Gene therapy approaches have great promise in the treatment of neurodegenerative disorders and malignant brain tumors. Neuwelt et al. review available viral-mediated gene therapy methods and their blood-brain-barrier (BBB) disruption delivery technique, briefly mentioning nonviral mediated gene therapy methods. This commentary discussed the BBB disruption delivery technique, viral and nonviral mediated gene therapy approaches to Parkinson's disease, and the potential use of antisense oligo to suppress malignant brain tumors.

This work was supported, in part, by a Stem Cell Network grant to Françoise Baylis and Jason Scott Robert and a CIHR grant to Françoise Baylis. We sincerely thank Alan Fine, Rich Campbell, Cynthia Cohen, and Tim Krahn for helpful comments on an earlier draft of this paper. Thanks are also owed to Tim Krahn for his research assistance. An earlier version of this paper was presented to the Department of Bioethics and the Novel Tech Ethics research team. We thank (...) the participants at each of these meetings for their helpful comments. (shrink)

Frailty is an age-related dynamic status, characterised by a reduced resistance to stressors due to the cumulative decline of multiple physiological systems. Several researches have highlighted a relationship between physical frailty and cognitive decline; however, the role of specific cognitive domains has not been deeply clarified yet. Current studies have hypothesised that physical frailty and neuropsychological deficits may share systemic inflammation and increased oxidative stress in different neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. However, the role of the (...) executive dysfunction should be investigated in a more detailed way using a multidimensional approach. With this aim, we conducted a review of the literature on the few experimental articles published to discuss the existence of a relationship between frailty and cognitive impairment in neurocognitive disorders, particularly focusing on the domain of executive dysfunction. The data suggest that physical frailty and cognitive decline, especially executive dysfunction, are two aspects strongly linked in mild and major neurocognitive disorders due to Alzheimer's and Parkinson's disease. In light of this, a new framework linking ageing, cognitive decline, and neurodegenerative diseases is needed. In order to analyse the effects that ageing processes have on neural decline and neurocognitive disease, and to identify relevant groups of users and patients, future longitudinal studies should adopt a multidimensional approach, in the field of primary prevention and in the continuum from mild to major neurocognitive disorder. (shrink)

Sensorimotor synchronization, the coordination of physical actions in time with a rhythmic sequence, is a skill that is necessary not only for keeping the beat when making music, but in a wide variety of interpersonal contexts. Being able to attend to temporal regularities in the environment is a prerequisite for event prediction, which lies at the heart of many cognitive and social operations. It is therefore of value to assess and potentially stimulate SMS abilities, particularly in aging and neurocognitive disorders, (...) to understand intra-individual communication in the later stages of life, and to devise effective music-based interventions. While a bulk of research exists about SMS and movement-based interventions in Parkinson’s disease, a lot less is known about other types of neurodegenerative disorders, such as Alzheimer’s disease, vascular dementia, or frontotemporal dementia. In this review, we outline the brain and cognitive mechanisms involved in SMS with auditory stimuli, and how they might be subject to change in healthy and pathological aging. Globally, SMS with isochronous sounds is a relatively well-preserved skill in old adulthood and in patients with NCDs. At the same time, natural tapping speed decreases with age. Furthermore, especially when synchronizing to sequences at slow tempi, regularity and precision might be lower in older adults, and even more so in people with NCDs, presumably due to the fact that this process relies on attention and working memory resources that depend on the prefrontal cortex and parietal areas. Finally, we point out that the effect of the severity and etiology of NCDs on sensorimotor abilities is still unclear: More research is needed with moderate and severe NCD, comparing different etiologies, and using complex auditory signals, such as music. (shrink)

Transfer RNAs (tRNAs) represent the most abundant class of RNA molecules in the cell and are key players during protein synthesis and cellular homeostasis. Aberrations in the extensive tRNA biogenesis pathways lead to severe neurological disorders in humans. Mutations in the tRNA splicing endonuclease (TSEN) and its associated RNA kinase cleavage factor polyribonucleotide kinase subunit 1 (CLP1) cause pontocerebellar hypoplasia (PCH), a heterogeneous group of neurodegenerative disorders, that manifest as underdevelopment of specific brain regions typically accompanied by microcephaly, profound (...) motor impairments, and child mortality. Recently, we demonstrated that mutations leading to specific PCH subtypes destabilize TSEN in vitro and cause imbalances of immature to mature tRNA ratios in patient‐derived cells. However, how tRNA processing defects translate to disease on a systems level has not been understood. Recent findings suggested that other cellular processes may be affected by mutations in TSEN/CLP1 and obscure the molecular mechanisms of PCH emergence. Here, we review PCH disease models linked to the TSEN/CLP1 machinery and discuss future directions to study neuropathogenesis. (shrink)

The emerging field of lipidomics has identified lipids as key players in disease physiology. Their physicochemical diversity allows precise control of cell structure and signaling events through modulation of membrane properties and trafficking of proteins. As such, lipids are important regulators of brain function and have been implicated in neurodegenerative and mood disorders. Importantly, environmental chronic stress has been associated with anxiety and depression and its exposure in rodents has been extensively used as a model to study these diseases. (...) With the accessibility to modern mass‐spectrometry lipidomic platforms, it is now possible to snapshot the extensively interconnected lipid network. Here, we review the fundamentals of lipid biology and outline a framework for the interpretation of lipidomic studies as a new approach to study brain pathophysiology. Thus, lipid profiling provides an exciting avenue for the identification of disease signatures with important implications for diagnosis and treatment of mood disorders. (shrink)

