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1.
Nature ; 574(7779): 532-537, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645730

RESUMO

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.


Assuntos
Colo/citologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Mutação , Sintomas Prodrômicos , Reto/citologia , Adenoma/genética , Adenoma/patologia , Idoso , Proteína Axina/genética , Carcinoma/genética , Carcinoma/patologia , Transformação Celular Neoplásica , Células Clonais/citologia , Células Clonais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Feminino , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Células-Tronco/citologia , Células-Tronco/metabolismo
3.
Undersea Hyperb Med ; 46(4): 503-507, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31509906

RESUMO

We hypothesized that heart rate variability (HRV) can be used as a physiological monitor of exposures to hypercapnia. HRV was analyzed in 15 male subjects breathing air and then air plus 4%, 5% or 6% carbon dioxide (CO2). A progressive elevation in randomness of HRV best depicted as a divergence of data on Poincar é plots of self-similarity occurred as CO2 increased, and resolved when returning sd to ambient conditions. Results indicate that HRV may be useful as a prompt (⟨ 2 minute) early warning of hypercapnia that occurs prior to overt symptomatology.


Assuntos
Frequência Cardíaca , Hipercapnia/diagnóstico , Administração por Inalação , Adulto , Ar , Dióxido de Carbono/administração & dosagem , Estudos Cross-Over , Eletrocardiografia , Humanos , Hipercapnia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nitrogênio/administração & dosagem , Oxigênio/administração & dosagem , Sintomas Prodrômicos , Adulto Jovem
4.
Postgrad Med ; 131(7): 501-508, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31483196

RESUMO

Objectives: Aiginition Longitudinal Biomarker Investigation Of Neurodegeneration (ALBION) is a longitudinal ongoing study initiated in 2018 that takes place in the Cognitive Disorders Clinic of Aiginition Hospital of the National and Kapodistrian University of Athens. Its aim is to address several research questions concerning the preclinical and prodromal stage of Alzheimer's disease and explore potential markers for early detection, prediction, and primary prevention of dementia. Methods: We here present the design and the preliminary baseline characteristics of ALBION. The sample of our study consists of people aged over 50 who are concerned about their memory but are cognitively normal (CN) or have mild cognitive deficits. Each participant undergoes an extensive assessment including several demographic, medical, social, environmental, clinical, nutritional, neuropsychological determinants and lifestyle activities. Furthermore, we are collecting data from portable devices, neuroimaging techniques and biological samples (blood, stools, CSF). All participants are assessed annually for a period of 10 years. Results: In total, 47 participants have completed the initial evaluation up to date and are divided in two groups, CN individuals (N = 26) and MCI patients (N = 21), based on their cognitive status. The participants are, on average, 64 years old, 46.3% of the sample is male with an average of 12.73 years of education. MCI patients report more comorbidities and have a lower score in the MMSE test. Regarding APOE status, 2 participants are ε4 homozygotes and 10 ε4 heterozygotes. CSF analyses (Aß42, Τ-tau, P-tau) revealed no differences between the two groups. Conclusion: The ALBION study offers an opportunity to explore preclinical dementia and identify new and tailored markers, particularly relating to lifestyle. Further investigation of these populations may provide a wider profile of the changes taking place in the preclinical phase of dementia, leading to potentially effective therapeutic and preventive strategies.


Assuntos
Doença de Alzheimer/prevenção & controle , Disfunção Cognitiva/metabolismo , Prevenção Primária , Sintomas Prodrômicos , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Biomarcadores , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Diagnóstico Precoce , Eletroencefalografia , Feminino , Neuroimagem Funcional , Grécia , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Dados Preliminares , Proteínas tau/líquido cefalorraquidiano
5.
Life Sci ; 235: 116843, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494172

