuropathological standard investigations to perform stageing for neurodegenerative disorders in brain tissue. We will list regions of interest for assessments in psychiatric disorder, propose a dissection scheme and describe preservation and storage conditions of tissue. These guidelines may be of value for future implementations of additional neuropsychiatric brain banks world-wide.

- by Jeanne Bell
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- Pathology, Psychology, Neurology, Psychiatry
- by Carmen Colica
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- Neurodegenerative Diseases

Dietary patterns high in refined starches, sugar, and saturated and trans-fatty acids, poor in natural antioxidants and fiber from fruits, vegetables, and whole grains, and poor in omega-3 fatty acids may cause an activation of the innate immune system, most likely by excessive production of proinflammatory cytokines associated with a reduced production of anti-inflammatory cytokines. The Mediterranean Diet (MedDiet) is a nutritional model inspired by the traditional dietary pattern of some of the countries of the Mediterranean basin. This dietary pattern is characterized by the abundant consumption of olive oil, high consumption of plant foods (fruits, vegetables, pulses, cereals, nuts and seeds); frequent and moderate intake of wine (mainly with meals); moderate consumption of fish, seafood, yogurt, cheese, poultry and eggs; and low consumption of red meat, processed meat products and seeds. Several epidemiological studies have evaluated the effects of a Mediterranean pattern as p...

- by Rosa Casas
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- Statistics, Applied Statistics, Atherosclerosis, Inflammation

Ascorbate (vitamin C) is a vital antioxidant molecule in the brain. However, it also has a number of other important functions, participating as a co-factor in several enzyme reactions including catecholamine synthesis, collagen production and regulation of HIF-1α. Ascorbate is transported into the brain and neurons via the Sodium-dependent Vitamin C Transporter-2 (SVCT2), which causes accumulation of ascorbate within cells against a concentration gradient. Dehydroascorbic acid, the oxidized form of ascorbate, is transported via glucose transporters of the GLUT family. Once in cells, it is rapidly reduced to ascorbate. The highest concentrations of ascorbate in the body are found in the brain and neuroendocrine tissues such as adrenal, although the brain is the most difficult organ to deplete of ascorbate. Combined with regional asymmetry in ascorbate distribution within different brain areas, these facts suggest an important role for ascorbate in the brain. Ascorbate is proposed as a neuromodulator of glutamatergic, dopaminergic, cholinergic and GABAergic transmission and related behaviors. Neurodegenerative diseases typically involve high levels of oxidative stress and thus ascorbate has been posited to have potential therapeutic roles against ischemic stroke, Alzheimer's disease, Parkinson's disease and Huntingdon's disease.

- by james may
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- Chemistry, Free Radicals, Medicine, Neurodegenerative Diseases

A B S T R A C T Multiple sclerosis (MS) is a high prevalence degenerative disease characterized at the cellular level by glial and neuronal cell death. The causes of cell death during the disease course are not fully understood. In this work we demonstrate that in a MS model induced by Theiler's murine encephalomyelitis virus (TMEV) infection, the inward rectifier (Kir) 4.1 potassium channel subunit is overexpressed in astrocytes. In voltage clamp experiments the inward current density from TMEV-infected astrocytes was significantly larger than in mock-infected ones. The cRNA hybridization analysis from mock-and TMEV-infected cells showed an upregulation of a potassium transport channel coding sequence. We validated this mRNA increase by RT-PCR and quantitative PCR using Kir 4.1 specific primers. Western blotting experiments confirmed the upregulation of Kir 4.1, and alignment between sequences provided the demonstration that the over-expressed gene encodes for a Kir family member. Flow cytometry showed that the Kir 4.1 protein is located mainly in the cell membrane in mock and TMEV-infected astrocytes. Our results demonstrate an increase in K + inward current in TMEV-infected glial cells, this increment may reduce the neuronal depolarization, contributing to cell resilience mechanisms.