Parkinsonism (PD) is a neurodegenerative disorder of the brain resulting in dopamine deficiency caused by the progressive death of dopaminergic neurons. PD is characterized by a combination of rigidity, poverty of movement, tremor and postural instability. Selegiline is a selective and irreversible propargylamine type B monoamine oxidase (MAO‐B) inhibitor. This drug, which inhibits dopamine metabolism, has been effectively used in the treatment of PD. However, its therapeutic effects are compromised by its many neurotoxic metabolites. To circumvent this obstacle, (...) a novel MAO‐B inhibitor, rasagiline, was developed. Paradoxically, the neuroprotective mechanism of propargylamines in different neuronal models appears to be independent of MAO‐B inhibition. Recent investigations into the neuroprotective mechanism of propargylamines indicate that glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH), MAO‐B and/or other unknown proteins may represent pivotal proteins in the survival of the injured neurons. Delineation of the mechanism(s) involved in the neuroprotective effects exerted by MAO‐B inhibitors may provide the key to preventive novel therapeutic modalities. BioEssays 26:80–90, 2004. © 2003 Wiley Periodicals, Inc. (shrink)

This study examined the relationship between individual differences in executive functions (EF; assessed by measures of working memory, Stroop, trail making, and verbal fluency) and ability to down-regulate and up-regulate responses to emotionally evocative film clips. To ensure a wide range of EF, 48 participants with diverse neurodegenerative disorders and 21 older neurologically normal ageing participants were included. Participants were exposed to three different movie clips that were designed to elicit a mix of disgust and amusement. While watching the (...) films they were either instructed to watch, down-regulate, and up-regulate their visible emotional responses. Heart rate and facial behaviours were monitored throughout. Emotion regulatory ability was operationalised as changes in heart rate and facial behaviour in the down- and up-regulation conditions, controlling for responses in the watch condition. Results indicated that higher verbal fluency scores were related to greater ability to regulate emotion in both the down-regulation and up-regulation conditions. This finding remained significant even after controlling for age and general cognitive functioning. No relationships were found between emotion regulation and the other EF measures. We believe these results derive from differences among EF measures, with verbal-fluency performance best capturing the complex sequence of controlled planning, activation, and monitoring required for successful emotion regulation. These findings contribute to our understanding of emotion–cognition interaction, suggesting a link between emotion-regulatory abilities and individual differences in complex executive functions. (shrink)

Deep brain stimulation is an invasive technique designed to stimulate certain deep brain regions for therapeutic purposes and is currently used mainly in patients with neurodegenerative disorders, such as Parkinson’s disease. However, DBS is also used increasingly for other experimental applications, such as the treatment of psychiatric disorders, weight reduction. Apart from its therapeutic potential, DBS can cause severe adverse effects, some that might also have a significant impact on the patient’s personality and autonomy by the external stimulation of (...) DBS which effects lie beyond the individual’s control and free will. The article’s purpose is to outline the procedures of DBS currently used in therapeutic and experimental applications and to discuss the ethical concerns regarding this procedure. It will address the clinical benefit-risk-ratio, the particular ethics of research in this field, and the ethical issues raised by affecting a patient’s or an individual’s personality and autonomous behaviour. Moreover, a potential ethical guideline, the Ulysses contract is discussed for the field of clinical application as well as the question of responsibility. (shrink)

Do sensory measurements deserve the label of “measurement”? We argue that they do. They fit with an epistemological view of measurement held in current philosophy of science, and they face the same kinds of epistemological challenges as physical measurements do: the problem of coordination and the problem of standardization. These problems are addressed through the process of “epistemic iteration,” for all measurements. We also argue for distinguishing the problem of standardization from the problem of coordination. To exemplify our claims, we (...) draw on olfactory performance tests, especially studies linking olfactory decline to neurodegenerative disorders. (shrink)

The ubiquitin–proteasome system (UPS) is the major proteolytic pathway that degrades intracellular proteins in a regulated manner. Deregulation of the UPS has been implicated in the pathogenesis of many neurodegenerative disorders like Alzheimer's disease, Parkinson's diseases, Huntington disease, Prion‐like lethal disorders, in the pathogenesis of several genetic diseases including cystic fibrosis, Angelman's syndrome and Liddle syndrome and in many cancers. Multiple lines of evidence have already proved that UPS has the potential to be an exciting novel therapeutic target for (...) the treatment of these diseases. Here I review how aberrant functions of various genes have implicated UPS in many human disorders including neurodegeneration and cancers. I also discuss the finding that some proteasome inhibitors possess a therapeutic potential as drugs against many such diseases. BioEssays 30:1172–1184, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

We investigate the long-term evolution of degree-degree correlations (assortativity) in functional brain networks from epilepsy patients. Functional networks are derived from continuous multi-day, multi-channel electroencephalographic data, which capture a wide range of physiological and pathophysiological activities. In contrast to previous studies which all reported functional brain networks to be assortative on average, even in case of various neurological and neurodegenerative disorders, we observe large fluctuations in time-resolved degree-degree correlations ranging from assortative to dissortative mixing. Moreover, in some patients these (...) fluctuations exhibit some periodic temporal structure which can be attributed, to a large extent, to daily rhythms. Relevant aspects of the epileptic process, particularly possible pre-seizure alterations, contribute marginally to the observed long-term fluctuations. Nevertheless, our findings suggest that physiological and pathophysiological activity may modify functional brain networks in a different and process-specific way. We evaluate factors that possibly influence the long-term evolution of degree-degree correlations. (shrink)

