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)

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.

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 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)

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)

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 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)

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.

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)

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.

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.

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)

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)

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)

Despite intense academic debate in the recent past over the use of ‘sham surgery’ control groups in research, there has been a recent resurgence in their use in the field of neurodegenerative disease. Yet the primacy of ethical arguments in favour of sham surgery controls is not yet established. Preliminary empirical research shows an asymmetry between the views of neurosurgical researchers and patients on the subject, while different ethical guidelines and regulations support conflicting interpretations. Research ethics committees faced with (...) a proposal involving sham surgery should be aware of its ethical complexities. An overview of recent and current placebo-controlled surgical trials in the field of Parkinson's Disease is provided here, followed by an analysis of the key ethical issues which such trials raise. (shrink)

Neurons have developed elaborate mechanisms for sorting of proteins to their destination in dendrites and axons as well as dynamic local trafficking. Recent evidence suggests that polarized axonal sorting of β‐site converting enzyme 1 (BACE1), a type I transmembrane aspartyl protease involved in Alzheimer's disease (AD) pathogenesis, entails an unusual journey. In hippocampal neurons, BACE1 internalized from dendrites is conveyed in recycling endosomes via unidirectional retrograde transport towards the soma and sorted to axons where BACE1 becomes enriched. In comparison to (...) other transmembrane proteins that undergo transcytosis or elimination in somatodendritic compartment, vectorial transport of internalized BACE1 in dendrites is unique and intriguing. Dysfunction of protein transport contributes to pathogenesis of AD and other neurodegenerative diseases. Therefore, characterization of BACE1 transcytosis is an important addition to the multiple lines of evidence that highlight the crucial role played by endosomal trafficking pathway as well as axonal sorting mechanisms in AD pathogenesis. (shrink)

The meaningful consideration of cultural practices, values and beliefs is a necessary component in the effective translation of advancements in neuroscience to clinical practice and public discourse. Society’s immense investment in biomedical science and technology, in conjunction with an increasingly diverse socio-cultural landscape, necessitates the study of how potential discoveries in neurodegenerative diseases such as Alzheimer disease are perceived and utilized across cultures. Building on the work of neuroscientists, ethicists and philosophers, we argue that the growing field of (...) neuroethics provides a pragmatic and constructive pathway to guide advancements in neuroscience in a manner that is culturally nuanced and relevant. Here we review a case study of one issue in culturally oriented neuroscience research where it is evident that traditional research ethics must be broadened and the values and needs of diverse populations considered for meaningful and relevant research practices. A global approach to neuroethics has the potential to furnish critical engagement with cultural considerations of advancements in neuroscience. (shrink)

Alzheimer's disease (AD) is a neurodegenerative disease exhibiting amyloid beta (Aβ) peptide accumulation as a key characteristic. Autophagy, which is dysregulated in AD, participates in the metabolism of Aβ. Unexpectedly, we recently found that autophagy, in addition to its degradative function, also mediates the secretion of Aβ. This finding adds Aβ to an increasing number of biomolecules, the secretion of which is mediated by autophagy. We also showed that inhibition of Aβ secretion through genetic deletion of autophagy leads to (...) intracellular Aβ accumulation, which enhanced neurodegeneration induced by autophagy deficiency. Hence, autophagy may play a central role in two pathological hallmarks of AD: Aβ amyloidosis and neurodegeneration. Herein, we summarize the role of autophagy in AD with focus on Aβ metabolism in light of the recently established role of autophagy in protein secretion. We discuss potential routes for autophagy‐mediated Aβ secretion and suggest experimental approaches to further elucidate its mechanisms. (shrink)

