RESUMO
In the past 20 years, more remarkable revelations about sleep and its varied functions have arguably been made than in the previous 200. Building on this swell of recent findings, this essay provides a broad sampling of selected research highlights across genetic, molecular, cellular, and physiological systems within the body, networks within the brain, and large-scale social dynamics. Based on this raft of exciting new discoveries, we have come to realize that sleep, in this moment of its evolution, is very much polyfunctional (rather than monofunctional), yet polyfunctional for reasons we had never previously considered. Moreover, these new polyfunctional insights powerfully reaffirm sleep as a critical biological, and thus health-sustaining, requisite. Indeed, perhaps the only thing more impressive than the unanticipated nature of these newly emerging sleep functions is their striking divergence, from operations of molecular mechanisms inside cells to entire group societal dynamics.
Assuntos
Sono , Animais , Humanos , Encéfalo/fisiologia , Sono/fisiologiaRESUMO
BACKGROUND: Alzheimer's disease (AD) pathology impairs cognitive function. Yet some individuals with high amounts of AD pathology suffer marked memory impairment, while others with the same degree of pathology burden show little impairment. Why is this? One proposed explanation is cognitive reserve i.e., factors that confer resilience against, or compensation for the effects of AD pathology. Deep NREM slow wave sleep (SWS) is recognized to enhance functions of learning and memory in healthy older adults. However, that the quality of NREM SWS (NREM slow wave activity, SWA) represents a novel cognitive reserve factor in older adults with AD pathology, thereby providing compensation against memory dysfunction otherwise caused by high AD pathology burden, remains unknown. METHODS: Here, we tested this hypothesis in cognitively normal older adults (N = 62) by combining 11C-PiB (Pittsburgh compound B) positron emission tomography (PET) scanning for the quantification of ß-amyloid (Aß) with sleep electroencephalography (EEG) recordings to quantify NREM SWA and a hippocampal-dependent face-name learning task. RESULTS: We demonstrated that NREM SWA significantly moderates the effect of Aß status on memory function. Specifically, NREM SWA selectively supported superior memory function in individuals suffering high Aß burden, i.e., those most in need of cognitive reserve (B = 2.694, p = 0.019). In contrast, those without significant Aß pathological burden, and thus without the same need for cognitive reserve, did not similarly benefit from the presence of NREM SWA (B = -0.115, p = 0.876). This interaction between NREM SWA and Aß status predicting memory function was significant after correcting for age, sex, Body Mass Index, gray matter atrophy, and previously identified cognitive reserve factors, such as education and physical activity (p = 0.042). CONCLUSIONS: These findings indicate that NREM SWA is a novel cognitive reserve factor providing resilience against the memory impairment otherwise caused by high AD pathology burden. Furthermore, this cognitive reserve function of NREM SWA remained significant when accounting both for covariates, and factors previously linked to resilience, suggesting that sleep might be an independent cognitive reserve resource. Beyond such mechanistic insights are potential therapeutic implications. Unlike many other cognitive reserve factors (e.g., years of education, prior job complexity), sleep is a modifiable factor. As such, it represents an intervention possibility that may aid the preservation of cognitive function in the face of AD pathology, both present moment and longitudinally.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Reserva Cognitiva , Sono de Ondas Lentas , Humanos , Idoso , Doença de Alzheimer/patologia , Imageamento por Ressonância Magnética , Peptídeos beta-Amiloides , Sono , Tomografia por Emissão de PósitronsRESUMO
Why does poor-quality sleep lead to atherosclerosis? In a diverse sample of over 1,600 individuals, we describe a pathway wherein sleep fragmentation raises inflammatory-related white blood cell counts (neutrophils and monocytes), thereby increasing atherosclerosis severity, even when other common risk factors have been accounted for. Improving sleep quality may thus represent one preventive strategy for lowering inflammatory status and thus atherosclerosis risk, reinforcing public health policies focused on sleep health.