Do sensory measurements deserve the label of “measurement”? We argue that they do. They fit with an epistemological view of measurement held in current philosophy of science, and they face the same kinds of epistemological challenges as physical measurements do: the problem of coordination and the problem of standardization. These problems are addressed through the process of “epistemic iteration,” for all measurements. We also argue for distinguishing the problem of standardization from the problem of coordination. To exemplify our claims, we (...) draw on olfactory performance tests, especially studies linking olfactory decline to neurodegenerative disorders. (shrink)

GraphicalExercise, neurotransmitters, growth factors, myokines, and potential effects on the brain.As human life expectancy increases, cognitive decline and memory impairment threaten independence and quality of life. Therefore, finding prevention and treatment strategies for memory impairment is an important health concern. Moreover, a better understanding of the mechanisms involved underlying memory preservation will enable the development of appropriate pharmaceuticals drugs for those who are activity limited. Exercise training as a non-pharmacological tool, has been known to increase the mean lifespan by maintaining (...) general body health and improving the cardiovascular and nervous systems function. Among different exercise training protocols, aerobic exercise has been reported to prevent the progression of memory decline, provided adequate exertion level, duration, and frequency. Mechanisms underlying exercise training effects on memory performance have not been understood yet. Convergent evidence suggest several direct and indirect mechanisms at molecular and supramolecular levels. The supramolecular level includes improvement in blood circulation, synaptic plasticity and neurogenesis which are under controls of complex molecular signaling of neurotransmitters, neurotrophic factors, exerkines, and epigenetics factors. Among these various factors, irisin/BDNF signaling seems to be one of the important mediators of crosstalk between contracted skeletal muscles and the brain during exercise training. This review provides an affordable and effective method to improve cognitive function in old ages, particularly those who are most vulnerable to neurodegenerative disorders. (shrink)

Trehalose is a natural disaccharide with a remarkable ability to stabilize biomolecules. In recent years, trehalose has received growing attention as a neuroprotective molecule and has been tested in experimental models for different neurodegenerative diseases. Although the underlying neuroprotective mechanism of trehalose's action is unclear, one of the most important hypotheses is autophagy induction. The chaperone‐like activity of trehalose and the ability to modulate inflammatory responses has also been reported. There is compelling evidence that the dysfunction of autophagy and (...) aggregation of misfolded proteins contribute to the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Therefore, given the linking between trehalose and autophagy induction, it appears to be a promising therapy for AD. Herein, the published studies concerning the use of trehalose as a potential therapy for AD are summarized, providing a rationale for applying trehalose to reduce Alzheimer's pathology. (shrink)

During development, large numbers of cells die by a process known as programmed cell death. This loss of cells plays a number of important roles, including the sculpting of the body form and the removal of vestigial tissues. Data obtained from a variety of organisms has suggested that a cell's ‘decision’ to die is a differentiative event, requiring the activation of specific sets of genes. Several putative ‘cell death’ genes have recently been cloned, and one has been identified as the (...) product of the polyubiquitin gene. Accumulation of ubiquitin has been observed not only during programmed cell death, but also in several neurodegenerative disorders, including Alzheimer's Disease. (shrink)

Variant Creutzfeldt–Jakob disease is a fatal, transmissible, neurodegenerative disorder for which there is currently no effective treatment. vCJD arose from the zoonotic spread of bovine spongiform encephalopathy. There is now compelling evidence for human to human transmission through blood transfusions from presymptomatic carriers and experts are warning that the real epidemic may be yet to come. Imperatives exist for the development of reliable, non-invasive presymptomatic diagnostic tests. Research into such tests is well advanced. In this article the ethical (...) implications of the availability of these tests are elaborated and comparisons drawn with predictive genetic testing for Huntington’s disease and screening for HIV. Paramount to considerations is the issue of whom to test, weighing up respect for personal autonomy against obligations to benefit and protect society. A paradigm is proposed similar to that used for HIV screening but with unique features: compulsory testing of all blood/organ donors and individuals undergoing surgery or invasive procedures who have a significant risk of disease transmission. (shrink)

First of all, we would like to gratefully thank all commentators for the attention and effort they have put into reading and responding to our review paper [this issue] and for useful observations that suggest novel applications for our framework. We understand and accept that some of our claims might appear controversial and raise skepticism, because the overall neural framework we have proposed is difficult to frame in established categories, given its strong multidisciplinary character. To make an example, Elsevier is (...) publishing the British Neuroscience Association (BNA) 2017 Special Issue Collection. However, our paper could not fully fit in any of their Special Issues—attention, motivation, behavior; sensory and motor systems; novel treatments and translational neuroscience; genetics and epigenetics; learning and memory; neurodegenerative disorders and ageing; developmental neuroscience; neuronal, glial and cellular mechanisms; neuroendocrine and autonomic nervous systems; psychiatry and mental health; methods and techniques. Perhaps because our paper was mathematically, physically, biologically (neuroscientifically), and phenomenologically motivated from the start? Nevertheless, venturing in novel, fresh, testable proposals is badly needed in contemporary neuroscience, so to break into “the utter darkness of the inner mechanism of psychic acts… during the production of the concomitant phenomena of perception and thought, namely, feelings, consciousness and volition”—as Cajal had already observed in his opus magnus ‘Textura’. But as he soberly confessed: “This ideal is still very distant” (Ramon y Cajal, 1899-1904, p. 1,141). In the pursuit of that very ideal, neuroscience and psychology have had, and continue to have, a plethora of movements and schools of thought: behaviorism, cognitivism, neural Darwinism, social constructivism, Bayesian optimization...In our paper, we propose to go a step further, via the notion of topodynamics, towards “projectionism.” In what follows, trying to elucidate the main features of this Emperor’s new clothing, we proceed with the responses to the comments received. (shrink)

