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2.
Phys Rev Lett ; 125(12): 128102, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-33016724

RESUMO

Neurodegenerative diseases, such as Alzheimer's or Parkinson's disease, show characteristic degradation of structural brain networks. This degradation eventually leads to changes in the network dynamics and degradation of cognitive functions. Here, we model the progression in terms of coupled physical processes: The accumulation of toxic proteins, given by a nonlinear reaction-diffusion transport process, yields an evolving brain connectome characterized by weighted edges on which a neuronal-mass model evolves. The progression of the brain functions can be tested by simulating the resting-state activity on the evolving brain network. We show that while the evolution of edge weights plays a minor role in the overall progression of the disease, dynamic biomarkers predict a transition over a period of 10 years associated with strong cognitive decline.


Assuntos
Demência/patologia , Modelos Neurológicos , Doenças Neurodegenerativas/patologia , Animais , Relógios Biológicos , Encéfalo/patologia , Encéfalo/fisiopatologia , Morte Celular/fisiologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Conectoma/métodos , Demência/fisiopatologia , Humanos , Camundongos , Doenças Neurodegenerativas/fisiopatologia , Neurônios/patologia
3.
J Stroke Cerebrovasc Dis ; 29(10): 105147, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912540

RESUMO

Hypertrophic olivary degeneration (HOD) is a rare phenomenon that occurs after various insults to the Guillain-mollaret triangle (GMT). HOD is unique because the degeneration of inferior olivary nucleus becomes hypertrophic rather than atrophic. In this study, a 31-year-old woman developed HOD after pontine cavernoma surgery had been performed. The clinical manifestation was involuntary intorsion of right lower extremity during walking, which has not been reported in the literature. The woman also presented with palatal tremor, the most classic symptom of HOD. HOD's imaging trait include olive hypertrophy with increased T2 signal intensity on MRI, which are corresponding to the pathological findings. HOD is a self-limiting disease and excessive treatments are unnecessary.


Assuntos
Distonia/etiologia , Pé/inervação , Perna (Membro)/inervação , Doenças Neurodegenerativas/etiologia , Procedimentos Neurocirúrgicos/efeitos adversos , Núcleo Olivar/patologia , Palato/inervação , Tremor/etiologia , Adulto , Distonia/fisiopatologia , Feminino , Humanos , Hipertrofia , Degeneração Neural , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Núcleo Olivar/diagnóstico por imagem , Núcleo Olivar/fisiopatologia , Tremor/fisiopatologia
4.
J Vis Exp ; (162)2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32865526

RESUMO

Battling human neurodegenerative pathologies and managing their pervasive socioeconomic impact is becoming a global priority. Notwithstanding their detrimental effects on the human life quality and the healthcare system, the majority of human neurodegenerative disorders still remain incurable and non-preventable. Therefore, the development of novel therapeutic interventions against such maladies is becoming a pressing urgency. Age-associated deterioration of neuronal circuits and function is evolutionarily conserved in organisms as diverse as the lowly worm Caenorhabditis elegans and humans, signifying similarities in the underlying cellular and molecular mechanisms. C. elegans is a highly malleable genetic model, which offers a well-characterized nervous system, body transparency and a diverse repertoire of genetic and imaging techniques to assess neuronal activity and quality control during ageing. Here, we introduce and describe methodologies utilizing some versatile nematode models, including hyperactivated ion channel-induced necrosis (e.g., deg-3(d) and mec-4(d)) and protein aggregate (e.g., α-syunclein and poly-glutamate)-induced neurotoxicity, to monitor and dissect the cellular and molecular underpinnings of age-related neuronal breakdown. A combination of these animal neurodegeneration models, together with genetic and pharmacological screens for cell death modulators will lead to an unprecedented understanding of age-related breakdown of neuronal function and will provide critical insights with broad relevance to human health and quality of life.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Caenorhabditis elegans , Modelos Animais de Doenças , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Animais , Morte Celular , Humanos , Canais Iônicos/metabolismo , Necrose , Doenças Neurodegenerativas/fisiopatologia , Neurônios/metabolismo , Neurônios/patologia , Qualidade de Vida
5.
PLoS One ; 15(9): e0234749, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32966291