- by Enrique Soto
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- Neuroscience, Neurodegenerative Diseases, Esclerosis Múltiple

We describe two sisters affected by pontocerebellar hypoplasia type 2 associated with microcephaly, hypertonia, severe choreiform movements, an almost complete lack of psychomotor development, and generalized tonic-clonic seizures. Clinical and neuroradiological ®ndings ruled out other conditions associated with pontocerebellar hypoplasia, i.e. pontocerebellar hypoplasia type 1, carbohydrate-de®cient glycoprotein syndrome, and olivopontocerebellar hypoplasia/atrophy. q

- by Germán Ramos
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- Health Care, Family history, Neurodegenerative Diseases, Cytomegalovirus

Cellular senescence is a potent anti-cancer mechanism that arrests the proliferation of mitotically competent cells to prevent malignant transformation. Senescent cells accumulate with age in a variety of human and mouse tissues where they express a complex 'senescence-associated secretory phenotype' (SASP). The SASP includes many pro-inflammatory cytokines, chemokines, growth factors and proteases that have the potential to cause or exacerbate age-related pathology, both degenerative and hyperplastic. While cellular senescence in peripheral tissues has recently been linked to a number of age-related pathologies, its involvement in brain aging is just beginning to be explored. Recent data generated by several laboratories suggest that both aging and age-related neurodegenerative diseases are accompanied by an increase in SASP-expressing senescent cells of non-neuronal origin in the brain. Moreover, this increase correlates with neurodegeneration. Senescent cells in the brain...

- by Judith Campisi
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- Aging, Neurodegenerative Diseases, Brain, Mice

Mutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified. Hum Mutat 29(12), 1373-1386, 2008. r r 2008 Wiley-Liss, Inc.

- by Marc Cruts
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- Genetics, Dementia, Family, Neurodegenerative Diseases

Spinal muscular atrophy (SMA) is a severe autosomal recessive disease caused by a genetic defect in the survival motor neuron 1 (SMN1) gene, which encodes SMN, a protein widely expressed in all eukaryotic cells. Depletion of the SMN protein causes muscle weakness and progressive loss of movement in SMA patients. The field of gene therapy has made major advances over the past decade, and gene delivery to the central nervous system (CNS) by in vivo or ex vivo techniques is a rapidly emerging field in neuroscience. Despite Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis being among the most common neurodegenerative diseases in humans and attractive targets for treatment development, their multifactorial origin and complicated genetics make them less amenable to gene therapy. Monogenic disorders resulting from modifications in a single gene, such as SMA, prove more favorable and have been at the fore of this evolution of potential gene therapies, and results to date have been promising at least. With the estimated number of monogenic diseases standing in the thousands, elucidating a therapeutic target for one could have major implications for many more. Recent progress has brought about the commercialization of the first gene therapies for diseases, such as pancreatitis in the form of Glybera, with the potential for other monogenic disease therapies to follow suit. While much research has been carried out, there are many limiting factors that can halt or impede translation of therapies from the bench to the clinic. This review will look at both recent advances and encountered impediments in terms of SMA and endeavor to highlight the promising results that may be applicable to various associated diseases and also discuss the potential to overcome present limitations.

The vulnerability of the nervous system to advancing age is all too often manifest in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. In this review article we describe evidence suggesting that two dietary interventions, caloric restriction (CR) and intermittent fasting (IF), can prolong the health-span of the nervous system by impinging upon fundamental metabolic and cellular signaling pathways that regulate lifespan. CR and IF affect energy and oxygen radical metabolism, and cellular stress response systems, in ways that protect neurons against genetic and environmental factors to which they would otherwise succumb during aging. There are multiple interactive pathways and molecular mechanisms by which CR and IF benefit neurons including those involving insulin-like signaling, FoxO transcription factors, sirtuins and peroxisome proliferatoractivated receptors. These pathways stimulate the production of protein chaperones, neurotrophic factors and antioxidant enzymes, all of which help cells cope with stress and resist disease. A better understanding of the impact of CR and IF on the aging nervous system will likely lead to novel approaches for preventing and treating neurodegenerative disorders.

