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.

Background:Smart Aging is a serious game (SG) platform that generates a 3D virtual reality environment in which users perform a set of screening tasks designed to allow evaluation of global cognition. Each task replicates activities of daily living performed in a familiar environment. The main goal of the present study was to ascertain whether Smart Aging could differentiate between different types and levels of cognitive impairment in patients with neurodegenerative disease.Methods:Ninety-one subjects (mean age = 70.29 ± 7.70 years)—healthy older (...) adults (HCs,n= 23), patients with single-domain amnesic mild cognitive impairment (aMCI,n= 23), patients with single-domain executive Parkinson's disease MCI (PD-MCI,n= 20), and patients with mild Alzheimer's disease (mild AD,n= 25)—were enrolled in the study. All participants underwent cognitive evaluations performed using both traditional neuropsychological assessment tools, including the Mini-Mental State Examination (MMSE), Montreal Overall Cognitive Assessment (MoCA), and the Smart Aging platform. We analyzed global scores on Smart Aging indices (i.e., accuracy, time, distance) as well as the Smart Aging total score, looking for differences between the four groups.Results:The findings revealed significant between-group differences in all the Smart Aging indices: accuracy (p< 0.001), time (p< 0.001), distance (p< 0.001), and total Smart Aging score (p< 0.001). The HCs outperformed the mild AD, aMCI, and PD-MCI patients in terms of accuracy, time, distance, and Smart Aging total score. In addition, the mild AD group was outperformed both by the HCs and by the aMCI and PD-MCI patients on accuracy and distance. No significant differences were found between aMCI and PD-MCI patients. Finally, the Smart Aging scores significantly correlated with the results of the neuropsychological assessments used.Conclusion:These findings, although preliminary due to the small sample size, suggest the validity of Smart Aging as a screening tool for the detection of cognitive impairment in patients with neurodegenerative diseases. (shrink)

Metabolic dysfunction is a ubiquitous underlying feature of many neurological conditions including acute traumatic brain injuries and chronic neurodegenerative conditions. A central problem in neurological patients, in particular those with traumatic brain injuries, is an impairment in the utilization of glucose, which is the predominant metabolic substrate in a normally functioning brain. In such patients, alternative substrates including ketone bodies and lactate become important metabolic candidates for maintaining brain function. While the potential neuroprotective benefits of ketosis have been recognized (...) for up to almost a century, the majority of work has focused on the use of ketogenic diets to induce such a state, which is inappropriate in cases of acute disease due to the prolonged periods of time (i.e., weeks to months) required for the effects of a ketogenic diet to be seen. The following review seeks to explore the neuroprotective effects of exogenous ketone and lactate preparations, which have more recently become commercially available and are able to induce a deep ketogenic response in a fraction of the time. The rapid response of exogenous preparations makes their use as a therapeutic adjunct more feasible from a clinical perspective in both acute and chronic neurological conditions. Potentially, their ability to globally moderate long-term, occult brain dysfunction may also be relevant in reducing lifetime risks of certain neurodegenerative conditions. In particular, this review explores the association between traumatic brain injury and contusion-related dementia, assessing metabolic parallels and highlighting the potential role of exogenous ketone and lactate therapies. (shrink)

For focal neurodegenerative diseases or brain tumors, localized delivery of protein or genetic vectors may be sufficient to alleviate symptoms, halt disease progression, or even cure the disease. One may circumvent the limitation imposed by the blood-brain barrier by transplantation of genetically altered cell grafts or focal inoculation of virus or protein. However, permanent gene replacement therapy for diseases affecting the entire brain will require global delivery of genetic vectors. The neurotoxicity of currently available viral vectors and the transient (...) nature of transgene expression invivomust be overcome before their use in human gene therapy becomes clinically applicable. (shrink)

The conventional approach to developing disease‐modifying treatments for neurodegenerative conditions has been to identify drivers of pathology and inhibit such pathways. Here we discuss the possibility that the efficacy of such approaches may be increasingly attenuated as disease progresses. This is based on experiments using mouse models of spinocerebellar ataxia type 1 and Huntington's disease (HD), where expression of the dominantly acting mutations could be switched off, as well as studies in human HD, which suggest that the primary genetic (...) driver of age‐of‐onset of disease is a much weaker determinant of disease progression in affected individuals. The idea that one may approach a point in the disease course where such rational therapeutic strategies based on targets which determine onset of disease have minimal efficacy, suggests that one needs to consider other approaches to therapies and clinical trial design, including initiation of therapies in presymptomatic individuals. (shrink)

In the future, policies surrounding end-of-life decisions will be faced with the question of whether competent people in a completely locked-in state should be enabled to make end-of-life decisions via brain-computer interfaces (BCI). This article raises ethical issues with acting through BCIs in the context of these decisions, specifically self-administration requirements within assisted suicide policies. We argue that enabling patients to end their life even once they have entered completely locked-in state might, paradoxically, prolong and uphold their quality of life.

