Neurodegeneration Research Papers - Academia.edu (original) (raw)

Roscovitine [CY-202, (R)-Roscovitine, Seliciclib] is a small molecule that inhibits cyclin-dependent kinases (CDKs) through direct competition at the ATP-binding site. It is a broad-range purine inhibitor, which inhibits CDK1, CDK2, CDK5 and CDK7, but is a poor inhibitor for CDK4 and CDK6. Roscovitine is widely used as a biological tool in cell cycle, cancer, apoptosis and neurobiology studies. Moreover, it is currently evaluated as a potential drug to treat cancers, neurodegenerative diseases, inflammation, viral infections, polycystic kidney disease and glomerulonephritis. This review focuses on the use of roscovitine in the disease model as well as clinical model research.

- by and +4
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- Cancer, Kidney diseases, Cell Cycle, Neurodegeneration

Neurodegenerative disorders can alter neural circuitry long before symptoms appear, but the path from early changes to later pathologies is obscure. In this issue of Neuron, Capizzi et al. (2021) show how early axonal growth defects in... more

- by V L Brandt and +1
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- Neurodevelopment, Neurodegeneration, Huntington's disease, Axon Guidance

Epilepsy in children leads to disorders in their psychomotor development or the loss of their acquired skills. Successful pharmacological treatment of epilepsy provides grounds for effective therapeutic measures. The goal of this article is to present the dynamics of neurodevelopmen-tal disorders in the course of the severe symptomatic epilepsy with status epileptici which affected a 10-year-old girl. As a result of longitudinal studies, four stages were distinguished which determined the dynamics of development of the disease: 1) up to the age of 10, when the child's psycho-motor development proceeded correctly, 2) between the ages of 10 and 15, when, because of epilepsy , the disorders in the cognitive, linguistic, emotional, behavioural, motor, and vegetative spheres occurred, which assumed the form of profound dementia, 3) between the ages of 16 and 17, when the balance of the bioelectric activity of the brain was achieved owing to the optimisation of pharmacological treatment, 4) between the ages of 17 and 25, when, after the multi-specialist therapy, there was a significant improvement in the functioning of all the disordered spheres, which enabled the patient to finish junior and senior high school, apply to a university, obtain very good results in learning, and to achieve spectacular successes in sport.

- by Logopedia Silesiana
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- Dementia, Agnosia, Neurodegeneration, Apraxia

We are facing an obesity epidemic, and obesity itself and its close companion, type 2 diabetes, are independent risk factors for neurodegeneration. While most medical treatments fail to induce a clinically meaningful improvement in neurodegenerative disorders, lifestyle interventions have emerged in the spotlight. A recently rediscovered approach is intermittent fasting (IF), which, compared to the classic caloric restriction regimens, limits only the time of eating, rather than the number of calories allowed per day. There is already a large amount of evidence from preclinical and clinical studies showing the beneficial effects of IF. In this review, we specifically focus on the effects of IF on brain metabolism. Key molecular players modified during IF and involved in its beneficial central effects (ketone bodies, BDNF, GABA, GH/IGF-1, FGF2, sirtuin-3, mTOR, and gut microbiota) are identified and discussed. Studies suggest that IF induces several molecular and cellular adaptations...

- by Alex Toto brocchi
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- Neuroscience, Nutrition and Dietetics, Neurogenesis, Obesity

The adult brain is not as hard-wired as traditionally thought. By modifying their small- or large-scale morphology, neurons can make new synaptic connections or break existing ones (structural plasticity). Structural changes accompany memory formation and learning, and are induced by neurogenesis, neurodegeneration and brain injury such as stroke. Exploring the role of structural plasticity in the brain can be greatly assisted by mathematical and computational models, as they enable us to bridge the gap between system-level dynamics and lower level cellular and molecular processes. However, most traditional neural network models have fixed neuronal morphologies and a static connectivity pattern, with plasticity merely arising from changes in the strength of existing synapses (synaptic plasticity). In The Rewiring Brain, the editors bring together, for the first time, contemporary modeling studies that investigate the implications of structural plasticity for brain function and pathology. Starting with an experimental background on structural plasticity in the adult brain, the book covers computational studies on homeostatic structural plasticity, the impact of structural plasticity on cognition and cortical connectivity, the interaction between synaptic and structural plasticity, neurogenesis-related structural plasticity, and structural plasticity in neurological disorders. Structural plasticity adds a whole new dimension to brain plasticity, and The Rewiring Brain shows how computational approaches may help to gain a better understanding of the full adaptive potential of the adult brain. The book is written for both computational and experimental neuroscientists. Key features: • Reviews the current state of knowledge of structural plasticity in the adult brain. • Gives a comprehensive overview of computational studies on structural plasticity. • Provides insights into the potential driving forces of structural plasticity and the functional implications of structural plasticity for learning and memory. • Serves as inspiration for developing novel treatment strategies for stimulating functional repair after brain damage. For a preview and to order the book, go to: https://www.elsevier.com/books/the-rewiring-brain/van-ooyen/978-0-12-803784-3