- by Stuart Maudsley
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- Genetics, Aging, Molecular Mechanics, Neurodegenerative Diseases

—Mathematical and computational modellings are the necessary tools for reviewing, analysing, and predicting processes and events in the wide spectrum range of scientific fields. Therefore, in a field as rapidly developing as neuroscience, the combination of these two modellings can have a significant role in helping to guide the direction the field takes. The paper combined mathematical and computational modelling to prove a weakness in a very precious model in neuroscience. This paper is intended to analyse all-or-none principle in Hodgkin-Huxley mathematical model. By implementation the computational model of Hodgkin-Huxley model and applying the concept of all-or-none principle, an investigation on this mathematical model has been performed. The results clearly showed that the mathematical model of Hodgkin-Huxley does not observe this fundamental law in neurophysiology to generating action potentials. This study shows that further mathematical studies on the Hodgkin-Huxley model are needed in order to create a model without this weakness.

- by S. Ali Sadegh Zadeh
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- Artificial Intelligence, Machine Learning, Data Mining, Alzheimer's Disease

The small circle of mitochondrial DNA (mtDNA) present in all human cells has proven to be a veritable Pandora's box of pathogenic mutations and rearrangements. In this review, we summarize the distinctive rules of mitochondrial genetics (maternal inheritance, mitotic segregation, heteroplasmy and threshold effect), stress the relatively high prevalence of mtDNA-related diseases, and consider recent additions to the already long list of pathogenic mutations (especially mutations affecting protein-coding genes). We then discuss more controversial issues, including the functional or pathological role of mtDNA haplotypes, the pathogenicity of homoplasmic mutations and the still largely obscure pathophysiology of mtDNA mutations.

- by Laura Greaves
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- Aging, DNA replication, Oxidative Stress, Neurodegenerative Diseases

Slices of developing brain tissue can be grown for several weeks as socalled organotypic slice cultures. Here we summarize and review studies using hippocampal slice cultures to investigate mechanisms and treatment strategies for the neurodegenerative disorders like stroke (cerebral ischemia), Alzheimer's disease (AD) and epilepsia. Studies of non-excitotoxic neurotoxic compounds and the experimental use of slice cultures in studies of HIV neurotoxicity, traumatic brain injury (TBI) and neurogenesis are included. For cerebral ischemia, experimental models with oxygen-glucose deprivation (OGD) and exposure to glutamate receptor agonists (excitotoxins) are reviewed. For epilepsia, focus is on induction of seizures with effects on neuronal loss, axonal sprouting and neurogenesis. For Alzheimer's disease, the review centers on the use of beta-amyloid (Abeta) in different models, while the section on repair is focused on neurogenesis and cell migration. The culturing techniques, set-up of models, and analytical tools, including markers for neurodegeneration, like the fluorescent dye propidium iodide (PI), are reviewed and discussed. Comparisons are made between hippocampal slice cultures and other in vitro models using dispersed cell cultures, experimental in vivo models, and in some instances, clinical trials. New techniques including slice culturing of hippocampal tissue from transgenic mice as well as more mature brain tissue, and slice cultures coupled to microelectrode arrays (MEAs), on-line biosensor monitoring, and time-lapse fluorescence microscopy are also presented.

- by Morten Blaabjerg
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- Epilepsy, Calcium, Neurodegenerative Diseases, Signal Transduction

Mitochondrial dysfunctions are supposed to be responsible for many neurodegenerative diseases dominating in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). A growing body of evidence suggests that defects in mitochondrial metabolism and particularly of electron transport chain may play a role in pathogenesis of AD. Structurally and functionally damaged mitochondria do not produce sufficient ATP and are more prominent in producing proapoptotic factors and reactive oxygen species (ROS), and this can be an early stage of several mitochondrial disorders, including neurodegenerative diseases. Mitochondrial dysfunctions may be caused by both mutations in mitochondrial or nuclear DNA that code mitochondrial components and by environmental causes. In the following review, common aspects of mitochondrial impairment concerned about neurodegenerative diseases are summarized including ROS production, impaired mitochondrial dynamics, and apoptosis. Also, damaged function of electron transport chain complexes and interactions between pathological proteins and mitochondria are described for AD particularly and marginally for PD and HD.

