Brain acetylcholinesterase activity in Alzheimer disease measured by positron emission tomography

Brain acetylcholinesterase activity was measured in 14 patients with Alzheimer disease and 14 age-matched control subjects by positron emission tomography with a radioactive acetylcholine analogue. Kinetic analysis was performed to calculate k3, an index of acetylcholinesterase activity. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala of all patients with Alzheimer disease, suggesting a loss of cholinergic innervation from the basal forebrain. Most profound reductions of k3 values were observed in the temporal (-30%) and parietal cortices (-31%), although reductions of k3 values were relatively uniform in the cerebral neocortex. This technique may be a powerful tool for early diagnosis of Alzheimer disease and also for therapeutic monitoring of acetylcholinesterase inhibitors in Alzheimer disease.     

A positron emission tomography study of 5-hydroxytryptamine-1A receptors in Alzheimer disease.

OBJECTIVE: The important role of serotonin-1A (5-hydroxytryptamine-1A [5-HT(1A)]) receptors in cognition, behavior, and drug response is increasingly being recognized. Postmortem studies suggest decreased 5-HT(1A) receptors in patients with Alzheimer disease (AD), but this has not been confirmed in vivo. Our primary objective was to assess the extent of 5-HT(1A) receptor losses in mild to moderate AD. METHODS: The authors examined 5-HT(1A) receptors in 10 patients with mild to moderate AD and 10 healthy volunteers with the same sex and similar age using positron emission tomography imaging with the selective 5-HT(1A) receptor radioligand, [(11)C]WAY-100635. Regions of interest (ROIs) were manually drawn on coregistered magnetic resonance images for the frontal, lateral temporal, medial temporal (MTC), parietal, and cerebellar cortices. Using the simplified reference tissue model, 5-HT(1A) binding potentials (BPs) were calculated relative to the cerebellum. RESULTS: After adjusting for partial volume effects, ROI analysis showed a significant group effect (AD versus comparison group) on BP. Analysis of between-subjects factors showed significantly decreased 5-HT(1A) BP in the right MTC, but not in the other ROIs. CONCLUSION: Given the strategic role of these receptors, loss of right medial temporal 5-HT(1A) receptors might play an important role in AD symptomatology.     

Wilson's disease studied with FDG and positron emission tomography

Four patients with Wilson's disease and eight normal controls were studied with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and positron emission tomography (PET). The patients had diffusely reduced glucose metabolism in all brain regions evaluated compared with controls, with the exception of the thalamus. The ratio of the cerebral metabolic rate for glucose in the lenticular nuclei to hemispheres declined from 1.23 (+/- 0.14 SD) in controls to 1.03 (+/- 0.06) (p less than 0.025) in Wilson's disease patients. Compared with Huntington's disease, the PET FDG results in Wilson's disease indicate relatively less focal involvement of the caudate nucleus, more severe focal changes in the lenticular nuclei, and more significant global changes in glucose metabolism.     

Subgroups in dementia of the Alzheimer type identified using positron emission tomography

We examined patterns of cerebral glucose metabolism in 33 patients with dementia of the Alzheimer type by applying principal component analysis to identify subgroups. Four subgroups were identified: one with predominant parietotemporal hypometabolism (15 patients); one with paralimbic metabolic deficits (8 patients); one with left hemisphere neocortical abnormality (5 patients); and one with frontal and parietotemporal deficit (5 patients). Differences among the subgroups were found in neuropsychological impairments and prevalence of psychiatric symptoms. These metabolic subgroups could not be explained on the basis of dementia severity, illness duration, or age, but were most likely related to an underlying pathology with a variable regional distribution.     

Blinded clinical evaluation of positron emission tomography for diagnosis of probable Alzheimer's disease.

We evaluated the sensitivity and specificity of positron emission tomography for diagnosis of probable Alzheimer's disease under conditions similar to those encountered in the routine clinical practice of nuclear medicine. We obtained tomographic images of regional cerebral blood flow from three groups of subjects: (1) 13 subjects, ages 69 to 84, who had probable Alzheimer's disease diagnosed by validated clinical criteria; (2) 15 subjects, ages 57 to 77, who had Parkinson's disease without dementia; and (3) 11 subjects, ages 65 to 83, who were normal. Three blinded reviewers, who had not previously seen the images, categorized them as normal, bilateral temporoparietal flow defects typical of Alzheimer's disease, or other abnormality. Consensus interpretation demonstrated sensitivity of 0.38 (5/13) and specificity of 0.88 (23/26) for identifying patients with probable Alzheimer's disease. Thus, the criterion of bilateral temporoparietal reduction in cerebral blood flow used in this study did not have sufficient sensitivity to be of clinical value. While other criteria may be developed to improve diagnostic accuracy, clinical utility can be established only by testing for validity in patients with a full spectrum of complicating neurologic and psychiatric conditions for whom diagnosis is uncertain and who are then followed longitudinally to determine clinical outcome or pathologic findings.     