RESUMO

Polycystic ovary syndrome (PCOS) is a multifactorial disease, which is resulted from the three common features, hyperandrogenism (HA), ovulatory dysfunction (OD), and polycystic ovarian morphology (PCOM). The environmental inducers (like diet, lifestyle, chemicals, drugs, and ageing) and cardiometabolic risk factors (such as insulin resistance, metabolic syndrome, and obesity) are involved in pathogenesis of PCOS. The growing body of evidence has been shown that there exist endothelial cell dysfunction (ECD) in women with PCOS independent of age, weight and metabolic abnormalities. It has been shown that a broad spectrum of cardiovascular risk markers are involved in ECD- induced cardiovascular disease. It is well described that there are no worldwide treatments for PCOS and all of pharmacological treatments are off -label without any approval. MNAM is one of potential therapeutic factor, which produced by nicotinamide N-methyltransferase (NNMT) via consumption of S-adenosyl methionine (SAM) and nicotinamide. Only one study has shown higher expression of its producer enzyme, NNMT, in the cumulus cells of women with PCOS. Therefore, we reviewed beneficial effects of MNAM on modulation of cardiometabolic risk factors, which are associated to PCOS and try to describe possible mode of action of MNAM in the regulation of these markers.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/complicações , Niacinamida/análogos & derivados , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/complicações , Sintomas Prodrômicos , Biomarcadores/sangue , Feminino , Humanos , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Fatores de Risco
6.
Ethiop J Health Sci ; 29(4): 439-446, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31447516

RESUMO

Background: Prodromal symptoms in individuals with risk factors remain challenging, even though myocardial infarction has been noted in research. This study determined the association of risk factors with patients' baseline myocardial infarction related prodromal symptoms. Methods: In a cross-sectional study, 154 Iranian men and women, mean age 59.62 ± 12.74 years were assessed in 2016-2017. The frequency besides severity of 33 prodromal symptoms and risk factors was assessed using McSweeney Prodromal Myocardial Infarction Symptom Survey. Results: The main cardiac prodromal symptoms experienced by patients were chest pain/discomfort (n = 99, 64.30%), unusual fatigue (n = 78, 50.60%), and sleep disturbance (n = 33, 20.40%). Women experienced more prodromal symptoms than men (33.26 ± 21.88 vs. 25.48 ± 17.75). Among risk factors, only sex was associated with prodromal symptoms score (P < 0.05). Conclusion: The frequently experienced prodromal symptoms, i.e., before MI were chest pain/discomfort, unusual fatigue, and sleep disturbance. A crucial finding was the significant association between sex and prodromal symptoms. Identifying prodromal symptoms in patients with risk factors can prevent the incidence of myocardial infarction.


Assuntos
Infarto do Miocárdio/epidemiologia , Sintomas Prodrômicos , Idoso , Dor no Peito/epidemiologia , Dor no Peito/etiologia , Estudos Transversais , Fadiga/epidemiologia , Fadiga/etiologia , Feminino , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Fatores de Risco , Fatores Sexuais , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/etiologia
7.
BMC Infect Dis ; 19(1): 739, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438872

RESUMO

BACKGROUND: Incidence of the opportunistic infection Pneumocystis jirovecii pneumonia (PJP) in solid organ transplant patients ranges from 5 to 15% with a mortality of up to 38%. CASE PRESENTATION: We present a liver transplant recipient who developed hypoxemic respiratory failure related to PJP soon after treatment for allograft rejection. His presentation was preceded by severe hypercalcemia of 14.6 mg/dL and an ionized calcium of 1.7 mmol/L which remained elevated despite usual medical management and eventually required renal replacement therapy. As approximately 5% of PJP cases have granulomas, here we review the role of pulmonary macrophages and inflammatory cytokines in the pathophysiology of granuloma-mediated hypercalcemia. We also discuss the interpretation of our patient's laboratory studies, response to medical therapy, and clinical risk factors which predisposed him to PJP. CONCLUSIONS: It is important for clinicians to consider PJP as an etiology of granulomatous pneumonia and non-parathyroid hormone mediated hypercalcemia in chronically immunosuppressed organ transplant recipients for timely diagnosis and management.


Assuntos
Hipercalcemia/diagnóstico , Transplante de Fígado , Pneumocystis carinii , Pneumonia por Pneumocystis/diagnóstico , Sintomas Prodrômicos , Transplantados , Idoso , Diagnóstico Diferencial , Humanos , Hipercalcemia/etiologia , Hospedeiro Imunocomprometido , Transplante de Fígado/efeitos adversos , Masculino , Infecções Oportunistas/complicações , Infecções Oportunistas/diagnóstico , Pneumonia por Pneumocystis/complicações , Índice de Gravidade de Doença
8.
J Clin Neurosci ; 69: 139-142, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31439483

