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Obstructive sleep apnea is associated with cognitive impairment and increased risk for neurodegenerative diseases. Obstructive sleep apnea treatment with positive airway pressure therapy helps to improve cognitive symptoms and reduces long-term dementia risk. To test whether these treatment effects are due to a reduction in neuronal damage, we examined longitudinal changes in the neurodegenerative serum neurofilament light chain and cognitive performance of patients with obstructive sleep apnea. In this study, 17 patients with obstructive sleep apnea completed baseline and follow-up (9 month after starting PAP treatment) investigation of sleep, daytime symptoms, cognitive testing and serum neurofilament light chain measurements. Depending on treatment adherence and efficacy, participants were assigned either to the effective treatment (n = 10) or non-effective treatment group (n = 7). As results at baseline lower mean oxygen saturation during sleep was associated with higher serum neurofilament light chain. Patients in the non-effective treatment group showed a significant increase of age-adjusted percentile of serum neurofilament light chain levels at follow-up, whereas serum neurofilament light chain values remained constant in the effective treatment group. At a functional level, effective treatment leads to an improvement in processing speed, which was not the case in the non-effective treatment group. Longitudinal changes of age-adjusted serum neurofilament light chain levels were associated with changes in cognitive performance. To conclude, this longitudinal observational study showed that effective obstructive sleep apnea treatment positively affects the amount of neuronal damage as well as working memory performance. As cognitive symptoms might not only be attributed to obstructive sleep apnea-related sleep deficiency, but also neurodegeneration, our results underline the importance of treatment adherence and efficacy for the prevention of neuronal damage and cognitive consequences.
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OBJECTIVES: To determine the contribution of cerebral amyloid angiopathy to cognitive impairment in MCI and dementia. METHODS: Patients with subjective memory impairment (SMI), amnestic and non-amnestic mild cognitive impairment ((n)aMCI), Alzheimer's disease (AD), mixed and vascular dementia (MD/VD) from our memory clinic were included in this retrospective analysis. Patients underwent neuropsychological testing and cranial magnetic resonance imaging (MRI). Magnetic resonance imaging data sets were analyzed regarding the presence of CAA-related MRI biomarkers to determine CAA prevalence. ANOVAs were used to investigate the contribution of CAA to cognitive impairment within diagnostic groups and to determine whether differences in cognitive test performance between the diagnostic groups are mediated by total CAA burden. RESULTS: 475 patients (222 male, 253 female) with SMI (n = 47), naMCI (n = 41), aMCI (n = 189), early AD (n = 9), AD (n = 114), MD (n = 71) and VD (n = 4) were included. Mean age was 73.2 (9.9) years. CAA prevalence was 14.9% in SMI, 14.6% in naMCI, 24.3% in aMCI, 22.2% in early onset AD, 18.4% in late onset AD, 46.5% in MD and 25% in VD. Patients with possible and probable CAA were older than patients without CAA. In particular, diagnosis of aMCI, early onset AD, MD and VD showed high CAA prevalence. In AD but not in aMCI, CAA diagnosis significantly influenced test performance in the CERAD word list recall (F (1,78) = 4505; p = 0.037; partial eta-square = 0.055). Differences in cognitive test performance between the diagnostic groups of naMCI, aMCI, AD and MD were mediated by total CAA burden within AAT simply nouns subtest (F (2,39) = 4059; p = 0.025; partial eta-square = 0.172) and in CERAD verbal fluency test (F (3,129) = 3533; p = 0.017; partial eta-square = 0.076). CONCLUSION: This retrospective analysis demonstrates high prevalence rates of CAA in cognitive diagnoses. Our data suggest that comorbid CAA independently impacts cognitive test performance in the course of AD with presumably stage-dependent effects. Especially in patients with AD comorbid CAA additionally impairs memory function. Total CAA small vessel disease burden further modulates psychometric differences in cognitive test performance between diagnostic groups regarding word finding and word fluency capabilities.
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Doença de Alzheimer , Angiopatia Amiloide Cerebral , Disfunção Cognitiva , Humanos , Masculino , Feminino , Idoso , Estudos Retrospectivos , Sintomas Prodrômicos , Prevalência , Cognição , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/epidemiologia , Doença de Alzheimer/psicologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico , Transtornos da Memória , Testes NeuropsicológicosRESUMO
Insomnia represents one of the most common syndromes with far-reaching health and socioeconomic consequences. After a long period of stagnation, recent years have seen promising advances in the nonpharmacological and pharmacological treatment of patients with chronic insomnia. This article highlights these new therapeutic approaches in the context of established treatment options.