The use of positron emission tomography in cerebrovascular disease

Even with rapid development of other neuroimaging modalities such as MR imaging and CT, PET is the only technique that provides accurate, quantitative measurements of regional hemodynamics and metabolism in human subjects. Through the use of these combined measurements, we have greatly expanded our knowledge of the pathophysiology of cerebrovascular disease of different types. It has been possible to document the compensatory responses of the brain to reductions in perfusion pressure and to directly relate these responses to prognosis. PET measurements of OEF identify a subgroup of patients who have carotid occlusion and who are at increased risk for recurrent stroke who cannot be identified by any other clinical or arteriographic means. These measurements of OEF are being used to identify high-risk patients for inclusion in a clinical trial to assess the efficacy of surgical revascularization in reducing the subsequence of ipsilateral ischemic stroke. In acute ischemic stroke, attempts have been made to define the "ischemic penumbra" and to predict tissue viability and clinical outcome, although the reliability of PET markers of ischemia in distinguishing viable from irreversibly damaged tissue needs to be confirmed with independent data sets. Much work has been devoted to the investigation of the metabolic effects of infarcts and hemorrhages on remote areas of the brain; the clinical importance of such findings appears to be minimal. Early studies of recovery from stroke suggested functional reorganization of the brain, but further investigations with more rigorous experimental design need to be performed. Given the case of performing such studies with functional MR imaging, it is likely that this technology will supplant PET for this specific indication. The importance of ischemia as a secondary mechanism of brain injury has been addressed in ICH and SAH. PET demonstrated that hematomas exert a primary depression of metabolism rather than inducing ischemia in the surrounding tissue. It also documented the integrity of autoregulation and provided clinically useful information regarding the safety of blood pressure reduction after ICH. Studies in SAH have differentiated the primary effects of the hemorrhage on cerebral hemodynamics and metabolism from those of vasospasm. PET studies are time-consuming, expensive, and require extensive facilities and technical support. In the field of cerebrovascular disease, PET has served as a specialized research tool at a few centers to help elucidate the pathophysiology of stroke. Up until now, however, PET scans in individual patients have not been demonstrated to be necessary for making patient care decisions. Whether the role of PET expands to impact the management of individual patients will depend on the results of investigations like the Carotid Occlusion Surgery Study that directly assess the ability of PET to influence patient outcome.     

11C-匹兹堡复合物B正电子发射断层摄影术脑显像在阿尔茨海默病早期诊断中的临床应用

目的 探讨N-甲基[11C]2-(4'-甲基氨基苯基-6-羟基苯并噻唑){N-methyl[11C]2-(4'-methylaminophenyl-6-Hydroxybenzathiazole),11C-PIB}PET脑显像在阿尔茨海默病(AD)早期诊断中的价值.方法 分别对6例AD患者、7例轻度认知功能障碍(MCI)患者及6名智能正常的老年对照者(NC)进行临床诊断、资料收集及11C-PIB PET脑显像,并对5、25和45 min PET图像进行分析.结果 视觉分析:AD患者3个时段放射性清除情况与NC组有明显不同,药物注射45 min后脑内放射性清除较NC组明显减低;MCI组图像呈不均一改变,与AD、NC组均有重叠.统计分析:3组受试者各脑区与小脑45 min标准吸收值(SUV)比值示:AD组顶叶、额叶、颞叶、枕叶及海马比值分别为1.91±0.21、2.09±0.41、1.92±0.35、1.66±0.41、1.55±0.28,高于NC组的1.48±0.53、1.57±0.64、1.36±0.53、1.27±0.40、1.17±0.33,差异具有统计学意义(t值分别为8.114、5.620、5.705、3.650、2.866,P值分别为0.0001、0.0002、0.0002、0.0045和0.0170),MCI组顶叶、额叶、颞叶、枕叶及海马的比值分别为1.48±0.53、1.57±0.64、l_36±0.53、1.27±0.40、1.17±0.33,均高于相应NC组,但差异无统计学意义.结论 11C-PIB PET脑显像能够鉴别早期AD患者与Nc,并对MCI患者有一定预测价值.     