- by Arjen van Ooyen
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- Neuroscience, Neurology, Developmental Neurobiology, Neuroimaging

Gaucher disease (GD), the commonest lysosomal storage disorder, results from the lack or functional deficiency of glucocerebrosidase (GCase) secondary to mutations in the GBA1 gene. There is an established association between GBA1 mutations and Parkinson’s disease (PD), and indeed GBA1 mutations are now considered to be the greatest genetic risk factor for PD. Impaired lysosomal-autophagic degradation of cellular proteins, including α-synuclein (α-syn), is implicated in the pathogenesis of PD, and there is increasing evidence for this also in GD and GBA1-PD. Indeed we have recently shown in a Drosophila model lacking neuronal GCase, that there are clear lysosomal-autophagic defects in association with synaptic loss
and neurodegeneration. In addition, we demonstrated alterations in mechanistic target of rapamycin complex 1 (mTORC1) signaling and functional rescue of the lifespan, locomotor defects and hypersensitivity
to oxidative stress on treatment of GCase-deficient flies with the mTOR inhibitor rapamycin. Moreover, a number of other recent studies have shown autophagy-lysosomal system (ALS) dysfunction, with specific
defects in both chaperone-mediated autophagy (CMA), as well as macroautophagy, in GD and GBA1-PD model systems. Lastly we discuss the possible therapeutic benefits of inhibiting mTOR using drugs such as
rapamycin to reverse the autophagy defects in GD and PD.

- by Jorge Iván Castillo-Quan
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- Neuroscience, Parkinson's Disease, Drosophila melanogaster, Autophagy

Neurodegenerative diseases are the most frequent cause of dementia, representing a burden for public health systems (especially in middle and middle-high income countries). Although most research on this issue is concentrated in first-world centers, growing efforts in South America are affording important breakthroughs. This emerging agenda poses new challenges for the region but also new opportunities
for the field. This book aims to integrate the community of experts across the globe and the region, and to establish new challenges and developments for future investigation. We present research focused on neurodegenerative research in South America. We introduce studies assessing the interplay among genetic, neural, and behavioral dimensions of these diseases, as well as articles on vulnerability factors, comparisons of findings from various countries, and works promoting multicenter and collaborative networking. More generally, our book covers a broad scope of human-research approaches (behavioral assessment, neuroimaging, electromagnetic techniques, brain connectivity, peripheral measures), animal methodologies (genetics, epigenetics, proteomics, metabolomics, other molecular biology tools), species (all human and non-human animals, sporadic, and genetic versions), and article types (original research, review, and opinion papers). Through this wide-ranging proposal, we hope to introduce a fresh approach to the challenges and opportunities of research on
neurodegeneration in South America.

- by Adolfo García
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- Neurodegeneration

Eye tracking (ET) studies are becoming increasingly popular due to rapid methodological and technological advances as well as the development of cost efficient and portable eye trackers. Although historically ET has been mostly employed in psychophysics or developmental cognition studies, there is also promising scope to use ET for movement disorders and measuring cognitive processes in neurodegeneration. Particularly, ET can be a powerful tool for cognitive and neuropsychological assessments of patients with pathologies affecting motor and verbal abilities, as tasks can be adapted without requiring motor (except eye movements) or verbal responses. In this review, we will examine the existing evidence of ET methods in neurodegenerative conditions and its potential clinical impact for cognitive assessment. We highlight that current evidence for ET is mostly focused on diagnostics of cognitive impairments in neurodegenerative disorders, where it is debatable whether it has any more sensitivity or specificity than existing cognitive assessments. By contrast, there is currently a lack of ET studies in more advanced disease stages, when patients’ motor and verbal functions can be significantly affected, and standard cognitive assessments are challenging or often not possible. We conclude that ET is a promising method not only for cognitive diagnostics but more importantly, for potential cognitive disease tracking in progressive neurodegenerative conditions.

Excess of carbohydrate intake typical for consumers of the Western diet may cause detrimental effects on metabolism and increase risks of the onset and progression of many neurodegenerative diseases (2–4). On the other hand, diets high in fat and low in carbohydrates decrease appetite, probabilities of food addiction and obesity, and are neuroprotective (5, 6). Carbohydrate restriction induces physiological changes which are very similar to the well documented beneficial effects of calorie restriction (7, 8). Conversely, the hallmark of high-carbohydrate diets is homeostatic inadequacy (9), an overproduction of reactive oxygen species and advanced glycation products, both of which are implicated in neuroinflammation and neurodegeneration (10–12). However, the meaning of “high” or “low” in diets' definition has been drifting away from the previously established quantitative criterion known as ketogenic ratio.