Many neurodegenerative and neuropsychiatric diseases and other brain disorders are accompanied by impairments in high-level cognitive functions including memory, attention, motivation, and decision-making. Despite several decades of extensive research, neuroscience is little closer to discovering new treatments. Key impediments include the absence of validated and robust cognitive assessment tools for facilitating translation from animal models to humans. In this review, we describe a state-of-the-art platform poised to overcome these impediments and improve the success of translational research, the Mouse Translational (...) Research Accelerator Platform (MouseTRAP), which is centered on the touchscreen cognitive testing system for rodents. It integrates touchscreen-based tests of high-level cognitive assessment with state-of-the art neurotechnology to record and manipulate molecular and circuit level activity in vivo in animal models during human-relevant cognitive performance. The platform also is integrated with two Open Science platforms designed to facilitate knowledge and data-sharing practices within the rodent touchscreen community, touchscreencognition and mousebytes. Touchscreencognition includes the Wall, showcasing touchscreen news and publications, the Forum, for community discussion, and Training, which includes courses, videos, SOPs, and symposia. To get started, interested researchers simply create user accounts. We describe the origins of the touchscreen testing system, the novel lines of research it has facilitated, and its increasingly widespread use in translational research, which is attributable in part to knowledge-sharing efforts over the past decade. We then identify the unique features of MouseTRAP that stand to potentially revolutionize translational research, and describe new initiatives to partner with similar platforms such as McGill’s M3 platform. (shrink)

Applying Behrendt & Young's (B&Y's) model of thalamocortical synchrony to complex visual hallucinations in neurodegenerative disorders, such as dementia with Lewy bodies and progressive supranuclear palsy, leads us to propose that the primary pathology may be cortical rather than thalamic. Additionally, the extinction of active hallucinations by eye closure challenges their conception of the role of reduced sensory input.

Glutamate is the major excitatory neurotransmitter in the mammalian brain, with receptors on every neuron in the central nervous system; it has major roles in fast synaptic transmission and in the establishment of certain forms of memory. More than 20 years ago Olney and his colleagues(1) described the [Excitotoxic Hypothesis] which postulates that, in addition to its normal function in the healthy brain, glutamate can kill neurons by prolonged, receptorsmediated depolarization resulting in irreversible disturbances in ion homeostasis. Therefore, glutamate is (...) a two‐edged sword; in certain undefined, adverse conditions it undergoes a transition from neurotransmitter to neurotoxin. Its toxicity has been implicated in the death of neurons in ischemia, epilepsy, and the neurodegenerative disorders such as Alzheimer's, Huntington's, and Parkinson's diseases(2–5). Recent advances in the molecular cloning of the genes for the glutamate family of receptors has revealed a plethora of receptor subtypes and an unexpected level of complexity in the mechanisms of receptor expression and function. (shrink)

It may soon be possible to diagnose neurodegenerative disorders, such as early onset Alzheimer's disease, with a high degree of accuracy well before these conditions become symptomatic. In a carefully argued and thought-provoking piece, Dena Davis maintains that preemptive suicide may be a rational option for those confronted with a preclinical diagnosis of impending dementia, and consequently that withholding the results of dementia research until effective treatments become available constitutes an unjustified infringement on patient autonomy. If suicide is indeed (...) a rational course of action for some people diagnosed with dementia, then contrary to received wisdom, biomarker information indicating a high risk of dementia may be ‘actionable’ even if there is no known treatment for the condition. Preemptive suicide, Davis argues, may be motivated and justified by a mixture of other-regarding and self-regarding considerations. These include, inter alia, the wish to avoid imposing significant financial or psychological hardships on one's family, the unwillingness to live without the capacities for meaningful independence or agency, and the desire to write a final chapter that is consistent with one's stable values and that does not distort or eclipse the overarching narrative of one's life. Dementia raises an ethical dilemma that does not arise in connection with other diseases with respect to which many believe suicide is a rational course of action. This dilemma arises from the fact that a person with impending dementia cannot wait until the disease takes hold to issue and carry out a decision to end his or her life, since dementia destroys the capacities that underpin rational decision-making. Because jurisdictions permitting suicide require, quite reasonably, that a …. (shrink)