- by NARENDRA SINGH
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- Technology, Mitochondria, Neurodegenerative Diseases, Biological Sciences

Aim As the population ages, the problem of dementia increases and affects a growing number of people. People with mental illness are known to be stigmatised and this has been the subject of numerous studies. There have been contradictory... more

- by Katarzyna M Lion
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- Neuroscience, Neurology, Psychiatry, Dementia

Background/Objectives. This pilot study evaluated the impact of a peer support program on improving multiple sclerosis (MS) related psychological functions (depression, anxiety, and stress) and enhancing quality of life. Methodology. Participants ( = 33) were recruited prospectively and received an 8-week group face-to-face peer support program. Assessments were at baseline (T1), 6 weeks after program (T2), and 12 months after program (T3), using validated questionnaires: Depression Anxiety Stress Scale (DASS), McGill Quality of Life (MQOL), and Brief COPE. Results. Participants' mean age was 52; the majority were female (64%) and married (64%). Median time since MS diagnosis was 16 years. At T2, participants reported improved psychological functioning (DASS "depression, " "anxiety, " and "stress" subscales, values −2.36, −2.22, and −2.54, moderate effect sizes ( ) 0.29, 0.28, and 0.32, resp.) and quality of life (MQOL SIS score −2.07, = 0.26) and were less likely to use "self-blame" as a coping mechanism (Brief COPE score −2.37, = 0.29). At T3, the positive improvements in stress (DASS stress subscale score −2.41, = 0.31) and quality of life were maintained (MQOL SIS, score −2.30, = 0.29). There were no adverse effects reported. of Hindawi Publishing Corporation

- by Bhasker Amatya
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- Neurodegenerative Diseases

The gut microbiota is essential to health and has recently become a target for live bacterial cell biotherapies for various chronic diseases including metabolic syndrome, diabetes, obesity and neurodegenerative disease. Probiotic biotherapies are known to create a healthy gut environment by balancing bacterial populations and promoting their favorable metabolic action. The microbiota and its respective metabolites communicate to the host through a series of biochemical and functional links thereby affecting host homeostasis and health. In particular, the gastroin-testinal tract communicates with the central nervous system through the gut–brain axis to support neuronal development and maintenance while gut dysbiosis manifests in neurological disease. There are three basic mechanisms that mediate the communication between the gut and the brain: direct neuronal communication, endocrine signaling mediators and the immune system. Together, these systems create a highly integrated molecul...

- by Nikita Lomis
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- Neuroscience, Physiology, Probiotics, Biology

Multiple forms of the ketogenic diet (KD) have been successfully used to treat drug-resistant epilepsy, however its mainstream use as a first-line therapy is still limited. Further investigation into its clinical efficacy as well as the molecular basis of activity is likely to assist in the reversal of any resistance to its implementation. In this review we shall attempt to elucidate the current state of experimental and clinical data concerning the neuroprotective and cognitive effects of the KD in both humans and animals. Generally, it has been shown by many research groups that effective implementation of KD exerts strong neuroprotective effects with respect to social behavior and cognition. We will also elucidate the role of KD in the interesting relationship between sleep, epilepsy and memory. Currently available evidence also indicates that, under appropriate control, and with further studies investigating any potential long-term side effects, the KD is also a relatively safe intervention, especially when compared to traditional anti-epileptic pharmacotherapeutics. In addition, due to its neuroprotective capacity, the KD may also hold potential benefit for the treatment of other neurological or neurodegenerative disorders.

- by Bronwen Martin
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- Cognition, Epilepsy, Neurodegenerative Diseases, Learning

Sub-Saharan African (SSA) countries are experiencing rapid transitions with increased life expectancy. As a result the burden of age-related conditions such as neurodegenerative diseases might be increasing. We conducted a systematic review of published studies on common neurodegenerative diseases, and HIV-related neurocognitive impairment in SSA, in order to identify research gaps and inform prevention and control solutions. We searched MEDLINE via PubMed, 'Banque de Données de Santé Publique' and the database of the 'Institut d'Epidemiologie Neurologique et de Neurologie Tropicale' from inception to February 2013 for published original studies from SSA on neurodegenerative diseases and HIV-related neurocognitive impairment. Screening and data extraction were conducted by two investigators. Bibliographies and citations of eligible studies were investigated. In all 144 publications reporting on dementia (n = 49 publications, mainly Alzheimer disease), Parkinsonis...