- by Tatiana M . Zilberter
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- Neuroscience, Nutrition, Metabolism, Alzheimer's Disease

Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer's disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed.

- by M. Berdasco and +1
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- Neurogenesis, Epigenetics, Neurodegeneration, Psychiatric Disorders

First described about three decades ago by D. Frank Benson and occasionally referred to as Benson's disease, posterior cortical atrophy (PCA) is a rare, debilitating, progressive neurodegenerative condition characterized mainly by declining visuoperceptual/spatial capabilities, and structurally by occipito-temporal/parietal lobe atrophy. Although research evidence suggests a 5% incidence of PCA amongst people diagnosed with Alzheimer's disease, standard epidemiological data for PCA remains relatively scarce, possibly due to a lack of clinical awareness of the condition and an under-recognition plus under-reporting of its variable phenotypic presentation. There also appears to be difficulties in consistency with the classification, as well as a lack of proper validation of congruous diagnostic criteria with regards to PCA. This case report describes the clinical presentation of a 55-year-old Caucasian female diagnosed with PCA and the management strategy. The report also highlights the role of multimodal imaging and neuropsychology in arriving at a potential diagnosis.

- by Journal of Geriatric Care and Research (JGCR) and +1
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- Psychology, Neuropsychology, Neurology, Radiology

Tissue engineering is the use of engineering methods to replace, replicate, or improve biological tissues. Neural tissue engineering involves the integrated use of biomaterials, cellular engineering, and drug delivery technologies with the purpose of protecting, repairing, or regenerating cells and tissues of the nervous system. Through the introduction of biochemical, topographic, immunomodulatory, and other types of cues, tissues can be therapeutically controlled to direct growth and tissue function in order to overcome biological constraints on tissue repair and regeneration. These strategies can be applied when injury or disease occurs in the brain, spinal cord, for damaged peripheral nerves, or to improve chronic functionality of implantable neural interfaces. In this chapter, we present an overview of neural tissue engineering using examples of therapeutic systems including nerve conduits, implantable hydrogels, delivery of neurotrophic factors and stem cells, genetic approaches to tissue engineering, immunomodulation, and electrical stimulation.

- by Johnathan Lyon
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- Biomedical Engineering, Biomaterials, Tissue Engineering, Traumatic Brain Injury

The 1st World Congress on Geriatrics and Neurodegenerative Disease Research (GeNeDis 2014), focused on recent advances in geriatrics and neurodegeneration, ranging from basic science to clinical and pharmaceutical developments, providing an international forum for the latest scientific discoveries, medical practices and care initiatives. Advances information technologies had been discussed along with their implications for various research, implementation and policy concerns. In addition, the conference addressed several European and global issues in the funding of long-term care and medico-social policies regarding elderly people. GeNeDis 2014 took place in Corfu, Greece, 10-13 April 2014. This volume focuses on the sessions that address Neurodegeneration.

- by Athanasios T Alexiou and +1
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- Neurodegeneration

Inflammation is a common denominator among the diverse list of neurodegenerative diseases. Marijuana derivatives have attracted special interest as a way to prevent brain disease and a treatment. Cannabidiol (CBD), which lacks psychotropic effect, may represent a very promising agent with the highest prospect for neuroprotective and anti-inflammatory properties.

- by Gary Chandler
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- Neuroscience, Alzheimer's Disease, Parkinson's Disease, Aging

Aromatherapy is an ancient scent treatment that has gained a lot of attention in the contemporary research for its various benefits. The role of olfactory stimulation leading to neuropoeisis has been a major consideration for treating neurodegenerative disorders like dementia, Alzheimer's and Parkinson's as well as psychiatric symptoms like mood disturbances, anxiety and sleep problems. The literature review has concentrated on the significance of the olfaction in the mammalian physiology and enlightened the hypothesis with noteworthy evidences to support the idea that with more research and clinical trials aromatherapy can attest to be a major breakthrough in treating Alzheimer's disease and reversing neurodegeneration.

- by Alvira Ali
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- Neuroscience, Neurodegeneration, Brain, Neurodegenerative disorders

Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are currently unknown. In ALS, protein aggregation has been described
for the SOD1, C9orf72, FUS and TDP-43 proteins. The latter is a nuclear protein normally binding to both DNA and RNA, contributing to gene expression and mRNA life cycle regulation. TDP-43 seems to have a specific role in ALS pathogenesis, and ubiquitinated and hyperphosphorylated cytoplasmic inclusions of aggregated TDP-43 are present in nerve cells in almost all sporadic ALS cases. ALS pathology appears to include metal imbalances, and environmental metal exposure is a known risk factor in ALS. However, studies on metal-to-TDP-43 interactions are scarce, even though this protein
seems to have the capacity to bind to metals. This review discusses the possible role of metals in TDP-43 aggregation, with respect to ALS pathology.