RESUMO

BACKGROUND: The determinants of restless legs syndrome (RLS) occurring in co-morbid association with Parkinson's disease (PD) are currently unknown. METHODS: We performed a skin biopsy in proximal and distal sites of lower limbs in four PD patients, in which RLS had emerged in the pre-motor phase. RESULTS: A reduced somato-sensory intraepidermal nerve fiber (IENF) density mainly in the proximal sites, indicative of non-length-dependent small fiber pathology (SFP), was found in all patients, in absence of electroneurographic signs of large fiber neuropathy. DISCUSSION: The lack of known secondary causes of SFP is consistent with a process intrinsic to PD and, likewise, the absence of known disease conditions associated to RLS, would support the view of a link between the latter disorder and the distal axonopathy. The non-length-dependent pattern of SFP suggest an involvement of the somato-sensory dorsal root ganglia small neurons, consistent with a somato-sensory neuronopathy, which characterizes the RLS in these patients. CONCLUSION: If these findings will be confirmed in a larger cohort of patients, the RLS co-morbid with PD should be regarded as an heterogeneous condition, since the one emerging in the pre-motor phase might represent a prodromal feature of the neurodegenerative disease as an epiphenomenon of somato-sensory SFP. In contrast, for the RLS developing in clinically manifest PD, a possible association with the impairment of the DAergic diencephalo-spinal pathway and the induction by chronic DAergic treatment has been hypothesized.


Assuntos
Doença de Parkinson/complicações , Síndrome das Pernas Inquietas/complicações , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sintomas Prodrômicos , Síndrome das Pernas Inquietas/epidemiologia
9.
Sleep Med Clin ; 14(3): 351-362, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31375203

RESUMO

In recent years, the diagnostic approach to rapid eye movement (REM) sleep behavior disorder (RBD) has become more objective and accurate. This was achieved mainly by introduction of methods to exactly quantify electromyographic (EMG) activity in various muscles during REM sleep. The most established muscle combination for RBD diagnosis is the mentalis and upper extremity EMG. Computer-assisted systems for this analysis have been described, and an increasing number of studies looked into analysis of video events. Recently, prodromal phases of isolated RBD have been recognized.


Assuntos
Eletromiografia , Polissonografia , Transtorno do Comportamento do Sono REM/diagnóstico , Progressão da Doença , Humanos , Processamento de Imagem Assistida por Computador , Mucosa Intestinal/metabolismo , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/fisiopatologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Medicina de Precisão , Sintomas Prodrômicos , Transtorno do Comportamento do Sono REM/metabolismo , Transtorno do Comportamento do Sono REM/fisiopatologia , Glândulas Salivares/metabolismo , Pele/metabolismo , Sono REM , /fisiopatologia , Gravação em Vídeo , alfa-Sinucleína/metabolismo
11.
Neurology ; 93(2): 72-79, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31167933

RESUMO

The development of in vivo imaging of the pathologic hallmark of Alzheimer disease (AD), ß-amyloid (Aß), altered the framing of its pathophysiology and formulation of inclusion criteria for clinical trials. Recent evidence suggests that in vivo measures of Aß deposition below a threshold indicative of Aß positivity carry critical information on future cognitive decline and accumulation of AD pathology, potentially already at a younger age. Here, we integrate the existing literature on histopathology of Aß and its convergence and divergence with in vivo Aß imaging. The evidence presented amounts to a reconceptualization, in which we advocate for a closer look into Aß accumulation rates in earlier life, the factors that promote accumulation, comparative studies with different markers of Aß, and longitudinal designs to elucidate when AD pathology rises and how it shifts from benign to malignant stages that ultimately define AD. These efforts open a new window of opportunity for disease-modifying interventions.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Doenças Assintomáticas , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva , Progressão da Doença , Humanos , Tomografia por Emissão de Pósitrons , Sintomas Prodrômicos , Prognóstico
12.
J Clin Neurosci ; 66: 26-32, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31153750