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Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/terapiaRESUMO
Normal pressure hydrocephalus (NPH) is prevalent in aging patient populations. Despite its clinical relevance, many patients with NPH may not receive adequate treatment. Because of the frequency of Alzheimer`s disease in these patients, there could be overlapping pathophysiological mechanisms that are as yet incompletely understood. Cerebral comorbidities seem to have negative effects on therapeutic response to ventriculoperitoneal shunting. In order to avoid unnecessary and unsuccessful surgery in highly vulnerable elderly patients, they have to be taken into consideration in the diagnostic process.
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Doença de Alzheimer , Hidrocefalia de Pressão Normal , Humanos , Idoso , Hidrocefalia de Pressão Normal/epidemiologia , Hidrocefalia de Pressão Normal/cirurgia , Doença de Alzheimer/complicações , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/terapia , Resultado do Tratamento , Derivação VentriculoperitonealRESUMO
Objective markers for the neurodegenerative disorder progressive supranuclear palsy (PSP) are needed to provide a timely diagnosis with greater certainty. Non-coding RNA (ncRNA), including microRNA, piwi-interacting RNA, and transfer RNA, are good candidate markers in other neurodegenerative diseases, but have not been investigated in PSP. Therefore, as proof of principle, we sought to identify whether they were dysregulated in matched serum and cerebrospinal fluid (CSF) samples of patients with PSP. Small RNA-seq was undertaken on serum and CSF samples from healthy controls (n = 20) and patients with PSP (n = 31) in two cohorts, with reverse transcription-quantitative PCR (RT-qPCR) to confirm their dysregulation. Using RT-qPCR, we found in serum significant down-regulation in hsa-miR-92a-3p, hsa-miR-626, hsa-piR-31068, and tRNA-ValCAC. In CSF, both hsa-let-7a-5p and hsa-piR-31068 showed significant up-regulation, consistent with their changes observed in the RNA-seq results. Interestingly, we saw no correlation in the expression of hsa-piR-31068 within our matched serum and CSF samples, suggesting there is no common dysregulatory mechanism between the two biofluids. While these changes were in a small cohort of samples, we have provided novel evidence that ncRNA in biofluids could be possible diagnostic biomarkers for PSP and further work will help to expand this potential.
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MicroRNAs , Paralisia Supranuclear Progressiva , Humanos , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/genética , Biomarcadores , MicroRNAs/genética , Regulação para BaixoRESUMO
BACKGROUND: Detailed examination of cognitive deficits in patients with mild cognitive impairment (MCI) yields substantial diagnostic and prognostic value, specifically with respect to memory. Magnitude and characteristics of subjective cognitive deficits, however, often receive less attention in this population at risk for developing dementia. METHODS: We investigated predictors of subjective cognitive deficits in patients with MCI, using a detailed assessment for such impairments associated with different cognitive domains, as well as demographic and clinical variables including magnetic resonance imaging data. RESULTS: The strongest predictor for subjective memory deficits was depressed mood, whereas subjective performance issues associated with attention or executive functions also corresponded to measurable impairments in the respective cognitive domains. Reduced hippocampal thickness and hemispheric entorhinal cortex thickness asymmetry were associated with objective memory impairment but not with subjective deficits or symptoms of depression. CONCLUSIONS: Whereas low objective memory performance and reduced cortical thickness within medial temporal lobe subregions could be associated with neurodegeneration, greater subjective memory deficits in patients with MCI may indicate psychological burden.
