Amyloid and metabolic positron emission tomography imaging of cognitively normal adults with Alzheimer's parents

This study examines the relationship between fibrillar beta-amyloid (Aβ) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimer's disease (AD). Forty-seven 40–80-year-old NL received positron emission tomography (PET) with ¹¹C-Pittsburgh compound B (PiB) and 18F-fluoro-2-deoxy-d-glucose (FDG). These included 19 NL with a maternal history (MH), 12 NL with a paternal history (PH), and 16 NL with negative family history of AD (NH). Automated regions of interest, statistical parametric mapping, voxel-wise intermodality correlations, and logistic regressions were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. The MH group showed higher PiB retention and lower metabolism in AD regions compared with NH and PH, which were negatively correlated in posterior cingulate, frontal, and parieto-temporal regions (Pearson r ≤ −0.57, p ≤ 0.05). No correlations were observed in NH and PH. The combination of Aβ deposition and metabolism yielded accuracy ≥ 69% for MH vs. NH and ≥ 71% for MH vs. PH, with relative risk = 1.9–5.1 (p values < 0.005). NL individuals with AD-affected mothers show co-occurring Aβ increases and hypometabolism in AD-vulnerable regions, suggesting an increased risk for AD.     

F-fluorodeoxyglucose positron emission tomography,aging, and apolipoprotein E genotype in cognitively normal persons

Our objective was to examine associations between glucose metabolism, as measured by ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET), and age and to evaluate the impact of carriage of an apolipoprotein E (APOE) ε4 allele on glucose metabolism and on the associations between glucose metabolism and age. We studied 806 cognitively normal (CN) and 70 amyloid-imaging-positive cognitively impaired participants (35 with mild cognitive impairment and 35 with Alzheimer's disease [AD] dementia) from the Mayo Clinic Study of Aging, Mayo Alzheimer's Disease Research Center and an ancillary study who had undergone structural MRI, FDG PET, and ¹¹C-Pittsburgh compound B (PiB) PET. Using partial volume corrected and uncorrected FDG PET glucose uptake ratios, we evaluated associations of regional FDG ratios with age and carriage of an APOE ε4 allele in CN participants between the ages of 30 and 95 years, and compared those findings with the cognitively impaired participants. In region-of-interest (ROI) analyses, we found modest but statistically significant declines in FDG ratio in most cortical and subcortical regions as a function of age. We also found a main effect of APOE ε4 genotype on FDG ratio, with greater uptake in ε4 noncarriers compared with carriers but only in the posterior cingulate and/or precuneus, lateral parietal, and AD-signature meta-ROI. The latter consisted of voxels from posterior cingulate and/or precuneus, lateral parietal, and inferior temporal. In age- and sex-matched CN participants the magnitude of the difference in partial volume corrected FDG ratio in the AD-signature meta-ROI for APOE ε4 carriers compared with noncarriers was about 4 times smaller than the magnitude of the difference between age- and sex-matched elderly APOE ε4 carrier CN compared with AD dementia participants. In an analysis in participants older than 70 years (31.3% of whom had elevated PiB), there was no interaction between PiB status and APOE ε4 genotype with respect to glucose metabolism. Glucose metabolism declines with age in many brain regions. Carriage of an APOE ε4 allele was associated with reductions in FDG ratio in the posterior cingulate and/or precuneus, lateral parietal, and AD-signature ROIs, and there was no interaction between age and APOE ε4 status. The posterior cingulate and/or precuneus and lateral parietal regions have a unique vulnerability to reductions in glucose metabolic rate as a function both of age and carriage of an APOE ε4 allele.     