Imaging the pathology of Alzheimer's disease: amyloid-imaging with positron emission tomography

The steep rise in the incidence of Alzheimer's disease (AD) has further added to the considerable public health burden caused by aging of the United States population. Among the most characteristic pathologic hallmarks of AD are neuritic plaques and neurofibrillary tangles. The capability to use positron emission tomography and selective markers for amyloid protein deposition promises to substantially alter the way we diagnosis and manage patients who have AD.     

Cutting-edge brain imaging with positron emission tomography

A review of recent advances in brain imaging using positron emission tomography (PET) is presented in this article. Some properties of the high-resolution research tomograph are described as examples of state-of-the-art PET instrumentation. A summary of current research topics in image reconstruction and quantification is given, with emphasis on the requirements of brain dynamic imaging. A brief overview of image analysis methods is presented, together with some examples of the contributions of quantitative PET imaging to the current understanding of brain function and disease. PET findings must be evaluated in the context of clinical observations and complemented by other imaging modalities whenever possible to ensure a proper interpretation of the data.     

阿尔茨海默病的早期诊断与治疗

老年性痴呆（又称阿尔茨海默病，Alzheimer disease，AD）是一种以认知功能减退、生活功能下降及精神行为异常为临床表现的神经系统退行性疾病，随着老龄人口的增加，痴呆的患病率逐年增加。根据Zhang等在1997--1998年对我国部分城市的流行病学调查，在55岁及以上的人群中，AD患病率为2．1％（732／34807）。围绕AD的发病机制，     

Early postischemic hyperperfusion: pathophysiologic insights from positron emission tomography.

Early postischemic hyperperfusion (EPIH) has long been documented in animal stroke models and is the hallmark of efficient recanalization of the occluded artery with subsequent reperfusion of the tissue (although occasionally it may be seen in areas bordering the hypoperfused area during arterial occlusion). In experimental stroke, early reperfusion has been reported to both prevent infarct growth and aggravate edema formation and hemorrhage, depending on the severity and duration of prior ischemia and the efficiency of reperfusion, whereas neuronal damage with or without enlarged infarction also may result from reperfusion (so-called "reperfusion injury"). In humans, focal hyperperfusion in the subacute stage (i.e., more than 48 hours after onset) has been associated with tissue necrosis in most instances, but regarding the acute stage, its occurrence, its relations with tissue metabolism and viability, and its clinical prognostic value were poorly understood before the advent of positron emission tomography (PET), in part because of methodologic issues. By measuring both CBF and metabolism, PET is an ideal imaging modality to study the pathophysiologic mechanism of EPIH. Although only a few PET studies have been performed in the acute stage that have systematically assessed tissue and clinical outcome in relation to EPIH, they have provided important insights. In one study, about one third of the patients with first-ever middle cerebral artery (MCA) territory stroke studied within 5 to 18 hours after symptom onset exhibited EPIH. In most cases, EPIH affected large parts of the cortical MCA territory in a patchy fashion, together with abnormal vasodilation (increased cerebral blood volume), "luxury perfusion" (decreased oxygen extraction fraction), and mildly increased CMRO2, which was interpreted as postischemic rebound of cellular metabolism in structurally preserved tissue. In that study, the spontaneous outcome of the tissue exhibiting EPIH was good, with late structural imaging not showing infarction. This observation was supported by another PET study, which showed, in a few patients, that previously hypoperfused tissue that later exhibited hyperperfusion after thrombolysis did not undergo frank infarction at follow-up. In both studies, clinical outcome was excellent in all patients showing EPIH except one, but in this case the hyperperfused area coexisted with an extensive area of severe hypoperfusion and hypometabolism. These findings from human studies therefore suggest that EPIH is not detrimental for the tissue, which contradicts the experimental concept of "reperfusion injury" but is consistent with the apparent clinical benefit from thrombolysis. However, PET studies performed in the cat have shown that although hyperperfusion was associated with prolonged survival and lack of histologic infarction when following brief (30-minute) MCA occlusion, it often was associated with poor outcome and extensive infarction when associated with longer (60-minute) MCA occlusion. It is unclear whether this discrepancy with human studies reflects a shorter window for tissue survival after stroke in cats, points to the cat being more prone to reperfusion injury, or indicates that EPIH tends not to develop in humans after severe or prolonged ischemia because of a greater tendency for the no-reflow phenomenon, for example. Nevertheless, the fact that the degree of hyperperfusion in these cat studies was related to the severity of prior flow reduction suggests that hyperperfusion is not detrimental per se. Preliminary observations in temporary MCA occlusion in baboons suggest that hyperperfusion developing even after 6 hours of occlusion is mainly cortical and associated with no frank infarction, as in humans. Overall, therefore, PET studies in both humans and the experimental animal, including the baboon, suggest that hyperperfusion is not a key factor in the development of tissue infarction and that it may be a harmless phenomenon     

