The Neuropsychological Impact of Insulin Levels: Roles of Insulin in Parkinson's Disease and Cognitive Functioning

Numerous studies demonstrate a relationship between insulin and Alzheimer's disease; however, little research exists on insulin's association to Parkinson's disease (PD) and Parkinson's disease dementia (PDD). The current study examined the connection between insulin and cognitive functioning in PD, PDD, and age-matched controls. A total of 22 older adult participants with PD completed the present study: 12 participants with PD (mean age = 67.50; 41.67% men; mean Mini Mental State Exam (MMSE) = 28.67) and 10 participants with PDD (mean age = 75.10; 90.00% men; mean MMSE = 22.90). Twenty-two non-demented older adults (mean age = 71.77; 63.64% men; mean MMSE = 29.23) from the University of Kansas Brain Aging Project served as the control group. Participants completed a neuropsychological assessment battery designed to represent cognitive domains of interest for individuals with PD and PDD as well as a two-hour glucose tolerance test. Total area under the curve (AUC) for blood insulin served as overall indices for insulin levels. PDD participants had lower absolute insulin values compared to PD participants and lower insulin levels were associated with decreased motor performance based on the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Contrary to predictions, higher insulin levels predicted poorer executive functioning performance for both PD and PDD participants. More research is needed to establish specific mechanisms to explain the relationship between higher insulin levels and reduced executive functioning performance. Additional research would also provide further evidence for insulin's role in cognitive changes for older adults with PD, PDD, and other neurodegenerative diseases

Rating scales for behavioural symptoms in Huntington's Disease: critique and recommendations

Behavioral symptoms are an important feature of Huntington’s disease and contribute to impairment in quality of life. The Movement Disorder Society commissioned the assessment of the clinimetric properties of rating scales in Huntington’s disease in order to make recommendations regarding their use, following previously used standardized criteria. A systematic literature search was conducted to identify the scales used to assess behavioral symptoms in Huntington’s disease. For the purpose of this review, seven behavioral domains were deemed significant in Huntington’s disease: irritability, anxiety, depression, apathy, obsessive-compulsive behaviors, psychosis and suicidal ideation. We included a total of 27 behavioral rating scales, 19 of which were of a single behavioral domain, and the remaining 8 scales included multiple behavioral domains. Three rating scales were classified as “recommended” exclusively for screening purposes: the Irritability Scale for irritability, and the Beck Depression Inventory-II and the Hospital Anxiety and Depression Scale for depression. There were no “recommended” scales for other purposes such as diagnosis, severity or change in time or to treatment. The main challenges identified for assessment of behavioral symptoms in Huntington’s disease are the co-occurrence of multiple behavioural symptoms, the particular features of a behavioral symptom in Huntington’s disease, as well as the need to address stage- and disease-specific features, including cognitive impairment and lack of insight. The committee concluded that there is a need to further validate currently available behavioral rating scales in Huntington’s disease to address gaps in scale validation for specific behavioral domains and purpose of use

What are the palliative care needs of people severely affected by neurodegenerative conditions, and how can a Specialist Palliative Care Service best meet these needs.

Background: There is increasing recognition of the need for service development for patients in the advanced stages of neurological conditions. This study explores the palliative care needs of people with advanced amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease and related disorders, and assesses the impact of a new specialist palliative care service (SPCS) Methods:. A mixed methods approach was adopted: • a qualitative needs assessment using in-depth interviews with patients and their family carers and focus groups of professionals involved in the care of this population. • a quantitative pilot-explorative randomized and controlled trial (RCT) to assess the impact of a new SPCS designed to meet the palliative care needs of the study population – using a waiting list methodology comparing the immediate provision of SPCS with standard care . Results: • Qualitative study: 22 patients, 21 family carers and 11 professionals participated to the needs assessment. The content analysis showed a high prevalence of problems. Professionals confirmed the high burden of problems, were positive about the creation of a new SPCS and their knowledge of specific palliative care topics seemed lacking. • Quantitative study: 50 patients, with 45 carers, participated in the explorative RCT. The comparison between the groups (FT-ST) after 16 weeks revealed significant improvement for the SPCS group for quality of life and in four physical symptoms - pain, breathlessness, sleep disturbance and intestinal symptoms Conclusions: This research confirms the high prevalence of physical symptoms, psychosocial issues and spiritual themes for people severely affected by advanced neurodegenerative disorders and that these can be helped by specialist palliative care. The input of a SPCS caused a significant improvement of the individual quality of life of the patients and improved symptom control for pain, breathlessness, quality of sleep and intestinal symptoms compared to standard best care alone