Neural correlates of delayed episodic memory in patients with mild cognitive impairment—A FDG PET study

Mild cognitive impairment (MCI) is characterized by cognitive deficits which do not yet reach the threshold of dementia but represent a putative preclinical state of Alzheimer's disease (AD). Little is known about the neural correlates of delayed episodic memory which is among the earliest signs of cognitive decline in patients at risk of developing AD. We performed resting state positron emission tomography (PET) with ¹⁸Fluorodeoxyglucose (FDG) in patients with MCI, and hypothesized a correlation between delayed episodic memory performance and frontal glucose metabolism since the latter is relatively spared in the preclinical phase of the disease. 43 patients (age: 69.7 ± 7.9 years; 24 male, 19 female) with MCI were investigated by FDG PET. Significant positive correlations with delayed episodic memory performance were calculated by statistical parametric mapping. To our knowledge the present study is the first to demonstrate by FDG PET the neural correlates of delayed episodic memory in patients with MCI. Our study revealed a pattern of cerebral glucose metabolism including bifrontal regions which may contribute to the delayed episodic memory performance of patients with MCI. Since not all patients with MCI will further deteriorate, AD specific mechanism may not be concluded from the present study but warrant longitudinal investigations.     

The neural basis of naming impairments in Alzheimer's disease revealed through positron emission tomography.

The naming impairments in Alzheimer's disease (AD) have been attributed to a variety of cognitive processing deficits, including impairments in semantic memory, visual perception, and lexical access. To further understand the underlying biological basis of the naming failures in AD, the present investigation examined the relationship of various classes of naming errors to regional brain measures of cerebral glucose metabolism as measured with 18 F-Fluoro-2-deoxyglucose (FDG) and positron emission tomography (PET). Errors committed on a visual naming test were categorized according to a cognitive processing schema and then examined in relationship to metabolism within specific brain regions. The results revealed an association of semantic errors with glucose metabolism in the frontal and temporal regions. Language access errors, such as circumlocutions, and word blocking nonresponses were associated with decreased metabolism in areas within the left hemisphere. Visuoperceptive errors were related to right inferior parietal metabolic function. The findings suggest that specific brain areas mediate the perceptual, semantic, and lexical processing demands of visual naming and that visual naming problems in dementia are related to dysfunction in specific neural circuits.     

Volumetric correlates of memory and executive function in normal elderly, mild cognitive impairment and Alzheimer's disease

In Alzheimer's disease (AD), atrophy negatively impacts cognition while in healthy adults, inverse relationships between brain volume and cognition may occur. We investigated correlations between gray matter volume and cognition in elderly controls, AD and mild cognitive impairment (MCI) patients with memory and executive deficits. AD demonstrated substantial loss in temporal, parietal and frontal regions while MCI exhibited moderate volume loss in temporal and frontal regions. In controls, memory and executive function were negatively correlated with frontal regions, while in AD, memory was positively correlated with temporal and frontal gyri, and executive function with frontal regions. The combination of the two patterns may explain the lack of correlations in MCI. Developmental versus pathological contributions to these relationships are discussed.     

Cognition, glucose metabolism and amyloid burden in Alzheimer's disease

The authors investigated relationships between glucose metabolism, amyloid load, and measures of cognitive and functional impairment in Alzheimer's disease (AD). Patients meeting criteria for probable AD underwent ¹¹C-labeled Pittsburgh Compound-B ([¹¹C]PIB) and 18F-fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET) imaging and were assessed on a set of clinical measures. The Pittsburgh Compound-B (PIB) Distribution volume ratios and fluorodeoxyglucose (FDG) scans were spatially normalized and average PIB counts from regions-of-interest (ROI) were used to compute a measure of global PIB uptake. Separate voxel-wise regressions explored local and global relationships between metabolism, amyloid burden, and clinical measures. Regressions reflected cognitive domains assessed by individual measures, with visuospatial tests associated with more posterior metabolism, and language tests associated with metabolism in the left hemisphere. Correlating regional FDG uptake with these measures confirmed these findings. In contrast, no correlations were found between either voxel-wise or regional PIB uptake and any of the clinical measures. Finally, there were no associations between regional PIB and FDG uptake. We conclude that regional and global amyloid burden does not correlate with clinical status or glucose metabolism in AD.     