BackgroundParkinson's disease is a chronic neurodegenerative disease, which can be alleviated in drug treatment, but with evident side effects. At the same time, increasing evidence shows that exercise can significantly improve the symptoms of patients with Parkinson's disease, with an effect that cannot be achieved by drug treatment. The related research on exercise on Parkinson's disease increases rapidly with the passage of time. However, the research analysis on Parkinson's disease by means of bibliometrics is rare. The purpose of this (...) study is to perform a bibliometric analysis of the research hotspots and development trends of the global movement on Parkinson's disease from 2012 to 2021.MethodsThe literature was derived from the Web of Science core collection database, and the social science citation index was set as SCI-EXPANDED. The language was set to English, and the literature category was set as article and review and published from 2012 to 2021. CiteSpace and other software were used to analyze the relationship among published documents, countries, institutions, journals, authors, references, disciplines, and keywords.ResultsA total of 2,222 articles were included in the analysis. The analysis showed that the publication volume increased with the increase in years, with a total of 76 countries and 546 academic journals published; the largest number was that of the United States. The journals are mainly concentrated in the fields of neurology, sports, and ophthalmology. Rush University and Movement Disorders journals are the main institutions and journals. The cited keywords show that trial, cognition, and interference are the research hotspots and development trends in recent years.ConclusionThe number of published articles on Parkinson's disease by exercise has increased rapidly in the past 10 years, and the bibliometric analysis can provide useful information for future research teams and researchers. (shrink)

Amyloid fibril formation plays a central role in the pathogenesis of a number of neurodegenerative diseases, including Alzheimer and Parkinson diseases. Transient prefibrillar oligomers forming during the aggregation process, exhibiting a small size and a large hydrophobic surface, can aberrantly interact with a number of molecular targets on neurons, including the lipid bilayer of plasma membranes, resulting in a fatal outcome for the cells. By contrast, the mature fibrils, despite presenting generally a high hydrophobic surface, are endowed (...) with a low diffusion rate and poorly penetrate the interior of the lipid bilayer. However, increasing evidence shows that both intracellular α‐synuclein fibrils, as well and as extracellular amyloid‐β and β2‐microglobulin fibrils, can release oligomers over time that quickly diffuse to reach the membrane of the neighboring cells. The persistent leakage of harmful oligomers from fibrils triggers an ongoing cascade of events resulting in a sustained injury to neurons and glia and also provides aggregates with the ability to cross biological membranes and diffuse between cells or cellular compartments. (shrink)

Euthanasia and physician-assisted suicide (PAS) by request and/or based on an advance directive are legal in The Netherlands under strict conditions, thus providing options for patients with Huntington's disease (HD) and other neurodegenerative diseases to stay in control and choose their end of life. HD is an inherited progressive disease characterised by chorea and hypokinesia, psychiatric symptoms and dementia. From a qualitative study based on interviews with 15 physicians experienced in treating HD, several ethical issues emerged. Consideration of (...) these aspects leads to a discussion about the professional role of a physician in relation to the personal autonomy of a patient. Such a discussion can raise awareness that talking about end-of-life wishes with an HD patient is part of the legal, professional and moral responsibility of the physician, and that a letter of intent on behalf of the physician can improve active participation in the process. Discussion of these issues can help to advance the debate on euthanasia and PAS in HD and other neurodegenerative diseases. (shrink)

Next SectionThe current focus on early intervention trials in Alzheimer's disease research raises particular ethical issues. These arise out of problems of validating study results and translating them into general practice for one thing and out of unwanted effects of an uncertain diagnosis for diagnosed people for another. The first addresses the demands of scientific research compared to those of medical practice, questioning how the medical value of clinical trials is evaluated. The second relates the scientific and medical value of (...) early intervention trials to the normative value of an uncertain diagnosis. Are people who are diagnosed with a potential early form of AD in clinical studies patients proper—although they would not have been diagnosed with the given “disease” in non-research-oriented medical settings? The very problem of framing this question in terms of diagnostic misconceptions connects conceptual with ethical issues of research into preclinical stages of neurodegenerative diseases. (shrink)