- by Sebastian K T S Wärmländer and +1
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- Biochemistry, Molecular Biochemistry, Neurodegeneration, Amyloid

Increasing evidence supports the idea that frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) share underlying causes and lie on opposite ends of a disease spectrum that leads to these disorders. The discovery of two different RNA binding proteins, TDP-43 and FUS/TLS, as common neuronal inclusions in FTD and ALS patients has strengthened this connection. Subsequent identification of mutations in TDP-43 and FUS that cause ALS, and FTD in rare cases, provides additional linkage between these diseases. Furthermore, autosomal dominant forms of FTD, ALS, or a combined phenotype can occur in the same family. Genetic studies have linked some of these cases to chromosome 9p21 and are known as c9FTD/ALS. Recently, an expanded GGGGCC hexanucleotide repeat in the C9ORF72 gene has been identified in c9FTD/ALS cases as well as sporadic forms of both diseases. Preliminary data suggest that the increased nucleotide repeats in C9ORF72 lead to RNA inclusions or foci in the nucleus of affected cells. Analogous to other repeat disorders such as myotonic dystrophy, expanded repeats in C9ORF72 may cause disease pathogenesis by sequestering RNA binding proteins and/or perturbing the splicing and regulation of key proteins regulating neuronal health and survival. Intriguingly, TDP-43 and FUS/TLS play fundamental roles in RNA regulation and splicing, and their mutation leads to dysfunctional regulation of their targets in model systems. Finally, defects in RNA splicing have been reported in sporadic ALS and a number of other genes involved in RNA metabolism (ANG, SETX, TAF15, ELP3, ATXN2) are associated with ALS. Based on these recent findings, we propose that defects in RNA metabolism are a common pathway linking FTD and ALS, and are responsible for disease pathogenesis in a significant portion of cases. Further research to test this hypothesis and determine if these proteins function within common biological pathways and share similar pathogenic mechanisms will ultimately open up new routes of therapy for these devastating disorders.

- by Current Enzyme Inhibition
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- Diversity & Inclusion, Neurodegeneration, Proteinopathies

Autophagy is a highly conserved cellular pro- cess, responsible for the degradation and recycling of damaged and/or outlived proteins and organelles. This is the major cellular pathway, acting throughout the forma- tion of cytosolic vesicles, called autophagosomes, for the delivering to lysosome. Recycling of cellular components through autophagy is a crucial step for cell homeostasis as well as for tissue remodelling during development. Impairment of this process has been related to the patho- genesis of various diseases, such as cancer and neurodegeneration, to the response to bacterial and viral infections, and to ageing. The ability of stem cells to self- renew and differentiate into the mature cells of the body renders this unique type of cell highly crucial to develop- ment and tissue renewal, not least in various diseases. During the last two decades, extensive knowledge about autophagy roles and regulation in somatic cells has been acquired; however, the picture about the role and the reg- ulation of autophagy in the different types of stem cells is still largely unknown. Autophagy is a major player in the quality control and maintenance of cellular homeostasis, both crucial factors for stem cells during an organism’s life. In this review, we have highlighted the most signifi- cant advances in the comprehension of autophagy regulation in embryonic and tissue stem cells, as well as in cancer stem cells and induced pluripotent cells.

- by Carlo Rodolfo
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- Stem Cells, Cancer, Autophagy, Neurodegeneration

Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large differences in the amino acid sequences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer’s disease amyloid-β (Aβ) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer’s disease should be expanded to include cross-interactions between Aβ and other amyloid proteins.

- by Sebastian K T S Wärmländer
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- Biochemistry, Biophysics, Alzheimer's Disease, Molecular Biophysics
- by Fanis Missirlis and +1
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- Drosophila melanogaster, Neurodegeneration, Neurodegenerative Diseases, Iron Metabolism

Nature has lots of flora-bearing fruits, vegetables with human beings. Berries contain a powerful source of natural antioxidants. Berries plays an essential role in prevention and therapy of various neurodegenerative diseases, like Alzheimer’s disease (AD), Parkinson’s disease and other neuronal dysfunctions as they are a diverse source of a large variety of nutritive, nonnutritive and bioactive compounds. Polyphenolic antioxidants present in different varieties of berries present in phyto-compounds which are present in nature may be used as a cure to delay neuro-degeneration, improvement of memory and cognitive function of frontal lobes. Berries such as Strawberry, Blueberry, Blackberry etc., have also confirmed neuroprotective effect against the AD. The molecular mechanism behind this therapeutic effect is the association of discrete signalling pathways by the work of phytonutrients which results in protein folding and neuro-inflammation. In Alzheimer’s, the neuroprotective properties of the diversely occurring bioactive components of the berries have been used and tabulated in this review.