Positron emission tomography metabolic correlates of apathy in Alzheimer disease

BACKGROUND: Apathy is the most common neuropsychiatric manifestation in Alzheimer disease (AD). Clinical, single-photon emission computed tomography, magnetic resonance imaging, and pathologic studies of apathy in AD have suggested an association with frontal dysfunction, most supportive of anterior cingulate abnormalities, but without a definitive localization. OBJECTIVE: To examine the association between apathy and cortical metabolic rate on positron emission tomography in AD. DESIGN: Forty-one subjects with probable AD underwent [(18)F] fluorodeoxyglucose positron emission tomography imaging and neuropsychiatric and cognitive assessments. Global subscale scores from the Scale for the Assessment of Negative Symptoms in Alzheimer Disease were used to designate the absence or presence of clinically meaningful apathy. Whole-brain voxel-based analyses were performed using statistical parametric mapping (SPM2; Wellcome Department of Imaging Neuroscience, London, England), which yielded significance maps comparing the 2 groups. RESULTS: Twenty-seven (66%) subjects did not have apathy, whereas 14 (34%) had apathy. Statistical parametric mapping analysis revealed significant reduced activity in the bilateral anterior cingulate region extending inferiorly to the medial orbitofrontal region (P < .001) and the bilateral medial thalamus (P = .04) in subjects with apathy. The results of the statistical parametric mapping analysis remained the same after individually covarying for the effects of global cognitive impairment, depressed mood, and education. CONCLUSIONS: Apathy in AD is associated with reduced metabolic activity in the bilateral anterior cingulate gyrus and medial orbitofrontal cortex and may be associated with reduced activity in the medial thalamus. These results reinforce the confluence of evidence from other investigational modalities in implicating medial frontal dysfunction and related neuronal circuits in the neurobiology of apathy in AD and other neuropsychiatric diseases.     

Role of fluorodeoxyglucose positron emission tomography in the diagnosis of neurosarcoidosis

A 45-year-old man developed seizures and myelopathy. MRI showed bitemporal and cervical spinal cord hyperintense lesions on T2-weighted and FLAIR images that contrast-enhanced. Initial evaluation for sarcoidosis was negative, including serum angiotensin converting enzyme (ACE) and chest X-ray. Whole body fluorodeoxyglucose positron emission tomography (FDG-PET) revealed multiple hypermetabolic hilar and mediastinal foci and spinal cord hypermetabolism at the site of MRI abnormality. Temporal lobe MRI lesions were hypometabolic. Mediastinal lymph node biopsy was consistent with sarcoidosis. The brain, spinal cord, and chest metabolic abnormalities together with the clinical presentation were interpreted as being most consistent with sarcoidosis. FDG-PET helped target the site of biopsy that subsequently confirmed the diagnosis histologically. In patients with perplexing neurologic presentations, whole body FDG-PET can help secure a timely and minimally invasive diagnosis of neurosarcoidosis.     

Instrumentation in positron emission tomography

The past 40 years have seen PET scanning evolve from a tool that was used predominantly for research to a valued clinical, imaging modality. Current PET scanners must perform high quality, whole-body, as well as brain, PET. There are several levels of PET devices that range from the dedicated, high-end scanners down to the hybrid PET-SPECT systems that offer varying levels of performance. The incorporation of PET into single, hybrid, multi-modality units that can provide functional and anatomic information is becoming extremely popular. Several manufacturers now provide hybrid PET-CT scanners. There is also a growing interest in dedicated devices for specific applications, such as high-resolution scanners for imaging small animals.     

临床前期阿尔茨海默症的早期诊断与干预

随着人口老龄化的加剧,以阿尔茨海默病（Alzheimer Disease,AD）为主的老年认知障碍问题日趋严重.作为一种多因素、多阶段并有伴随疾病的临床综合征,老年认知障碍在临床症状出现后将进展成不可逆性痴呆.因此,在无症状性临床前期AD症（PCAD）阶段进行早期诊断与干预成为了国内外研究的热点.现对PCAD的危险因素和针对其诊断干预的探索性研究进行综述,试图寻找在早期病理进程中新的可用于临床早期诊断的生物标记物及早期干预的药物靶点.