Variant Creutzfeldt–Jakob disease is a fatal, transmissible, neurodegenerative disorder for which there is currently no effective treatment. vCJD arose from the zoonotic spread of bovine spongiform encephalopathy. There is now compelling evidence for human to human transmission through blood transfusions from presymptomatic carriers and experts are warning that the real epidemic may be yet to come. Imperatives exist for the development of reliable, non-invasive presymptomatic diagnostic tests. Research into such tests is well advanced. In this article the ethical (...) implications of the availability of these tests are elaborated and comparisons drawn with predictive genetic testing for Huntington’s disease and screening for HIV. Paramount to considerations is the issue of whom to test, weighing up respect for personal autonomy against obligations to benefit and protect society. A paradigm is proposed similar to that used for HIV screening but with unique features: compulsory testing of all blood/organ donors and individuals undergoing surgery or invasive procedures who have a significant risk of disease transmission. (shrink)

Background: The research community has a mandate to discover effective treatments for neurodegenerative disorders. The ethics landscape surrounding this mandate is in a constant state of flux, and ongoing challenges place ever greater demands on investigators to be accountable to the public and to answer questions about the implications of their work for health care, society, and policy. Methods: We surveyed US-based investigators involved in neurodegenerative diseases research about how they value ethics-related issues, what motivates them to give (...) consideration to those issues, and the barriers to doing so. Using the NIH CRISP database we identified 1,034 researchers with relevant, active grants and invited them to complete an online questionnaire. We received 193 responses. We used exploratory factor analysis to transform individual survey questions into a smaller set of factors, and linear regression to understand the effect of key variables of interest on the factor scores. Results: Ethics-related issues clustered into two groups: research ethics and external influences. Heads of research groups viewed issues of research ethics to be more important than the other respondents. Concern about external influences was related to overall interest in ethics. Motivators clustered into five groups: ensuring public understanding, external forces, requirements, values, and press and public. Heads of research groups were more motivated to ensure public understanding of research than the other respondents. Barriers clustered into four groups: lack of resources, administrative burden, relevance to the research, and lack of interest. Perceived lack of ethics resources was a particular barrier for investigators working in drug discovery. Conclusions: The data suggest that senior level neuroscientists working in the field of neurodegeneration (ND), and drug discovery specifically, are motivated to consider ethics issues related to their work, but the perceived lack of ethics resources thwarts their efforts. With bioethics centres at more than 50% of the institutions at which these respondents reside, the neuroscience and bioethics communities appear to be disconnected. Dedicated ethical, legal and social implications (ELSI) programs, such as those fully integrated into genetics and regenerative medicine, provide models for achieving meaningful partnerships not yet adequately realized for scholars and trainees interested in drug discovery for ND. (shrink)

A substantial portion of the human genome has been found to consist of simple sequence repeats, including microsatellites and minisatellites. Microsatellites, tandem repeats of 1–6 nucleotides, form the template for dynamic mutations, which involve heritable changes in the lengths of repeat sequences. In recent years, a large number of human disorders have been found to be caused by dynamic mutations, the most common of which are trinucleotide repeat expansion diseases. Dynamic mutations are common to numerous nervous system disorders, including Huntington's (...) disease, various spinocerebellar ataxias, fragile X syndrome, fragile X tremor/ataxia syndrome, Friedreich ataxia and other neurodegenerative disorders. The involvement of dynamic mutations in brain disorders will be reviewed, with a focus on the large group caused by CAG/glutamine repeat expansions. We will also outline a proposed role of tandem repeat polymorphisms (TRPs), with unique ‘digital’ genetic distributions, in modulating brain development and normal function, so as to generate additional mutational diversity upon which natural selection may act. BioEssays 29:525–535, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Alzheimer's disease is the most common neurodegenerative disorder in today's developed world that is also increasingly picked out as a focal theme in fictional literature. In dealing with the subjectivity of human experience, such literature enhances the reader's empathy and is able to teach about moral, emotional and philosophical issues, offering the chance to see situations from a position otherwise possibly never taken by the reader. The understanding and insight so gained may well be unscientific, but the literary (...) approach offers an insight into the whole person's perspective and the particularity and uniqueness of a situation that includes ethical conflicts. A key motif of fictional literature centred around dementia remains the burden the adult-child carer is confronted with, considering the parent's remorseless decline and personality change, the sudden demand for devoted and continuous care, and the constantly changing relationship with the declining parent. In the context of an ever increasing demand for a constructive public discussion regarding end-of-life treatment of demented patients, Christine Devars (Le Piano Désaccordé) and Andrés Barba (Ahora Tocad Música de Baile) illustrate how powerful and burdensome the impact of Alzheimer's disease is on both patient and carer and what extremes may be reached under such truly exceptional circumstances. (shrink)

Parkinson's disease has long been perceived as a pure motor disorder, partly due to its initial description by James Parkinson, who suggested that "senses and intellect remain intact", and partly due to the fact that patients with PD did not survive long, before effective treatment became available. As the survival time of patients with Parkinson's disease has substantially increased due to modern treatment, it has become apparent that cognitive deficits and dementia are also frequent features, especially in elderly patients. (...) With the progression of the disease and age, dementia develops in a substantial number of patients and constitutes a major therapeutic challenge. Dementia has thus increasingly been the focus of research and practice in recent years and a large body of knowledge has been accumulated. Despite these developments there has been no single volume dedicated to this topic. This book provides an extensive overview of the current status of knowledge pertaining to cognitive impairment and dementia associated with Parkinson's disease, intended as a reference book for general neurologists, neurology residents and also those with a special interest in movement disorders. In this edited volume experts in the field describe in detail all aspects of cognitive impairment and dementia in Parkinson's disease, including epidemiology, spectrum of clinical features, pathology, neurochemistry and genetics, findings in auxiliary investigations, relation to other neurodegenerative disorders, diagnostic process and management, and rounded up by discussion of future research directions and expectations. The text is complemented and enriched with tables, figures and heavily referenced to encompass all relevant literature. (shrink)