Assuntos
Vasos Sanguíneos/patologia , Privação do Sono/complicações , Actigrafia , Idoso , Aterosclerose/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Índice de Gravidade de DoençaRESUMO
Trait anxiety has been associated with altered activity within corticolimbic pathways connecting the amygdala and rostral anterior cingulate cortex (rACC), which receive rich dopaminergic input. Though the popular culture uses the term "chemical imbalance" to describe the pathophysiology of psychiatric conditions such as anxiety disorders, we know little about how individual differences in human dopamine neurochemistry are related to variation in anxiety and activity within corticolimbic circuits. We addressed this issue by examining interindividual variability in dopamine release at rest using [11C]raclopride positron emission tomography (PET), functional connectivity between amygdala and rACC using resting-state functional magnetic resonance imaging (fMRI), and trait anxiety measures in healthy adult male and female humans. To measure endogenous dopamine release, we collected two [11C]raclopride PET scans per participant. We contrasted baseline [11C]raclopride D2/3 receptor binding and D2/3 receptor binding following oral methylphenidate administration. Methylphenidate blocks the dopamine transporter, which increases extracellular dopamine and leads to reduced [11C]raclopride D2/3 receptor binding via competitive displacement. We found that individuals with higher dopamine release in the amygdala and rACC self-reported lower trait anxiety. Lower trait anxiety was also associated with reduced rACC-amygdala functional connectivity at baseline. Further, functional connectivity showed a modest negative relationship with dopamine release such that reduced rACC-amygdala functional connectivity was accompanied by higher levels of dopamine release in these regions. Together, these findings contribute to hypodopaminergic models of anxiety and support the utility of combining fMRI and PET measures of neurochemical function to advance our understanding of basic affective processes in humans.SIGNIFICANCE STATEMENT It is common wisdom that individuals vary in their baseline levels of anxiety. We all have a friend or colleague we know to be more "tightly wound" than others, or, perhaps, we are the ones marveling at others' ability to "just go with the flow." Although such observations about individual differences within nonclinical populations are commonplace, the neural mechanisms underlying normal variation in trait anxiety have not been established. Using multimodal brain imaging in humans, this study takes initial steps in linking intrinsic measures of neuromodulator release and functional connectivity within regions implicated in anxiety disorders. Our findings suggest that in healthy adults, higher levels of trait anxiety may arise, at least in part, from reduced dopamine neurotransmission.
Assuntos
Ansiedade/diagnóstico por imagem , Ansiedade/metabolismo , Dopamina/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Adolescente , Adulto , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Racloprida/metabolismo , Racloprida/farmacologia , Adulto JovemRESUMO
Dopaminergic signaling in striatum is strongly implicated in executive functions including cognitive flexibility. However, there is a paucity of multimodal research in humans defining the nature of relationships between endogenous dopamine, striatal network activity, and cognition. Here, we measured dopamine synthesis capacity in young and older adults using the PET tracer 6-[18F]fluoro-l- m-tyrosine and examined its relationship with cognitive performance and functional connectivity during an fMRI study of task switching. Aging is associated with alteration in dopamine function, including profound losses in dopamine receptors but an apparent elevation in dopamine synthesis. A compensatory benefit of upregulated dopamine synthesis in aging has not been established. Across young and older adults, we found that cognitive flexibility (low behavioral switch cost) was associated with stronger task-related functional connectivity within canonical fronto-striato-thalamic circuits connecting left inferior frontal gyrus, dorsal caudate nucleus (DCA) and ventral lateral/ventral anterior thalamic nuclei. In young adults, functional connectivity mediated the influence of DCA dopamine synthesis capacity on switch cost. For older adults, these relationships were modified such that DCA synthesis capacity and connectivity interacted to influence switch cost. Older adults with most elevated synthesis capacity maintained the pattern of connectivity-cognition relationships observed in youth, whereas these relationships were not evident for older adults with low synthesis capacity. Together, these findings suggest a role of dopamine in tuning striatal circuits to benefit executive function in young adults and clarify the functional impact of elevated dopamine synthesis capacity in aging.
Assuntos
Envelhecimento/metabolismo , Envelhecimento/psicologia , Encéfalo/metabolismo , Cognição/fisiologia , Dopamina/metabolismo , Função Executiva/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Individualidade , Imageamento por Ressonância Magnética , Masculino , Imagem Multimodal , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Tempo de Reação , Adulto JovemRESUMO
BACKGROUND: Adenoid cystic carcinoma (ACC), a rare tumor of epithelial cell origin, commonly arises from the major salivary glands. Uncommonly it may be found outside the salivary glands and it's especially rare in the nasal cavity. CASE PRESENTATION: A 71-year female had complaints of swelling at the base of nose, Fine needle aspiration (FNA) from the swelling revealed features of adenoid cystic carcinoma; cell block & IHC for CD-117 was positive. CONCLUSIONS: Sino-nasal ACC (SNACC) continues to pose diagnostic and therapeutic challenges to clinicians. Due to its rarity & vague presentation, early diagnosis requires a high index of suspicion. FNA can be used as an invaluable diagnostic tool in the evaluation of these lesions. Since it's incidence in sinonasal region is rare; our attempt to report this case will heighten the physician's awareness of this disease, helping further treatment.