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Transtornos Cognitivos , Disfunção Cognitiva , Cognição , Transtornos Cognitivos/diagnóstico , Disfunção Cognitiva/complicações , Disfunção Cognitiva/patologia , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Transtornos da Memória/diagnóstico , Testes NeuropsicológicosRESUMO
The limited proliferative capacity of neuroprogenitor cells (NPCs) within the periventricular germinal niches (PGNs) located caudal of the subventricular zone (SVZ) of the lateral ventricles together with their high proliferation capacity after isolation strongly implicates cell-extrinsic humoral factors restricting NPC proliferation in the hypothalamic and midbrain PGNs. We comparatively examined the effects of norepinephrine (NE) as an endogenous candidate regulator of PGN neurogenesis in the SVZ as well as the periventricular hypothalamus and the periaqueductal midbrain. Histological and neurochemical analyses revealed that the pattern of NE innervation of the adult PGNs is inversely associated with their in vivo NPC proliferation capacity with low NE levels coupled to high NPC proliferation in the SVZ but high NE levels coupled to low NPC proliferation in hypothalamic and midbrain PGNs. Intraventricular infusion of NE decreased NPC proliferation and neurogenesis in the SVZ-olfactory bulb system, while pharmacological NE inhibition increased NPC proliferation and early neurogenesis events in the caudal PGNs. Neurotoxic ablation of NE neurons using the Dsp4-fluoxetine protocol confirmed its inhibitory effects on NPC proliferation. Contrarily, NE depletion largely impairs NPC proliferation within the hippocampus in the same animals. Our data indicate that norepinephrine has opposite effects on the two fundamental neurogenic niches of the adult brain with norepinephrine being a negative regulator of adult periventricular neurogenesis. This knowledge might ultimately lead to new therapeutic approaches to influence neurogenesis in hypothalamus-related metabolic diseases or to stimulate endogenous regenerative potential in neurodegenerative processes such as Parkinson's disease.
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Células-Tronco Neurais/citologia , Norepinefrina/farmacologia , Nicho de Células-Tronco , Animais , Proliferação de Células/efeitos dos fármacos , Hipocampo/citologia , Ventrículos Laterais/citologia , Mesencéfalo/citologia , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Bulbo Olfatório/citologia , Fenótipo , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
In gene therapy for Duchenne muscular dystrophy there are two potential immunological obstacles. An individual with Duchenne muscular dystrophy has a genetic mutation in dystrophin, and therefore the wild-type protein is "foreign," and thus potentially immunogenic. The adeno-associated virus serotype-6 (AAV6) vector for delivery of dystrophin is a viral-derived vector with its own inherent immunogenicity. We have developed a technology where an engineered plasmid DNA is delivered to reduce autoimmunity. We have taken this approach into humans, tolerizing to myelin proteins in multiple sclerosis and to proinsulin in type 1 diabetes. Here, we extend this technology to a model of gene therapy to reduce the immunogenicity of the AAV vector and of the wild-type protein product that is missing in the genetic disease. Following gene therapy with systemic administration of recombinant AAV6-microdystrophin to mdx/mTRG2 mice, we demonstrated the development of antibodies targeting dystrophin and AAV6 capsid in control mice. Treatment with the engineered DNA construct encoding microdystrophin markedly reduced antibody responses to dystrophin and to AAV6. Muscle force in the treated mice was also improved compared with control mice. These data highlight the potential benefits of administration of an engineered DNA plasmid encoding the delivered protein to overcome critical barriers in gene therapy to achieve optimal functional gene expression.
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DNA , Dependovirus/genética , Terapia Genética/métodos , Vetores Genéticos , Força Muscular/genética , Distrofia Muscular de Duchenne/terapia , Plasmídeos , Animais , DNA/genética , DNA/farmacocinética , Modelos Animais de Doenças , Distrofina/genética , Distrofina/imunologia , Distrofina/metabolismo , Vetores Genéticos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos mdx , Força Muscular/imunologia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/imunologia , Distrofia Muscular de Duchenne/metabolismo , Plasmídeos/genética , Plasmídeos/farmacologiaRESUMO
This article provides an overview of the prevalence, cause and treatment of insomnia in common neurological diseases (restless legs syndrome, stroke, multiple sclerosis, Parkinson´s disease and Alzheimer´s disease) with an additional focus on the bidirectional relationship between sleep and neurological disorders.Insomnia is prevalent, but frequently unrecognized in the context of neurological diseases. Although it is widely known that sleep has a relevant impact on quality of life in general and cerebral function in particular, sleep disorders receive little attention in the prevention and treatment of neurological diseases.
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Doenças do Sistema Nervoso , Síndrome das Pernas Inquietas , Distúrbios do Início e da Manutenção do Sono , Transtornos do Sono-Vigília , Humanos , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/terapia , Qualidade de Vida , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Distúrbios do Início e da Manutenção do Sono/terapia , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/terapiaRESUMO
We present a 56-year-old patient suffering from frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The history included a three-generation pedigree and the patient was found to be a mutation carrier. The diagnosis was hindered by late appearance of the hypokinetic movement disorder. For clinicians, it is important to consider rare neurodegenerative disease variants in early-onset familial dementia syndromes with behavioral, cognitive, and motor symptoms.
