Real-Time Quaking-Induced Conversion Analysis for the Diagnosis of Sporadic Creutzfeldt-Jakob Disease in Korea

MethodsThis study applied a highly sensitive RT-QuIC assay using recombinant human PrP to detect PrP^Sc in the CSF of 81 patients with sporadic CJD (sCJD) in Korea.ResultsRT-QuIC analysis of the CSF samples based on the expression levels of 14-3-3 and total tau proteins revealed positivity in 62 of 81 sCJD patients (sensitivity of 76.5%) but no positive results in the 100 non-CJD patients.ConclusionsThe sensitivity of the RT-QuIC in this study was similar to that in some previous reports, and the specificity of RT-QuIC was higher than that of 14-3-3 in CSF, suggesting that RT-QuIC analysis can complement the weakness of the specificity of 14-3-3 for the diagnosis of sCJD. These results indicate that RT-QuIC might be very useful for the rapid and specific diagnosis of sCJD and provide a practical novel method for the ante-mortem diagnosis of human prion diseases.     

Regional cerebral glucose metabolism in autopsy-confirmed Creutzfeldt-Jakob disease

Regional cerebral glucose metabolism was measured in a 72-year-old man, with Creutzfeldt-Jakob disease (CJD), by positron emission tomography using [¹⁸F]-2-fluoro-2-deoxy-D-glucose as the tracer. The diagnosis of CJD, a rare neurodegenerative disorder, was confirmed at autopsy 13 months later. Compared with five unaffected elderly men, the patient had reduced metabolism heterogeneously distributed throughout the brain. The hypometabolism was most evident in the right hemisphere, particularly in the posterior frontal, parietal, Sylvian, and temporal regions. This left-right asymmetry is more extensive than that previously reported in Alzheimer's disease, and may provide a useful metabolic marker for early diagnosis of CJD.     

散发性Creutzfeldt-Jakob病的临床和影像学特点

目的探讨散发性Creutzfeldt-Jakob病(sCJD)的临床和影像学特点。方法回顾性分析4例sCJD患者的临床资料。结果4例sCJD患者均表现为亚急性起病,进行性痴呆,伴有肌阵挛;头颅MRI显示对称性或非对称性大脑皮质彩带样和(或)基底节弥散加权成像(DWI)高信号。结论sCJD的临床特点为进展性痴呆伴肌阵挛,头颅MRI特别是DWI出现高信号为其病变特点。     

Creutzfeldt-Jakob病脑脊液14-3-3蛋白变化特征及其影响因素分析

目的分析47例临床可能或很可能克雅氏病(CJD)患者的脑脊液(CSF)14-3-3蛋白特征,为CJD早期临床评估及诊断提供参考。方法收集2013年1月至2016年1月以"可疑CJD"诊断在首都医科大学宣武医院住院的患者,对其一般资料及CSF 14-3-3蛋白特征进行分析。比较CSF 14-3-3蛋白阳性组与阴性组年龄、病程、临床表现及脑电图(EEG)、磁共振(MRI)的特点,并采用Spearman法分析CJD患者CSF 14-3-3蛋白与年龄、病程、MRI、EEG及临床表现的相关性。结果 47例患者中有46例患者进行了腰椎穿刺并送检CSF 14-3-3蛋白,其中有5例既往CSF 14-3-3蛋白检查为阴性者在复查后结果转为阳性,由阴性转为阳性时间为1~3个月。最终CSF 14-3-3蛋白阳性的患者占58.70%(27/46),14-3-3蛋白阳性组锥体束(P=0.015)、小脑症状(P=0.012)和视力障碍(P=0.044)均高于阴性组,仅磁共振(MRI)阳性率阳性组低于阴性组(P=0.025),且Spearman法相关性分析显示CJD患者CSF 14-3-3蛋白与锥体束(P=0.029)、视力障碍(P=0.039)及MRI(P=0.006)相关。结论 1 CSF 14-3-3蛋白含量可能与锥体束、小脑症状等运动系统及视力损害有关系,可间接反应CJD患者大脑神经细胞的功能状态;2 CSF 14-3-3蛋白为CJD早期诊断提供参考依据之一,CSF14-3-3蛋白含量随病情进展发生变化,对于首次检查阴性的患者实际工作中要注意复查,以免漏诊。     