The etiology of Tauopathies, a diverse class of neurodegenerative diseases associated with the Microtubule Associated Protein (MAP) Tau, is usually described by a common mechanism in which Tau dysfunction results in the loss of axonal microtubule stability. Here, we reexamine and build upon the canonical disease model to encompass other Tau functions. In addition to regulating microtubule dynamics, Tau acts as a modulator of motor proteins, a signaling hub, and a scaffolding protein. This diverse array of functions is related (...) to the dynamic nature of Tau isoform expression, post‐translational modification (PTM), and conformational flexibility. Thus, there is no single mechanism that can describe Tau dysfunction. The effects of specific pathogenic mutations or aberrant PTMs need to be examined on all of the various functions of Tau in order to understand the unique etiology of each disease state. (shrink)

The ubiquitin proteasome system is a potent regulatory mechanism used to control protein stability in numerous cellular processes, including neural development. Many neurodegenerative diseases are featured by the accumulation of UPS‐associated proteins, suggesting the UPS dysfunction may be crucial for pathogenesis. Recent experiments have highlighted the UPS as a key player during synaptic development. Here we summarize recent discoveries centered on the role of the UPS in synapse remodeling and draw attention to the potential link between the synaptic UPS (...) dysfunction and the pathology of neurodegenerative diseases. BioEssays 30:1075–1083, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Online personalized genetic testing services offer accessible and convenient options for satisfying personal curiosity about health and obtaining answers about one’s genetic provenance. They are especially attractive to healthy people who wish to learn about their future risk of disease, as Paul Mason’s case study of “Jordan” illustrates. In this response, we consider how online genetic testing services are used by people diagnosed with a common neurodegenerative disease, Parkinson’s disease, to gain a sense of certainty regarding the future.

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)

Neurodegenerative diseases are becoming increasingly common as life expectancy increases. Recent years have seen tremendous progress in the identification of genes that cause these diseases. While mutations have been found and cellular processes defined that are altered in the disease state, the identification of treatments and cures has proven more elusive. The process of finding drugs and therapies to treat human diseases can be slow, expensive and frustrating. Can model organisms such as Drosophila speed the process of finding cures (...) and treatments for human neurodegenerative diseases? We pose three questions, (1) can one mimic the essential features of human diseases in an organism like Drosophila, (2) can one cure a model organisms of human disease and (3) will these efforts accelerate the identification of useful therapies for testing in mice and ultimately humans? Here we focus on the use of Drosophila to identify potential treatments for neurodegenerative diseases such as Huntington's and we discuss how well these therapies translate into mammalian systems. BioEssays 26:485–496, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Aphantasia is a heterogeneous neuropsychological syndrome consisting of the inability to create mental images. We argue that its progressive form may be a harbinger of dementia. Aphantasia may manifest as the inability to create any mental images or to create complex scenes, inability to spontaneously initiate generation of mental images, and/or inability to visualize a sequence of events.

Magnetic resonance imaging (MRI) is an imaging technique with a rapidly expanding application range. This methodology, which relies on quantum physics and substance magnetic properties, is now being routinely used in the clinics and medical research. With the advent of measuring functional brain activity with MRI (functional MRI), this methodology has reached a larger section of the neuroscience community (e.g. psychologists, neurobiologists). In the past, the use of MRI as a biomarker or as an assay to probe tissue pathophysiological condition (...) was limited. However, with the new applications of MRI: molecular imaging, contrast‐enhanced imaging and diffusion imaging, MRI is turning into a powerful tool for in vivo characterization of tissue pathophysiology. This review focuses on the diffusion MRI. Although it only measures the averaged Brownian translational motion of water molecules, using different analysis schemes, one can extract a wide range of quantitative indices that represent tissue morphology and compartmentalization. Statistical and visualization routines help to relate these indices to biologically relevant measures such as cell density, water content and size distribution. The aim of this review is to shed light on the potential of this methodology to be used in biological research. To that end, this review is intended for the non‐MRI specialists who wish to pursue biological research with this methodology. We will overview the current applications of diffusion MRI and its relation to cellular biology of brain tissue. BioEssays 30:1235–1245, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The extracellular‐signal regulated kinases 1/2 (ERK or ERKs) are involved in the regulation of important neuronal functions, including neuronal plasticity in normal and pathological conditions. We present findings that support the notion that the kinetics and localization of ERK are intrinsically linked, in that the duration of ERK activation dictates its subcellular compartmentalization and/or trafficking. The latter, in turn, dictates whether ERK‐expressing cells would enter a program of cell death, survival or differentiation. We summarize experimental data showing that chronic activation (...) of ERK plays a role in the mechanisms that trigger neurodegeneration. We also discuss how MKPs, members of the subclass of dual specificity phosphatases, might be the link between ERK kinetics and its subcellular localization. BioEssays 25:1085–1095, 2003. © 2003 Wiley Periodicals, Inc. (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)