RESUMO

Traumatic brain injury (TBI) can lead to neurodegeneration in the injured circuitry, either through primary structural damage to the neuron or secondary effects that disrupt key cellular processes. Moreover, traumatic injuries can preferentially impact subpopulations of neurons, but the functional network effects of these targeted degeneration profiles remain unclear. Although isolating the consequences of complex injury dynamics and long-term recovery of the circuit can be difficult to control experimentally, computational networks can be a powerful tool to analyze the consequences of injury. Here, we use the Izhikevich spiking neuron model to create networks representative of cortical tissue. After an initial settling period with spike-timing-dependent plasticity (STDP), networks developed rhythmic oscillations similar to those seen in vivo. As neurons were sequentially removed from the network, population activity rate and oscillation dynamics were significantly reduced. In a successive period of network restructuring with STDP, network activity levels returned to baseline for some injury levels and oscillation dynamics significantly improved. We next explored the role that specific neurons have in the creation and termination of oscillation dynamics. We determined that oscillations initiate from activation of low firing rate neurons with limited structural inputs. To terminate oscillations, high activity excitatory neurons with strong input connectivity activate downstream inhibitory circuitry. Finally, we confirm the excitatory neuron population role through targeted neurodegeneration. These results suggest targeted neurodegeneration can play a key role in the oscillation dynamics after injury.


Assuntos
Lesões Encefálicas Traumáticas/fisiopatologia , Simulação por Computador , Modelos Neurológicos , Rede Nervosa/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Potenciais de Ação , Encéfalo/fisiologia , Encéfalo/fisiopatologia , Lesões Encefálicas Traumáticas/complicações , Humanos , Rede Nervosa/fisiologia , Doenças Neurodegenerativas/etiologia , Plasticidade Neuronal , Neurônios/patologia , Neurônios/fisiologia
6.
Nat Commun ; 11(1): 4413, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887883

RESUMO

The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation-dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which prominently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed transcriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.


Assuntos
Envelhecimento/patologia , Barreira Hematoencefálica , Encéfalo/fisiopatologia , Células Endoteliais/metabolismo , Exenatida/farmacologia , Doença de Alzheimer/fisiopatologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/fisiopatologia , Capilares/metabolismo , Células Cultivadas , Humanos , Camundongos , Microglia/efeitos dos fármacos , Doenças Neurodegenerativas/fisiopatologia , Transcriptoma/efeitos dos fármacos
7.
PLoS One ; 15(8): e0235810, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810171

RESUMO

Anomia is common in Primary Progressive Aphasia (PPA), and there is considerable evidence that semantic problems (as opposed to impaired access to output word phonology) exist in many PPA individuals irrespective of their strict subtype, including a loss of representations from semantic memory, which is typical for people with the semantic variant of PPA. In this manuscript we present a straightforward novel clinical algorithm that quantifies this degree of semantic storage impairment. We sought to produce an algorithm by employing tasks that would measure key elements of semantic storage loss: a) whether an unrecalled name could be retrieved with cues; b) if performance for items was consistent across tasks; and c) the degree to which a participant's performance was related to general severity of cognitive impairment rather than semantic loss. More specifically, these tasks were given to 28 individuals with PPA (12 participants had a clinical diagnosis of atypical Alzheimer's Disease with the logopenic variant of PPA; the remaining 16 participants received a clinical diagnosis of Frontotemporal dementia (11 were classified as the non-fluent variant of PPA and five were the semantic variant of PPA). Scores from these tasks produced a single omnibus semantic memory storage loss score (SSL score) for each person that ranged from 0.0 to 1.0, with scores closer to 0 more indicative of semantic storage loss. Indeed, supporting the hypothesis that our scores measure the degree of semantic storage loss, we found participants with the semantic variant of PPA had the lowest scores, and SSL scores could predict the degree of hypometabolism in the anterior temporal lobe; even when only people with the logopenic variant of PPA were examined. Thus, these scores show promise quantitating the degree of a person's semantic representation loss.