Neuroimaging in epilepsy

Epilepsy is a common neurological disorder with diverse etiologies. Neuroimaging plays an important role in workup of patients with epilepsy. It helps to identify brain pathologies that require specific treatment; and also in formulating syndromic and etiological diagnoses so as to give patients and their relatives an accurate prognosis. Magnetic resonance imaging, specially the 3 tesla MRI is the imaging of choice because of its ability to detect small lesions like mesial temporal sclerosis, cortical dysplasias, small tumors, etc that are not detected by conventional MR or CT scan of brain. Identification of these lesions often helps in managing refractory epilepsies more effectively. However, cost and non-availability of MR in large part of the country necessitate the use of CT as an alternative. CT is often the initial investigation and also useful in acute situations. Functional imagings are used for pre-surgical work-up of refractory epilepsy cases with an aim to identify the epileptogenic focus and to delineate functional areas nearing the focus.     

脑脊液14-3-3蛋白定量检测对散发性Creutzfeldt-Jakob病的诊断价值

目的探讨脑脊液14-3-3蛋白定量检测对散发性Creutzfeldt-Jakob病(sCJD)的诊断价值。方法采用Capture Assay方法定量检测14例sCJD患者(sCJD组)、10例痴呆患者(OD组)、12例非痴呆患者(ND组)脑脊液14-3-3蛋白的含量。结果脑脊液中14-3-3蛋白含量中位数(MD)sCJD组为40.00ng/mg,OD组为2.65ng/mg,ND组为3.10ng/mg;sCJD组脑脊液中14-3-3蛋白含量明显高于OD组及ND组(均P<0.01)。以脑脊液14-3-3蛋白含量≥9ng/ml为分界值时,其对sCJD诊断的敏感性为86.7%,特异性为86.4%,阳性预测值为81.3%,阴性预测值为90.5%。结论应用Capture Assay方法定量检测脑脊液中14-3-3蛋白含量对于临床可疑sCJD的患者有较高的敏感性和特异性。     

Deafness: an unusual onset of genetic Creutzfeldt-Jakob disease

We describe a case of genetic Creutzfeldt-Jakob disease (CJD) with deafness at the onset. We report clinical features, 14-3-3 protein positivity, electroencephalography and brain stem auditory evoked potential abnormalities, and high signal on magnetic resonance imaging in basal ganglia and temporal cortex. Similarities with CJD Heidenhain variant are discussed. Received: 27 October 1999 / Accepted in revised form: 30 January 2000     

国人Creutzfeldt-Jakob病临床、病理、免疫组化、PrP基因、14-3-3蛋白及动物传递的研究

目的 探讨国人Ｃｒｅｕｔｚｆｅｌｄｔ－Ｊａｋｏｂ病（ＣＪＤ）的临床、病理及免疫组化、ＰｒＰ基因、１４－３－３蛋白及实验鼠传递结果。方法 统计２４例ＣＪＤ患者的临床资料,进行脑组织病理检查。其中１０例脑切片作ＰｒＰ免疫组化染色,１０例进行ＰｒＰ基因表达,５例脑脊液行１４－３－３蛋白检测,７例进行实验鼠传递。结果 （１）２４例ＣＪＤ中散发１９例,可能为医源性３例,家族性１例,与Ａｌｚｈｅｉｍｅｒ病并存１例;（２）国人ＣＪＤ急性、亚急性发病高达９６％,急性发病者病程短,脑萎缩不明显;（３）脑组织石蜡切片以ＰｒＰ抗血清为第一抗体免疫组化染色,均呈突触型阳性;（４）１４－３－３蛋白表达对ＣＪＤ的临床诊断有特异性;（５）活检脑组织对实验鼠传递成功。结论 国人ＣＪＤ发病过程和临床表现有若干特殊性,通过１４－３－３蛋白表达,可     