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)

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)

Neurodegenerative syndromes present as proteinopathies – does ribosomal infidelity contribute to the protein toxicity that is the driving force for neuronal cell loss? Intracellular and extracellular protein aggregates overwhelm the clearance capacity of cells and tissues. Proteins aggregate when hydrophobic residues are exposed. Hydrophobic residues become exposed when proteins are misfolded. Protein misfolding can originate from translational errors at the ribosome. Indeed, the most error‐prone process in gene expression is translation at the ribosome. Recent evidence indicates that manipulating the (...) ribosomal accuracy impacts on the lifespan of model organisms and a reduced translational accuracy is accompanied by neurodegeneration. The first hit in aging‐associated neurodegenerative disease may be the well‐documented decline of cellular buffering capacity by aging. A second hit that impacts on the quality of protein synthesis could be the driving force for the observed loss of proteostasis in neurodegeneration. This hypothesis provides an explanation for the late onset of most neurodegenerative diseases. (shrink)

Neurodegenerative Parkinson's Disease is one of the common incurable diseases among the elderly. Clinical assessments are characterized as standardized means for PD diagnosis. However, relying on medical evaluation of a patient's status can be subjective to physicians' experience, making the assessment process susceptible to human errors. The use of ICT-based tools for capturing the status of patients with PD can provide more objective and quantitative metrics. In this vein, the Personalized Serious Game Suite and intelligent Motor Assessment Tests, produced (...) within the i-PROGNOSIS European project, are explored in the current study. More specifically, data from 27 patients with PD at Stage 1 and Stage 3 produced from their interaction with PGS/iMAT are analyzed. Five feature vector scenarios are set, including features from PGS or iMAT scores or their combination, after also taking into consideration the age of patients with PD. These FVs are fed into three machine learning classifiers, i.e., K-Nearest Neighbor, Support Vector Machines, and Random Forest, to infer the stage of each patient with PD. A Leave-One-Out Cross-Validation method is adopted for testing the classification performance. The experimental results show that a high classification accuracy is achieved from both data sources, justifying the effectiveness of PGS/iMAT to efficiently reflect the motor skill status of patients with PD and further potentiating PGS/iMAT enhancement with a machine learning a part to infer for the stage of patients with PD. Clearly, this integrated approach provides new opportunities for remote monitoring of the stage of patients with PD, contributing to a more efficient organization and set up of personalized interventions. (shrink)

Research on dyscalculia in neurodegenerative diseases is still scarce, despite high impact on patients’ independence and activities of daily living function. Most studies address Alzheimer’s Disease; however, patients with Parkinson’s Disease also have a higher risk for cognitive impairment while the relation to arithmetic deficits in financial contexts has rarely been studied. Therefore, the current exploratory study investigates deficits in two simple arithmetic tasks in financial contexts administered within the Clinical Dementia Rating in a sample of 100 PD patients. (...) Patients were classified as cognitively normal or mildly impaired according to Level I consensus criteria, and assessed using a comprehensive neuropsychological test battery, neurological motor examination, and sociodemographic and clinical questionnaires. In total, 18% showed arithmetic deficits: they were predominately female, had longer disease duration, more impaired global cognition, but minor signs of depression compared to PD patients without arithmetic deficits. When correcting for clinical and sociodemographic confounders, greater impairments in attention and visuo-spatial/constructional domains predicted occurrence of arithmetic deficits. The type of deficit did not seem to be arbitrary but seemed to involve impaired place × value processing frequently. Our results argue for the importance of further systematic investigations of arithmetic deficits in PD with sensitive tests to confirm the results of our exploratory study that a specific subgroup of PD patients present themselves with dyscalculia. (shrink)