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition

Theoretical and experimental considerations of selective vulnerability In Parkinson's disease

Les maladies neurodégénératives sont typiquement caractérisées en fonction de leurs symptômes et des observations pathologiques effectuées après le décès. Les symptômes spécifiques à la maladie sont également normalement associés aux dysfonctionnements et à la dégénérescence de certaines sous- populations spécifiques de neurones dans le système nerveux. La maladie de Parkinson (MP) est une maladie neurodégénérative principalement caractérisée par des symptômes moteurs dus à la dégénérescence spécifique des neurones dopaminergiques (DA) de la substantia nigra pars compacta (SNpc/SNc). Il semble cependant que les neurones DA de la SNc ne soient pas la seule population de neurones qui dégénère dans la MP. L'analyse post-mortem, l'imagerie in vivo et les symptômes cliniques démontrent que le dysfonctionnement et la dégénérescence se produisent dans plusieurs autres régions du système nerveux, incluant par exemple des neurones noradrénergiques (NA) du locus coeruleus (LC), des neurones sérotoninergiques des noyaux du raphé et des neurones cholinergiques du noyau moteur dorsal du nerf vague (DMV) et du noyau pédonculopontin. Comme d'autres maladies neurodégénératives, la MP est causée par plusieurs facteurs, tant génétiques qu'environnementaux. De nombreuses observations suggèrent que ces facteurs soient associés au dysfonctionnement de plusieurs systèmes ou fonctions cellulaires incluant la production d’énergie par la mitochondrie, l’élimination de protéines dysfonctionnelles par le protéasome et le lysosome, la régulation de l’équilibre entre la production d'espèces oxydatives réactives et les mécanismes antioxydants, la régulation des niveaux de calcium intracellulaire et l’inflammation. Il semble donc que le dysfonctionnement de ces facteurs converge pour provoquer la dégénérescence neuronale dans le contexte du vieillissement. Ce qui rend les neurones de certaines régions du système nerveux intrinsèquement plus vulnérables aux facteurs associés à la MP est une question fondamentale qui n’est pas résolue pour le moment. Les travaux de cette thèse sont basés sur l’hypothèse proposant que cette vulnérabilité sélective découle de propriétés communes retrouvées chez les neurones vulnérables. En particulier, les neurones vulnérables auraient en commun d’être des neurones de projections dotés d’un axone complexe qui projette sur de longues distances, formant un nombre très élevé de terminaisons axonales sur de vastes territoires du système nerveux. De plus, ces neurones présenteraient des propriétés physiologiques distinctives, incluant notamment une décharge autonome (pacemaker). Ensemble, ces caractéristiques pourraient contribuer à placer ces neurones dans des conditions de fonctionnement aux limites de leur capacités bioénergétiques et homéostatiques, rendant difficile toute adaptation aux dysfonctionnements cellulaires associés au vieillissement et causés par les facteurs de risques de la MP. Dans cette thèse, je présenterai une revue systématique de la littérature sur la perte de neurones dans le cerveau des personnes atteintes de la maladie de Parkinson, montrant que l'identité neurochimique précise des neurones qui dégénèrent dans la maladie de Parkinson, et l'ordre temporel dans lequel cela se produit, n’est pas clair. Cependant, en analysant les points de vue présentés dans les publications citant cette revue, nous avons remarqué que la majorité de ceux-ci ne reflètent pas le message central de notre publication. Puisque l’identification de l’identité des neurones vulnérables et non vulnérables à la MP est fondamentale pour le développement de théories et hypothèses sur les causes de la MP, nous suivons cette première publication avec une lettre réaffirmant l'importance de faire face aux problèmes identifiés dans notre revue. Nous présentons ensuite des données in vitro montrant que les neurones vulnérables à la MP, comparés à ceux qui sont moins vulnérables, ont une capacité intrinsèque à développer des champs axonaux plus importants et plus complexes, avec un nombre plus élevé de sites actifs de libération de neurotransmetteurs. De plus, nous constatons que ces observations sont corrélées à une vulnérabilité plus élevée face à un stress oxydatif pertinent pour la MP. Ces données sont en accord avec l'hypothèse selon laquelle le domaine axonal, et en particulier le nombre de sites de libération de neurotransmetteurs par neurone, est un facteur important qui contribue à rendre un neurone sélectivement vulnérable dans le contexte de la MP. Enfin, nous présentons une méthode d’analyse d’image open-source visant à aider les biologistes et les neuroscientifiques à automatiser la quantification du nombre de neurones dans des cultures primaires de neurones, telle qu’utilisée dans les travaux de cette thèse. Nous proposons que cet algorithme simple — mais