- by Rahul Singh
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- Neuroscience, Food Science, Nutrition, Molecular Biology

Glutamate, first identified in 1866, is the primary excitatory neurotransmitter in the brain. While it is critically important in
many highly regulated cortical functions such as learning and memory, glutamate can be much like the magic the Sorcerer’s Apprentice used in Goethe’s poem: when conjured under unregulated conditions glutamate can get quickly out of control and lead to deleterious consequences. Two broad types of glutamate receptors, the ionotropic and metabotropic, facilitate glutamatergic neurotransmission in the CNS and play key roles in regulating cognitive function. Excessive activation of these receptors leads to excitotoxicity, especially in brain regions that are developmentally and regionally vulnerable to this kind of injury. Dysregulation of glutamate signaling leads to
neurodegeneration that plays a role in a number of neuropsychiatric diseases, prompting the development and utilization of novel strategies to balance the beneficial and deleterious potential of this important neurotransmitter. Inhibition of the enzyme glutamate carboxypeptidase II (GCPII) is one method of manipulating glutamate neurotransmission. Positive outcomes (decreased neuronal loss, improved cognition) have been demonstrated in preclinical models of ALS, stroke, and Multiple Sclerosis due to inhibition of GCPII,
suggesting this method of glutamate regulation could serve as a therapeutic means for treating neurodegeneration and cognitive impairment.

Alzheimer's disease (AD), the commonest cause of dementia in ageing adults, is characterized by gradual cognitive impairment and severe functional disability. Key pathophysiological hallmarks involve amyloid-β (Aβ) accumulation, tau hyper-phosphorylation and neuronal loss. Despite extensive basic and clinical investigations, the etiology of the disease remains elusive, although several risk factors have been associated with its development. Current pharmacotherapies including achetylocholinesterase inhibitors and memantine fail to halt disease progression. Interestingly, type 2 diabetes mellitus (T2DM) and AD share several common characteristics, including Aβ deposition, insulin resistance, degeneration, mitochondrial dysfunction, oxidative stress and excessive inflammation. Recent experimental and clinical evidence indicates that dipeptidyl peptidase-4 (DPP-4) inhibitors, being currently used for T2DM therapy, may also prove effective for AD treatment. They may specifically suppress Aβ accumulation, tau hyper-phosphorylation, neuroinflammation, mitochondrial dysfunction and reactive oxygen species (ROS) formation, resulting in the inhibition of cognitive impairment. In this review, we discuss the encouraging current data regarding the molecular and clinical effects of DPP-4 inhibitors in AD, highlighting the need of future studies elucidating their functional role in addressing this incurable disease.

- by Thalia Angelopoulou and +1
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- Neurology, Molecular Biology, Alzheimer's Disease, Diabetes

Over 90% of PDD patients show at least one neuropsychiatric symptom (NPS); in the 60–70% two or more NPS are present. Their incidence is important in terms of prognosis and severity of pathology. However, among all NPS, apathy is often the most disturbing, associated with greater caregiver's burden. Similar to other NPS, apathy may be due to a dysfunction of the nigrostriatal pathway, even though, not all the PD patients become apathetic, indicating that apathy should not entirely be considered a dopamine-dependent syndrome, and in fact it might also be related to acetylcholine defects. Apathy has been treated in many ways, without sure benefits; among these, Rivastigmine may present benefic properties. We present a series of 48 patients, suffering from PDD, treated with Rivastigmine, and followed-up for one year; they have been devotedly studied for apathy, even though all the other NPS disorders have been registered. Rivastigmine did not have a prolonged benefic effect on apathy, in our work, on the contrary of what had been observed in the literature, probably due to the longer follow-up of our patients.

- by Raffaele Pilla
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- Alzheimer's Disease, Cancer, Epilepsy, Neurodegeneration
- by Zaal Kokaia
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- Stem Cells, Clinical Trial, Neurodegeneration, Stem Cell

The personal identity relation is of great interest to philosophers, who often consider fictional scenarios to test what features seem to make persons persist through time. But often real examples of neuroscientific interest also provide important tests of personal identity. One such example is the case of Phineas Gage – or at least the story often told about Phineas Gage. Many cite Gage’s story as example of severed personal identity; Phineas underwent such a tremendous change that Gage “survived as a different man.” I discuss a recent empirical finding about judgments about this hypothetical. It is not just the magnitude of the change that affects identity judgment; it is also the negative direction of the change. I present an experiment suggesting that direction of change (improvement or deterioration) also affects neuroethical judgments. I conclude we should consider carefully the way in which improvements and deteriorations affect attributions of personal identity. This is particularly important since a number of the most crucial neuroethical decisions involve varieties of cognitive enhancements (improvements) or deteriorations.