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Cromossomos Humanos Par 17/genética , Demência Frontotemporal/genética , Proteínas tau/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , LinhagemRESUMO
BACKGROUND: Stiffening of the aortic wall is a phenomenon consistently observed in age and in abdominal aortic aneurysm (AAA). However, its role in AAA pathophysiology is largely undefined. METHODS AND RESULTS: Using an established murine elastase-induced AAA model, we demonstrate that segmental aortic stiffening precedes aneurysm growth. Finite-element analysis reveals that early stiffening of the aneurysm-prone aortic segment leads to axial (longitudinal) wall stress generated by cyclic (systolic) tethering of adjacent, more compliant wall segments. Interventional stiffening of AAA-adjacent aortic segments (via external application of surgical adhesive) significantly reduces aneurysm growth. These changes correlate with the reduced segmental stiffness of the AAA-prone aorta (attributable to equalized stiffness in adjacent segments), reduced axial wall stress, decreased production of reactive oxygen species, attenuated elastin breakdown, and decreased expression of inflammatory cytokines and macrophage infiltration, and attenuated apoptosis within the aortic wall, as well. Cyclic pressurization of segmentally stiffened aortic segments ex vivo increases the expression of genes related to inflammation and extracellular matrix remodeling. Finally, human ultrasound studies reveal that aging, a significant AAA risk factor, is accompanied by segmental infrarenal aortic stiffening. CONCLUSIONS: The present study introduces the novel concept of segmental aortic stiffening as an early pathomechanism generating aortic wall stress and triggering aneurysmal growth, thereby delineating potential underlying molecular mechanisms and therapeutic targets. In addition, monitoring segmental aortic stiffening may aid the identification of patients at risk for AAA.
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Aneurisma da Aorta Abdominal/etiologia , Rigidez Vascular , Adulto , Idoso , Envelhecimento/patologia , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica , Humanos , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Elastase Pancreática/toxicidade , Estresse Mecânico , Adesivos Teciduais , UltrassonografiaRESUMO
PURPOSE OF REVIEW: In recent years progress has been made in the detection and evaluation of nonmotor symptoms in Parkinson's disease. The pathophysiology is better understood and new treatment is available, which will be discussed in this review. RECENT FINDINGS: The most intriguing recent finding is the fact that Parkinson's disease may be a spreading disease. From the environment a toxin, bacteria, or virus may start in genetically susceptible patients a cascade of α-synuclein aggregation which reaches via the olfactory and the enteric system of the gut the brain where further spreading causes symptoms, such as sleep disturbances, motor impairment, and neuropsychiatric symptoms. New treatment should address the abnormal α-synuclein folding. If this would be achieved premotor signs, such as hyposmia, rapid eye movement-sleep behavior disorder, constipation, or depression may be a kind of biomarkers which allow together with other diagnostic tools, such as parenchymal sonography, iodobenzamide-scintigraphy and dopamine transporter scans the prediction whether somebody might be under way to develop the full-blown Parkinson's disease syndrome. SUMMARY: Parkinson's disease seems to be a spreading disease which causes not only a dopaminergic deficit as major cause for the movement disorder but also impairs function of many other brain centers which leads to a multitransmitter malfunction.