Assuntos
Afasia Primária Progressiva/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Semântica , Lobo Temporal/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Afasia Primária Progressiva/etiologia , Afasia Primária Progressiva/metabolismo , Feminino , Demência Frontotemporal/complicações , Demência Frontotemporal/metabolismo , Demência Frontotemporal/fisiopatologia , Humanos , Masculino , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/metabolismo , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Lobo Temporal/metabolismo
8.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(1): 100-106, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32621411

RESUMO

The morbidity of neurodegenerative diseases are increased in recent years, however, the treatment is limited. Poly ADP-ribosylation (PARylation) is a post-translational modification of protein that catalyzed by poly(ADP-ribose) polymerase (PARP). Studies have shown that PARylation is involved in many neurodegenerative diseases such as stroke, Parkinson's diseases, Alzheimer's disease, amyotrophic lateral sclerosis and so on, by affecting intracellular translocation of protein molecules, protein aggregation, protein activity, and cell death. PARP inhibitors have showed neuroprotective efficacy for neurodegenerative diseases in pre-clinical studies and phase Ⅰ clinical trials. To find new PARP inhibitors with more specific effects and specific pharmacokinetic characteristics will be the new direction for the treatment of neurodegenerative diseases. This paper reviews the recent progress on PARylation in neurodegenerative diseases.


Assuntos
ADP-Ribosilação , Doenças Neurodegenerativas , Poli Adenosina Difosfato Ribose , Humanos , Doenças Neurodegenerativas/fisiopatologia , Poli(ADP-Ribose) Polimerases/metabolismo
9.
Nat Rev Drug Discov ; 19(9): 609-633, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32709961

RESUMO

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner - a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.


Assuntos
Envelhecimento/fisiologia , Encéfalo/fisiologia , Metabolismo Energético/fisiologia , Doenças Neurodegenerativas/fisiopatologia , Animais , Glicólise/fisiologia , Humanos , Fosforilação Oxidativa
10.
Hist Philos Life Sci ; 42(2): 26, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32529381

RESUMO

In the early 1990s, Microcebus murinus, a small primate endemic to Madagascar, emerged as a potential animal model for the study of aging and Alzheimer's disease. This paper traces the use of the lesser mouse lemur in research on aging and associated neurodegenerative diseases, focusing on a basic material precondition that made this possible, namely, the conversion of a wild animal into an experimental organism that lives, breeds, and survives in the laboratory. It argues that the "old" mouse lemur model can be considered as an eco-zootechnical acquisition. This is shown by examining how, since the early 1970s, French mouse lemur researchers have articulated colony productivity and viability with the influence of environmental factors on the demographics and physiology of the species. The appearance and maintenance of a growing number of old mouse lemurs in French research facilities are related to three developments: the application of the ecological notion of "social stress" to the understanding and management of the behavior of the captive population; the experimental demonstration that a variety of seasonal physiological changes in the species were influenced by the photoperiod; and the related attempt to accelerate aging in mouse lemurs through the manipulation of annual light conditions.


Assuntos
Envelhecimento , Cheirogaleidae/fisiologia , Modelos Animais , Animais , Modelos Animais de Doenças , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia
11.
Croat Med J ; 61(2): 159-166, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32378382

RESUMO

Health can be defined as a harmony, or homeostasis, of the activities of thousands of different proteins, whereas aging and diseases result from their disharmony manifested at the levels of cells and tissues. Such disharmony is caused primarily by dysfunction and toxicity of misfolded proteins damaged by oxidation. This is an overview of key data that inspired new concepts allowing interpretation and integration of the scientific literature on aging and age-related diseases. These concepts suggest strategies for prevention and attenuation of age-related degenerative and malignant diseases mimicking the life of super-centenarians.


Assuntos
Envelhecimento/fisiologia , Neoplasias , Doenças Neurodegenerativas , Proteínas , Idoso , Dano ao DNA , Humanos , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Oxirredução , Redobramento de Proteína , Proteínas/química , Proteínas/metabolismo , Proteólise
12.
Adv Exp Med Biol ; 1194: 351-358, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468551

RESUMO

Protein homeostasis is a dynamic network that plays a pivotal role in systems' maintenance within a cell. This quality control system involves a number of mechanisms regarding the process of protein folding. Chaperones play a critical role in the folding, refolding, and unfolding of proteins. Aggregation of misfolded proteins is a common characteristic of neurodegenerative diseases. Chaperones act in a variety of pathways in this critical interplay between protein homeostasis network and misfolded protein's load. Moreover, ER stress-induced cell death mechanisms (such as the unfolded protein response) are activated as a response. Therefore, there is a critical balance in the accumulation of misfolded proteins and ER stress response mechanisms which can lead to cell death. Our focus is in understanding the different mechanisms that govern ER stress signaling in health and disease in order to represent the regulation of protein homeostasis and balance of protein synthesis and degradation in the ER. Our proposed model describes, using hybrid modeling, the function of chaperones' machinery for protein folding.