Resting state glucose utilization and the CERAD cognitive battery in patients with Alzheimer's disease

The present study examined the cortical functional representation of neuropsychological domains in Alzheimer's disease (AD) using positron emission tomography (PET) and the neuropsychological assessment battery of the Consortium to Establish a Registry of Alzheimer's Disease (CERAD). Thirty patients with clinical probable AD and 10 elderly healthy controls underwent (18)FDG brain PET imaging during a resting state. Correlations between metabolic values and cognitive measures were determined using a region of interest analysis with NEUROSTAT (University of Michigan, USA) and a voxel-based analysis with SPM96 (Wellcome Department, London, UK). Specific correlations were seen between measures of episodic memory, verbal fluency and naming and left hemispheric temporal and prefrontal metabolism. Drawing was correlated with metabolism in left prefrontal and left inferior parietal regions. The presented data support the use of metabolic-cognitive correlations to demonstrate the neuronal substrates of cognitive impairment in AD. Subtests of the CERAD battery give a good representation of left, but not of right hemisphere function in AD.     

Glucose metabolism and PIB binding in carriers of a His163Tyr presenilin 1 mutation

Six young related pre-symptomatic carriers of a His163Tyr mutation in the presenilin 1 gene who will develop early onset familial Alzheimer's disease (eoFAD), and a control group of 23 non-carriers underwent ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET). The mutation carriers were followed-up after 2 years. Multivariate analysis showed clear separation of carriers from non-carriers on both occasions, with the right thalamus being the region contributing most to group differentiation. Statistical parametric mapping (SPM) revealed in the carriers non-significantly lower thalamic cerebral glucose metabolism (CMRglc) at baseline and significantly decreased CMRglc in the right thalamus at follow-up. One mutation carrier was followed-up with FDG PET 10 years after baseline and showed reductions in cognition and CMRglc in the posterior cingulate and the frontal cortex. This subject was diagnosed with AD 1 year later and assessed with an additional FDG as well as an ¹¹C-PIB PET scan 12 years after baseline. Global cortical CMRglc and cognition were distinctly decreased. PIB binding was comparable with sporadic AD patterns but showing slightly higher striatal levels.     

Relationship between personality trait and regional cerebral glucose metabolism assessed with positron emission tomography

There have been no studies systematically investigating relationships between biogenetic temperament dimensions and patterns of brain glucose metabolism. Nineteen healthy subjects were evaluated regarding the biogenetic temperament using Cloninger's Temperament and Character Inventory (TCI). In addition, [¹⁸F] fluorodeoxyglucose (FDG) positron emission tomography (PET) was used to measure regional brain glucose metabolism. Voxel-based correlation analysis was used to test correlations between regional brain glucose metabolism and scores on the TCI. We identified that each temperament dimension, such as Novelty Seeking, Harm Avoidance, and Reward Dependence, was significantly correlated with specific brain regions. The majority of correlations were observed in the areas of paralimbic regions and temporal lobes. The current study provides evidence linking each biogenetic temperament dimension with specific brain areas and provides a promising base for future personality research.     

Sleep deprivation PET correlations of Hamilton symptom improvement ratings with changes in relative glucose metabolism in patients with depression

BACKGROUND: This PET study is a continuing investigation of the effects of antidepressant medication and one night of total sleep deprivation on cerebral metabolism in depressed patients. This study was undertaken to confirm previous correlations between symptom improvement ratings and regional changes in glucose metabolism, using a higher resolution scanner than in previous investigations. In addition, we also studied the effect of concomitant antidepressant medication in conjunction with sleep depression. METHOD: Six depressed patients were administered the selective serotonin reuptake inhibitor sertraline for a week and then underwent positron emission tomography (FDG PET) before and after sleep deprivation. Changes in relative glucose metabolism were correlated with symptom improvement ratings in Hamilton Depression Rating Scale scores. RESULTS: Positive correlations (defined as reduced HDRS scores associated with areas having reduced relative cerebral glucose metabolism after TSD) were found in the inferior frontal gyrus and inferior frontal/orbital frontal cortex. Negative correlations (defined as reduced HDRS scores associated with areas of increased relative cerebral glucose metabolism after TSD) were found in the dorsolateral prefrontal cortex. LIMITATIONS: Limitations of this study are that the number of subjects was small (n=6) and they were scanned at a 7.6 mm resolution. CONCLUSIONS: The results of this study support previous findings on the effects of sleep deprivation and antidepressant medications in the treatment of unipolar and bipolar depression, with an emphasis on the significance of cerebral glucose metabolic changes in the ventral and DLPF cortex in mood regulation.     