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Doenças do Sistema Nervoso Autônomo/fisiopatologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , alfa-Sinucleína/fisiologia , Doenças do Sistema Nervoso Autônomo/etiologia , Doenças Cardiovasculares/fisiopatologia , Discinesias/fisiopatologia , Diagnóstico Precoce , Disfunção Erétil/etiologia , Fadiga/etiologia , Gastroenteropatias/fisiopatologia , Humanos , Masculino , Transtornos Mentais/etiologia , Transtornos dos Movimentos/fisiopatologia , Transtornos do Olfato/fisiopatologia , Dor/etiologia , Doença de Parkinson/complicações , Transtornos do Sono-Vigília/fisiopatologia , Doenças Urológicas/fisiopatologiaRESUMO
Telomere extension has been proposed as a means to improve cell culture and tissue engineering and to treat disease. However, telomere extension by nonviral, nonintegrating methods remains inefficient. Here we report that delivery of modified mRNA encoding TERT to human fibroblasts and myoblasts increases telomerase activity transiently (24-48 h) and rapidly extends telomeres, after which telomeres resume shortening. Three successive transfections over a 4 d period extended telomeres up to 0.9 kb in a cell type-specific manner in fibroblasts and myoblasts and conferred an additional 28 ± 1.5 and 3.4 ± 0.4 population doublings (PDs), respectively. Proliferative capacity increased in a dose-dependent manner. The second and third transfections had less effect on proliferative capacity than the first, revealing a refractory period. However, the refractory period was transient as a later fourth transfection increased fibroblast proliferative capacity by an additional 15.2 ± 1.1 PDs, similar to the first transfection. Overall, these treatments led to an increase in absolute cell number of more than 10(12)-fold. Notably, unlike immortalized cells, all treated cell populations eventually stopped increasing in number and expressed senescence markers to the same extent as untreated cells. This rapid method of extending telomeres and increasing cell proliferative capacity without risk of insertional mutagenesis should have broad utility in disease modeling, drug screening, and regenerative medicine.
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Senescência Celular/fisiologia , Fibroblastos/metabolismo , Pulmão/metabolismo , Mioblastos/metabolismo , Telomerase/metabolismo , Telômero/genética , Western Blotting , Divisão Celular , Proliferação de Células , Células Cultivadas , Feto/citologia , Feto/metabolismo , Fibroblastos/citologia , Citometria de Fluxo , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Pulmão/citologia , Mioblastos/citologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Telomerase/genéticaRESUMO
AIMS: Heme oxygenase-1 (HO-1) confers protection to the vasculature and suppresses inflammatory properties of monocytes and macrophages. It is unclear how HO-1 determines the extent of vascular dysfunction in mice and humans. METHODS AND RESULTS: Decreased HO-1 activity and expression was paralleled by increased aortic expression and activity of the nicotinamide dinucleotide phosphate oxidase Nox2 in HO-1 deficient Hmox1â»/â» and Hmox1(âº/â») compared with Hmox1âº/⺠mice. When subjected to angiotensin II-infusion, streptozotocin-induced diabetes mellitus and aging, HO-1 deficient mice showed increased vascular dysfunction inversely correlated with HO activity. In a primary prevention population-based cohort, we assessed length polymorphisms of the HMOX1 promoter region and established a bipolar frequency pattern of allele length (long vs. short repeats) in 4937 individuals. Monocytic HMOX1 mRNA expression was positively correlated with flow-mediated dilation and inversely with CD14 mRNA expression indicating pro-inflammatory monocytes in 733 hypertensive individuals of this cohort. Hmox1â»/â» mice showed drastically increased expression of the chemokine receptor CCR2 in monocytes and the aorta. Angiotensin II-infused Hmox1â»/â» mice had amplified endothelial inflammation in vivo, significantly increased aortic infiltration of pro-inflammatory CD11b⺠Ly6C(hi) monocytes and Ly6G⺠neutrophils and were marked by Ly6C(hi) monocytosis in the circulation and an increased blood pressure response. Finally, individuals with unfavourable HMOX1 gene promoter length had increased prevalence of arterial hypertension and reduced cumulative survival after a median follow-up of 7.23 years. CONCLUSIONS: Heme oxygenase-1 is a regulator of vascular function in hypertension via determining the phenotype of inflammatory circulating and infiltrating monocytes with possible implications for all-cause mortality.