Parkinson´s disease (PD) is a neurodegenerative disorder characterized by motor symptoms following dopaminergic depletion in the substantia nigra. Besides motor impairments however, several non-motor detriments can have the potential to considerably impact subjectively perceived quality of life in patients. Particularly emotion recognition of facial expressions has been shown to be affected in PD, and especially the perception of negative emotions like fear, anger or disgust is impaired. While emotion processing generally refers to automatic implicit as well as conscious (...) explicit processing, the focus of most previous studies in PD was on explicit recognition of emotions only, while largely ignoring implicit processing deficits. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is widely accepted as therapeutic measure in the treatment of PD and has been shown to advantageously influence motor problems. Among various concomitant non-motor effects of STN-DBS, modulation of facial emotion recognition under subthalamic stimulation has been investigated in previous studies with rather heterogeneous results. While there seems to be consensus regarding the processing of disgust which significantly deteriorates under STN stimulation, findings concerning emotions like fear or happiness report heterogeneous data and seem to depend on various experimental settings and measurements. In the present review, we summarized previous investigations focusing on STN-DBS influence on recognition of facial emotional expressions in patients suffering from PD. In a first step, we provide a synopsis of disturbances and problems in facial emotion processing observed in patients with PD. Secondly, we present findings of STN-DBS influence on facial emotion recognition and especially highlight different impacts of stimulation on implicit and explicit emotional processing. (shrink)

Both blood vessels and nerves are guided to their target. Vascular endothelial growth factor (VEGF)A is a key signal in the induction of vessel growth (a process termed angiogenesis). Though initial studies, now a decade ago, indicated that VEGF is an endothelial cell‐specific factor, more recent findings revealed that VEGF also has direct effects on neural cells. Genetic studies showed that mice with reduced VEGF levels develop adult‐onset motor neuron degeneration, reminiscent of the human neurodegenerative disorder amyotrophic lateral (...) sclerosis (ALS). Additional genetic studies confirmed that VEGF is a modifier of motor neuron degeneration in humans and in SOD1G93A mice—a model of ALS. Reduced VEGF levels may promote motor neuron degeneration by limiting neural tissue perfusion and VEGF‐dependent neuroprotection. VEGF also affects neuron death after acute spinal cord or cerebral ischemia, and has also been implicated in other neurological disorders such as diabetic and ischemic neuropathy, nerve regeneration, Parkinson's disease, Alzheimer's disease and multiple sclerosis. These findings have raised growing interest in assessing the therapeutic potential of VEGF for neurodegenerative disorders. BioEssays 26:943–954, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Neuronal ceroid lipofuscinoses are a group of lethal inherited neurodegenerative disorders in humans and many animal species. Critical reflections on a range of ethical issues concerning NCL have been instigated by my research on sheep and cattle affected with NCL, the claim that these sheep and cattle are useful models for the disease in humans, and engagement with families and support groups. My reflections on moral status of animals and validity of animal models are outlined in this paper.

Ubiquitin is the most phylogenetically conserved protein known. This 8,500 Da polypeptide can be covalently attached to cellular proteins as a posttranslational modification. In most cases, the addition of multiple ubiquitin adducts to a protein targets it for rapid degradation by a multisubunit protease known as the 26S proteasome. While the ubiquitin/26S proteasome pathway is responsible for the degradation of the bulk of cellular proteins during homeostasis, it may also be responsible for the rapid loss of protein during the programmed (...) death of certain cells, such as skeletal muscle during insect metamorphosis. In addition, alterations in the expression and regulation of ubiquitin may play significant roles in pathological disorders. For example, dramatic increases in ubiquitin and ubiquitin‐protein conjugates are observed in a wide variety of neurodegenerative disorders, including Alzheimer's disease. Patients suffering from the autoimmune disease systemic lupus erythematosus generate antibodies reacting with ubiquitin and ubiquitinated histones. At present, it is not known whether these changes in ubiquitin expression and regulation initiate pathological changes in these diseases or if they are altered as a consequence of these disorders. (shrink)

Polyglutamine (polyQ) diseases are genetically inherited neurodegenerative disorders. They are caused by mutations that result in polyQ expansions of particular proteins. Mutant proteins form intranuclear aggregates, induce cytotoxicity and cause neuronal cell death. Protein interaction data suggest that polyQ regions modulate interactions between coiled‐coil (CC) domains. In the case of the polyQ disease spinocerebellar ataxia type‐1 (SCA1), interacting proteins with CC domains further enhance aggregation and toxicity of mutant ataxin‐1 (ATXN1). Here, we suggest that CC partners interacting with the (...) polyQ region of a mutant protein, increase its aggregation while partners that interact with a different region reduce the formation of aggregates. Computational analysis of genetic screens revealed that CC‐rich proteins are highly enriched among genes that enhance pathogenicity of polyQ proteins, supporting our hypothesis. We therefore suggest that blocking interactions between mutant polyQ proteins and their CC partners might constitute a promising preventive strategy against neurodegeneration. (shrink)