Fluorodeoxyglucose positron emission tomography: emerging roles in the evaluation of putative Alzheimer's disease-modifying treatments

Alzheimer's disease (AD) is associated with characteristic and progressive reductions in flourodeoxyglucose positron emission tomography (FDG PET) measurements of the regional cerebral metabolic rate for glucose. These reductions begin years before the onset of symptoms, are correlated with clinical severity, and may help predict an affected patient's clinical course and neuropathological diagnosis. Like several other AD biomarkers, FDG PET has the potential to accelerate the evaluation of AD-modifying treatments, particularly in the earliest clinical and preclinical stages. This article considers FDG PET's role in the detection and tracking of AD, its emerging roles in the evaluation of disease-slowing treatments, some of the issues involved in the acquisition, analysis, and interpretation of FDG PET data, and the evidence needed to help qualify FDG PET and other biomarkers for use in the accelerated approval of AD-slowing treatments. It recommends scientific strategies and public policies to further establish the role of FDG PET and other AD biomarkers in therapeutic trials and find demonstrably effective disease-modifying and presymptomatic AD treatments as quickly as possible.     

Multimodality imaging characteristics of dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease (AD). Our objective was to determine whether the (11)C-Pittsburgh Compound-B (PiB) retention and regional hypometabolism on positron emission tomography (PET) and regional cortical atrophy on magnetic resonance imaging (MRI) are complementary in characterizing patients with DLB and differentiating them from AD. We studied age-, gender-, and education-matched patients with a clinical diagnosis of DLB (n = 21), AD (n = 21), and cognitively normal subjects (n = 42). Hippocampal atrophy, global cortical PiB retention and occipital lobe metabolism in combination distinguished DLB from AD better than any of the measurements alone (area under the receiver operating characteristic = 0.98). Five of the DLB and AD patients who underwent autopsy were distinguished through multimodality imaging. These data demonstrate that magnetic resonance imaging and PiB positron emission tomography contribute to characterizing the distinct pathological mechanisms in patients with AD compared with DLB. Occipital and posterior parietotemporal lobe hypometabolism is a distinguishing feature of DLB and this regional hypometabolic pattern is independent of the amyloid pathology.     

Neural correlates of dementia: regional brain metabolism (FDG-PET) and the CERAD neuropsychological battery.

The present Investigation examined the biological correlates of the cognitive deficits of Alzheimer's disease and related dementias using the neuropsychological assessment battery of the Consortium to Establish a Registry of Alzheimer's Disease (CERAD) and positron emission tomography (PET). Resting state cerebral glucose metabolism was measured using the labelled radiotracer, [18F] Fluoro-2-deoxyglucose (FDG), in a sample of patients with mild to moderate dementia (n = 66). Specific and predictable relationships were seen between regional brain metabolism (left and right, frontal, temporal, and parietal lobes) and the neuropsychological measures of verbal fluency, constructional praxis, and verbal list learning. On tests of naming and delayed verbal recall only diminished FDG uptake in the left frontal lobe and the left temporal lobe, respectively, approached significance. This study demonstrates the expected relationships between neuropsychological performance and regional cerebral metabolism, thereby providing support for the CERAD battery as a valid measure in the clinical evaluation of dementia and for the use of FDG-PET in brain-behavior studies of dementia.     