Assuntos
Modelos Biológicos , Chaperonas Moleculares , Dobramento de Proteína , Humanos , Chaperonas Moleculares/química , Doenças Neurodegenerativas/fisiopatologia , Biossíntese de Proteínas , Proteínas/metabolismo , Deficiências na Proteostase , Transdução de Sinais , Resposta a Proteínas não Dobradas
13.
Adv Exp Med Biol ; 1194: 409-421, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468556

RESUMO

MotivationNeurodegenerative diseases (NDs), including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease, occur as a result of neurodegenerative processes. Thus, it has been increasingly appreciated that many neurodegenerative conditions overlap at multiple levels. However, traditional clinicopathological correlation approaches to better classify a disease have met with limited success. Discovering this overlap offers hope for therapeutic advances that could ameliorate many ND simultaneously. In parallel, in the last decade, systems biology approaches have become a reliable choice in complex disease analysis for gaining more delicate biological insights and have enabled the comprehension of the higher order functions of the biological systems.ResultsToward this orientation, we developed a systems biology approach for the identification of common links and pathways of ND, based on well-established and novel topological and functional measures. For this purpose, a molecular pathway network was constructed, using molecular interactions and relations of four main neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease). Our analysis captured the overlapped subregions forming molecular subpathways fully enriched in these four NDs. Also, it exported molecules that act as bridges, hubs, and key players for neurodegeneration concerning either their topology or their functional role.ConclusionUnderstanding these common links and central topologies under the perspective of systems biology and network theory and greater insights are provided to uncover the complex neurodegeneration processes.


Assuntos
Doenças Neurodegenerativas , Biologia de Sistemas , Humanos , Vias Neurais/patologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/fisiopatologia
14.
Pharmacol Ther ; 213: 107579, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32442437

RESUMO

Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.


Assuntos
Neoplasias/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Ubiquitina/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Resistência a Medicamentos/fisiologia , Fator de Transcrição E2F4/metabolismo , Holoenzimas , Humanos , Gotículas Lipídicas/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas Musculares/metabolismo , NF-kappa B/metabolismo , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteassoma/uso terapêutico , Proteostase/fisiologia , Proteína Supressora de Tumor p53/metabolismo
15.
Nat Commun ; 11(1): 1962, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327659

RESUMO

Topoisomerase 1 (TOP1) relieves torsional stress in DNA during transcription and facilitates the expression of long (>100 kb) genes, many of which are important for neuronal functions. To evaluate how loss of Top1 affected neurons in vivo, we conditionally deleted (cKO) Top1 in postmitotic excitatory neurons in the mouse cerebral cortex and hippocampus. Top1 cKO neurons develop properly, but then show biased transcriptional downregulation of long genes, signs of DNA damage, neuroinflammation, increased poly(ADP-ribose) polymerase-1 (PARP1) activity, single-cell somatic mutations, and ultimately degeneration. Supplementation of nicotinamide adenine dinucleotide (NAD+) with nicotinamide riboside partially blocked neurodegeneration, and increased the lifespan of Top1 cKO mice by 30%. A reduction of p53 also partially rescued cortical neuron loss. While neurodegeneration was partially rescued, behavioral decline was not prevented. These data indicate that reducing neuronal loss is not sufficient to limit behavioral decline when TOP1 function is disrupted.


Assuntos
DNA Topoisomerases Tipo I/deficiência , Instabilidade Genômica , Doenças Neurodegenerativas/enzimologia , Neurônios/enzimologia , Animais , Apoptose/efeitos dos fármacos , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Dano ao DNA , DNA Topoisomerases Tipo I/genética , Hipocampo/enzimologia , Hipocampo/patologia , Inflamação , Camundongos , Camundongos Knockout , Mortalidade Prematura , Atividade Motora , Mutação , NAD/administração & dosagem , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Poli(ADP-Ribose) Polimerase-1/metabolismo
16.
Fortschr Neurol Psychiatr ; 88(3): 184-193, 2020 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-32232807