Belgian physicians recently reported on organ donation after euthanasia. In patients suffering mainly from a neurodegenerative disorder, the organ donation procedure starts after cardiac death due to euthanasia. The Church condemns the act of euthanasia. The act of procuring organs after euthanasia cannot be approved either, since those who procure the organs must cooperate closely with those who perform the euthanasia. Although the act of organ donation itself can be an act of charity, participation in organ donation after (...) euthanasia suggests approval of euthanasia. A patient may, because of a difficult medical situation, choose to accept an organ obtained after euthanasia but should dissociate himself explicitly from the act of euthanasia itself. National Catholic Bioethics Quarterly 12.3 (Autumn 2012): 431–437. (shrink)

Have you ever gotten chills while listening to a particularly gorgeous piece of music? Or felt a sense of calm while gazing at a painting of a serene landscape? We have experiences like those every day, but rarely stop to consider what's happening internally to cause them. In Your Brain on Art, founder of the International Arts + Mind Lab at Johns Hopkins University School of Medicine Susan Magsamen and Google designer Ivy Ross explain how, by understanding how we biologically (...) react to aesthetic experiences, we can not only heal as individuals but thrive as communities. Using the new science of neuroaesthetics, which explores our physiological reactions to art, Magsamen and Ross show us how, for instance, gardening can help a person heal from trauma or listening to a major fifth interval can snap the body out of a fight-or-flight response. Beyond enjoyment and abstraction, art can change the way we operate on a daily, practical level. And, in addition to helping each of us heal from stress, anxiety, burnout, and other malaises of modern life, neuroaesthetics can effect major change in society writ large, whether through public art murals in high-crime areas or music and dance therapy for patients experiencing neurodegenerative disorders. (shrink)

Poly(ADP‐ribosyl)ation is an immediate DNA‐damage‐dependent post‐translational modification of histones and other nuclear proteins that contributes to the survival of injured proliferating cells. Poly(ADP‐ribose) polymerases (PARPs) now constitute a large family of 18 proteins, encoded by different genes and displaying a conserved catalytic domain in which PARP‐1 (113 kDa), the founding member, and PARP‐2 (62 kDa) are so far the sole enzymes whose catalytic activity has been shown to be immediately stimulated by DNA strand breaks. A large repertoire of sequences encoding (...) novel PARPs now extends considerably the field of poly(ADP‐ribosyl)ation reactions to various aspects of the cell biology including cell proliferation and cell death. Some of these new members interact with each other, share common partners and common subcellular localizations suggesting possible fine tuning in the regulation of this post‐translational modification of proteins. This review summarizes our present knowledge of this emerging superfamily, which might ultimately improve pharmacological strategies to enhance both antitumor efficacy and the treatment of a number of inflammatory and neurodegenerative disorders. A provisional nomenclature is proposed. BioEssays 26:882–893, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Activating the ERK pathway (extracellular signal‐regulated kinase pathway) has proven beneficial in several models of Huntington's disease (HD), and drugs that are protective in HD models have recently been found to activate ERK. Thus, the ERK cascade may be a potential target for therapeutic intervention in this currently untreatable disorder. HD is caused by an expanded polyglutamine repeat in the huntingtin (Htt) protein that actuates a diverse set of pathogenic mechanisms. In response to mutant Htt, ERK is activated and (...) directs a protective transcriptional response and inhibits caspase activation. Paradoxically, Htt also interferes with several signaling events of the ERK pathway. Mutant Htt compromises the ERK‐dependent transcriptional response to corticostriatal BDNF signaling. Mutant Htt also hinders glutamate uptake from the synaptic cleft by down‐regulating ERK‐dependent expression of glutamate transporters, leaving cells vulnerable to excitotoxicity. Some of this cellular complexity can be capitalized on to achieve selective activation of ERK, which can be protective. (shrink)

Trinucleotide repeat expansions are now a well‐established mutational mechanism in human genetic disease. An unstable CAG repeat is known to be responsible for three neurodegenerative disorders: Huntington's disease, spinal and bulbar musclar atrophy and spinocerebellar ataxia type 1. Similarities in the genetics of these diseases, the size of the repeat expansions and the position of the unstable repeat within the gene (when known) suggest a common basis to the observed phenotypes. The cloning of two regions at which chromosome breakage (...) can be induced (FRAXA and FRAXE) has in each case uncovered an unstable CG‐rich triplet repeat which becomes methylated when fully expanded. In addition to these two classes of mutation, the presence of an expanded CTG repeat in the 3′ untranslated region of a protein kinase causes myotonic dystrophy. The size of the respective expansions, repeat stability, mutational origins and possible mechanisms of action are discussed. (shrink)

The insulin/insulin‐like growth factor‐1 (IGF‐1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine‐tuned cascade of signaling events induced by insulin/IGF‐1, which is precisely controlled by post‐translational modifications. The ubiquitin/proteasome‐system (UPS) influences the functionality of IIS through inducible ubiquitylation pathways that regulate internalization of the insulin/IGF‐1 receptor, the stability of downstream insulin/IGF‐1 signaling targets, and activity of nuclear receptors for control of gene expression. An age‐related (...) decline in UPS activity is often associated with an impairment of IIS, contributing to pathologies such as cancer, diabetes, cardiovascular, and neurodegenerative disorders. Recent findings identified a key role of diverse ubiquitin modifications in insulin signaling decisions, which governs dynamic adaption upon environmental and physiological changes. In this review, we discuss the mutual crosstalk between ubiquitin and insulin signaling pathways in the context of cellular and organismal homeostasis. (shrink)