- by Kevin Tobia
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- Psychology, Cognitive Psychology, Law, Philosophy

Progressive deterioration of social cognition and emotion processing are core symptoms of the behavioral variant of frontotemporal dementia (bvFTD). Here we investigate whether bvFTD is also associated with impaired recognition of static (Experiment 1) and dynamic (Experiment 2) bodily expressions. In addition, we compared body expression processing with processing of static (Experiment 3) and dynamic (Experiment 4) facial expressions, as well as with face identity processing (Experiment 5). The results reveal that bvFTD is associated with impaired recognition of static and dynamic bodily and facial expressions, while identity processing was intact. No differential impairments were observed regarding motion (static vs. dynamic) or category (body vs. face). Within the bvFTD group, we observed a significant partial correlation between body and face expression recognition, when controlling for performance on the identity task. Voxel-Based Morphometry (VBM) analysis revealed that body emotion recognition was positively associated with grey matter volume in a region of the inferior frontal gyrus (pars orbitalis/triangularis). The results are in line with a supramodal emotion recognition deficit in bvFTD.

- by Jan Van den Stock and +4
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- Emotion, Neurodegeneration

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.

- by Thalia Angelopoulou and +1
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- Neuroscience, Cognitive Science, Neurology, Alzheimer's Disease

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, nowadays considered as suitable candidate for autologous stem therapy with bone marrow (BM). A careful characterization of BM stem cell (SC) compartment is mandatory before its extensive application to clinic. Indeed, widespread systemic involvement has been recently advocated given that non-neuronal neighboring cells actively influence the pathological neuronal loss. We therefore investigated BM samples from 21 ALS patients and reported normal hematopoietic biological properties while an atypical behavior and impaired SC capabilities affected only the mesenchymal compartment. Moreover, by quantitative real-time approach, we observed altered Collagen IV and Metalloproteinase-9 levels in patients' derived mesenchymal stem cells (MSCs). Widespread metalloproteinase (MMPs) and their tissue inhibitor (TIMPs) alterations were established by multiplex ELISA analysis, demonstrating diffuse enzymatic variations i...

- by Patrizia Bossolasco and +3
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- Neuroscience, Molecular Medicine, Neurodegeneration, Stem Cell
- by Adrian A Chrobak and +1
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- Lithium, Neurodegeneration, Neuroprotection, Cerebellum
- by Fabiane Eh Felipe
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- Music, Musicology, Theatre Studies, Film Studies

The already established and widely used intravenous application of recombinant tissue plasminogen activator as a reopening strategy for acute vessel occlusion in ischemic stroke was recently added by mechanical thrombectomy, representing a fundamental progress in evidence-based medicine to improve the patient's outcome. This has been paralleled by a swift increase in our understanding of pathomechanisms underlying many neurovascular diseases and most prevalent forms of dementia. Taken together, these current advances offer the potential to overcome almost two decades of marginally successful translational research on stroke and dementia, thereby spurring the entire field of translational neuroscience. Moreover, they may also pave the way for the renaissance of classical neuroprotective paradigms. This review reports and summarizes some of the most interesting and promising recent achievements in neurovascular and dementia research. It highlights sessions from the 9th International Symposium on Neuroprotection and Neurorepair that have been discussed from April 19th to 22nd in Leipzig, Germany. To acknowledge the emerging culture of interdisciplinary collaboration and research, special emphasis is given on translational stories ranging from fundamental research on neurode-and-regeneration to late stage translational or early stage clinical investigations.

- by Marietta Zille
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- Neuroscience, Neuroregeneration, Neurodegeneration, Neurodegenerative Diseases

Background: Social cognition is critically compromised across neurodegenerative diseases, including the behavioral variant frontotemporal dementia (bvFTD), Alzheimer's disease (AD), and Parkinson's disease (PD). However, no previous study has used social cognition and other cognitive tasks to predict diagnoses of these conditions, let alone reporting the brain correlates of prediction outcomes. Objective: We performed a diagnostic classification analysis using social cognition, cognitive screening (CS), and executive function (EF) measures, and explored which anatomical and functional networks were associated with main predictors.

- by Roberto Furlan
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- Neuroscience, Multiple sclerosis, Inflammation, Neurodegeneration

SUMMARY Introduction: Alzheimer's disease is a common pathology of the modern world, especially with ageing populations. This is due to both hereditary components and as a result of numerous injuries to neuronal structures and components of the central nervous system. Therefore, research from multiple perspectives is necessary to discern the complex mechanisms that give rise to this neurodegenerative disease. One perspective is with the use of imaging, and this paper illustrates the usefulness of this approach. Methodology: The material presented in this paper addresses the issues of the etiology of Alzheimer's disease and its effects on nerve cells and changes to the central nervous system. In order to illustrate this, information relating to patients, in the form of CT images, are detailed. Results: From an analysis of the imaging tests presented in this paper, it is noted that the changes occur on the structures of the central nervous system: brain, cerebella cortical brain sharp, periventricular white matter. Beside specific changes, CT exam shows other structures, such as paranasal sinuses, mastoid cells or orbits, do undergo change. Differentiating between these structures is important for diagnosis. Conclusion: The changes taking place in relation to the central nervous system components have consequences on the patient's life. The implication is that Alzheimer's disease should be studied from different perspectives, including the studying of images to support clinical assessments. Imaging can aid the accuracy of diagnosis through the identification of specific areas and causes connection with particular types of dementia.