RESUMO
Aging is accompanied by profound changes in the brain's dopamine system that affect cognitive function. Evidence of powerful individual differences in cognitive aging has sharpened focus on identifying biological factors underlying relative preservation versus vulnerability to decline. Dopamine represents a key target in these efforts. Alterations of dopamine receptors and dopamine synthesis are seen in aging, with receptors generally showing reduction and synthesis demonstrating increases. Using the PET tracer 6-[18F]fluoro-l-m-tyrosine, we found strong support for upregulated striatal dopamine synthesis capacity in healthy older adult humans free of amyloid pathology, relative to young people. We next used fMRI to define the functional impact of elevated synthesis capacity on cognitive flexibility, a core component of executive function. We found clear evidence in young adults that low levels of synthesis capacity were suboptimal, associated with diminished cognitive flexibility and altered frontoparietal activation relative to young adults with highest synthesis values. Critically, these relationships between dopamine, performance, and activation were transformed in older adults with higher synthesis capacity. Variability in synthesis capacity was related to intrinsic frontoparietal functional connectivity across groups, suggesting that striatal dopamine synthesis influences the tuning of networks underlying cognitive flexibility. Together, these findings define striatal dopamine's association with cognitive flexibility and its neural underpinnings in young adults, and reveal the alteration in dopamine-related neural processes in aging. SIGNIFICANCE STATEMENT: Few studies have combined measurement of brain dopamine with examination of the neural basis of cognition in youth and aging to delineate the underlying mechanisms of these associations. Combining in vivo PET imaging of dopamine synthesis capacity, fMRI, and a sensitive measure of cognitive flexibility, we reveal three core findings. First, we find evidence supporting older adults' capacity to upregulate dopamine synthesis. Second, we define relationships between dopamine, cognition, and frontoparietal activity in young adults indicating high levels of synthesis capacity are optimal. Third, we demonstrate alteration of these relationships in older adults, suggesting neurochemical modulation of cognitive flexibility changes with age.
Assuntos
Envelhecimento/fisiologia , Cognição/fisiologia , Dopamina/fisiologia , Neurônios Dopaminérgicos/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Dopamina/biossíntese , Função Executiva/fisiologia , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Neostriado/metabolismo , Testes Neuropsicológicos , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/fisiologia , Tomografia por Emissão de Pósitrons , Tempo de Reação/fisiologia , Adulto JovemRESUMO
ß-amyloid (Aß) and tau pathology become increasingly prevalent with age, however, the spatial relationship between the two pathologies remains unknown. We examined local (same region) and non-local (different region) associations between these 2 aggregated proteins in 46 normal older adults using [18F]AV-1451 (for tau) and [11C]PiB (for Aß) positron emission tomography (PET) and 1.5T magnetic resonance imaging (MRI) images. While local voxelwise analyses showed associations between PiB and AV-1451 tracer largely in the temporal lobes, k-means clustering revealed that some of these associations were driven by regions with low tracer retention. We followed this up with a whole-brain region-by-region (local and non-local) partial correlational analysis. We calculated each participant's mean AV-1451 and PiB uptake values within 87 regions of interest (ROI). Pairwise ROI analysis demonstrated many positive PiB-AV-1451 associations. Importantly, strong positive partial correlations (controlling for age, sex, and global gray matter fraction, p<.01) were identified between PiB in multiple regions of association cortex and AV-1451 in temporal cortical ROIs. There were also less frequent and weaker positive associations of regional PiB with frontoparietal AV-1451 uptake. Particularly in temporal lobe ROIs, AV-1451 uptake was strongly predicted by PiB across multiple ROI locations. These data indicate that Aß and tau pathology show significant local and non-local regional associations among cognitively normal elderly, with increased PiB uptake throughout the cortex correlating with increased temporal lobe AV-1451 uptake. The spatial relationship between Aß and tau accumulation does not appear to be specific to Aß location, suggesting a regional vulnerability of temporal brain regions to tau accumulation regardless of where Aß accumulates.