Background: Parkinson’s disease is a neurodegenerative disease in which the progressive loss of dopaminergic neurons leads to initially sporadic and eventually widespread damage of the nervous system resulting in significant musculoskeletal and cognitive deterioration. Loss of motor function alongside increasing cognitive impairment is part of the natural disease progression. Gait is often considered an automatic activity; however, walking is the result of a delicate balance of multiple systems which maintain the body’s center of mass over an ever-changing base of (...) support. It is a complex motor behavior that requires components of attention and memory to prevent falls and injury. In addition, evidence points to the critical role of salient visual information to gait adaptability. There is a growing understanding that treatment for PD needs to address movement as it occurs naturally and walking needs to be practiced in more complex environments than traditional therapy has provided.MethodsIn this single-blinded randomized-controlled pilot study, an immersive treadmill training was piloted to determine feasibility and preliminary efficacy on gait and cognition in people with PD. Eighteen participants with Hoehn and Yahr stages I-III PD were randomized to either an intervention or a waitlist control group. Following baseline data collection, the intervention group trained for 30 min, three times/week for 4 weeks on a split belt treadmill combined with a first-person immersive video game targeting visuospatial skills and working memory. Assessment was repeated after 4 weeks of training for the experimental group and 1-month after baseline for the control group. Primary motor outcomes were captured with the APDM Opal sensors during 6 MWT, TUG, and TUG Cognitive. Secondary outcomes of cognition were measured with the Montreal Cognitive Assessment, Verbal Fluency and the Symbol Digit Modality Test. Within subject differences were calculated using the Wilcoxon Signed Ranked Test and between subject comparisons were analyzed using the Mann Whitney U-test.ResultsThis novel treadmill training program was well-tolerated with all participants in the intervention group completing 4 weeks of training three times a week without any adverse effects. After immersive cognitive motor training, the experimental group made clinically relevant improvements in gait speed and walking distance during the 6 MWT while members of the control group showed no change or decreased gait speed and walking distance over the 1-month trial. In addition, the experimental group demonstrated significant improvement for the TUG Cognitive and those changes were greater than the control group. The experimental group also improved scores on MoCA and SDMT cognitive outcome measures while the control group did not.ConclusionThe use of immersive gaming technology to engage specific areas of cognition related to gait is feasible in PD. The treadmill training program paired with a customized interactive video game improved walking velocity in addition to non-significant but consistent improvements in other gait measures and cognitive performance in participants with early to mid-stage PD. (shrink)

Alzheimer’s disease (AD) in its most common form results in cognitive changes in memory function leading to dementia due to underlying neurodegenerative disease. Recent research advancements in AD...

Background: The field of voice and speech analysis has become increasingly popular over the last 10 years, and articles on its use in detecting neurodegenerative diseases have proliferated. Many studies have identified characteristic speech features that can be used to draw an accurate distinction between healthy aging among older people and those with mild cognitive impairment and Alzheimer's disease. Speech analysis has been singled out as a cost-effective and reliable method for detecting the presence of both conditions. In (...) this research, a systematic review was conducted to determine these features and their diagnostic accuracy.Methods: Peer-reviewed literature was located across multiple databases, involving studies that apply new procedures of automatic speech analysis to collect behavioral evidence of linguistic impairments along with their diagnostic accuracy on Alzheimer's disease and mild cognitive impairment. The risk of bias was assessed by using JBI and QUADAS-2 checklists.Results: Thirty-five papers met the inclusion criteria; of these, 11 were descriptive studies that either identified voice features or explored their cognitive correlates, and the rest were diagnostic studies. Overall, the studies were of good quality and presented solid evidence of the usefulness of this technique. The distinctive acoustic and rhythmic features found are gathered. Most studies record a diagnostic accuracy over 88% for Alzheimer's and 80% for mild cognitive impairment.Conclusion: Automatic speech analysis is a promising tool for diagnosing mild cognitive impairment and Alzheimer's disease. The reported features seem to be indicators of the cognitive changes in older people. The specific features and the cognitive changes involved could be the subject of further research. (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.