Parkinson’s disease (PD) is a common neurodegenerative disorder of the nervous system that affects about 1 in 800 people and for which we have symptomatic but not curative therapies. At the core of the disease is the loss of a specific population of dopaminergic neurons within the brain, and replacement of dopamine through drug therapies has provided clinically significant benefit for many patients. However this therapy only ever offers a temporary amelioration of symptoms and with time this symptomatic (...) therapy becomes less efficacious and produces its own unique side-effects. As a result more effective curative therapies have been sought, including the use of cell based therapies to replace the lost dopaminergic neurons. In this review I am going to discuss PD and its possible repair using neural transplants. In particular I am going to discuss which type of cells are best considered as a reparative therapy, where they should be transplanted in the brain, when in the disease course and in which type of patient. By considering these issues, I hope to be able to make some recommendations as to the future use of this approach in PD. (shrink)

Optogenetics is being optimistically presented in contemporary media for its unprecedented capacity to control cell behavior through the application of light to genetically modified target cells. As such, optogenetics holds obvious potential for application in a new generation of invasive medical devices by which to potentially provide treatment for neurological and psychiatric conditions such as Parkinson's disease, addiction, schizophrenia, autism and depression. Design of a first-in-human optogenetics experimental trial has already begun for the treatment of blindness. Optogenetics trials involve a (...) combination of highly invasive genetic and electronic interventions that results in irreversible and permanent modifications of an individual's nervous system. Given its novelty, its uncertain benefit to patients, and its unique risk profile of irreversible physiological alteration, optogenetics requires a reassessment of the ethical challenges for protecting human participants in clinical trials, particularly at formative stages of clinical evaluation. This study explores the evolving ethical issues surrounding optogenetics’ potential harm to participants within trial design, especially focusing on whether Phase 1 trials should incorporate efficacy as well as safety endpoints in ways that are fair and respectful to research trial participants. (shrink)

The prelims comprise: Why Embryonic Stem Cells? Stem Cells for Organ and Tissue Transplant Immortality A Guarded Welcome for Stem Cell Research The Precautionary Principle The Ethics of ES Cell Research Stem Cells from Early Embryos The Moral Status of the Embryo Lessons from Sexual Reproduction Establishing a Pregnancy by Sexual Reproduction The Incoherence of Current US Federal Law The Symbolic Value of Life ART and Spare Embryos Tissue from Fetuses Doing Something Good is Better than Doing Nothing! Interim Conclusions (...) Genetic Identity Moral Complicity Acknowledgments. (shrink)

Adenosine 5′-triphosphate (ATP) was identified in 1970 as the transmitter responsible for non-adrenergic, non-cholinergic neurotransmission in the gut and bladder and the term ‘purinergic’ was coined. Purinergic cotransmission was proposed in 1976 and ATP is now recognized as a cotransmitter in all nerves in the peripheral and central nervous systems. P1 (adenosine) and P2 (ATP) receptors were distinguished in 1978. Cloning of these receptors in the early 1990s was a turning point in the acceptance of the purinergic signalling hypothesis. There (...) are both short-term purinergic signalling in neurotransmission, neuromodulation and secretion and long-term (trophic) purinergic signalling of cell proliferation, differentiation and death in development and regeneration. Much is known about the mechanisms of ATP release and its breakdown by ectonucleotidases. Recently, there has been emphasis on purinergic pathophysiology, including neurodegenerative and neuropsychiatric disorders. Purinergic therapeutic strategies are being developed for treatment of gut, kidney, bladder, lung, skeletal and reproductive system disorders, pain and cancer. (shrink)

Virtual reality (VR) technology has emerged as a promising tool for studying and rehabilitating gait disturbances in different cohorts of patients (such as Parkinson's disease, post-stroke, or other neurological disorders) as it allows patients to be engaged in an immersive and artificial environment, which can be designed to address the particular needs of each individual. This review demonstrates the state of the art in applications of virtual walking techniques and related technologies for gait therapy and rehabilitation of people with movement (...) disorders makes recommendations for future research and discusses the use of VR in the clinic. However, the potential for using these techniques in gait rehabilitation is to provide a more personalized approach by simulate the experience of natural walking, while patients with neurological disorders are maintained localized in the real world. The goal of our work is to investigate how the human nervous system controls movement in health and neurodegenerative disease. (shrink)

This book is a discussion of the most timely and contentious issues in the two branches of neuroethics: the neuroscience of ethics; and the ethics of neuroscience. Drawing upon recent work in psychiatry, neurology, and neurosurgery, it develops a phenomenologically inspired theory of neuroscience to explain the brain-mind relation. The idea that the mind is shaped not just by the brain but also by the body and how the human subject interacts with the environment has significant implications for free will, (...) moral responsibility, and moral justification of actions. It also provides a better understanding of how different interventions in the brain can benefit or harm us. In addition, the book discusses brain imaging techniques to diagnose altered states of consciousness, deep-brain stimulation to treat neuropsychiatric disorders, and restorative neurosurgery for neurodegenerative diseases. It examines the medical and ethical trade-offs of these interventions in the brain when they produce both positive and negative physical and psychological effects, and how these trade-offs shape decisions by physicians and patients about whether to provide and undergo them. (shrink)