Mapping surface hydrophobic interactions in proteins is key to understanding molecular recognition,
biological functions, and is central to many protein misfolding diseases. Herein, we report synthesis
and application of new BODIPY-based hydrophobic sensors (HPsensors) that are stable and highly
fluorescent for pH values ranging from 7.0 to 9.0. Surface hydrophobic measurements of proteins
(BSA, apomyoglobin, and myoglobin) by these HPsensors display much stronger signal compared to
8-anilino-1-naphthalene sulfonic acid (ANS), a commonly used hydrophobic probe; HPsensors show a
10- to 60-fold increase in signal strength for the BSA protein with affinity in the nanomolar range. This
suggests that these HPsensors can be used as a sensitive indicator of protein surface hydrophobicity. A
first principle approach is used to identify the molecular level mechanism for the substantial increase in
the fluorescence signal strength. Our results show that conformational change and increased molecular
rigidity of the dye due to its hydrophobic interaction with protein lead to fluorescence enhancement.

- by Nethaniah Dorh and +1
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- Neuroscience, Surface Science, Neurodegenerative Diseases, Protein Chemistry

Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) are diseases associated with the accumulation of tau or a-synuclein. In AD, b-amyloid (Ab)-associated caspase activation and cleavage of tau at Asp 421 (DTau) may be an early step in neurofibrillary tangle (NFT) formation. To examine whether DTau accumulates in other diseases not characterized by extracellular Ab accumulation, we examined PiD, PSP, and CBD cases in comparison to those without extensive tau accumulation including frontotemporal lobar degeneration without Pick bodies (FTLD) and control cases. Additionally, we studied DTau accumulation in DLB cases associated with intracellular a-synuclein. DTau was observed in all disease cases except non-PiD FTLD and controls. These results demonstrate that the accumulation of DTau may represent a common pathway associated with abnormal accumulation of intracellular tau or a-synuclein and may be relatively less dependent on the extracellular accumulation of Ab in non-AD dementias.

- by Elizabeth Head and +2
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- Progressive Supranuclear Palsy, Immunohistochemistry, Confocal Microscopy, Neurodegenerative Diseases

Spatial navigation offers a fresh approach to the identification and early diagnosis of dementia, including Alzheimer's disease in the pre-clinical phase. The Sea Hero Quest game has been developed to detect subtle impairments in navigational performance at a very early stage. It has been found to perform better than traditional dementia screening tools and memory assessment scales currently used for identifying persons genetically at-risk of developing Alzheimer's disease.

- by Journal of Geriatric Care and Research (JGCR) and +1
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- Dementia, Alzheimer's Disease, Video Games, Biomarkers

Ketosis, meaning elevation of D-¯-hydroxybutyrate (R-3hydroxybutyrate) and acetoacetate, has been central to starving man's survival by providing nonglucose substrate to his evolutionarily hypertrophied brain, sparing muscle from destruction for glucose synthesis. Surprisingly, D-¯-hydroxybutyrate (abbreviated "¯OHB") may also provide a more ef cient source of energy for brain per unit oxygen, supported by the same phenomenon noted in the isolated working perfused rat heart and in sperm. It has also been shown to decrease cell death in two human neuronal cultures, one a model of Alzheimer's and the other of Parkinson's disease. These observations raise the possibility that a number of neurologic disorders, genetic and acquired, might bene t by ketosis. Other bene cial effects from¯OHB include an increased energy of ATP hydrolysis (1G 0 ) and its linked ionic gradients. This may be signi cant in drug-resistant epilepsy and in injury and anoxic states. The ability of¯OHB to oxidize co-enzyme Q and reduce NADP + may also be important in decreasing free radical damage. Clinical maneuvers for increasing blood levels of¯OHB to 2 -5 mmol may require synthetic esters or polymers of¯OHB taken orally, probably 100 to 150 g or more daily. This necessitates advances in food-science technology to provide at least enough orally acceptable synthetic material for animal and possibly subsequent clinical testing. The other major need is to bring the technology for the analysis of multiple metabolic "phenotypes" up to the level of sophistication of the instrumentation used, for example, in gene science or in structural biology. This technical strategy will be critical to the characterization of polygenic disorders by enhancing the knowledge gained from gene analysis and from the subsequent steps and modi cations of the protein products themselves. IUBMB Life, 51: 241 -247, 2001