Assuntos
Envelhecimento/patologia , Peptídeos beta-Amiloides/metabolismo , Lobo Temporal/patologia , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/análise , Compostos de Anilina , Carbolinas , Radioisótopos de Carbono , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tiazóis , Proteínas tau/análiseRESUMO
Electroconvulsive therapy (ECT) is one of the most effective treatments in psychiatry. However, it has many cognitive and non-cognitive adverse effects (AEs). There are lacunae in the literature on systematic assessment of non-cognitive AEs. There is a need for a standard, comprehensive and specific clinical tool to evaluate this. Hence, a checklist of short-term AEs of ECT (SAVE) with a 2-phase assessment was developed. Content validation was done using 15 experts' ratings and predefined content validity ratio and index (CVR and CVI) in a two-stage modified Delphi method. The checklist had a good CVR and CVI with a final tool of 39 items. The tool was sensitive and identified the non-cognitive AEs after ECT. Cardiovascular and musculoskeletal systems displayed the highest incidence. Many participants exhibited delayed recovery in orientation, gait, and stance, highlighting a necessity for meticulous monitoring. SAVE is the first standardised tool to assess short-term ECT-related AEs systematically. This checklist likely identifies clinically significant incidences of adverse effects. Its regular use may enhance the safety of ECT and patient comfort by supporting early identification and intervention for AEs. However, given the transient nature of AEs, further studies are needed to determine their predictive validity for long-term consequences.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Eletroconvulsoterapia , Humanos , Eletroconvulsoterapia/efeitos adversos , Eletroconvulsoterapia/métodos , Lista de Checagem , Resultado do Tratamento , PrevisõesRESUMO
Insufficient sleep impairs glucose regulation, increasing the risk of diabetes. However, what it is about the human sleeping brain that regulates blood sugar remains unknown. In an examination of over 600 humans, we demonstrate that the coupling of non-rapid eye movement (NREM) sleep spindles and slow oscillations the night before is associated with improved next-day peripheral glucose control. We further show that this sleep-associated glucose pathway may influence glycemic status through altered insulin sensitivity, rather than through altered pancreatic beta cell function. Moreover, we replicate these associations in an independent dataset of over 1,900 adults. Of therapeutic significance, the coupling between slow oscillations and spindles was the most significant sleep predictor of next-day fasting glucose, even more so than traditional sleep markers, relevant to the possibility of an electroencephalogram (EEG) index of hyperglycemia. Taken together, these findings describe a sleeping-brain-body framework of optimal human glucose homeostasis, offering a potential prognostic sleep signature of glycemic control.
Assuntos
Ondas Encefálicas , Sono , Adulto , Humanos , Sono/fisiologia , Eletroencefalografia , Glucose , HomeostaseRESUMO
INTRODUCTION: Breast cancer is rapidly emerging as the leading cause of cancer in Indian women. Robust cytopathology and histopathology services are required to tackle this growing burden. The use of rapid on-site evaluation (ROSE) and the International Academy of Cytology (IAC) Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy (FNAB) Cytopathology, which offers structured protocols, are expected to improve breast cytopathology reporting. METHODS: We retrieved the cytopathology slides, categorized them by the IAC Yokohama System and histopathology data of all the patients who had been investigated for breast lesions from September 2016 to December 2018, and compared the cytopathology and histopathology. Risk of malignancy (ROM) and performance metrics, like sensitivity, specificity, predictive values, accuracy, and area under the curve were computed. RESULTS: A total of 1,147 FNABs were evaluated, of which 442 (38.5%) underwent ROSE and 624 (54.4%) histopathology. Reported using IAC categories, our cohort recorded 4.9% inadequate, 65.3% benign, 7.8% atypical, 3.3% suspicious for malignancy, and 18.7% malignant lesions. The overall sensitivity and specificity for identifying in situ and malignant lesions were 99.1% and 99.3%, respectively, and were substantially improved by ROSE. ROSE improved the concordance between cytopathology and histopathology from 76.9% to 90.2%, by reducing inadequate (p < 0.001) cases. The ROM increased along a gradient from inadequate to malignant categories, with the gradient being sharpened by ROSE. The false negativity rate was 0.7% and false positivity rate 0%. CONCLUSION: Incorporating ROSE and the IAC Yokohama System for breast cytopathology reporting improves accurate diagnosis of breast lesions, prevents missed diagnoses, and provides reliable estimates of ROM. These protocols also aid in standardizing a reproducible system for monitoring and auditing of breast pathology services, identify areas that need strengthening, and improve training at pathology centers.