RESUMO

Past research has revealed a variety of olfactory deficits associated with psychiatric and neurodegenerative disorders. These deficits are evident in psychophysical olfactory testing as well as neurophysiological and neuroanatomical examinations. The specific type of olfactory dysfunction appears disorder specific. For example, with regard to affective disorders, the functional and anatomical overlap between olfactory and emotion-specific brain areas has been suggested as a major underlying factor for olfactory dysfunction. Based on converging evidence of changes in olfactory perception related to Major Depression, Schizophrenia, Alzheimer's and Parkinson's Disease, olfactory testing has been discussed as an important additional diagnostic marker. Hence, valid methods for objective and reliable olfactory testing as well as guidelines for the interpretation of the respective diagnostic findings are required. The aim of this review is to provide an overview of reported olfactory deficits in psychiatric and neurodegenerative disorders. In addition, a selection of olfactory tests, available in German-speaking countries, with regard to the respective disorder-related olfactory deficit in question are presented and classified. Original data regarding an empirical validation of the Düsseldorf Odour Discrimination Test in a clinical population are presented.


Assuntos
Transtornos Mentais/complicações , Transtornos Mentais/diagnóstico , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/diagnóstico , Transtornos do Olfato/complicações , Transtornos do Olfato/diagnóstico , Encéfalo/fisiopatologia , Humanos , Transtornos Mentais/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Transtornos do Olfato/fisiopatologia , Olfato
17.
PLoS One ; 15(4): e0232232, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348342

RESUMO

BACKGROUND AND OBJECTIVES: Patients with neurodegenerative disorders often experience impairments in visual function. In research and clinical care, visual problems are primarily understood as objective visual impairments. Subjective complaints, referring to complaints from a patient's perspective, receive less attention, while they are of utmost clinical importance to guide assessment and rehabilitation. A 21-item Screening of Visual Complaints questionnaire (SVC) was developed for the assessment of subjective visual complaints in patients with neurodegenerative disorders. This prospective study aims to evaluate the psychometric properties of the SVC in a large community sample. METHODS: A stratified convenience sample of 1,461 healthy Dutch participants (18-95 years) without severe self-reported neurological, ophthalmological or psychiatric conditions completed the SVC, Cerebral Visual Complaints questionnaire (CVC-q), National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25), Behavior Rating Inventory of Executive Function-A (BRIEF-A), Questionnaire for Experiences of Attention Deficits (Fragebogen erlebter Defizite der Aufmerkzamkeit; FEDA), Depression Anxiety Stress Scale-21 (DASS-21) and the Structured Inventory for Malingered Symptomatology (SIMS) online. After two weeks, 66 participants completed the SVC again. We evaluated the factor structure, internal consistency, convergent and divergent validity, and test-retest reliability of the SVC. RESULTS: The sample was split in two subsamples to perform exploratory and confirmatory factor analyses. In the first subsample, the exploratory factor analysis extracted three factors from the SVC: diminished visual perception, altered visual perception and ocular discomfort. The confirmatory factor analysis showed this model to be valid in the second subsample. The SVC showed satisfactory convergent validity (NEI-VFQ-25: r = -0.71; CVC-q: r = 0.84) and divergent validity (SIMS: r = 0.26; BRIEF-A: r = 0.29; FEDA: r = 0.40; DASS-21: r = 0.34) and good internal consistency (Cronbach's alpha = 0.85) and test-retest reliability (ICC = 0.82). CONCLUSIONS: The SVC is a valid and reliable tool for the assessment of subjective visual complaints in a community sample and appears promising for clinical use in patients with neurodegenerative disorders.


Assuntos
Doenças Neurodegenerativas/complicações , Transtornos da Visão/complicações , Transtornos da Visão/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Análise Fatorial , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Países Baixos , Doenças Neurodegenerativas/fisiopatologia , Doenças Neurodegenerativas/psicologia , Estudos Prospectivos , Psicometria/métodos , Psicometria/estatística & dados numéricos , Reprodutibilidade dos Testes , Inquéritos e Questionários , Transtornos da Visão/fisiopatologia , Adulto Jovem
18.
Proc Natl Acad Sci U S A ; 117(19): 10565-10574, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32345721