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Endotélio Vascular/fisiopatologia , Heme Oxigenase-1/fisiologia , Hipertensão/fisiopatologia , Animais , Estudos Transversais , Feminino , Heme Oxigenase-1/deficiência , Heme Oxigenase-1/genética , Humanos , Hipertensão/mortalidade , Masculino , Camundongos , Monócitos/fisiologia , Neutrófilos/fisiologia , Estresse Oxidativo/fisiologia , Fenótipo , Polimorfismo Genético , RNA Mensageiro/metabolismoRESUMO
Endothelial nitric-oxide synthase (eNOS) uncoupling and increased inducible NOS (iNOS) activity amplify vascular oxidative stress. The role of inflammatory myelomonocytic cells as mediators of these processes and their impact on tetrahydrobiopterin availability and function have not yet been defined. Angiotensin II (ATII, 1 mg/kg/day for 7 days) increased Ly6C(high) and CD11b(+)/iNOS(high) leukocytes and up-regulated levels of eNOS glutathionylation in aortas of C57BL/6 mice. Vascular iNOS-dependent NO formation was increased, whereas eNOS-dependent NO formation was decreased in aortas of ATII-infused mice as assessed by electron paramagnetic resonance (EPR) spectroscopy. Diphtheria toxin-mediated ablation of lysozyme M-positive (LysM(+)) monocytes in ATII-infused LysM(iDTR) transgenic mice prevented eNOS glutathionylation and eNOS-derived N(ω)-nitro-L-arginine methyl ester-sensitive superoxide formation in the endothelial layer. ATII increased vascular guanosine triphosphate cyclohydrolase I expression and biopterin synthesis in parallel, which was reduced in monocyte-depleted LysM(iDTR) mice. Vascular tetrahydrobiopterin was increased by ATII infusion but was even higher in monocyte-depleted ATII-infused mice, which was paralleled by a strong up-regulation of dihydrofolate reductase expression. EPR spectroscopy revealed that both vascular iNOS- and eNOS-dependent NO formation were normalized in ATII-infused mice following monocyte depletion. Additionally, deletion as well as pharmacologic inhibition of iNOS prevented ATII-induced endothelial dysfunction. In summary, ATII induces an inflammatory cell-dependent increase of iNOS, guanosine triphosphate cyclohydrolase I, tetrahydrobiopterin, NO formation, and nitro-oxidative stress as well as eNOS uncoupling in the vessel wall, which can be prevented by ablation of LysM(+) monocytes.
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Angiotensina II/imunologia , Monócitos/enzimologia , Óxido Nítrico Sintase Tipo III/imunologia , Estresse Oxidativo , Angiotensina II/genética , Animais , Biopterinas/análogos & derivados , Biopterinas/imunologia , Endotélio Vascular/enzimologia , Endotélio Vascular/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Óxido Nítrico/imunologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Óxido Nítrico Sintase Tipo III/genéticaRESUMO
OBJECTIVE: Immune cells contribute to angiotensin II (ATII)-induced vascular dysfunction and inflammation. Interferon-γ (IFN-γ), an inflammatory cytokine exclusively produced by immune cells, seems to be involved in ATII-driven cardiovascular injury, but the actions and cellular source of IFN-γ remain incompletely understood. APPROACH AND RESULTS: IFN-γ(-/-) and Tbx21(-/-) mice were partially protected from ATII-induced (1 mg/kg per day of ATII, infused subcutaneously by miniosmotic pumps) vascular endothelial and smooth muscle dysfunction, whereas mice overexpressing IFN-γ showed constitutive vascular dysfunction. Absence of T-box expressed in T cells (T-bet), the IFN-γ transcription factor encoded by Tbx21, reduced vascular superoxide and peroxynitrite formation and attenuated expression of nicotinamide adenosine dinucleotide phosphate oxidase subunits as well as inducible NO synthase, monocyte chemoattractant protein 1, and interleukin-12 in aortas of ATII-infused mice. Compared with controls, IFN-γ(-/-) and Tbx21(-/-) mice were characterized by reduced ATII-mediated vascular recruitment of both natural killer (NK)1.1(+) NK-cells as the major producers of IFN-γ and CD11b(+)Gr-1(low) interleukin-12 secreting monocytes. Selective depletion and adoptive transfer experiments identified NK-cells as essential contributors to vascular dysfunction and showed that T-bet(+)lysozyme M(+) myelomonocytic cells were required for NK-cell recruitment into vascular tissue and local IFN-γ production. CONCLUSIONS: We provide first evidence that NK-cells play an essential role in ATII-induced vascular dysfunction. In addition, we disclose the T-bet-IFN-γ pathway and mutual monocyte-NK-cell activation as potential therapeutic targets in cardiovascular disease.