散发型克雅病7例患者的临床、脑电图及影像学分析

目的 探讨散发型克雅病(sCJD)的临床、脑电图及影像学特点。方法 回顾性分析7例散发型克雅病患者的临床表现、脑电图、影像学特点。结果 本组亚急性起病5例,慢性起病2例,主要的临床症状和体征有进行性痴呆、精神行为异常、视觉障碍、头晕、共济失调、肌阵挛、言语笨拙、锥体外系症状和锥体束征等; EEG检查均有异常,其中6例脑电图检查示典型的周期性三相波发放,1例患者入院脑电图检查未见异常波发放,1月后复查脑电图发现周期性三相波; 7例均行颅脑MRI检查,T₂加权序列(T₂WI)、液体衰减反转恢复序列(T₂ FLAIR)及弥散加权成像(DWI)在皮质、尾状核、壳核等发现异常高信号,其中1例在DWI像上发现随着疾病进展尾状核、壳核、皮层信号先明显增高,后稍微下降; 6例行脑脊液14-3-3蛋白检测,其中4例为阳性,2例为阴性。结论 临床上对快速进展型痴呆的患者,应考虑克雅病的可能,尽早行脑电图、颅脑MRI以及脑脊液14-3-3蛋白检测有助于临床早期诊断; 脑电图、颅脑MRI在疾病早期可无典型改变,则应短期内复查,动态观察。     

脑脊液14-3-3蛋白和神经元特异性烯醇化酶对Creutzfeldt-Jakob病的诊断价值

目的探讨脑脊液14-3-3蛋白和神经元特异性烯醇化酶(NSE)对Creutzfeldt-Jakob病(CJD)的诊断价值。方法采用capture assay方法及酶联免疫吸附法分别定量检测14例CJD患者(CJD组)、10例其他痴呆患者(OD组)及12例非痴呆患者(ND组)脑脊液14-3-3蛋白和NSE的含量,并进行特异性和敏感性分析。结果脑脊液中14-3-3蛋白含量CJD组为40.0ng/ml,OD组为2.65ng/ml,ND组为3.10ng/ml;NSE含量CJD组为(48.43±30.39)ng/ml,OD组为(14.00±11.52)ng/ml,ND组为(20.50±25.67)ng/ml;CJD组脑脊液中14-3-3蛋白及NSE含量明显高于OD组及ND组(均P<0.01)。以脑脊液14-3-3蛋白≥9ng/ml为分界值时,其对CJD诊断的敏感性为86.7%,特异性为86.4%;以NSE≥24ng/ml为分界值时,其敏感性为78.6%,特异性为77.3%;当以14-3-3>9ng/ml及NSE>24ng/ml为分界值,对CJD诊断的敏感性、特异性分别为90%、92.9%。结论脑脊液14-3-3蛋白对CJD的诊断价值高于NSE,两者联合将提高对CJD诊断的敏感性和特异性。     

Heidenhain Variant of Creutzfeldtjakob Disease: Diffusion-Weighted MRI and PET Characteristics

Creutzfeldt-Jakob disease (CJD) is characterized by rapidly progressive dementia with a variety of neurological disorders and a fatal outcome. The authors present a case with visual disturbance as a leading symptom and rapid deterioration in global cognitive functions. The cerebrospinal fluid was positive for 14-3-3 protein, and diffusion-weighted magnetic resonance imaging (MRI) showed marked hyperintensity in the parieto-occipital cortices, where hypometabolism was clearly detected on positron emission tomography (PET). Pattern-reversal visual evoked potentials showed prolonged P100 latencies and increased N/5/P100 amplitudes. All these findings supported a diagnosis of the Heidenhain variant of CJD, whereas a long clinical course, a lack of myoclonus, and an absence of periodic synchronous discharges on electroencephalography were atypical. Diffusion-weighted MRI and PE1 in combination with visual evoked potential recording and 14-3-3 protein detection may be useful for the early diagnosis of CJD.     