RESUMO

The aim of the current study is to determine the predictive value of alpha-synuclein (AS) aggregation in stomach surgical specimens in combination with selected clinical prodromal markers (CPMs) for development of Parkinson disease (PD) in a normal population. We organized a prospective, long-term, clinicopathologic cohort of patients without neurological diseases who received a radical operation for early gastric cancer (EGC) between ages 50 and 65 years. The participants will be followed for up to 10 years and screened for CPMs and motor symptoms by annual telephone interview. If a participant reports one or more positive answers to screening questions about motor symptoms, they will be regarded as having possible parkinsonism. A movement disorder specialist will then evaluate whether that participant has PD. The primary outcome is the development of PD during the 10-year follow-up. The recruitment period has been completed, and the baseline clinical characteristics are compared between participants with and without possible parkinsonism. A total of 718 participants (mean age: 60.1 ±â€¯5.9) was recruited. The motor symptom screening questionnaire revealed 65 patients with possible parkinsonism (9.0%) at baseline. Patients with possible parkinsonism answered that they had subjective loss of smell more than those without parkinsonism at the time of recruitment (18.5% vs 8.3%) and operation (15.4% vs 6.3%). However, the objective odor discrimination test showed no difference between patients with and without possible parkinsonism. Baseline assessments revealed a sufficient number of patients with possible parkinsonism, which will be confirmed as PD or not in subsequent follow-up visits.


Assuntos
Detecção Precoce de Câncer/métodos , Doença de Parkinson/diagnóstico , Doença de Parkinson/epidemiologia , Sintomas Prodrômicos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiologia , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Estudos Prospectivos , Neoplasias Gástricas/fisiopatologia
13.
Undersea Hyperb Med ; 46(1): 1-6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31154680

RESUMO

Hypoxia is one of the main problems an underwater diver may have to face. The probability of experiencing hypoxia is related to the type of dive and the equipment used. Hypoxia in diving is a potentially fatal event for the diver, as it can lead to the loss of brain functions and consequently to the loss of breathing control, all in the absence of specific premonitory symptoms. It is a risk that may be encountered more frequently by divers who use a closed-circuit rebreather (CCR). For those who use this type of equipment, hypoxia is usually the most frequent cause of death [1]. Our study was aimed at the detection of peripheral oxygen saturation in order to identify, in the future, a preclinical hypoxic condition. We combined the use of pulse oximetry with two forehead sensors on an underwater diver subject who was using an electronic closed-circuit rebreather (ECCR). Despite the known limits of this method and the preliminary status of these findings [2], the recorded data show a clear validity in the use of pulse oximetry in immersion for the detection of peripheral oxygen saturation. In the future, the pulse oximeter could become part of the instrumentation of the diver who uses CCR gear. The device could easily be implemented in these rebreathers. The possibility of being able to perform a basic instrumental analysis means that the diver can become more quickly aware of imminent hypoxia, characterized by the absence of clearly identifiable warning symptoms, and can put in place all the correct procedures for an emergency ascent, avoiding serious consequences.


Assuntos
Mergulho/efeitos adversos , Desenho de Equipamento , Hipóxia/diagnóstico , Oximetria , Oxigênio/sangue , Adulto , Gasometria/instrumentação , Gasometria/métodos , Equipamentos para Diagnóstico , Humanos , Hipóxia/sangue , Hipóxia/etiologia , Imersão , Masculino , Oximetria/instrumentação , Oximetria/métodos , Sintomas Prodrômicos , Água do Mar , Avaliação de Sintomas/instrumentação , Temperatura Ambiente
15.
Neurosci Lett ; 706: 43-50, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31067492

RESUMO

Niemann-Pick disease type C (NPC) is a fatal neurodegenerative condition with no FDA-approved therapy. Previous studies demonstrated that neuroinflammation is an early pathologic event and a disease modifier of NPC, affecting symptomatic onset and overall lifespan. Therefore, NPC-specific anti-inflammatory therapy may result in clinical benefit. However, to date, the initial trigger of the inflammatory onset and the mechanism driving the sustained chronic neuroinflammation remain unknown. In this study, we utilized a genome-wide transcriptome analysis to identify the key pathways involved in early NPC. Our results showed that an atypical pattern of interferon downstream signaling that involves both IFN-γ- and IFN-α-responsive genes is activated in pre-symptomatic Npc1-/- cerebella. Functional analysis of the differentially expressed genes highlighted microglial activation, anti-viral response, and T-lymphocyte activation and chemotaxis pathways. Multiplex protein analysis confirmed that a potent IFN-γ-responsive cytokine, IP-10/CXCL10 was significantly upregulated in the pre-symptomatic stage and further exacerbated in the terminal stage. In addition, several IFN-γ-responsive cytokines were elevated in the terminal stage Npc1-/- cerebella, including MIG/CXCL9, MCP-1/CCL2, MIP-1α/CCL3, MIP-1ß/CCL4, RANTES/CCL5, M-CSF, and IL-1α. Together, our results describe a novel activation pattern of interferon downstream signaling in pre-symptomatic NPC, as well as key inflammatory mediators that could serve as potential targets for NPC-specific anti-inflammatory therapy.