- by Tim Sandle
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- Medical Sciences, Surgery, History of Medicine, Dementia

"This review summarizes the current tendencies observed in the past 5 years in the development of A(1) and A(2A) adenosine receptor antagonists performed in various academia and industry. A(1) and A(2A) AR antagonists are as well xanthines as heteroaromatic derivatives and are most commonly 6:5 fused heteroatomic compounds. Among xanthine-based compounds, some common features could be pointed out. The recent A(1) AR ligands which show good biological profile, possess long alkyl chains in position 1 and 3 as well as bulky C(8)-substituent, while A(2A) AR antagonists with a high A(2A) AR affinity are C(8)-styryl substituted with N(1)-alkyl/alkynyl moiety or fused tricyclic xanthines possessing heteroatom(s) in the third cycle. The research in the field of heteroaromatic A(1) and A(2A) ARs antagonists impressively has a wide range. Ligands are as well non-fused monocyclic substituted compounds as fused bi- and tricyclic derivatives with the nitrogen, oxygen and sulfur heteroatoms. Most often, adenosine A(1) receptor non-xanthine antagonists are adenine-based, having substituted amino group and variable nitrogen atoms positions in the molecules. A(2A) AR ligands show good affinity when furanyl function, which is crucial for binding, is present in the fused bicyclic and tricyclic analogs. Moreover, tricyclic nitrogen containing antagonists in order to be active, frequently possess long-alkylphenyl moiety."

- by Olya Yuzlenko and +1
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- Alzheimer's Disease, Parkinson's Disease, Neurodegeneration, Neurodegenerative Diseases

Diabetic retinopathy (DR), commonly classified as a microvascular complication of diabetes, is now recognized as a neurovascular complication or sensory neuropathy resulting from disruption of the neurovascular unit. Current therapies for DR target the vascular complication of the disease process, including neovascularization and diabetic macular edema. Since neurodegeneration is an early event in the pathogenesis of DR, it will be important to unravel the mechanisms that contribute to neuroretinal cell death in order to develop novel treatments for the early stages of DR. In this review we comment on how inflammation, the metabolic derangements associated with diabetes, loss of neuroprotective factors, and dysregulated glutamate metabolism may contribute to retinal neurodegeneration during diabetes. Promising potential therapies based on these specific aspects of DR pathophysiology are also discussed. Finally, we stress the importance of developing and validating new markers of visual function that can be used to shorten the duration of clinical trials and accelerate the delivery of novel treatments for DR to the public.

In the pathogenesis of Alzheimer’s disease
(AD), it is well established that the self-association of Ab
peptides into amyloid fibrils and/or plaque like aggregates
causes neurotoxicity. As there is no cure for AD till date,
identification of specific compounds that either inhibit the
formation of Ab-fibrils or help in the dissolution of already
formed amyloid plaques makes an appealing therapeutic
and preventive strategy in the development of drugs. In the
present study, four synthetic flavonoid derivatives (1, 2, 3
and4) were examined for docking studies with Amyloid
beta (PDB Code: 1IYT) and Amyloid fibril (PDB Code:
2BEG). Of these, compound1and 4were found to be
potential inhibitors, as supported by computational
molecular docking studies with adequate pharmacokinetic
properties. Compound 1 was further tested in vivo in
transgenic AD model of Drosophila. The disease causing human Ab42 peptide was expressed in the compound eye
by driving UAS-Ab42with ey-GAL4, which caused severe
degeneration in eye tissues ranging from loss of bristles,
ommatidial holes to severe ommatidial disruption as
revealed by digital camera imaging and scanning electron
microscopy. When the Ab42expressing larvae were grown
in medium containing Compound 1, *70 % rescue of the
rough eye phenotype was observed at 75 and 100lM
concentrations. This is further corroborated by significant
reduction in amyloid plaques in eye imaginal disks of
compound1treated larvae as revealed by immuno-confocal imaging studies. Further, rescue of locomotor deficit
and improved life span in compound1treated Abflies also
confirm the neuroprotective activity of this compound.
Thus, our results support the neuroprotective efficacy of
compound 1 in preventing Ab42-induced neurotoxicity
in vivo and identify it as a future therapeutic agent against
AD.