The effect of sleep deprivation on cerebral glucose metabolic rate in normal humans assessed with positron emission tomography.

This study is the first report on the effects of total sleep deprivation (about 32 h) on regional cerebral glucose metabolism during wakefulness in man, using positron emission tomography (PET) with F-18 deoxyglucose (FDG). Sleep deprivation leads to a significant reorganization of regional cerebral metabolic activity, with relative decreases in the temporal lobes and increases in visual cortex. Absolute glucose metabolic measurements indicate a decrease in thalamus, basal ganglia, white matter, and cerebellum. No overall decrease in whole brain metabolism was noted after sleep deprivation. As expected, sleep deprivation significantly reduced visual vigilance as assessed by the continuous performance test and this decrease was correlated significantly with reduced metabolic rate in thalamic, basal ganglia, and limbic regions.     

Hippocampal and cortical atrophy in amyloid-negative mild cognitive impairments: comparison with amyloid-positive mild cognitive impairment

Although patients with amnestic mild cognitive impairment (aMCI) are at higher risk of developing Alzheimer's disease (AD), their pathologies could be heterogeneous. We aimed to evaluate structural changes in amyloid-negative and amyloid-positive aMCI patients. Forty-eight aMCI patients who underwent Pittsburgh compound B (PiB) positron emission tomography were recruited. They were classified as PiB (−) aMCI (N = 16) and PiB (+) (N = 32). Hippocampal shape and regional cortical thickness were compared with 41 subjects with normal cognition (NC). Relative to NC, PiB(−) aMCI exhibited hippocampal deformity in the right cornu ammonis 1, whereas PiB(+) aMCI exhibited hippocampal deformity in bilateral subiculum and cornu ammonis 1 subregions. Relative to NC, PiB(−) aMCI showed cortical thinning in the left medial prefrontal and right anterior temporal regions, whereas PiB(+) aMCI exhibited cortical thinning in bilateral medial temporal regions, temporoparietal junctions and precuneus, and prefrontal cortices. Our findings suggest that structural changes in PiB(−) aMCI might be due to several possible pathologic changes, whereas structural changes in PiB(+) aMCI reflect AD-like structural changes.     

Changes in vascular factors 28 years from midlife and late-life cortical thickness

We assessed midlife blood pressure (BP), body mass index, total cholesterol, and their changes over time in relation to cortical thickness on magnetic resonance imaging 28 years later in 63 elderly at risk of dementia. Participants in the population-based Cardiovascular Risk Factors, Aging, and Dementia study were first examined at midlife. A first follow-up was conducted after 21 years, and a second follow-up after an additional 7 years. Magnetic resonance images from the second follow-up were analyzed using algorithms developed at McGill University, Montreal, Canada. Midlife hypertension was related to thinner cortex in several brain areas, including insular, frontal, and temporal cortices. In elderly with thinner insular cortex, there was a continuous decline in systolic BP and an increase in pulse pressure after midlife, while in elderly with thicker insular cortex the decline in systolic BP started at older ages, paralleled by a decline in pulse pressure. No associations were found between body mass index, cholesterol, or apolipoprotein E ε4 allele and cortical thickness in this group of elderly at risk individuals.     