Frontotemporal dementia is a neurodegenerative disease that affects the prefrontal cortex, and impairs various aspects relevant to social cognition. Such impairments can emerge as a visible phenomenon in social interaction and therefore can have very real consequences for those who interact with the afflicted. In this article, I examine how attitudes toward FTD patients are indexed through speech features employed by their interlocutors. I focus on three different speech features typically employed by adults and directed towards subordinates or children: (...) directives, let’s/we framed sequences, and initiation-response-evaluation sequences. These forms are used as strategies to affect and guide FTD patient behaviors, and index how FTD patients are socially constructed as ‘child-like’ and in need of assistance and guidance though not necessarily warranted. Thus, FTD patients may be subject to a diminished status as a result of their social impairments. (shrink)

For focal neurodegenerative diseases or brain tumors, localized delivery of protein or genetic vectors may be sufficient to alleviate symptoms, halt disease progression, or even cure the disease. One may circumvent the limitation imposed by the blood-brain barrier by transplantation of genetically altered cell grafts or focal inoculation of virus or protein. However, permanent gene replacement therapy for diseases affecting the entire brain will require global delivery of genetic vectors. The neurotoxicity of currently available viral vectors and the transient (...) nature of transgene expression invivomust be overcome before their use in human gene therapy becomes clinically applicable. (shrink)

The hereditary neurodegenerative disease spinal muscular atrophy (SMA) with childhood onset is one of the most common genetic causes of infant mortality. The disease is characterized by selective loss of spinal cord motor neurons leading to muscle atrophy and is the result of mutations in the survival motor neuron (SMN) gene. The SMN protein has been implicated in diverse nuclear processes including splicing, ribosome formation and gene transcription. Even though the genetic basis of SMA is well understood, it is (...) not clear how defects in these ubiquitous processes result in motor neuron degeneration leaving other tissues unaffected. Recent evidence from animal and cell culture models of SMA points to roles for SMN in neurite outgrowth and axonal transport. Disruption of these functions might be particularly detrimental to motor neurons given their high metabolic demands and precise connectivity requirements, thus providing a possible explanation for the specificity of motor neuron susceptibility in SMA. Understanding the molecular mechanisms of SMN activity in neuronal processes may generate new targets for future therapeutic strategies. BioEssays 27:946–957, 2005. © 2005 Wiley Periodicals, Inc. (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 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)

This article adopts a population-level bioethics approach to analyzing the ethical implications of novel deep-brain stimulation (DBS) technologies. I claim that a microlevel focus on costs and benefits is necessary but insufficient to address the concerns of social justice and health equity that attend the potential utilization of DBS technologies. A macrosocial, population-based analysis notes two ethically significant trends regarding novel health technologies: (1) that they are the prime mover of hyperinflationary health cost trajectories, and (2) that even where they (...) improve overall population health such technologies may expand health inequalities. Such an expansion could exacerbate what Powers and Faden have identified as “densely-woven patterns of disadvantage,” and therein could contravene mandates of social justice. Such concerns of justice and equity are sharpened by the fact that those populations that bear the highest risk of suffering the injuries and illnesses for which DBS technologies might be warranted are among the most disadvantaged groups in American society. Accordingly, ethical analysis of DBS technologies must include an assessment of the evidence suggesting that in their capacity to improve health and compress health inequalities, whole-population approaches that address the upstream factors that shape distributions of neuropsychiatric injuries and illness may be preferable to acute health interventions. However, the article warns against the false-choice fallacy, and notes that whole-population policies and acute care interventions can be simultaneously endorsed. The article concludes by suggesting that the ethical issue of relative priority between these approaches is best framed via a population-level analysis. (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)

This contribution aims to be a concrete proof of how fertile, rich and innovative dialogue and confrontation between transcendental phenomenology and naturalising sciences can be. Through the phenomenological-transcendental analysis of the neurodegenerative pathology of dementia, an attempt will be made to propose, within the debate on the possible naturalisation of phenomenology, the perspective of an actual mutual enlightenment, as proposed by Gallagher. Not a naturalisation of consciousness in the sense of a reduction to neural process, but a pluralisation of (...) the valid and rigorous perspectives through which it can be investigated. The phenomenological-transcendental eidetic study of dementia thus becomes complementary to the neurobiological one, revealing what the subject feels ‘from within’, his losses, but also what persists in the patient until the most advanced stages. Such a study, in synergy with the biological one, would greatly help in the holistic understanding of dementia in this particular case and, in general, of consciousness phenomena. (shrink)