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Angiotensina II/farmacologia , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Monócitos/metabolismo , Doenças Vasculares/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Interferon gama/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Estresse Oxidativo/imunologia , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Valores de Referência , Doenças Vasculares/imunologiaRESUMO
Aiming to apply automatic arousal detection to support sleep laboratories, we evaluated an optimized, state-of-the-art approach using data from daily work in our university hospital sleep laboratory. Therefore, a machine learning algorithm was trained and evaluated on 3423 polysomnograms of people with various sleep disorders. The model architecture is a U-net that accepts 50 Hz signals as input. We compared this algorithm with models trained on publicly available datasets, and evaluated these models using our clinical dataset, particularly with regard to the effects of different sleep disorders. In an effort to evaluate clinical relevance, we designed a metric based on the error of the predicted arousal index. Our models achieve an area under the precision recall curve (AUPRC) of up to 0.83 and F1 scores of up to 0.81. The model trained on our data showed no age or gender bias and no significant negative effect regarding sleep disorders on model performance compared to healthy sleep. In contrast, models trained on public datasets showed a small to moderate negative effect (calculated using Cohen's d) of sleep disorders on model performance. Therefore, we conclude that state-of-the-art arousal detection on our clinical data is possible with our model architecture. Thus, our results support the general recommendation to use a clinical dataset for training if the model is to be applied to clinical data.
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Nível de Alerta , Aprendizado de Máquina , Polissonografia , Transtornos do Sono-Vigília , Sono , Humanos , Nível de Alerta/fisiologia , Polissonografia/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/fisiopatologia , Adulto , Sono/fisiologia , Algoritmos , IdosoRESUMO
Introduction: Deep brain stimulation (DBS) is a highly effective treatment option in Parkinson's disease. However, the underlying mechanisms of action, particularly effects on neuronal plasticity, remain enigmatic. Adult neurogenesis in the subventricular zone-olfactory bulb (SVZ-OB) axis and in the dentate gyrus (DG) has been linked to various non-motor symptoms in PD, e.g., memory deficits and olfactory dysfunction. Since DBS affects several of these non-motor symptoms, we analyzed the effects of DBS in the subthalamic nucleus (STN) and the entopeduncular nucleus (EPN) on neurogenesis in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats. Methods: In our study, we applied five weeks of continuous bilateral STN-DBS or EPN-DBS in 6-OHDA-lesioned rats with stable dopaminergic deficits compared to 6-OHDA-lesioned rats with corresponding sham stimulation. We injected two thymidine analogs to quantify newborn neurons early after DBS onset and three weeks later. Immunohistochemistry identified newborn cells co-labeled with NeuN, TH and GABA within the OB and DG. As a putative mechanism, we simulated the electric field distribution depending on the stimulation site to analyze direct electric effects on neural stem cell proliferation. Results: STN-DBS persistently increased the number of newborn dopaminergic and GABAergic neurons in the OB but not in the DG, while EPN-DBS does not impact neurogenesis. These effects do not seem to be mediated via direct electric stimulation of neural stem/progenitor cells within the neurogenic niches. Discussion: Our data support target-specific effects of STN-DBS on adult neurogenesis, a putative modulator of non-motor symptoms in Parkinson's disease.
RESUMO
Disease-modifying therapeutics in the α-synucleinopathies multiple system atrophy (MSA) and Parkinson's Disease (PD) are in early phases of clinical testing. Involving patients' preferences including therapy-associated risk willingness in initial stages of therapy development has been increasingly pursued in regulatory approval processes. In our study with 49 MSA and 38 PD patients, therapy-associated risk willingness was quantified using validated standard gamble scenarios for varying severities of potential drug or surgical side effects. Demonstrating a non-gaussian distribution, risk willingness varied markedly within, and between groups. MSA patients accepted a median 1% risk [interquartile range: 0.001-25%] of sudden death for a 99% [interquartile range: 99.999-75%] chance of cure, while PD patients reported a median 0.055% risk [interquartile range: 0.001-5%]. Contrary to our hypothesis, a considerable proportion of MSA patients, despite their substantially impaired quality of life, were not willing to accept increased therapy-associated risks. Satisfaction with life situation, emotional, and nonmotor disease burden were associated with MSA patients' risk willingness in contrast to PD patients, for whom age, and disease duration were associated factors. An individual approach towards MSA and PD patients is crucial as direct inference from disease (stage) to therapy-associated risk willingness is not feasible. Such studies may be considered by regulatory agencies in their approval processes assisting with the weighting of safety aspects in a patient-centric manner. A systematic quantitative assessment of patients' risk willingness and associated features may assist physicians in conducting individual consultations with patients who have MSA or PD by facilitating communication of risks and benefits of a treatment option.