利用Micro-PET显像技术分析阿尔茨海默病小鼠模型的脑糖代谢

目的 利用小动物PET（Micro-PET）影像技术18氟-脱氧葡萄糖（¹⁸F-FDG）摄取率分析阿尔茨海默病(AD)小鼠模型的脑糖代谢,探索评价治疗AD药物的影像分析技术。 方法 正常对照组、APP^swe/PSΔE9转基因模型组和安理申［2 mg/(kg&#8226;d)］治疗组小鼠共9只,自腹腔注射放射性示踪剂¹⁸F-FDG,采集脑部Micro-PET图像,通过软件IRW计算并比较各组小鼠大脑与额叶、颞叶感兴趣区（ROI）每克组织¹⁸F-FDG的摄取率。 结果 利用¹⁸F-FDG 的Micro-PET影像分析可以检测AD小鼠模型的脑糖代谢,并发现APP^swe/PSΔE9转基因小鼠的脑糖摄取明显降低,与人类AD患者表现的脑糖摄取降低一致,安理申治疗可以提升APP^swe/PSΔE9转基因小鼠的脑糖摄取。 结论 ¹⁸F-FDG Micro-PET影像分析可以用于小鼠AD模型脑葡萄糖代谢水平的检测,并可以作为阿尔茨海默病治疗药物提升脑糖代谢作用的分析技术。     

Differences of regional cerebral glucose metabolism between presenile and senile dementia of Alzheimer type.

The effect of age on regional cerebral metabolic rate of glucose (rCMRGl) was studied in 14 patients with presenile dementia of Alzheimer type (DAT) and 24 patients suffering from senile DAT in comparison to 20 age-matched normal subjects by positron emission tomography (PET) of 2-(18F)-fluoro-2-deoxy-D-glucose (FDG). The metabolic pattern was condensed to a single metabolic ratio. It was calculated as the quotient of rCMRGl in regions typically affected by AD (frontal and temporoparietal cortex) divided by that in regions typically not affected. In normals this ratio was 1.05 +/- 0.04 and did not depend on age. In patients, the metabolic ratio was generally smaller and there was a significant difference between presenile (0.82 +/- 0.1) and senile DAT (0.90 +/- 0.1). This was due to a different metabolic pattern in the two age groups: metabolic impairment was focused on frontal and temporo-parietal cortex in presenile DAT, whereas more global rCMRGl reductions were present in senile DAT. The results suggest a more generalized disorder in senile dementia impairing metabolism globally in addition to the more localized changes that are typical for DAT.     

Lack of association between prior depressive episodes and cerebral [11C]PiB binding

Depressive symptoms are frequent in Alzheimer's disease (AD), but it is controversial whether depression is a risk factor for AD. This study measured for the first time cortical amyloid-β (Aβ) levels using [(11)C] Pittsburgh Compound B (PiB) positron emission tomography (PET) in a group of nondemented patients with prior depressive episodes. Twenty-eight elderly patients (mean age 61 years, range 51-75, 18 women) with onset of first depressive episode more than 6 years ago but now remitted from depression and 18 healthy subjects (mean age 61 years, range 50-76, 12 women) were included. All subjects were investigated with cognitive testing, 3T magnetic resonance imaging (MRI) and [(11)C]PiB high resolution research tomography (HRRT) positron emission tomography scan. There was no between-groups difference in [(11)C]PiB binding (p = 0.5) and no associations to number of depressive episodes, cognitive performance, or antidepressant treatment. Patients with late onset of depression had increased severity of white matter lesions (p = 0.04). In this study depressive episodes were not associated with increased levels of [(11)C]PiB. Thus, our results do not support the notion that depressive episodes previously in life are a risk factor for developing AD.     

Coupling of theta activity and glucose metabolism in the human rostral anterior cingulate cortex: an EEG/PET study of normal and depressed subjects

In rodents, theta rhythm has been linked to the hippocampal formation, as well as other regions, including the anterior cingulate cortex (ACC). To test the role of the ACC in theta rhythm, concurrent measurements of brain electrical activity (EEG) and glucose metabolism (PET) were performed in 29 subjects at baseline. EEG data were analyzed with a source localization technique that enabled voxelwise correlations of EEG and PET data. For theta, but not other bands, the rostral ACC (Brodmann areas 24/32) was the largest cluster with positive correlations between current density and glucose metabolism. Positive correlations were also found in right fronto-temporal regions. In control but not depressed subjects, theta within ACC and prefrontal/orbitofrontal regions was positively correlated. The results reveal a link between theta and cerebral metabolism in the ACC as well as disruption of functional connectivity within frontocingulate pathways in depression.