robuste — permettra aux biologistes d'automatiser le comptage des neurones avec une grande précision, quelque chose de difficile à effectuer avec les autres approches open-source disponibles présentement. Nous espérons que les travaux présentés dans cette thèse permettront de contribuer à raffiner les théories visant à expliquer l’origine de la MP et à terme, de développer de nouvelles approches thérapeutiques.Neurodegenerative diseases are typically characterized based on their symptoms, and pathological factors identified after death. The disease-specific symptoms are due to the dysfunction and degeneration of specific subpopulations of neurons, which cause dysfunction in particular brain functions. Parkinson's disease (PD) is a neurodegenerative disease primarily characterized by motor symptoms due to the specific degeneration of dopamine (DA) neurons of the substantia nigra pars compacta (SNpc/SNc): a population of neurons essential for motor control. SNc DA neurons are, however, not the only population of neurons that degenerate in PD. Post-mortem analysis, in vivo imaging, and clinical symptoms demonstrate that dysfunction and degeneration occur in several other neuronal nuclei. These include, but are not limited to, noradrenergic (NA) locus coeruleus (LC) neurons, serotonin neurons of the raphe nuclei, and cholinergic neurons of the dorsal motor nucleus of the vagus (DMV) and pedunculopontine nucleus. Like other neurodegenerative diseases, PD is linked to several risk factors, both genetic and environmental. The evidence suggests that these risk factors are associated with the dysfunction in systems of cellular bioenergetics (including mitochondrial function); proteostatic homeostasis; endolysosomal function; an imbalance between the production of reactive oxidative species (ROS), and antioxidant mechanisms; calcium homeostasis; alpha-synuclein misfolding; and neuroinflammation. Consequently, together with aging, these risk factors converge on causing the selective degeneration of "PD-vulnerable" nuclei. What makes these neurons intrinsically vulnerable to PD-associated risk factors is a fundamental question — and understanding these neurons will reveal biological mechanisms that we can target to protect these cells from degeneration. Our best hypotheses to explain why these neurons are based on the observations that most PD- vulnerable neurons are long-range projection neuromodulatory neurons sharing common characteristics: projecting to voluminous territories, having very long and highly branched unmyelinated axonal domains with vast numbers of neurotransmitter release sites, and exhibiting a unique physiology such as pacemaker firing. Taken together, this suggests that these neurons function at the tail-end of their bioenergetic and homeostatic capacity, unable to tolerate any further demands, such as those incurred in the presence of risk factors associated with PD. In this thesis, I will present a systematic review on the literature on purported cell loss in PD brains, showing that — given the actual primary evidence — the precise neurochemical identity of neurons that degenerate in PD, and the temporal order of this degeneration, is far less clear than described by most publications. This review — at the time of writing — has gone on to be highly cited. However, analyzing the claims made in publications citing this review, we discover that the majority of claims do not reflect the core message of our publication. Since the identity of PD-vulnerable and non-PD-vulnerable neurons is fundamental to theory and hypotheses when trying to understand PD, we follow this first publication with a letter restating the importance to address our observations. We then present in vitro data showing that classically PD-vulnerable neurons, when compared to non-PD vulnerable neurons, have an intrinsic capacity to develop larger and more complex axonal domains, with higher numbers of active neurotransmitter release sites. Moreover, we find that these observations correlate to elevated vulnerability to PD-relevant stress assays. These data provide additional support for the hypothesis that the axonal domain — and in particular — the number of active neurotransmitter sites per neuron, is a cell-autonomous factor rendering a neuron selectively vulnerable in the context of PD. Finally, we present an open-source tool to support biologists and neuroscientists in automating the quantification of neuron numbers in medium-throughput primary cell cultures. Where the application of other open-source solutions is either too simplistic for the use-case or technically challenging to implement, this simple — yet robust algorithm — allows biologists with limited computational nous to automate neuron counting with high precision. We hope that the work presented in this thesis will contribute to the refinement of theories aimed at explaining the origin of PD and, ultimately, to the development of new therapeutic approaches