Assuntos
Cerebelo/metabolismo , Interferons/metabolismo , Doença de Niemann-Pick Tipo C/metabolismo , Transdução de Sinais/genética , Animais , Citocinas/metabolismo , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Interferons/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Knockout , Doença de Niemann-Pick Tipo C/genética , Sintomas Prodrômicos
16.
Riv Psichiatr ; 54(2): 59-66, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30985830

RESUMO

Neuropsychiatric symptoms (NPS) are common in the prodromal stage of dementia and can precede the onset of cognitive impairment. The presence of NPS in cognitively normal patients or in patients with Mild Cognitive Impairment (MCI) is associated with an increased risk of progression along the neurodegenerative process. The need to identify, in the early stages of the disease, the population at risk of cognitive decline has led to the formulation of the concept of Mild Behavioral Impairment (MBI). This neurobehavioral syndrome is characterized by late-onset sustained psychiatric symptoms, in patients without cognitive deficits or in those with MCI, identifying a condition associated with an increased probability of conversion into dementia. MBI represents the neurobehavioral axis of pre-dementia risk states, as a complement to the neurocognitive axis of MCI. For some, MBI may be the initial manifestation of neurodegenerative disease, observed before cognitive impairment is apparent. The Mild Behavioral Impairment-Checklist (MBI-C) was developed on the basis of the MBI diagnostic criteria, established by the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The MBI-C allows to identify, in a standardized way, patients with MBI and to follow the course of their neurodegenerative disease. This article describes the creation of the MBI-C scale and presents its Italian version.


Assuntos
Lista de Checagem , Disfunção Cognitiva/diagnóstico , Sintomas Prodrômicos , Avaliação de Sintomas , Idoso , Disfunção Cognitiva/etiologia , Demência/etiologia , Progressão da Doença , Humanos , Itália , Doenças Neurodegenerativas/complicações
17.
Maturitas ; 123: 45-54, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31027677

RESUMO

BACKGROUND: Motoric cognitive risk syndrome (MCR) is a pre-dementia stage, which associates slow walking speed with subjective cognitive impairment (SCI). MCR's clinical utility for the prediction of dementia and its pathophysiology are unclear. The aim of this systematic review and meta-analysis is to examine the association of MCR with incident cognitive impairment, cognitive performance and brain structures. METHODS: A systematic search was conducted using the Medical Subject Heading terms "Walking" and "Cognition disorders" combined with the terms "Subjective cognitive impairment", "Subjective cognitive decline" and "Motoric cognitive risk". A total of 11 studies were included in the systematic review and meta-analysis: 3 studies had dementia as the outcome, 3 studies had cognitive performance as the outcome, 4 studies had brain structures as the outcome and one study examined the incidence of both major neurocognitive disorders and cognitive impairment. RESULTS: MCR was found to be associated with incident cognitive impairment (pooled hazard ratio (HR) = 1.70, 95% CI, 1.46-1.98 with P-value <0.001) and dementia (pooled HR = 2.50, 95% CI, 1.75-2.39 with P-value <0.001). MCR was also found to be associated with low grey matter volume involving the premotor and the prefrontal cortex, and lacunar lesions in the frontal lobe. No significant association was found with white matter abnormalities. CONCLUSION: MCR predicts cognitive impairment and dementia, suggesting that it may be used as a screening syndrome for dementia in a primary care setting. Its significant association with both low grey matter volume and lacunar lesions makes its pathophysiology unclear and suggests multiple pathways.


Assuntos
Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/epidemiologia , Demência/epidemiologia , Sintomas Prodrômicos , Velocidade de Caminhada , Encéfalo/patologia , Cognição/fisiologia , Transtornos Cognitivos/epidemiologia , Disfunção Cognitiva/diagnóstico por imagem , Autoavaliação Diagnóstica , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Incidência , Testes Neuropsicológicos , Tamanho do Órgão , Modelos de Riscos Proporcionais , Fatores de Risco , Síndrome
18.
N Engl J Med ; 380(15): 1408-1420, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30970186

RESUMO

BACKGROUND: Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aß). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. RESULTS: The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.).