Glucose metabolism in sporadic Creutzfeldt-Jakob disease: a statistical parametric mapping analysis of (18) F-FDG PET

Background and purpose: Reports describing functional neuroimaging techniques, such as positron emission tomography (PET) and single‐photon emission computed tomography (SPECT), in sporadic Creutzfeldt–Jakob disease (sCJD) have consistently suggested that these tools are sensitive for the identification of areas of hypoperfusion or hypometabolism, even in the early stages of sCJD. However, there are few reports on the use of [18F]fluoro‐2‐deoxy‐D‐glucose (FDG) PET in sCJD, and most of them are single case reports. Only two small cohort studies based on visual inspection or a region of interest method have been published to date. Using a statistical parametric mapping (SPM) analysis of ¹⁸F‐FDG PET, we investigated whether there are brain regions preferentially affected in sCJD. Methods: After controlling for age and gender, using SPM 2, we compared the glucose metabolism between (i) 11 patients with sCJD and 35 controls and (ii) the subset of five patients with the Heidenhain variant of sCJD and 35 controls. Results: The patients with sCJD showed decreased glucose metabolism in bilateral parietal, frontal and occipital cortices. The Heidenhain variant of sCJD showed glucose hypometabolism mainly in bilateral occipital areas. Conclusions: Glucose hypometabolism in sCJD was detected in extensive cortical regions; however, it was not found in the basal ganglia or thalamus, which are frequently reported to be affected on diffusion‐weighted images. The medial temporal area, which is possibly resistant to the prion deposits, was also less involved in sCJD.     

Neuroimaging study of placebo analgesia in humans

Placebo has been reported to exert beneficial effects in patients regarding the treatment of pain. Human functional neuroimaging technology can study the intact human brain to elucidate its functional neuroanatomy and the neurobiological mechanism of the placebo effect. Blood flow measurement using functional magnetic resonance imaging and positron emission tomography (PET) has revealed that analgesia is related to decreased neural activities in pain-modulatory brain regions, such as the rostral anterior cingulate cortex (rACC), insula, thalamus, and brainstem including periaqueductal gray (PAG) and ventromedial medulla. The endogenous opioid system and its activation of μ-opioid receptors are thought to mediate the observed effects of placebo. The μ-opioid receptor-selective radiotracer-labeled PET studies show that the placebo effects are accompanied by reduction in activation of opioid neural transmission in pain-sensitive brain regions, including rACC, prefrontal cortex, insula, thalamus, amygdala, nucleus accumbens (NAC) and PAG. Further PET studies with dopamine D2/D3 receptor-labeling radiotracer demonstrate that basal ganglia including NAC are related to placebo analgesic responses. NAC dopamine release induced by placebo analgesia is related to expectation of analgesia. These data indicate that the aforementioned brain regions and neurotransmitters such as endogenous opioid and dopamine systems contribute to placebo analgesia.     

Diffusion‐Weighted MRI in Creutzfeldt‐Jakob Disease: A Better Diagnostic Marker Than CSF Protein 14‐3‐3?

Two middle-aged patients presented with rapidly progressive dementia and ataxia, nonspecific electroencephalography findings, and negative cerebrospinal fluid (CSF) protein 14-3-3. Both patients underwent brain magnetic resonance imaging (MRI) scans that demonstrated abnormalities on diffusion-weighted imaging (DWI) sequences, and both were later confirmed to have Creutzfeldt-Jakob disease. (CJD) by tissue examination. Because a recent position paper from the American Academy of Neurology characterized CSF protein 14-3-3 as a gold standard for clinically diagnosing CJD, the authors reviewed studies of CJD in which DWI-MRI imaging and CSF protein 14-3-3 studies were both performed. Among 19 reported cases of CJD with DWI-MRI lesions, CSF protein 14-3-3 was negative in 6 cases and positive in 2 others. The authors' findings suggest that multifocal cortical and subcortical hyperintensities confined to gray matter regions in DWI-MRI may be a more useful noninvasive diagnostic marker for CJD than CSF protein 14-3-3. These observations provide a compelling rationale for a prospective comparative study.     