- by Joanne Clark
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- Transcription Regulation, Oxidative Stress, Neurodegeneration, Nrf2

Several effects of the endogenous opioid peptide dynorphin A (Dyn A) are not mediated through the opioid receptors. These effects are generally excitatory, and result in cell loss and induction of chronic pain and paralysis. The mechanism(s) is not well defined but may involve formation of pores in cellular membranes. In the 17-amino acid peptide Dyn A we have recently identified L5S, R6W, and R9C mutations that cause the dominantly inherited neurodegenerative disorder Spinocerebellar ataxia type 23. To gain further insight into non-opioid neurodegenerative mechanism(s), we studied the perturbation effects on lipid bilayers of wild type Dyn A and its mutants in large unilamellar phospholipid vesicles encapsulating the fluorescent dye calcein. The peptides were found to induce calcein leakage from uncharged and negatively charged vesicles to different degrees, thus reflecting different membrane perturbation effects. The mutant Dyn A R6W was the most potent in producing leakage with negatively charged vesicles whereas Dyn A L5S was virtually inactive. The overall correlation between membrane perturbation and neurotoxic response [3] suggests that pathogenic Dyn A actions may be mediated through transient pore formation in lipid domains of the plasma membrane.

Peripheral nerve axons require a well-organized axonal microtubule network for efficient transport to ensure the constant crosstalk between soma and synapse. Mutations in more than 80 different genes cause Charcot-Marie-Tooth disease, which is the most common inherited disorder affecting peripheral nerves. This genetic heterogeneity has hampered the development of therapeutics for Charcot-Marie-Tooth disease. The aim of this study was to explore whether histone deacetylase 6 (HDAC6) can serve as a therapeutic target focusing on the mutant glycyl-tRNA synthetase (GlyRS/GARS)-induced peripheral neuropathy. Peripheral nerves and dorsal root ganglia from the C201R mutant Gars mouse model showed reduced acetylated a-tubulin levels. In primary dorsal root ganglion neurons, mutant GlyRS affected neurite length and disrupted normal mitochondrial transport. We demonstrated that GlyRS co-immunoprecipitated with HDAC6 and that this interaction was blocked by tubastatin A, a selective inhibitor of the deacetylating function of HDAC6. Moreover, HDAC6 inhibition restored mitochondrial axonal transport in mutant GlyRS-expressing neurons. Systemic delivery of a specific HDAC6 inhibitor increased a-tubulin acetylation in peripheral nerves and partially restored nerve conduction and motor behaviour in mutant Gars mice. Our study demonstrates that a-tubulin deacetylation and disrupted axonal transport may represent a common pathogenic mechanism underlying Charcot-Marie-Tooth disease and it broadens the therapeutic potential of selective HDAC6 inhibition to other genetic forms of axonal Charcot-Marie-Tooth disease. Abbreviations: CMAP = compound muscle action potential; CMT = Charcot-Marie-Tooth disease; DRG = dorsal root ganglion; GlyRS = glycyl-tRNA synthetase; SNAP = sensory nerve action potential

- by Robert Prior and +1
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- Neurodegeneration, CMT, HDAC inhibition, Charcot Marie Tooth Disease
- by Amy Price and +2
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- Neurodegeneration
- by Rommy von Bernhardi
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- Neuroscience, Immunology, Inflammation, Neurodegeneration

Natural products once served humankind as the source of all
drugs, and higher plants provided most of these therapeutic agents.
Natural products continue to provide useful drugs in their own
right but also provide templates for the development of other
compounds. A major advantage of natural products approach to
drug delivery is that it is capable of providing complex molecules
that is not accessible by other routes. Among CNS disorders,
neurodegenerative disorders affects majority of population
worldwide. Neurodegenerative disorders such as Parkinson's
disease (PD), Alzheimer's disease (AD), Huntington's disease
(HD) and amyotrophic lateral sclerosis (ALS) are currently
incurable pathologies with huge social and economic impacts
closely related to the increasing of life expectancy in modern
times. Although the clinical and neuropathological aspects of these
debilitating disorders are distinct, they share a pattern of
neurodegeneration in anatomically or functionally related regions.
The majority of the compounds examined to date with a direct
relevance to AD are primarily from plants, from animal, marine
and microbial sources. Successful drugs achieved so far are found
to act by inhibiting acetyl cholinesterase enzyme. In future, more
emphasis should be given in finding new targets for AD therapies.
The review focuses on the natural products that might underlie the
purported beneficial improvements in memory and cognition,
neurovascular function, and in neuroprotection. It may be
concluded that natural product chemistry brings tremendous
diversity and historical precedent to a huge area of unmet medical
need. Cooperative effort from all the technical disciplines related
to drug discovery should be continued to make plant-derived
natural product research an essential contributor in future.