RESUMO

Numerous mutations that impair retrograde membrane trafficking between endosomes and the Golgi apparatus lead to neurodegenerative diseases. For example, mutations in the endosomal retromer complex are implicated in Alzheimer's and Parkinson's diseases, and mutations of the Golgi-associated retrograde protein (GARP) complex cause progressive cerebello-cerebral atrophy type 2 (PCCA2). However, how these mutations cause neurodegeneration is unknown. GARP mutations in yeast, including one causing PCCA2, result in sphingolipid abnormalities and impaired cell growth that are corrected by treatment with myriocin, a sphingolipid synthesis inhibitor, suggesting that alterations in sphingolipid metabolism contribute to cell dysfunction and death. Here we tested this hypothesis in wobbler mice, a murine model with a homozygous partial loss-of-function mutation in Vps54 (GARP protein) that causes motor neuron disease. Cytotoxic sphingoid long-chain bases accumulated in embryonic fibroblasts and spinal cords from wobbler mice. Remarkably, chronic treatment of wobbler mice with myriocin markedly improved their wellness scores, grip strength, neuropathology, and survival. Proteomic analyses of wobbler fibroblasts revealed extensive missorting of lysosomal proteins, including sphingolipid catabolism enzymes, to the Golgi compartment, which may contribute to the sphingolipid abnormalities. Our findings establish that altered sphingolipid metabolism due to GARP mutations contributes to neurodegeneration and suggest that inhibiting sphingolipid synthesis might provide a useful strategy for treating these disorders.


Assuntos
Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Esfingolipídeos/metabolismo , Animais , Modelos Animais de Doenças , Endossomos/metabolismo , Ácidos Graxos Monoinsaturados/farmacologia , Feminino , Fibroblastos/metabolismo , Complexo de Golgi/metabolismo , Masculino , Camundongos , Camundongos Mutantes Neurológicos , Doença dos Neurônios Motores/genética , Doença dos Neurônios Motores/metabolismo , Doença dos Neurônios Motores/patologia , Neurônios Motores/metabolismo , Células-Tronco Embrionárias Murinas , Mutação , Malformações do Sistema Nervoso/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Transporte Proteico , Proteômica , Proteínas de Transporte Vesicular/metabolismo
19.
Brain Behav Immun ; 87: 34-39, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32298803

RESUMO

The coronavirus disease 19 (COVID-19) pandemic is a significant psychological stressor in addition to its tremendous impact on every facet of individuals' lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future precipitate anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addition to pandemic-associated psychological distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunologic response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunological underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunology into epidemiologic studies of pandemics.


Assuntos
Infecções por Coronavirus/psicologia , Síndrome da Liberação de Citocina/psicologia , Transtornos Mentais/psicologia , Doenças do Sistema Nervoso/psicologia , Pneumonia Viral/psicologia , Doença Aguda , Ansiedade/etiologia , Ansiedade/imunologia , Ansiedade/psicologia , Translocação Bacteriana , Betacoronavirus , Doença Crônica , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/terapia , Doenças Desmielinizantes/etiologia , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/fisiopatologia , Doenças Desmielinizantes/psicologia , Depressão/etiologia , Depressão/imunologia , Depressão/psicologia , Humanos , Fatores Imunológicos/efeitos adversos , Transtornos Mentais/etiologia , Transtornos Mentais/imunologia , Saúde Mental , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/imunologia , Doenças do Sistema Nervoso/fisiopatologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/fisiopatologia , Doenças Neurodegenerativas/psicologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Psiconeuroimunologia , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/imunologia , Transtornos Psicóticos/psicologia , Saúde Pública , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/imunologia , Transtornos de Estresse Pós-Traumáticos/psicologia
20.
Dtsch Med Wochenschr ; 145(6): 399-405, 2020 03.
Artigo em Alemão | MEDLINE | ID: mdl-32191980

RESUMO

Severe stroke and neurodegenerative diseases often cause limitations in communication and willing capability. Decision processes in these conditions assume primarily a positive medical indication for any intervention. If not obtainable from an individual by itself, by a disposal or by a legal custodian, the presumed will of a patient has to be detected carefully. Evidence can be raised by an interview of relatives or an individual case discussion in a local ethical comitee. Stroke and dementia can raise the need for palliative care, especially a sufficient analgesia as well as other severe illnesses. Pain in demented persons is often underrated and undertreated. The diagnosis of dementia alone does not limit the indication for curative therapy in general. Ethical comitees or ethical visits are helpful instruments to find out an adequate decision in difficult situations.


Assuntos
Tomada de Decisão Clínica , Doenças Neurodegenerativas , Acidente Vascular Cerebral , Humanos , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/fisiopatologia , Doenças Neurodegenerativas/terapia , Cuidados Paliativos , Prognóstico , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/terapia
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