Neuroimaging in bipolar disorder

Objective: The authors reviewed neuroimaging studies of bipolar disorder in order to evaluate how this literature contributes to the current understanding of the neurophysiology of the illness.

Method: Papers were reviewed as identified, using the NIMH PubMed literature search systems that reported results of neuroimaging studies involving a minimum of five bipolar disorder patients compared with healthy comparison subjects.

Results: Structural neuroimaging studies report mixed results for lateral and third ventriculomegaly. Recent studies suggest subcortical structural abnormalities in the striatum and amygdala, as well as the prefrontal cortex. Proton spectroscopic studies suggest that abnormalities in choline metabolism exist in bipolar disorder, particularly in the basal ganglia. Additionally, phosphorous MRS suggests that there may be abnormalities in frontal phospholipid metabolism in bipolar disorder. Functional studies have identified affective state‐related changes in cerebral glucose metabolism and blood flow, particularly in the prefrontal cortex during depression, but no clear abnormalities specific to bipolar disorder have been consistently observed.

Conclusions: The current literature examining the neurophysiology of bipolar disorder using neuroimaging is limited. Nonetheless, abnormalities in specific frontal‐subcortical brain circuits seem likely. Additional targeted studies are needed to capitalize on this burgeoning technology to advance our understanding of the neurophysiology of bipolar disorder.     

Neuroimaging,Gut Peptides and Obesity: Novel Studies of the Neurobiology of Appetite

Two major biological players in the regulation of body weight are the gut and the brain. Peptides released from the gut convey information about energy needs to areas of the brain involved in homeostatic control of food intake. There is emerging evidence that human food intake is also under the control of cortical and subcortical areas related to reward and cognition. The extent to which gut hormones influence these brain areas is not fully understood. Novel methods combining the study of neural activity and hormonal signalling promise to advance our understanding of gut–brain interactions. Here, we review a growing number of animal and human studies using neuroimaging methods (functional magnetic resonance imaging, positron emission tomography) to measure brain activation in relation to nutrient loads and infusion of gut peptides. Implications for current and future pharmacological treatments for obesity are discussed.     

Transcranial ultrasound of the basal ganglia in sporadic Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) is characterized by the core symptoms of rapid progressive dementia, myoclonus, and typical periodic sharp wave complexes (PSWC) on electroencephalography (EEG). In recent years, imaging techniques have become more and more important in the diagnostic process of CJD. Magnetic resonance imaging (MRI) is very characteristic and the most accurate imaging technique to be of help in diagnosing CJD. In this study, we applied transcranial color-coded ultrasound (TCCS) in three cases of sporadic CJD. We found that all of them had in common a typical ultrasound tissue image of the lentiform nucleus, best to be described as a blurry inhomogeneous hyperechogenic signal pattern where usually the echogenicity is mostly homogeneously hypoechogenic.     

Autopsy-proven Creutzfeldt-Jakob disease in a patient with a negative 14-3-3 assay and nonspecific EEG and MRI

Abstract. Detection of 14-3-3 protein in cerebrospinal fluid (CSF), in combination with findings on electroencephalography (EEG) and magnetic resonance imaging (MRI), is a highly sensitive and specific diagnostic test for sporadic Creutzfeldt-Jakob disease (CJD) in patients premortem. We present a case of classic, sporadic CJD, confirmed on autopsy and by Western blot. However, all routine premorbid testing was negative, the CSF was negative for the 14-3-3 protein, EEG did not show periodic sharp wave complexes (PSWC), and MRI failed to show hyperintense signal in the basal ganglia. Thus, laboratory support for the diagnosis of CJD was not obtained premortem. The chances of all three diagnostic testing modalities to be negative in a single case of sporadic CJD are extremely remote. Autopsy with neuropathologic confirmation remains the only definitive way to make a diagnosis of CJD.