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)

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)

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)

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)

In this article, caring, remembering and sharing memory are presented as moral responses, the case study being Alzheimer’s disease (AD). Memory connects memories and images, while care connects individuals, which is an ethical issue. When a person’s memory is lost, the care of others becomes the only thread connecting them to the world. AD deprives a person of memories, body control, makes it impossible to remember, communicate, move, recognize the environment, and disrupts consciousness. Caring for a patient with a (...) class='Hi'>neurodegenerative brain disease requires constant reminding and reiteration; the presence of a caring person reminds of what the patient themselves can no longer remember. Lost memories do not mean that life or relational values have also lost their meaning. The description of the memory movement emphasizes the importance of repetition in the moral act. Highlighting the matter of care, also in scientific work, is the aim of this text. To care is to remember, on behalf of the AD patient, about the patient’s life. Within bioethical research, moral responses are an important point for projects which seek to improve the condition of patients—not only the condition of health but also the comfort of life. This improvement will not be possible without attentive, committed caregivers and their responsible attitude in the face of the phenomenon of memory loss. (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)

In the United States alone, the prevalence of AD is expected to more than double from six million people in 2019 to nearly 14 million people in 2050. Meanwhile, the track record for developing treatments for AD has been marked by decades of failure. But recent progress in genetics, neuroscience and gene editing suggest that effective treatments could be on the horizon. The arrival of such treatments would have profound implications for the way we diagnose, triage, study, and allocate resources (...) to Alzheimer’s patients. Because the disease is not rare and because it strikes late in life, the development of therapies that are expensive and efficacious but less than cures, will pose particular challenges to healthcare infrastructure. We have a window of time during which we can begin to anticipate just, equitable and salutary ways to accommodate a disease-modifying therapy Alzheimer’s disease. Here we consider the implications for caregivers, clinicians, researchers, and the US healthcare system of the availability of an expensive, presymptomatic treatment for a common late-onset neurodegenerative disease for which diagnosis can be difficult. (shrink)

ObjectiveWe wished to explore Parkinson's disease subtypes by clustering analysis based on the multimodal magnetic resonance imaging indices amplitude of low-frequency fluctuation and gray matter volume. Then, we analyzed the differences between PD subtypes.MethodsEighty-six PD patients and 44 healthy controls were recruited. We extracted ALFF and GMV according to the Anatomical Automatic Labeling partition using Data Processing and Analysis for Brain Imaging software. The Ward linkage method was used for hierarchical clustering analysis. DPABI was employed to compare differences in ALFF (...) and GMV between groups.ResultsTwo subtypes of PD were identified. The “diffuse malignant subtype” was characterized by reduced ALFF in the visual-related cortex and extensive reduction of GMV with severe impairment in motor function and cognitive function. The “mild subtype” was characterized by increased ALFF in the frontal lobe, temporal lobe, and sensorimotor cortex, and a slight decrease in GMV with mild impairment of motor function and cognitive function.ConclusionHierarchical clustering analysis based on multimodal MRI indices could be employed to identify two PD subtypes. These two PD subtypes showed different neurodegenerative patterns upon imaging. (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)

Alzheimer’s disease is an insidious onset neurodegenerative syndrome without effective treatment or cure. It is rapidly becoming a global health crisis that is overwhelming healthcare, society, and individuals. The clinical nature of neurocognitive decline creates significant challenges in bidirectional communication between caregivers and persons with Alzheimer’s disease that can negatively impact quality-of-life. This paper sought to understand how and to what extent would awareness training about the levels of consciousness in AD influence the quality-of-life interactions in the caregiver-patient dyad. (...) A literature review of multiple databases was conducted utilizing a transdisciplinary approach. The sum of findings indicates a positive relationship between enhanced caregiver awareness and training, positive interactions, and improved QOL measures among patients and caregivers. A multidirectional relationship was found among healthcare policies, training and education resources, caregivers, and persons with AD. Specifically, the current lack of policy and inadequate training and educational resources has various detrimental effects on patients and caregivers, while improvements in training and education of caregivers yields positive outcomes in communication and QOL. Furthermore, evidence of preserved consciousness in persons with AD was demonstrated from multiple disciplines, including neurobiological, psychological, and biopsychosocial models. The literature further revealed several methods to access the preserved consciousness in persons with AD and related dementias, including sensory, emotional, and cognitive stimulations. The evidence from the literature suggests a reframed approach to our understanding and treatment of persons with AD is not only warranted, but crucial to address the needs of those affected by AD. (shrink)