- by R. Veech
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- Epilepsy, Energy Metabolism, Neurodegenerative Diseases, Brain

Abstrak Meningkatnya usia harapan hidup penduduk di Indonesia, menyebabkan jumlah penduduk usia lanjut terus meningkat dari tahun ke tahun. Salah satu permasalahan yang sering timbul pada lansia salah satunya berupa demensia atau yang sering kita sebut dengan pikun. Demensia atau pikun adalah suatu sindroma neurodegeneratif yang timbul karena adanya kelainan yang bersifat kronis dan progesifitas disertai dengan gangguan fungsi luhur multiple seperti berhitung, kapasitas belajar, bahasa, dan mengambil keputusan sehingga mempengaruhi aktivitas sosial dan aktivitas sehari-hari. Demensia bukanlah suatu penyakit yang spesifik, melainkan suatu gejala yang bisa disebabkan oleh berbagai kelainan yang mempengaruhi otak. Angka kejadian demensia di dunia pada tahun 2019 diperkirakan terdapat 47,47 juta, diperkirakan akan meningkat menjadi 75,63 juta pada tahun 2030 dan 135,46 juta pada tahun 2050. Jumlah lansia yang mengalami demensia di dunia sebesar 30 juta jiwa dan di Indonesia sebesar 15 % dari jumlah lansianya mengalami demensia. Demensia merupakan penyebab kematian ke-4 pada lansia setelah penyakit jantung, kanker dan stroke. Kasus demensia yang terdiagnosis sering tidak mendapat penatalaksanaan yang memadai sehingga pasien tidak mencapai kualitas hidup optimal. Maka dari itu, sebaiknya kita mengenali lebih awal apa itu demensia, faktor resiko demensia, gejala-gejala demensia, dan cara pencegahannya sehingga kita dapat menunda bahkan mencegah kepikunan. Abstract The increasing life expectancy of the population in Indonesia, causes the number of elderly population continues to increase from year to year. One of the problems that often arises in the elderly one of which is dementia or what we often call senile. Dementia or senile dementia is a neurodegenerative syndrome that arises due to chronic and progressive disorders accompanied by multiple sublime functions such as arithmetic, learning capacity, language, and decision making that affect social activities and daily activities. Dementia is not a specific disease, but rather a symptom that can be caused by various disorders that affect the brain. The incidence of dementia in the world in 2019 is estimated to be 47.47 million, is expected to increase to 75.63 million in 2030 and 135.46 million in 2050. Dementia is the 4th leading cause of death in the elderly after heart disease, cancer and stroke. The number of elderly people with dementia in the world is 30 million people and in Indonesia 15% of the total population has dementia. Cases of diagnosed dementia often do not get adequate management so that patients do not achieve optimal quality of life. Therefore, we should recognize early what is dementia, risk factors of dementia, symptoms of dementia, and how to prevent it so that we can delay or even prevent senility.

The c-Jun N-terminal kinase (JNKs), also known as stress-activated protein kinase (SAPK)

- by Deepak Sharma
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- Cognitive Science, Molecular Neuroscience, Enzyme Inhibitors, Brain development

Microglia are resident immune cells in the brain and spinal cord. These cells provide immune surveillance and are mobilized in response to disparate diseases and injuries. Although microglial activation is often considered neurotoxic, microglia are essential defenders against many neurodegenerative diseases. It also seems increasingly likely that microglial dysfunction can underlie certain neurological diseases without an obvious immune component.

- by Adriano Aguzzi
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- Science, Multidisciplinary, Neurodegenerative Diseases, Microglia