Assuntos
Doenças Mamárias/patologia , Neoplasias da Mama/patologia , Mama/patologia , Adulto , Biópsia por Agulha Fina , Feminino , Humanos , Índia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Tempo , Fluxo de Trabalho , Adulto JovemRESUMO
The 18F-AV-1451 PET tracer binds to tau, an Alzheimer's disease biomarker. The standardized uptake value ratio (SUVR) 80-100 min window is widely used to quantify tau binding, although 18F-AV-1451 continues increasing relative to a reference region in regions with tau deposition. Left uncorrected, acquisition time inaccuracies can lead to errors from -4% to 6% in 20-min SUVR measurements in subjects with Alzheimer's disease. In 40 subjects with scans from 75-115 min following 18F-AV-1451 injection, we created 20-min reconstructions (4×5 min) of start-times ranging from 75-85 min, as proxies of offset scans and calculated the mean in regions of interest (ROIs). We developed a segmented least squares (SLS) method to obtain error-minimizing weighting coefficients for 18F-AV-1451 ROIs that best predict SUVR 80-100 from weighted means of SUVRs from offset start-times. We compared residual errors of our SLS method to those in: 1) uncorrected offset 20-min-SUVRs; 2) the mean of five-min frames within the 80-100 window; and 3) a least-squares interpolation method. We evaluated errors induced by start-time offset on SUVRs for each method. TheSLS, which corrected using least-squares coefficients of 5-min components, consistently reduced errors across all offset starttimes. Effect size analysis for simulated clinical longitudinal 18F-AV-1451 drug trials showed that uncorrected 20-min offset SUVRs would require up to 20% more participants to detect treatment effects compared with using SLS. Correction of SUVR scan-time errors by SLS minimizes errors compared with other correction methods and may be extended to other scanners and tracers.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Biomarcadores/análise , Carbolinas/administração & dosagem , Cintilografia/métodos , Proteínas tau/análise , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico por imagem , Simulação por Computador , Meios de Contraste , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Método de Monte Carlo , Reprodutibilidade dos TestesAssuntos
Antipsicóticos , Clozapina , Adulto , Humanos , Antipsicóticos/uso terapêutico , Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Clozapina/uso terapêutico , Eletroconvulsoterapia/métodos , Estudos de Viabilidade , Esquizofrenia/tratamento farmacológico , Esquizofrenia Resistente ao Tratamento/tratamento farmacológico , Resultado do Tratamento , FemininoRESUMO
BACKGROUND: Histoplasma capsulatum is a dimorphic fungus predominately found in soils enriched with bird and bat excreta. Although several cases of histoplasmosis have been reported in India, diagnosis using cytology has been done in very few cases. CASE PRESENTATION: We report here a case of disseminated histoplasmosis in a 46-year-old Indian man. CONCLUSION: Skin scrape cytology is a simple, safe, and rapid technique to establish the initial diagnosis, thus promoting early treatment and favorable outcome, in cutaneous fungal infections.
Assuntos
Histoplasma/isolamento & purificação , Histoplasmose/diagnóstico , Pele , Diagnóstico Precoce , Intervenção Médica Precoce/métodos , Histoplasmose/etiologia , Histoplasmose/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Pele/microbiologia , Pele/patologiaRESUMO
Positron Emission Tomography (PET) imaging allows the estimation of multiple aspects of dopamine function including dopamine synthesis capacity, dopamine release, and D2/3 receptor binding. Though dopaminergic dysregulation characterizes a number of neuropsychiatric disorders including schizophrenia and addiction, there has been relatively little investigation into the nature of relationships across dopamine markers within healthy individuals. Here we used PET imaging in 40 healthy adults to compare, within individuals, the estimates of dopamine synthesis capacity (Ki) using 6-[18F]fluoro-l-m-tyrosine ([18F]FMT; a substrate for aromatic amino acid decarboxylase), baseline D2/3 receptor-binding potential using [11C]raclopride (a weak competitive D2/3 receptor antagonist), and dopamine release using [11C]raclopride paired with oral methylphenidate administration. Methylphenidate increases synaptic dopamine by blocking the dopamine transporter. We estimated dopamine release by contrasting baseline D2/3 receptor binding and D2/3 receptor binding following methylphenidate. Analysis of relationships among the three measurements within striatal regions of interest revealed a positive correlation between [18F]FMT Ki and the baseline (placebo) [11C]raclopride measure, such that participants with greater synthesis capacity showed higher D2/3 receptor-binding potential. In contrast, there was no relationship between [18F]FMT and methylphenidate-induced [11C]raclopride displacement. These findings shed light on the nature of regulation between pre- and postsynaptic dopamine function in healthy adults, which may serve as a template from which to identify and describe alteration with disease.