Assuntos
Doença de Alzheimer/prevenção & controle , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Disfunção Cognitiva/tratamento farmacológico , Óxidos S-Cíclicos/uso terapêutico , Tiadiazinas/uso terapêutico , Idoso , Peptídeos beta-Amiloides/análise , Química Encefálica , Disfunção Cognitiva/patologia , Óxidos S-Cíclicos/efeitos adversos , Progressão da Doença , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Feminino , Hipocampo/patologia , Humanos , Análise de Intenção de Tratamento , Imagem por Ressonância Magnética , Masculino , Tamanho do Órgão , Placa Amiloide/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Sintomas Prodrômicos , Tiadiazinas/efeitos adversos , Falha de Tratamento
19.
Neurology ; 92(19): e2261-e2272, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-30944240

RESUMO

OBJECTIVE: Given the limited information on cognitive function before Parkinson disease (PD) clinical onset in the general population, we sought to assess prodromal PD (pPD) probability and relate it to detailed cognitive performance in a community cohort. METHODS: In a population-based cohort of 1,629 dementia-free and PD-free participants ≥65 years of age in Greece, we assessed probability of pPD according to the International Parkinson and Movement Disorder Society's criteria. Clinical cognitive diagnoses (cognitively unimpaired, mild cognitive impairment [MCI], dementia) considering neuropsychological testing and functional status were assigned in consensus conferences. Cognitive performance in 5 cognitive domains was assessed by a detailed neuropsychological battery and summarized in the form of z scores. We investigated associations between pPD probability (and its individual constituents) and cognitive outcomes. RESULTS: The median probability of pPD was 1.81% (0.2%-96.7%). Participants with MCI had higher probability of pPD compared to those with normal cognition (p < 0.001). Higher probability of pPD was related to lower performance in all cognitive domains (memory, language, executive, attention, and visuospatial function) (p < 0.001). Lower cognitive performance was further associated with certain nonmotor markers of pPD, such as daytime somnolence, depression, urinary dysfunction, constipation, and subthreshold parkinsonism (p < 0.001). CONCLUSIONS: Higher probability of pPD was associated with lower cognitive performance in all domains and higher probability of MCI. This may reflect a widespread pathologic process although future studies are warranted to infer causality. These results suggest to clinicians that they should assess cognition early, and to researchers that they should further look into the possible mechanisms that may underlie this observation.


Assuntos
Cognição/fisiologia , Disfunção Cognitiva/psicologia , Doença de Parkinson/psicologia , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/complicações , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/complicações , Sintomas Prodrômicos
20.
Psychiatry Res ; 275: 315-325, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953877

RESUMO

Prodromal symptoms of bipolar disorder (BD) and early onset schizophrenia spectrum disorder (EOSSD) overlap. To date, there has been no study directly comparing the prodromal stage of both disorders. Thus, the current study is aimed at determining which prodromal symptom clusters differentiate BD and EOSSD. One hundred twenty one adolescents (33 BD-1, 30 EOSSD, 58 healthy controls) were evaluated for the presence of 79 prodromal symptoms, divided into 7 prodromal symptom clusters. Great than 2 subsyndromal manic symptoms and ADHD comorbidity were significantly more specific for BD than schizophrenia; brief limited intermittent psychotic symptoms (BLIPS) were more likely to be part of EOSSD. In contrast, attenuated psychotic symptoms, and negative symptoms were not specifically related to the diagnosis of EOSSD. In conclusion, subsyndromal manic symptoms, BLIPS, and ADHD might be useful for predicting the trajectory of an emerging affective disorder versus schizophrenia and thus valuable for early detection, and intervention strategies.


Assuntos
Transtorno Bipolar/diagnóstico , Diagnóstico Precoce , Transtornos do Humor/diagnóstico , Sintomas Prodrômicos , Esquizofrenia/diagnóstico , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno Bipolar/psicologia , Comorbidade , Feminino , Humanos , Masculino , Transtornos do Humor/psicologia , Negativismo , Transtornos Psicóticos/psicologia , Síndrome
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